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Антитромбоцитарные средства для предотвращения тромбоза после шунтирования периферических артерий

Editorial note

This review has been superseded by Cochrane Reviews: 'Antithrombotics after infra‐inguinal bypass grafting' (https://doi.org/10.1002/14651858.CD015141) and 'Antithrombotics after infra‐inguinal peripheral endovascular treatment' (https://doi.org/10.1002/14651858.CD015142).

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Abstract

Background

Peripheral arterial disease (PAD) may cause occlusions (blockages) in the main arteries of lower limbs. One treatment option is bypass surgery using autologous (the patient's own tissue) vein graft or prosthetic (artificial) graft. A number of factors influence occlusion rates in these patients, including the material used. To prevent graft occlusion patients are usually treated with antiplatelet, antithrombotic drugs, or a combination of both.

Objectives

To determine the effects of antiplatelet agents for the prevention of thrombosis in people with lower limb atherosclerosis who were undergoing femoropopliteal or femorodistal bypass grafting. Outcomes included the overall success of therapy (graft patency and limb salvage rates) and complications of treatment.

Search methods

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co‐ordinator searched the Specialised Register (last searched June 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 5). We sought additional trials through screening the reference lists of relevant papers.

Selection criteria

Two review authors, RB and AL, independently reviewed studies found in the search and evaluated them based on the inclusion and exclusion criteria, resolving disagreements through discussion.

Data collection and analysis

RB and AL independently extracted details of the selected studies for the update. We compared the treatment and control groups for important prognostic factors and differences described. If any data were unavailable, we sought further information from study authors. We synthesised data by comparing group results. We addressed unit of analysis issues by subgroup analysis.

Main results

We include 16 studies with 5683 randomised participants. Nine different treatment groups were evaluated: aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus placebo or nothing (six studies); ASA or ASA/DIP versus pentoxifylline (two studies); ASA/DIP versus indobufen (one study); ASA or ASA/DIP versus vitamin K antagonists (two studies); ASA/DIP versus low molecular weight heparin (one study); ticlopidine versus placebo (one study); ASA versus prostaglandin E1 (one study); ASA versus naftidrofuryl (one study); and clopidogrel and ASA versus ASA alone (one study). The treatment comparisons were evaluated separately, and, where possible, we performed subgroup analysis for venous grafts and prosthetic grafts and at different follow‐up time points. The quality of evidence was low to moderate as many of the treatment comparisons had very few studies to contribute data, several of the included studies had unit of analysis issues, the treatment dosages varied between studies, and data for many outcomes important to this review were not given in any of the studies, or differed greatly between studies. Overall study quality was moderate, with the largest problem being that the majority of studies did not describe their methods of randomisation, allocation concealment or blinding of outcome assessors, leading to risk ratings of 'unclear'. The other main issue with study quality was studies not blinding participants or personnel.

The treatment comparison with the most number of included studies, which allowed for robust conclusions, was that of aspirin (ASA) or ASA and dipyridamole (ASA/DIP) versus placebo or nothing, covered by six studies. For this treatment group, there was improved graft patency in the ASA or ASA/DIP treatment group, odds ratio (OR) 0.42 (95% confidence interval (CI) 0.22 to 0.83; P = 0.01; 952 participants). This effect was not seen for venous grafts alone at any of the time points, but was observed for all time points in prosthetic grafts, including the final time point of 12 months (OR 0.19, 95% CI 0.10 to 0.36; P < 0.00001; 222 participants). Only a single study evaluated secondary patency, for which there was no difference between treatment groups. For the comparison ASA or ASA/DIP versus placebo or nothing there was no difference for any of the side effects, including general, gastrointestinal, bleeding and wound/graft infection. Amputations, cardiovascular events and mortality were also similar between the treatment groups. The comparison of ASA or ASA/DIP versus vitamin K antagonists included two studies, one of which was very large, with over 2000 participants. There were no differences between treatment for primary graft patency at three, six, 12 or 24 months, and there was also no evidence of a difference for limb amputation, cardiovascular events or mortality. One large study (851 participants) evaluated clopidogrel and ASA versus ASA alone, and for all grafts there was no evidence of a difference of primary patency at 24 months. There was evidence of increased total bleeding in the clopidogrel and ASA group (OR 2.65, 95% CI 1.69 to 4.15) from an increase in mild (OR 2.34, 95% CI 1.37 to 4.00), and moderate bleeding (OR 4.13, 95% CI 1.37 to 12.45), but no difference in severe or fatal bleeding. There was no difference between the treatment groups for limb amputation or mortality. For the remaining treatment comparisons there is not currently enough evidence to draw any robust conclusions about the efficacy or safety of the treatment on graft patency after peripheral bypass.

Authors' conclusions

Antiplatelet therapy with aspirin or with aspirin plus dipyridamole had a beneficial effect on primary patency of peripheral bypass grafts compared to placebo or no treatment. This effect was not evident when evaluating venous grafts alone, but antiplatelet therapy did have a beneficial effect on patency in those who had prosthetic grafts. There was no evidence of differences in side effects (including general, gastrointestinal, bleeding or infection), amputation, cardiovascular events or mortality between the treatment groups. However, the number of participants included in this analysis might be too small to detect a statistically significant effect for side effects, amputation, cardiovascular morbidity or mortality. We found no difference in primary graft patency when aspirin or aspirin with dipyridamole was compared to a vitamin K antagonist or when clopidogrel with aspirin was compared to aspirin alone. However, there was evidence of increase bleeding in the clopidogrel with aspirin group for the latter comparison. The remaining six treatment comparisons did not include enough data to draw any robust conclusions about their efficacy or safety at this time.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

Резюме на простом языке

Антитромбоцитарные средства для предотвращения несостоятельности периферических артериальных шунтов

Актуальность

Симптоматические заболевания периферических артерий у людей с атеросклерозом могут проявляться как перемежающаяся хромота, боль при ходьбе, лишающая трудоспособности, или как критическая ишемия конечности с болью в покое, образованием язв, гангрены и риском потери конечности. Одной из возможностей лечения является установка шунта или импровизированного кровеносного сосуда, который обходит участок блокады в основной артерии бедра. Использование собственной иссечённой вены из ноги пациента является часто лучшим методом, чем установка искусственных или протезных материалов, таких как Дакрон или политетрафторэтилен, которые захватывают тромбоциты и могут привести к свертыванию крови и блокированию шунта. Другие факторы, влияющие на проходимость шунта (как долго обходной анастомоз остается открытым) включают длину шунта, место, где шунт соединяется с существующей артерией и отток крови от шунта. Стеноз (сужение) шунта наиболее часто происходит в месте хирургического соединения, вследствие гиперплазии, или увеличения числа гладкомышечных клеток во внутреннем слое сосуда, часто сопровождающееся формированием тромбоза (сгустка) в месте стеноза.

Характеристика исследований

В этот обзор мы включили 16 исследований с 5683 рандомизированными участниками. Были оценены девять различных групп лечения: аспирин (АСК) или аспирин и дипиридамол (АСК/ДИП) против плацебо или отсутствия лечения (шесть исследований); АСК или АСК/ДИП против пентоксифиллина (два исследования); АСК/ДИП против индобуфена (одно исследование); АСК или АСК/ДИП против антагониста витамина К (два исследования); АСК/ДИП против низкомолекулярного гепарина (одно исследование); тиклопидин против плацебо (одно исследование); АСК против простагландина Е1 (одно исследование); АСК против нафтидрофурила (одно исследование); и клопидрогрел и АСК против только АСК (одно исследование). Мы оценили различные сравнения видов лечения отдельно, и, где возможно, мы оценили отдельно тех участников, которым были установлены различные виды шунтов, венозные или протезные.

