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Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass
Eur J Vasc Endovasc Surg (2016)
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‘EVIDENCE DRIVEN’ CLINICAL SCENARIO
Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass E. Gándara
a,b,*
, D. Hammond c, S. Nagpal
d
a
Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Hospital, Ottawa, Canada Ottawa Hospital Research Institute, Ottawa, Canada c Department of Medicine, University of Toronto, Toronto, Canada d Division of Vascular Surgery, Department of Surgery, University of Ottawa, Ottawa Hospital, Ottawa, Canada b
Clinical vignette: Despite being the most common antithrombotic strategy in trials comparing venous with prosthetic grafts, the use of vitamin K antagonists (VKAs) to improve the outcome of venous bypass remains the subject of debate. In this systematic review, evidence supporting the use of VKAs for improving venous patency following infrainguinal venous bypass is provided. Clinical question: A 67 year old man with lifestyle limiting claudication underwent a successful infrainguinal venous bypass. Can VKAs help preserve patency after venous bypass surgery? Methods: A systematic review of electronic databases, including MEDLINE and Embase, was conducted. Only randomized controlled studies comparing VKAs with aspirin (ASA) were included. The main outcome was bypass patency. Results: Four studies using different intensities of anticoagulation ASA were identified. All but one showed a benefit of VKAs over ASA with respect to primary patency. However, this benefit was also accompanied by an increased risk of bleeding. The Dutch Bypass Oral Anticoagulants, or ASA, study was the largest included and showed that VKAs (without concomitant ASA) were superior to ASA alone for the prevention of graft occlusion (hazard ratio 0.69, 95% confidence interval 0.54e0.88). Conclusion: Current evidence suggests that VKAs are superior to ASA for the prevention of infrainguinal autologous venous graft thrombosis. Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 14 August 2015, Accepted 23 March 2016, Available online XXX Keywords: Peripheral vasculature, Vein bypass, Vitamin K antagonists
CLINICAL SCENARIO A 67 year old man, who is a former smoker, with lifestyle limiting claudication, develops progressive worsening of his condition, leading to rest pain. He is admitted to hospital where it is determined that he requires a femorotibial bypass. His greater saphenous vein is in good condition and the bypass is successful. Could vitamin K antagonists (VKAs) help preserve patency after venous bypass surgery? BACKGROUND In patients with infrainguinal arterial disease requiring a bypass, the use of autologous venous grafts remains the preferred conduit option given their better patency results.1 Although this continues to be the primary antithrombotic * Corresponding author. Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Hospital, Ottawa, Canada. E-mail address: [email protected] (E. Gándara). 1078-5884/Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2016.03.026
strategy in trials comparing venous with prosthetic grafts,2e 5 some systematic reviews suggest that VKAs are superior to aspirin (ASA) at maintaining patency following infrainguinal venous bypass.6,7 In general, guidelines support the use of ASA dipyridamole following any type of surgical intervention for peripheral arterial disease (PAD).8e15 Two guidelines do not support the use of VKAs following bypass,10,13 two recommend VKAs þ ASA for bypass patients at high risk of re-thrombosis,9,11 and three suggest using VKAs after venous bypass when the risk of bleeding is low (see Table 1 for a summary of the recommendations).8,14,15 The aim of this systematic review is to evaluate the evidence supporting the role of VKAs following an infrainguinal venous bypass. METHODS An electronic review of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from 1946 to May 2015 (the search strategies and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist are presented in Appendix 1) was performed. Hand searches of relevant articles, abstract books from
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
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Table 1. Current guideline recommendation for antithrombotic therapy following an infrainguinal venous bypass. Role of VKAs? No role
Guideline ACCP 201210
AHA 201313
Only for high risk bypass
ACCP 200812
CCS 201011
German S39
Consider for venous bypass
ESC 20118
ESVS 201115
TASC 200714
Suggestion
One of the following antithrombotic regimens is recommended to be continued long term in most patients following peripheral artery bypass graft surgery over no antithrombotic treatment: ASA 75e100 mg daily or clopidogrel 75 mg daily (all recommendation grade 1A) Single antiplatelet therapy over antiplatelet therapy and warfarin is recommended (recommendation grade 1B) ASA, typically in daily doses of 75e325 mg, or clopidogrel, is recommended as a safe and effective antiplatelet therapy to reduce the risk of MI, stroke, and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia (level of evidence II) The combination of ASA and clopidogrel may be considered to reduce the risk of cardiovascular events in patients with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia, and who are not at increased risk of bleeding and who have a high perceived cardiovascular risk (level of evidence II) For patients receiving routine autogenous vein infrainguinal bypass, ASA (75e100 mg, begun pre-operatively) is recommended (recommendation grade 1A) It is suggested that VKAs not be used routinely in patients undergoing infrainguinal vein bypass (recommendation grade 2B) For those at high risk of bypass occlusion and limb loss, VKA þ ASA is suggested (recommendation grade 2B) For those undergoing infrainguinal reconstruction with venous conduits, low-dose ASA is recommended (recommendation grade 1A). Anticoagulation with VKAs is not recommended for routine post-operative use (recommendation grade 2A) In those with infrainguinal grafts with a high risk of thrombosis and limb loss, combination VKA þ ASA therapy may be of benefit in select cases (recommendation grade 2B) In patients with infrainguinal, femoropopliteal, or distal venous bypass, oral anticoagulants should not be used routinely given that the risk of bleeding is significantly increased (recommendation grade A, level of evidence II) In individuals at a very high risk for a bypass closure, oral anticoagulants or oral anticoagulants combined with ASA should be considered (recommendation grade 0, level of evidence V) Antiplatelet treatment with ASA or a combination of ASA and dipyridamole is recommended after infrainguinal bypass surgery Antithrombotic treatment with VKAs may be considered after autogenous vein infrainguinal bypass (level of evidence IIb) Following vein bypass surgery for CLI, ASA or ASA þ dipyridamole is efficient in lowering the incidence of thrombotic occlusions (level of evidence IIb; Grade B) VKAs are superior when closely monitored and should be preferred in suitable patients during early follow up, particularly for below-the-knee bypass (level of evidence Ib; Grade B) Antiplatelet therapy should be started pre-operatively and continued as adjuvant pharmacotherapy after an endovascular or surgical procedure [A]. Unless subsequently contraindicated, this should be continued indefinitely [A] Autogenous grafts may be treated with warfarin, but this is accompanied by a risk of hemorrhage and this decision must be made on an individual patient basis
Note. VKA ¼ vitamin K antagonist; ACCP ¼ American College of Chest Physicians; AHA ¼ American Heart Association; MI ¼ myocardial infarction; PAD ¼ peripheral arterial disease; CLI ¼ critical limb ischemia; CCS ¼ Canadian Cardiovascular Society; ESC ¼ European Society of Cardiology; ESVS ¼ European Society of Vascular Surgery; TASC ¼ Inter-Society Consensus for the Management of Peripheral Arterial Disease.