Качество доказательств

Качество доказательств в обзоре было от низкого до среднего, так как было мало исследований, которые предоставили доказательства для различных сравнений; несколько из включенных исследований рандомизировали и анализировали участников таким образом, что могли возникнуть смещения; и многие из предварительно определённых исходов обзора не были изучены в исследованиях, или были представлены различными способами в разных исследованиях. Дозировки лекарств также варьировали в различных исследованиях. В целом качество исследований было средним, с наибольшей проблемой заключающейся в том, что большинство исследований не описывали своих методов рандомизации и ослепления тех, кто оценивал исходы. Другой важной проблемой с качеством исследований было отсутствие ослепления участников или персонала по отношению к получаемому лечению.

Основные результаты

Сравнение АСК или АСК и дипиридамола (АСК/ДИП) против плацебо или отсутствия лечения, включило большинство исследований (шесть), которые позволили провести глубокий анализ. Для этих групп лечения, проходимость шунта была улучшена в группах лечения АСК или АСК/ДИП. Улучшение было у тех, кому был установлен протезный шунт, но не у тех, кому имплантировали венозный шунт. Только одно исследование оценивало вторичную проходимость, для которой не было различий между группами лечения. Для этого сравнения не было различий по какому‐либо из побочных эффектов, включая общие, желудочно‐кишечные, кровотечения и инфицирование раны/шунта. Ампутации, сердечно‐сосудистые события и смерти от любых причин были также сходными между группами лечения. Сравнения АСК или АСК/ДИП против антагонистов витамина К включили два исследования, одно из которых было очень большим, с более чем 2000 участниками. Не было различий между лечением первичной проходимости шунта на третий, шестой, 12 или 24 месяцы, и также не было доказательств о различиях по ампутации конечности, сердечно‐сосудистых событий или смертности. Одно большое исследование оценивало клопидогрел и АСК против только АСК, и для всех шунтов (включая протезные и венозные шунты) не было доказательств о различиях в первичной проходимости через 24 месяца. Имеются доказательства повышения частоты кровотечений в группе клопидогреля и АСК в целом, за счёт увеличения числа легких и умеренных кровотечений. Не было различий в тяжелых и фатальных кровотечениях. Не было различий между группами лечения в ампутации конечности или смерти от любой причины. Для оставшихся сравнений, в настоящее время нет достаточных доказательств, чтобы делать какие‐либо достоверные выводы об эффективности и безопасности сравниваемых видов лечения в отношении проходимости шунта после периферического шунтирования.

Authors' conclusions

Implications for practice

There is evidence to suggest that the administration of platelet inhibitors such as ASA or ASA/DIP will result in improved venous and prosthetic graft patency compared to no treatment. However, patients with a prosthetic graft may benefit more from ASA or ASA/DIP administration than those with a venous graft, but this needs further investigation. The results of this review should be interpreted with caution, due to the unit of analysis issues described within the review, as well as the fact that many of the comparisons were only reported in a single study, and that the dosages often differed between studies.

Implications for research

Further high‐quality randomised clinical trials, with adequate sample sizes, are required to evaluate the efficacy of antiplatelet medications for graft patency in infrainguinal venous and prosthetic grafts for all treatment comparisons. Presentation of data should be detailed and not only show survival curves for overall patency. Tables showing the raw data would improve the transparency of the trial performance and allow comparison of endpoints at consecutive time points. The reader would be able to identify the number of occlusions, or other endpoints, at different time points in each comparison group as well as in subgroups defined by bypass material, above‐ and below‐knee anastomosis, and inflow and outflow conditions. Other concerns for research within this area would be determining the optimal dosage of antiplatelet medications and also outcome stratification by co‐morbidities, such as diabetes. A more complete outcome profile should be evaluated, such as assisted primary patency. Uniformity of unit of analysis issues should be addressed in studies of peripheral vascular disease, as there needs to be clarity around single and multiple grafts and the time points at which these occurred.

Background

Description of the condition

Symptomatic, chronic peripheral arterial disease (PAD) of the lower extremities may present either as intermittent claudication (IC), pain on walking, or as critical limb ischaemia (CLI), which is a more progressive stage with pain at rest, ulceration and gangrene (Becker 2011). The implantation of a femoropopliteal or femorodistal bypass graft (a makeshift blood vessel used to bypass a blockage in the main artery of the thigh) is one treatment option for people who are at risk of losing a limb or whose walking ability is greatly impaired because of the disease. By placing a graft in the groin area (an infrainguinal graft) the blocked arterial segment is bypassed, thereby improving blood flow in the limb. This then relieves the symptoms of claudication or rest pain and decreases the potential for amputation due to ulceration and gangrene, termed limb salvage.

The patency rate for femoropopliteal and femorodistal grafts, or the number of bypasses remaining open after a certain period of time, depends on several risk factors. These include whether or not the patient has acute lower limb ischaemia (Baril 2013), graft material, length of the bypass, site of the distal anastomosis (surgical connection of the graft to the existing artery), outflow conditions in the calf (flow of blood out of the graft) and female gender (Cooper 1990; Tangelder 2000). Autologous saphenous vein (using a vein from the patient's calf or thigh or both) is superior to prosthetic (artificial) materials such as Dacron or polytetrafluoroethylene (PTFE) (Rutherford 1988). Where the distal anastomosis is above the knee there is a lower risk of graft failure, and patients with two or three patent calf arteries have a better outcome than those with only one patent artery. Graft failure most frequently occurs at the site of either the distal or proximal anastomosis, when smooth muscle cells of the medial (middle) layer of the vessel wall grow into the intimal (inner) layer, which is known as intimal hyperplasia. This in turn causes the diameter of the perfused graft to become smaller, known as stenosis. When blood flow through the vessel is significantly reduced intermittent claudication may be experienced. Graft occlusion (closure) can occur by formation of a thrombosis (clot) at the stenotic site. If blood flow in the failed graft cannot be restored and further bypass surgery is not possible, then blood flow may be so poor that the limb cannot remain viable and amputation is required. Successful prevention of graft failure and thus the need for surgical re‐intervention is of major clinical and economic importance. Occlusion rates one year after the operation vary between 15% and 75% depending on the various risk factors described above (Abbott 1997; Consensus 1991). In addition, patients with lower limb atherosclerosis (progressive hardening of the arteries) frequently experience increased platelet aggregation, leading to clot formation. Moreover, the body's physiological stress response to surgery is a prothrombotic state (where the body is preparing to form a blood clot).

Description of the intervention

Antiplatelet treatment is used to prevent formation of blood clots by preventing platelet aggregation (NICE 2013). Antiplatelet agents work by improving blood rheology and also by suppressing the advancement of in‐ and outflow atherosclerosis (reducing the rate of development of stenosis) as well as coronary artery atherosclerosis, indirectly optimising cardiac function and circulation.

For patients receiving bypass surgery, the intensity of platelet uptake by the graft material has been shown to be inversely related to graft patency at one year, indicating the need for antiplatelet intervention. In animal experiments, antiplatelet drug administration started before bypass surgery has been shown to increase patency in prosthetic grafts when compared to no treatment (Fujitani 1988).

To prevent graft occlusion patients are usually treated with either an antiplatelet or an anticoagulant drug, or a combination of both. It is not known which regimen is best to prevent infrainguinal graft occlusion. The aim of this review was to evaluate whether antiplatelet treatment improves graft patency, limb salvage and survival in patients with chronic PAD who are undergoing infrainguinal bypass surgery.

Why it is important to do this review

Another Cochrane review was recently undertaken to also evaluate the prevention of thrombosis after infrainguinal arterial bypass, but this review focused on the use of antithrombotic therapies (Geraghty 2011). Overall their findings were inconclusive, with a possible benefit of antithrombotics for autologous vein grafts. Also, there may be higher economic costs and adverse haemorrhagic events associated with the use of anticoagulants compared with antiplatelet therapy. If the efficacy of antiplatelets is acceptable then it may be a more economical alternative to anticoagulant therapy following bypass graft surgery in the legs.

Objectives

To determine the effects of antiplatelet agents for the prevention of thrombosis in patients with lower limb atherosclerosis who were undergoing femoropopliteal or femorodistal bypass grafting. Outcomes include the overall success of therapy (graft patency and limb salvage rates) and complications of treatment.

Methods

Criteria for considering studies for this review

Types of studies

Trials in which participants were randomly allocated to receive either antiplatelet therapy versus placebo, one antiplatelet regimen versus another or antiplatelet therapy versus an alternative treatment. We include trials using alternation (allocation of treatment alternating between two interventions) and consider them as quasi‐randomised clinical trials (qRCTs).

Types of participants

All people undergoing femoropopliteal or femorodistal bypass grafting for the treatment of intermittent claudication and critical limb ischaemia. We excluded people undergoing bypass surgery for trauma.

Types of interventions

Antiplatelet therapy versus placebo, one antiplatelet regimen versus another, or antiplatelet therapy versus an alternative treatment. We excluded studies that included the same antiplatelet agent in both treatment groups, unless another antiplatelet was also used, but in only one treatment arm. We recorded the type of therapy, dosage, time of starting compared to surgery (pre‐ or postoperatively) and duration of the therapy.

Types of outcome measures

Primary outcomes

(1) Primary graft patency: patency rates after surgery with no further intervention, as determined by clinical examination, measurement of the ankle‐brachial pressure index (ABPI), duplex ultrasonography, angiography.
(2) Assisted primary patency: patency rates after intervention to improve blood flow in a graft which has not occluded.

We analysed primary patency and primary assisted patency for all grafts and for venous or prosthetic (artificial) grafts separately.

Secondary outcomes

  1. Secondary graft patency: patency rates following secondary intervention to restore blood flow to the graft

  2. Objective assessment of lower limb blood flow: ABPI, exercise tolerance test

  3. Side effects of treatment and complications

  4. Limb salvage rate: survival rates with limb intact (or limb amputation)

  5. Incidence of other cardiovascular events and mortality

  6. Participants' quality of life

Search methods for identification of studies

Electronic searches

For this update the Cochrane Peripheral Vascular Diseases Group Trials Search Co‐ordinator (TSC) searched the Specialised Register (last searched June 2014) and the Cochrane Central Register of Controlled Trials (CENTRAL) 2014, Issue 5, part of The Cochrane Library (www.thecochranelibrary.com). See Appendix 1 for details of the search strategy used to search CENTRAL. The Specialised Register is maintained by the TSC and is constructed from weekly electronic searches of MEDLINE, EMBASE, CINAHL, AMED, and through handsearching relevant journals. The full list of the databases, journals and conference proceedings which have been searched, as well as the search strategies used, are described in the Specialised Register section of the Cochrane Peripheral Vascular Diseases Group module in The Cochrane Library.

Searching other resources

We scanned reference lists of studies and reviews identified by the search for relevant studies.

Data collection and analysis

Selection of studies

In this update, Rachel Bedenis (RB) and Anne Lethaby (AL) independently selected trials for inclusion or exclusion, resolving disagreements by discussion between them.

Data extraction and management

For newly‐included studies RB and AL independently extracted the number of participants originally allocated to each treatment group and performed an intention‐to‐treat analysis. Data collection on each trial consisted of: inclusion and exclusion criteria; participant details (age, gender, co‐morbidity); severity of arterial occlusive disease (as determined by the ABPI and the European Consensus (Consensus 1991) definition of critical limb ischaemia); type of graft (autologous vein, prosthetic, human umbilical vein, composite graft); level of proximal graft anastomosis (common superficial femoral artery) and distal anastomosis (above‐knee popliteal, below‐knee popliteal, distal arteries); type of antiplatelet therapy used (dose, commencement of therapy relative to surgery, duration of therapy, compliance); and outcome (as mentioned in the section 'Criteria for considering studies for this review'). We compared the treatment and control groups for important prognostic factors. If any of the above data were not available, we sought further information from the authors.

Assessment of risk of bias in included studies

RB and AL independently assessed the methodological quality of included trials, using the 'Risk of bias' tool from The Cochrane Collaboration (Higgins 2011). We assessed the following five domains: selection bias (random sequence generation, allocation concealment), performance bias (blinding of participants and personnel and blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting) and other potential sources of bias. We classified the domains as being at low risk of bias, high risk of bias or unclear risk of bias according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The two review authors assessing bias resolved disagreements by discussion.

Measures of treatment effect

We extracted dichotomous data and transformed them into odds ratios (ORs) with 95% confidence intervals (CIs) in the meta‐analysis.

Unit of analysis issues

The majority of the included studies use individual participants as the unit of analysis, although four studies were not consistent in this method (Clyne 1987; Donaldson 1985; Kohler 1984; Lucas 1984). Kohler 1984 reported on grafts rather than participants: 14 participants were re‐entered and re‐randomised after graft failure; participants with bilateral reconstructions were followed for patency of both grafts but were randomised only after the first reconstruction. There were 102 grafts in 88 participants in this study. In Donaldson 1985, the aspirin group recorded 35 grafts in 33 participants and the placebo group recorded 38 grafts in 32 participants. These additional grafts were due to bilateral grafts. In Clyne 1987, 148 grafts were undertaken in 140 participants. Lucas 1984 examined a mixture of single and multiple bypasses, using different materials, and also included thromboendarterectomy; there were considerable sources of heterogeneity within this study. The remaining papers appeared to report on one graft per individual.

For the meta‐analyses, we used the number of participants randomised where possible and not the number of grafts, in order to maintain consistency with the majority of included studies. We have included the four studies using grafts as the unit of analysis (Clyne 1987; Donaldson 1985; Kohler 1984; Lucas 1984) in the meta‐analysis, but we have excluded them from a subsequent sensitivity analysis, to assess the influence these studies may have on the overall results.

Dealing with missing data

Where data were missing, we contacted study authors for more information. Where possible, we performed analyses on an intention‐to‐treat basis.

Assessment of heterogeneity

To test for heterogeneity, we used the I² statistic (Higgins 2003). Where heterogeneity was high (I² > 50%), we used a random‐effects model for data synthesis.

Assessment of reporting biases

We obtained data from full papers, conference abstracts and unpublished sources, where found. If at least ten studies were included in a meta‐analysis, we constructed a funnel plot to look at issues around publication bias.

Data synthesis

Where possible, we calculated the number of events occurring within the sample for each of the outcomes. We generated ORs with 95% CIs to evaluate the effect of treatment, using a fixed‐effect model. Where heterogeneity was high (I² > 50%) we used a random‐effects model for data synthesis.

Subgroup analysis and investigation of heterogeneity

We subgrouped data for graft patency at follow‐up (that is, at 1, 3, 6, 9, 12 and 24 months, where data were available) and for whether the graft was venous or prosthetic.

Sensitivity analysis

We performed sensitivity analysis to evaluate the effect of studies with unit of analysis concerns. Please see Unit of analysis issues for more detail.

Results

Description of studies

Results of the search

See Figure 1 for study flow diagram.


Study flow diagram.

Study flow diagram.

For the current update of the review, we considered 19 reports of 12 studies retrieved by the search. We included one additional study with four reports (CASPAR 2010). We deemed six studies with six citations not to be relevant, and we added another three studies with four reports to the excluded studies (Burdess 2010; EUCTR2007 2008; Monaco 2012). We added five new reports of two studies to previously included studies (BOA 2000; McCollum 1991) and eight previously excluded reports to two included studies (BOA 2000; McCollum 1991).

Included studies

For this update there was one additional study included (CASPAR 2010) making a total of 16 studies (Becquemin 1997; BOA 2000; CASPAR 2010; Clyne 1987; D'Addato 1992; Donaldson 1985; Edmondson 1994; Goldman 1984; Green 1982; Gruss 1991; Kohler 1984; Lucas 1984; McCollum 1991; Noppeney 1988; Raithel 1987; Schneider 1979) which were included in this analysis. See Characteristics of included studies for full details.

We conducted comparisons of the following interventions:

  1. Aspirin (ASA) or aspirin and dipyridamole (ASA/DIP) versus placebo or nothing (Clyne 1987; Donaldson 1985; Goldman 1984; Green 1982; Kohler 1984; McCollum 1991)

  2. ASA or ASA/DIP versus pentoxifylline (PTX) (Lucas 1984; Raithel 1987)

  3. ASA/DIP versus indobufen (IND), a reversible cyclo‐oxygenase inhibitor (D'Addato 1992)

  4. ASA or ASA/DIP versus vitamin K antagonists (VKA) (BOA 2000; Schneider 1979)

  5. ASA/DIP versus low molecular weight heparin (LMWH) (Edmondson 1994)

  6. Ticlopidine (TIC) versus placebo (Becquemin 1997)

  7. ASA versus prostaglandin E1 (Gruss 1991)

  8. ASA versus naftidrofuryl (Noppeney 1988)

  9. Clopidogrel and ASA versus ASA alone (CASPAR 2010)

Details of the study designs are shown in the table 'Characteristics of included studies' and in Table 1.

Open in table viewer
Table 1. Patient characteristics

Study ID

% CLI

% below knee

% vein

% 1‐vessel run‐off

dose

preoperative start of treatment

treatment duration

randomisation

ABI pre‐op to postop

Becquemin 1997

> 70

nd

100

nd

TIC 250 mg vs placebo

between the 3rd and 14th post‐op day

24 months

post‐op

nd

BOA 2000

50

52

58.5

nd

ASA 80 mg vs coumarin INR 3.0 ‐ 4.5 reached in 50%

within 5 days until 1 month post‐op

21 months

before surgery

nd

CASPAR 2010

66

100

70

nd

ASA 75 ‐ 100 mg plus clopidogrel 75 mg vs ASA 75 ‐ 100 mg plus placebo

2 to 4 days post‐op

24 months

post‐op

nd

Clyne 1987

70

85

63

24

ASA 2 x 300 mg, DIP 2 x 200 mg

48 hours pre‐op

6 weeks

before surgery

0.38 to 0.78

D'Addato 1992

70

25

0

56

ASA 900 mg plus DIP 225 mg vs 400 mg IND

48 h

12 months

before surgery

nd

Donaldson 1985

0

32

0

37

ASA 3 x 330 mg plus DIP 75 mg

Evening prior to surgery

12 months

before surgery

0.62 to nd

Edmondson 1994

46

31

27

20

3 x 300 mg ASA plus 3 x 100 mg DIP versus 2500 IU LMWH

LMWH 2 hours pre‐op; ASA/DIP 1 week post‐op

3 months

post‐op

nd

Goldman 1984

80

47

0

nd

ASA 3 x 300 mg plus DIP 3 x 75 mg

2 days ASA/DIP

12 months

before surgery

nd

Green 1982

82

47

0

nd

ASA 3 x 325 mg, or ASA 3 x 325 mg plus DIP 3 x 75 mg

2 days ASA/DIP

12 months

before surgery

0.42 to 1.01

Gruss 1991

nd

nd

100

nd

3 x 0.5 g ASA plus 15,000 IU heparin versus PGE1, 0.2 ng per kg body weight/min plus 15,000 IU heparin

post‐op

10 days

nd

nd

Kohler 1984

76

52

69

nd

ASA 3 x 325 mg plus DIP 3 x 75 mg

first post‐op day

24 months

before surgery

nd

Lucas 1984

55

nd

27

nd

ASA 1050 mg, DIP 150 mg or 1200 mg PTX

pre‐op

6 months

before surgery

0.4

McCollum 1991

60

59

100

nd; vein < 4 mm:38

ASA 2 x 300 mg plus DIP 2 x 150 mg

2 days ASA/DIP

continuing indefinitely

before surgery

0.47 to nd

Noppeney 1988

nd

nd

nd

nd

ASA 1500 mg vs naftidrofuryl 600 mg daily orally

day 1 post‐op

12 months

before surgery

nd

Raithel 1987

95

nd

0

56

ASA 1500 mg vs PTX 1200 mg

48 h

12 months

before surgery

nd

Schneider 1979

nd

nd

100

nd

ASA 1000 mg, or ASA 1000 mg plus DIP 225 mg vs coumarin

post‐op

24 months

post‐op

nd

ASA: Aspirin
CLI: critical limb ischaemia
DIP: dipyridamole
h: hour
IU: international unit
LMWH: low molecular weight heparin
mg: milligram
nd: no data
ng: nanogram
PGE1: prostaglandin E1
PTX: pentoxifylline
TIC: ticlopidine
vs: versus

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.

Excluded studies

For this update we excluded an additional three studies (Burdess 2010; EUCTR2007 2008; Monaco 2012), making a total of 20 excluded studies (Böhmig 1995; Burdess 2010; DeWeese 1971; Ehersmann 1977; EUCTR2007 2008; Gorter 2001; Harjola 1981; Jivegard 2005; Johnson 2002; Johnson 2004; Kibbe 2002; Lassila 1991; Monaco 2012; Nevelsteen 1991; Raithel 1987b; Reichle 1979; Rosenthal 1987; Satiani 1985; Shionoya 1990; Smout 2004).The reasons for exclusion varied and include, among others: lack of a control group, not a randomised controlled trial, a heterogeneous cohort of participants, intervention not within the scope of the review, and too little information to determine inclusion.

See Characteristics of excluded studies for full descriptions of excluded studies.

Risk of bias in included studies

See Figure 2and Figure 3 for 'Risk of bias' evaluation.


Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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.

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Random sequence generation methods were adequately described in six studies (Becquemin 1997; BOA 2000; CASPAR 2010; Edmondson 1994; Kohler 1984; Lucas 1984). The remaining 10 studies did not sufficiently describe how they generated their random sequence, leading to a rating of 'unclear' (Clyne 1987; D'Addato 1992; Donaldson 1985; Goldman 1984; Green 1982; Gruss 1991; McCollum 1991; Noppeney 1988; Raithel 1987; Schneider 1979).

Six studies described allocation concealment methods that were low‐risk (BOA 2000; CASPAR 2010; Edmondson 1994; Green 1982; Lucas 1984; McCollum 1991), while the remaining 10 studies did not describe their methods adequately (Becquemin 1997; Clyne 1987; D'Addato 1992; Donaldson 1985; Goldman 1984; Gruss 1991; Kohler 1984; Noppeney 1988; Raithel 1987; Schneider 1979).

Blinding

Blinding of participants and personnel was adequate in seven studies (Becquemin 1997; CASPAR 2010; Donaldson 1985; Goldman 1984; Green 1982; Kohler 1984; McCollum 1991). Six studies were unblinded, leading to a high risk of performance bias (BOA 2000; Clyne 1987; Edmondson 1994; Gruss 1991; Noppeney 1988; Raithel 1987). The remaining three studies mentioned blinding but did not adequately describe their methods (D'Addato 1992; Lucas 1984; Schneider 1979), and are rated at unclear risk.

Blinding of outcome assessors was only described in two studies (Becquemin 1997; CASPAR 2010), while the remaining were at unclear risk of detection bias, with no description of assessor blinding.

Incomplete outcome data

The majority of studies had no issues with attrition bias, but five studies were at unclear risk, with Donaldson 1985 having a higher rate of drop‐outs in the intervention arm, Gruss 1991 not reporting drop‐outs or withdrawals, Kohler 1984 inconsistently reporting drop‐outs between treatment groups, Raithel 1987 only reporting participants available for follow‐up but not the number initially randomised, and Schneider 1979 not having enough information for us to adequately assess whether attrition bias was a problem.

Selective reporting

Selective reporting was a concern in three studies, which we evaluated as 'unclear' (Green 1982; Gruss 1991; Schneider 1979). For Green 1982 adverse events were not clearly reported, and for both Gruss 1991 and Schneider 1979 there was not enough information in the text to determine the risk of reporting bias. All remaining studies were at low risk of reporting bias.

Other potential sources of bias

Other bias was a concern in five studies (Clyne 1987; Donaldson 1985; Goldman 1984; McCollum 1991; Raithel 1987), with the rest at low risk of other bias. For Clyne 1987 and Donaldson 1985 all the data were presented by number of bypasses and not by the number of participants. Goldman 1984, McCollum 1991, and Raithel 1987 had differences in the treatment groups at baseline, and McCollum 1991 may be at risk of being underpowered, as the study power calculation required a study population of 800 participants to detect a 10% reduction in occlusion rate, but only 549 participants were randomised.

Effects of interventions

For the outcome 'primary patency' the numbers recorded for analyses were actually the number of grafts that occluded during the specified time period as reported by the trialists. We used these numbers due to the properties of odds ratios (ORs), and we found this method more straightforward to interpret. Both patency and occlusion are used to describe the treatment outcomes within the included studies and within this review, which should be kept in mind when interpreting the presented data.

Analysis for secondary graft patency, side effects of treatment and complications, limb amputation, cardiovascular events and mortality are only described when sufficient data were available. Otherwise, these outcomes are not mentioned.

None of the included studies reported on assisted primary patency, objective assessment of lower limb blood flow or participant quality of life.

None of the meta‐analyses included 10 or more studies, so we could not construct funnel plots to evaluate possible publication bias.

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

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.

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

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.

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

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).

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

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).

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

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).

Ticlopidine (TIC) versus nothing

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).

Aspirin versus prostaglandin E1 (PGE1)

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.

Aspirin versus naftidrofuryl

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).

Clopidogrel and ASA (clopidogrel/ASA) versus ASA alone

CASPAR 2010 was the only study to compare clopidogrel/ASA to ASA alone. Outcomes were reported at 24 months as a whole population and split by subgroups based on whether participants received venous or prosthetic grafts.

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).

Discussion

Summary of main results

Antiplatelet therapy effect on bypass patency

In the present meta‐analysis we evaluated the effect of postoperatively administered antiplatelet treatment in people with peripheral arterial disease (PAD) receiving infrainguinal bypasses. It was shown that antiplatelet treatment with aspirin (ASA) or a combination of ASA and dipyridamole (ASA/DIP) has an overall positive effect on primary patency 12 months after the procedure. Interestingly, the size of the effect differed between participants receiving prosthetic grafts and those receiving venous grafts. When we limited the analysis to the subgroups receiving prosthetic (polytetrafluoroethylene (PTFE) or Dacron) grafts, the effect was statistically significant at all time points. In contrast, there was no evidence to support an effect of ASA or ASA/DIP in participants receiving venous graft bypasses. The evidence for secondary patency is too limited to draw any conclusions at this time. It should be noted that we did not perform a formal test for interaction to statistically demonstrate a differential effect of antiplatelet agents by graft type.

There was no difference in primary patency for the comparison between ASA/DIP versus pentoxifylline (PTX) at one, three, six and 12 months. However, for most of the time points we evaluated only a single study. For the comparisons between ASA and DIP versus indobufen (prosthetic grafts only), ASA or ASA/DIP versus vitamin K antagonists (VKA), as well as ASA/DIP versus low molecular weight heparin (LMWH), there were no differences between the treatment groups in primary patency at any time point. The analyses of indobufen and LMWH only had single study reporting and VKA included only two studies.

A single study evaluated ticlopidine versus placebo in participants receiving venous graphs only. Primary patency was significantly improved at six, 12 and 24 months after the procedure, but not in the first month post‐procedure. Thus, ticlopidine seems to be the only antiplatelet agent achieving a favourable effect on venous graft patency. ASA versus prostaglandin E1, also only with venous grafts, was reported in a single study, with few outcome events and no difference between the treatment groups for early occlusions. Comparing ASA with naftidrofuryl in a single study, there was no difference in primary patency at 12 months.

Clopidogrel with ASA versus ASA alone was reported in a single study, with no difference in primary patency at 24 months for all participants, as well as no difference for venous grafts. Prosthetic grafts showed improvement in patency at 24 months for the clopidogrel with ASA group.

Side effects and limb amputations

For the comparison of ASA or ASA/DIP versus placebo or nothing, there were no differences between the treatment groups for any of the evaluated side effects, complications or amputations. Comparing ASA or ASA/DIP to PTX there was a possible increase in gastric intolerance, but no differences for gastric haemorrhage, vertigo or amputations. There were also no differences in amputation comparing ASA or ASA/DIP to VKA. Both general and gastrointestinal side effects were increased in the ASA group, compared with naftidrofuryl, but vertigo and stomach bleeding were similar between the two groups. Comparing clopidogrel/ASA with ASA alone, there were increased total, mild and moderate bleeding events in the one study that evaluated this treatment comparison, in all participants, but no difference for severe or fatal bleeding events. In venous grafts within this study, there was an increase in mild and moderate events, but no difference in severe bleeding events, and there was no difference in any of the bleeding categories for prosthetic grafts. Within this comparison, amputations were similar between treatment groups for all participants, including venous grafts, but there was a slight decrease in amputations in the clopidogrel/ASA group.

Cardiovascular events and mortality

For the comparisons of ASA or ASA/DIP versus placebo or nothing and ASA or ASA/DIP versus VKA there were no differences between the treatment groups for cardiovascular events or mortality. There was also no difference in mortality when comparing ASA or ASA/DIP versus PTX, ASA versus naftidrofuryl, or clopidogrel/ASA versus ASA alone; cardiovascular events were not evaluated within these comparisons.

Although very few events were reported in the single study, there appeared to be decreased mortality in the ASA/DIP treatment group, compared with LMWH.

In conclusion, the results of our meta‐analysis suggest that the administration of platelet inhibitors such as ASA or ASA/DIP could result in improved venous and prosthetic graft patency compared to no treatment. However, subgroup analysis by graft type, i.e. venous versus PTFE or Dacron, shows that participants receiving a prosthetic graft are likely to benefit more from ASA or ASA and DIP administration than those treated with a venous graft. For most of the comparisons included in this review, there is currently not enough data to draw any conclusions.

Overall completeness and applicability of evidence

With 16 studies included in the review and meta‐analysis, there was much relevant data available to provide evidence for the review question. However, we separately evaluated a total of nine different comparisons, with only one comparison having more than two studies providing data for meta‐analysis. Therefore, while this review does bring many trials together touching on many antiplatelet treatments, the review does not reach a meaningful level of evidence for all of the predefined comparisons. Also, none of the included studies addressed the outcomes of assisted primary patency, objective assessment of blood flow or quality of life, and many studies did not report on any of the other outcomes. Assisted primary patency as an outcome is of specific importance, as even a highly stenotic graft may remain patent, and a graft at a highly stenotic stage would be more easily treated, both technically and for the patient, than a fully occluded graft. Therefore, knowing whether antiplatelet treatments help reduce full occlusion and allow treatment at a stenotic but not occluded stage would be of clinical importance.

Data presentation did not distinguish by graft type for the site of the distal anastomosis. Furthermore, the number of grafts frequently differed from the number of participants, without appropriate explanation. Insufficient information was available in the included studies to assess the effects of antiplatelet agents in different clinical settings such as diabetes and other co‐morbidities. Another concern with the applicability of evidence is the fact that different dosages of the various treatments were used between the included studies. Further information on the dosages can be found in Characteristics of included studies tables.

Quality of the evidence

This review included 16 studies with a total of 5683 randomised participants. Currently we can only draw a robust conclusion regarding antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery for the comparison between ASA or ASA/DIP versus placebo or nothing, showing a positive reduction in occlusion at 12 months in participants who received ASA or ASA/DIP. The comparisons of ASA or ASA/DIP versus vitamin K antagonists and of clopidogrel and ASA versus ASA alone only included one or two studies, but they encompassed a large number of participants. Neither comparison found any difference in primary graft patency at any of the time points. All other comparisons only included one or two smaller studies. Also limiting the quality of the evidence is the fact that several included studies provided their results by the number of bypasses and not by the number of participants, indicating bilaterally‐treated patients. This could alter results, although currently only a few studies provided results in this manner, with few participants in their study population receiving multiple bypasses. Also of concern is the reporting of outcomes at varying time points, which vary between studies. This reduces our ability to combine outcome data in the most robust way possible.

Overall, study quality was moderate, with the largest problem being that the majority of studies did not adequately describe their methods of randomisation or outcome assessor blinding. The other main issue with study quality was not blinding participants or personnel to the treatment received. These concerns, along with the previously reported issues with paucity of data for many of the comparisons, unit of analysis issues, variation of treatment dosages and lack of data on our review's prespecified outcomes, leaves the quality of the evidence of the review moderate to low. We expect that with future updates and more high‐quality studies, the quality of evidence will improve.

Potential biases in the review process

In order to reduce potential bias two review authors assessed studies for inclusion and performed data extraction and quality assessment. We made every attempt to include all relevant studies, but it is still possible that we did not identify all studies.

The majority of included studies randomised individuals as the unit for analysis, but four studies included participants with multiple or bilateral reconstructions or re‐randomised participants, and used grafts as the unit of analysis. In order to include these data we performed analyses with the four studies with unit of analyses issues, but also performed sensitivity analyses by excluding them to see if the results were affected. Only the comparison between ASA or ASA/DIP versus nothing or placebo contained enough studies to evaluate the effects of the unit of analysis issues by sensitivity analysis, and within this comparison we could not evaluate all outcomes. Overall there was very little change in the results when the studies were removed, but when the odds ratios (ORs) did change, it was an expected attenuation and decreasing of power due to a reduction in the overall number of participants included in the calculation. Readers should keep in mind our methods of addressing these unit of analysis issues when evaluating the results of this review, as other reviews may take a different approach.

For the outcome 'primary patency', the numbers recorded for analyses were actually the number of grafts that occluded during the specified time period as reported by the trialists. Both patency and occlusion are used to describe the treatment outcomes within the included studies and within this review, which should be kept in mind when interpreting the presented data. As assisted primary patency was not reported by the trialists of the included studies, it is unclear if the reported occlusion is actual occlusion i.e. thrombosis of the graft, or if it also includes participants whose grafts were revised prior to occlusion/thrombosis.

We calculated data for graft failure from the survival curves if raw data were not reported or were unavailable after contacting the authors of the trials.

Agreements and disagreements with other studies or reviews

A systematic review and meta‐analysis that was published in 1999 also set out to evaluate antiplatelet therapy (specifically aspirin) in the prevention of graft occlusion after infrainguinal bypass surgery (Tangelder 1999). This review differs from our own, as it was interested in oral anticoagulants, as well as antiplatelet agents, and they used risk ratios (RRs) and not odds ratios for their dichotomous outcomes. The Tangelder 1999 review included five studies that we also included in our own review, and an additional two studies, one of which was specific to oral anticoagulants, while the other compared an anticoagulant with aspirin to aspirin alone. The findings in Tangelder 1999 were similar to our own meta‐analyses findings for the comparison between ASA or ASA/DIP versus nothing or placebo. They found a decrease in bypass occlusions in the aspirin group (RR 0.78, 95% CI 0.64 to 0.95), and no difference between the treatment groups for total mortality (RR 0.92, 95% CI 0.64 to 1.32).

Study flow diagram.

Figures and Tables -
Figure 1

Study flow diagram.

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figures and Tables -
Figure 2

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.

Figures and Tables -
Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 1: Primary graft patency at 12 months

Figures and Tables -
Analysis 1.1

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 1: Primary graft patency at 12 months

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 2: Side effects and complications

Figures and Tables -
Analysis 1.2

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 2: Side effects and complications

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 3: Limb amputation

Figures and Tables -
Analysis 1.3

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 3: Limb amputation

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 4: Cardiovascular events

Figures and Tables -
Analysis 1.4

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 4: Cardiovascular events

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 5: Mortality

Figures and Tables -
Analysis 1.5

Comparison 1: ASA or ASA/DIP vs placebo or nothing, all grafts, Outcome 5: Mortality

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 1: Primary graft patency, venous grafts, 1 month

Figures and Tables -
Analysis 2.1

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 1: Primary graft patency, venous grafts, 1 month

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 2: Primary graft patency, venous grafts, 3 months

Figures and Tables -
Analysis 2.2

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 2: Primary graft patency, venous grafts, 3 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 3: Primary graft patency, venous grafts, 6 months

Figures and Tables -
Analysis 2.3

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 3: Primary graft patency, venous grafts, 6 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 4: Primary graft patency, venous grafts, 12 months

Figures and Tables -
Analysis 2.4

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 4: Primary graft patency, venous grafts, 12 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 5: Primary graft patency, venous grafts, 24 months

Figures and Tables -
Analysis 2.5

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 5: Primary graft patency, venous grafts, 24 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 6: Primary graft patency, prosthetic grafts, 1 month

Figures and Tables -
Analysis 2.6

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 6: Primary graft patency, prosthetic grafts, 1 month

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 7: Primary graft patency, prosthetic grafts, 3 months

Figures and Tables -
Analysis 2.7

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 7: Primary graft patency, prosthetic grafts, 3 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 8: Primary graft patency, prosthetic grafts, 6 months

Figures and Tables -
Analysis 2.8

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 8: Primary graft patency, prosthetic grafts, 6 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 9: Primary graft patency, prosthetic grafts, 9 months

Figures and Tables -
Analysis 2.9

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 9: Primary graft patency, prosthetic grafts, 9 months

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 10: Primary graft patency, prosthetic grafts, 12 months

Figures and Tables -
Analysis 2.10

Comparison 2: ASA or ASA/DIP vs placebo or nothing, subgroups, Outcome 10: Primary graft patency, prosthetic grafts, 12 months

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 1: Primary graft patency, 1 month

Figures and Tables -
Analysis 3.1

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 1: Primary graft patency, 1 month

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 2: Primary graft patency, 3 months

Figures and Tables -
Analysis 3.2

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 2: Primary graft patency, 3 months

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 3: Primary graft patency, 6 months

Figures and Tables -
Analysis 3.3

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 3: Primary graft patency, 6 months

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 4: Primary graft patency, 12 months

Figures and Tables -
Analysis 3.4

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 4: Primary graft patency, 12 months

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 5: Side effects

Figures and Tables -
Analysis 3.5

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 5: Side effects

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 6: Limb amputation

Figures and Tables -
Analysis 3.6

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 6: Limb amputation

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 7: Mortality

Figures and Tables -
Analysis 3.7

Comparison 3: ASA or ASA/DIP versus pentoxifylline (PTX), all grafts, Outcome 7: Mortality

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 1: Primary graft patency, 3 months

Figures and Tables -
Analysis 4.1

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 1: Primary graft patency, 3 months

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 2: Primary graft patency, 6 months

Figures and Tables -
Analysis 4.2

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 2: Primary graft patency, 6 months

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 3: Primary graft patency, 9 months

Figures and Tables -
Analysis 4.3

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 3: Primary graft patency, 9 months

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 4: Primary graft patency, 12 months

Figures and Tables -
Analysis 4.4

Comparison 4: ASA/DIP versus indobufen, prosthetic grafts, Outcome 4: Primary graft patency, 12 months

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 1: Primary graft patency, 3 months

Figures and Tables -
Analysis 5.1

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 1: Primary graft patency, 3 months

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 2: Primary graft patency, 6 months

Figures and Tables -
Analysis 5.2

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 2: Primary graft patency, 6 months

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 3: Primary graft patency, 12 months

Figures and Tables -
Analysis 5.3

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 3: Primary graft patency, 12 months

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 4: Primary graft patency, 24 months

Figures and Tables -
Analysis 5.4

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 4: Primary graft patency, 24 months

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 5: Limb amputation

Figures and Tables -
Analysis 5.5

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 5: Limb amputation

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 6: Cardiovascular events

Figures and Tables -
Analysis 5.6

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 6: Cardiovascular events

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 7: Mortality

Figures and Tables -
Analysis 5.7

Comparison 5: ASA or ASA/DIP versus vitamin K antagonists, all grafts, Outcome 7: Mortality

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 1: Primary graft patency, 6 months

Figures and Tables -
Analysis 6.1

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 1: Primary graft patency, 6 months

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 2: Primary graft patency, 12 months

Figures and Tables -
Analysis 6.2

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 2: Primary graft patency, 12 months

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 3: Mortality

Figures and Tables -
Analysis 6.3

Comparison 6: ASA/DIP versus LMWH, all grafts, Outcome 3: Mortality

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 1: Primary graft patency, 1 month

Figures and Tables -
Analysis 7.1

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 1: Primary graft patency, 1 month

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 2: Primary graft patency, 6 months

Figures and Tables -
Analysis 7.2

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 2: Primary graft patency, 6 months

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 3: Primary graft patency, 12 months

Figures and Tables -
Analysis 7.3

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 3: Primary graft patency, 12 months

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 4: Primary graft patency, 24 months

Figures and Tables -
Analysis 7.4

Comparison 7: Ticlopidine versus placebo, venous grafts, Outcome 4: Primary graft patency, 24 months

Comparison 8: ASA versus prostaglandin (PGE1), venous grafts, Outcome 1: Early occlusion

Figures and Tables -
Analysis 8.1

Comparison 8: ASA versus prostaglandin (PGE1), venous grafts, Outcome 1: Early occlusion

Comparison 9: ASA versus naftidrofuryl, Outcome 1: Primary graft patency at 12 months

Figures and Tables -
Analysis 9.1

Comparison 9: ASA versus naftidrofuryl, Outcome 1: Primary graft patency at 12 months

Comparison 9: ASA versus naftidrofuryl, Outcome 2: Side effects

Figures and Tables -
Analysis 9.2

Comparison 9: ASA versus naftidrofuryl, Outcome 2: Side effects

Comparison 9: ASA versus naftidrofuryl, Outcome 3: Mortality

Figures and Tables -
Analysis 9.3

Comparison 9: ASA versus naftidrofuryl, Outcome 3: Mortality

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 1: Primary graft patency at 24 months

Figures and Tables -
Analysis 10.1

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 1: Primary graft patency at 24 months

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 2: Side effects

Figures and Tables -
Analysis 10.2

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 2: Side effects

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 3: Limb amputation

Figures and Tables -
Analysis 10.3

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 3: Limb amputation

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 4: Mortality

Figures and Tables -
Analysis 10.4

Comparison 10: Clopidogrel and ASA versus ASA alone, all grafts, Outcome 4: Mortality

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 1: Primary graft patency, venous grafts, 24 months

Figures and Tables -
Analysis 11.1

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 1: Primary graft patency, venous grafts, 24 months

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 2: Primary graft patency, prosthetic grafts, 24 months

Figures and Tables -
Analysis 11.2

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 2: Primary graft patency, prosthetic grafts, 24 months

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 3: Side effects

Figures and Tables -
Analysis 11.3

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 3: Side effects

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 4: Limb amputation

Figures and Tables -
Analysis 11.4

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 4: Limb amputation

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 5: Mortality

Figures and Tables -
Analysis 11.5

Comparison 11: Clopidogrel and ASA versus ASA alone, subgroups, Outcome 5: Mortality

Table 1. Patient characteristics

Study ID

% CLI

% below knee

% vein

% 1‐vessel run‐off

dose

preoperative start of treatment

treatment duration

randomisation

ABI pre‐op to postop

Becquemin 1997

> 70

nd

100

nd

TIC 250 mg vs placebo

between the 3rd and 14th post‐op day

24 months

post‐op

nd

BOA 2000

50

52

58.5

nd

ASA 80 mg vs coumarin INR 3.0 ‐ 4.5 reached in 50%

within 5 days until 1 month post‐op

21 months

before surgery

nd

CASPAR 2010

66

100

70

nd

ASA 75 ‐ 100 mg plus clopidogrel 75 mg vs ASA 75 ‐ 100 mg plus placebo

2 to 4 days post‐op

24 months

post‐op

nd

Clyne 1987

70

85

63

24

ASA 2 x 300 mg, DIP 2 x 200 mg

48 hours pre‐op

6 weeks

before surgery

0.38 to 0.78

D'Addato 1992

70

25

0

56

ASA 900 mg plus DIP 225 mg vs 400 mg IND

48 h

12 months

before surgery

nd

Donaldson 1985

0

32

0

37

ASA 3 x 330 mg plus DIP 75 mg

Evening prior to surgery

12 months

before surgery

0.62 to nd

Edmondson 1994

46

31

27

20

3 x 300 mg ASA plus 3 x 100 mg DIP versus 2500 IU LMWH

LMWH 2 hours pre‐op; ASA/DIP 1 week post‐op

3 months

post‐op

nd

Goldman 1984

80

47

0

nd

ASA 3 x 300 mg plus DIP 3 x 75 mg

2 days ASA/DIP

12 months

before surgery

nd

Green 1982

82

47

0

nd

ASA 3 x 325 mg, or ASA 3 x 325 mg plus DIP 3 x 75 mg

2 days ASA/DIP

12 months

before surgery

0.42 to 1.01

Gruss 1991

nd

nd

100

nd

3 x 0.5 g ASA plus 15,000 IU heparin versus PGE1, 0.2 ng per kg body weight/min plus 15,000 IU heparin

post‐op

10 days

nd

nd

Kohler 1984

76

52

69

nd

ASA 3 x 325 mg plus DIP 3 x 75 mg

first post‐op day

24 months

before surgery

nd

Lucas 1984

55

nd

27

nd

ASA 1050 mg, DIP 150 mg or 1200 mg PTX

pre‐op

6 months

before surgery

0.4

McCollum 1991

60

59

100

nd; vein < 4 mm:38

ASA 2 x 300 mg plus DIP 2 x 150 mg

2 days ASA/DIP

continuing indefinitely

before surgery

0.47 to nd

Noppeney 1988

nd

nd

nd

nd

ASA 1500 mg vs naftidrofuryl 600 mg daily orally

day 1 post‐op

12 months

before surgery

nd

Raithel 1987

95

nd

0

56

ASA 1500 mg vs PTX 1200 mg

48 h

12 months

before surgery

nd

Schneider 1979

nd

nd

100

nd

ASA 1000 mg, or ASA 1000 mg plus DIP 225 mg vs coumarin

post‐op

24 months

post‐op

nd

ASA: Aspirin
CLI: critical limb ischaemia
DIP: dipyridamole
h: hour
IU: international unit
LMWH: low molecular weight heparin
mg: milligram
nd: no data
ng: nanogram
PGE1: prostaglandin E1
PTX: pentoxifylline
TIC: ticlopidine
vs: versus

Figures and Tables -
Table 1. Patient characteristics
Comparison 1. ASA or ASA/DIP vs placebo or nothing, all grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1.1 Primary graft patency at 12 months Show forest plot

6

952

Odds Ratio (M‐H, Random, 95% CI)

0.42 [0.22, 0.83]

1.2 Side effects and complications Show forest plot

6

Odds Ratio (M‐H, Fixed, 95% CI)

Subtotals only

1.2.1 Side effects‐ general

5

913

Odds Ratio (M‐H, Fixed, 95% CI)

1.55 [1.00, 2.41]

1.2.2 Gastrointestinal side effects

6

952

Odds Ratio (M‐H, Fixed, 95% CI)

1.44 [0.92, 2.24]

1.2.3 Major bleeding

2

598

Odds Ratio (M‐H, Fixed, 95% CI)

1.88 [0.85, 4.16]

1.2.4 Minor bleeding

1

148

Odds Ratio (M‐H, Fixed, 95% CI)

0.73 [0.31, 1.70]

1.2.5 Wound or graft infection

1

549

Odds Ratio (M‐H, Fixed, 95% CI)

1.07 [0.67, 1.71]

1.3 Limb amputation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

1.4 Cardiovascular events Show forest plot

4

811

Odds Ratio (M‐H, Random, 95% CI)

1.27 [0.43, 3.80]

1.5 Mortality Show forest plot

4

799

Odds Ratio (M‐H, Fixed, 95% CI)

0.84 [0.56, 1.26]

Figures and Tables -
Comparison 1. ASA or ASA/DIP vs placebo or nothing, all grafts
Comparison 2. ASA or ASA/DIP vs placebo or nothing, subgroups

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

2.1 Primary graft patency, venous grafts, 1 month Show forest plot

2

642

Odds Ratio (M‐H, Fixed, 95% CI)

0.76 [0.26, 2.25]

2.2 Primary graft patency, venous grafts, 3 months Show forest plot

2

642

Odds Ratio (M‐H, Fixed, 95% CI)

0.85 [0.54, 1.35]

2.3 Primary graft patency, venous grafts, 6 months Show forest plot

2

642

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.59, 1.31]

2.4 Primary graft patency, venous grafts, 12 months Show forest plot

2

642

Odds Ratio (M‐H, Fixed, 95% CI)

0.69 [0.48, 0.99]

2.5 Primary graft patency, venous grafts, 24 months Show forest plot

2

620

Odds Ratio (M‐H, Random, 95% CI)

1.03 [0.32, 3.28]

2.6 Primary graft patency, prosthetic grafts, 1 month Show forest plot

3

157

Odds Ratio (M‐H, Fixed, 95% CI)

0.14 [0.04, 0.51]

2.7 Primary graft patency, prosthetic grafts, 3 months Show forest plot

4

222

Odds Ratio (M‐H, Fixed, 95% CI)

0.31 [0.14, 0.66]

2.8 Primary graft patency, prosthetic grafts, 6 months Show forest plot

4

222

Odds Ratio (M‐H, Fixed, 95% CI)

0.21 [0.11, 0.41]

2.9 Primary graft patency, prosthetic grafts, 9 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

2.10 Primary graft patency, prosthetic grafts, 12 months Show forest plot

4

222

Odds Ratio (M‐H, Fixed, 95% CI)

0.19 [0.10, 0.36]

Figures and Tables -
Comparison 2. ASA or ASA/DIP vs placebo or nothing, subgroups
Comparison 3. ASA or ASA/DIP versus pentoxifylline (PTX), all grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

3.1 Primary graft patency, 1 month Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.2 Primary graft patency, 3 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.3 Primary graft patency, 6 months Show forest plot

2

151

Odds Ratio (M‐H, Fixed, 95% CI)

1.32 [0.56, 3.11]

3.4 Primary graft patency, 12 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5 Side effects Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5.1 Gastric intolerance

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5.2 Gastric haemorrhage

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.5.3 Vertigo

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.6 Limb amputation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

3.7 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 3. ASA or ASA/DIP versus pentoxifylline (PTX), all grafts
Comparison 4. ASA/DIP versus indobufen, prosthetic grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

4.1 Primary graft patency, 3 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.2 Primary graft patency, 6 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.3 Primary graft patency, 9 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

4.4 Primary graft patency, 12 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 4. ASA/DIP versus indobufen, prosthetic grafts
Comparison 5. ASA or ASA/DIP versus vitamin K antagonists, all grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

5.1 Primary graft patency, 3 months Show forest plot

2

2781

Odds Ratio (M‐H, Fixed, 95% CI)

0.88 [0.68, 1.14]

5.2 Primary graft patency, 6 months Show forest plot

2

2781

Odds Ratio (M‐H, Random, 95% CI)

0.72 [0.27, 1.96]

5.3 Primary graft patency, 12 months Show forest plot

2

2781

Odds Ratio (M‐H, Random, 95% CI)

0.68 [0.27, 1.69]

5.4 Primary graft patency, 24 months Show forest plot

2

2781

Odds Ratio (M‐H, Random, 95% CI)

0.64 [0.25, 1.63]

5.5 Limb amputation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.6 Cardiovascular events Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.6.1 Myocardial infarction

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.6.2 Stroke

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

5.7 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 5. ASA or ASA/DIP versus vitamin K antagonists, all grafts
Comparison 6. ASA/DIP versus LMWH, all grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

6.1 Primary graft patency, 6 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6.2 Primary graft patency, 12 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

6.3 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 6. ASA/DIP versus LMWH, all grafts
Comparison 7. Ticlopidine versus placebo, venous grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

7.1 Primary graft patency, 1 month Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.2 Primary graft patency, 6 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.3 Primary graft patency, 12 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

7.4 Primary graft patency, 24 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 7. Ticlopidine versus placebo, venous grafts
Comparison 8. ASA versus prostaglandin (PGE1), venous grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

8.1 Early occlusion Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 8. ASA versus prostaglandin (PGE1), venous grafts
Comparison 9. ASA versus naftidrofuryl

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

9.1 Primary graft patency at 12 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2 Side effects Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2.1 Side effects‐ general

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2.2 Gastrointestinal side effects

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2.3 Vertigo

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.2.4 Stomach bleeding

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

9.3 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 9. ASA versus naftidrofuryl
Comparison 10. Clopidogrel and ASA versus ASA alone, all grafts

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

10.1 Primary graft patency at 24 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2 Side effects Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2.1 Bleeding‐ total

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2.2 Bleeding‐ mild

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2.3 Bleeding‐ moderate

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2.4 Bleeding‐ severe

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.2.5 Bleeding‐ fatal

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.3 Limb amputation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

10.4 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 10. Clopidogrel and ASA versus ASA alone, all grafts
Comparison 11. Clopidogrel and ASA versus ASA alone, subgroups

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

11.1 Primary graft patency, venous grafts, 24 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.2 Primary graft patency, prosthetic grafts, 24 months Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3 Side effects Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.1 Bleeding‐ mild, venous grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.2 Bleeding‐ mild, prosthetic grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.3 Bleeding‐ moderate, venous grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.4 Bleeding‐ moderate, prosthetic grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.5 Bleeding‐ severe, venous grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.3.6 Bleeding‐ severe, prosthetic grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.4 Limb amputation Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.4.1 Amputation, venous grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.4.2 Amputation, prosthetic grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.5 Mortality Show forest plot

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.5.1 Mortality, venous grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

11.5.2 Mortality, prosthetic grafts

1

Odds Ratio (M‐H, Fixed, 95% CI)

Totals not selected

Figures and Tables -
Comparison 11. Clopidogrel and ASA versus ASA alone, subgroups