international meetings, and published reviews were also conducted. Randomized controlled trials (RCTs) were included if they reported outcomes for patients with infrainguinal disease who were treated with venous bypass, and compared VKAs
( ASA) with ASA alone for the prevention of graft occlusion. Trials using other forms of anticoagulation (i.e., low molecular weight heparin) or an antiplatelet other than ASA were excluded. In order to provide a more relevant answer, we analyzed outcomes according to International
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Role of Vitamin K Antagonists
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Normalized Ratio (INR) targets and by the use of concomitant ASA in patients treated with VKAs. The rationale for this approach is based on the different degrees of efficacy/ safety associated with different INR ranges,16 and with the use of concomitant ASA in patients treated with VKAs.17
Data extraction and quality assessment All potentially relevant articles were reviewed in full text to ensure that they satisfied the inclusion criteria. Two reviewers (D.H. and E.G.) independently assessed the eligibility of all articles identified in the initial search strategy. A third reviewer adjudicated all discrepancies if needed. Data regarding VKA strategy (drug, target range, and use of concomitant ASA), ASA strategy (dose), patients enrolled, indication, bypass outcomes, vascular outcomes, deaths, bleeding outcomes, and follow up were collected.
Outcome measure
IdenƟficaƟon
The primary outcome was bypass patency. Secondary outcome measures included major bleeding, death, and amputation.
Data synthesis and analysis If two or more studies reported the outcomes of a similar intervention (same INR range and use of ASA), it was planned to pool data using the random-effects model generating odds ratios (ORs), along with the corresponding 95% confidence intervals (CIs). The I2 statistic was used to quantify heterogeneity among the pooled estimates across trials. An I2 value < 25% was considered low level heterogeneity, 25e 50% as moderate level, and > 50% as high level. RESULTS As shown in Fig. 1, the search identified 10,723 relevant abstracts, of which 57 were reviewed in full text. The search identified four trials using different intensities of anticoagulation ASA.18e21 The doses of ASA (81 mge1 g) and target INR varied significantly. The methodological quality, inclusion criteria, design, main outcome, adjudication, and number of patients lost to follow up also varied significantly across studies (see Tables 2 and 3), precluding any pooling of information. Most of the studies showed a significant benefit of VKAs.18e20 Two studies compared VKAs without concomitant ASA versus ASA alone,18,20 and another two studies
Records idenƟfied through database searching (n = 10,723)
Eligibility
Screening
Records aŌer duplicates removed (n = 10,723 )
Records screened (n = 10,723)
Records excluded (n = 10,666)
Full-text arƟcles assessed for eligibility (n = 57)
Excluded (n =53): - Review papers (n = 5) - Endovascular intervenƟon (n = 7) - Overlapping paƟents from another study (n = 2) - Not able to translate to English (n = 3) - Lacks primary outcome at relevant Ɵme points (n = 36)
Included
Studies included in qualitaƟve synthesis (n = 4 )
Studies included in quanƟtaƟve synthesis (meta-analysis) (n = 0)
Figure 1. Flow diagram. Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Bollinger20
Sarac et al.19
Acenocoumarol vs. ASA 1g vs. ASA 1 g/dipyridamole 225 mg 1980 Austria NR Yes
4
Jonhson and Williford21
WafarineASA 325 mg vs. ASA 325 mg 1998 USA Single center NA; only veins
The Dutch Bypass Oral anticoagulants or Aspirin study18 Phenprocoumon or acenocoumarol vs. ASA 80 mg 2000 The Netherlands 77 Yes
WafarineASA 325 mg vs. ASA 325 mg 2002 USA 17 Yes
30/60 30e34% of the Quick value NR
37/27 INR 2e3 2; bridged with heparin
784/762 INR 3.0e4.5 5 from procedure
231/227 INR 1.4e2.8 As soon as fluids were tolerated
2y Angiographically proven patent artery postprocedure
3y Suboptimal venous conduits
Mean of 21 mo Patients who required an infrainguinal bypass graft
Exclusion criteria reported Main outcome Mean age (y) Claudicants I/C% Female I/C N(%) Diabetes (%) Randomization
Yes Patency at 2 y 63.9 All 37% NR NR NR
Blinding Type of analysis Adjudication of events
No ITT Open label
Yes Patent but failing graft 69/66 NR 18/25 53/79 Computer-assisted random number generator matched for sex No ITT NR
Up to 5 y (mean 39 mo) All patients scheduled for elective bypass b Yes Assisted primary patency 65/64 NR NR 51.5/51.8 Stratified by center and by bypass material
% loss to follow up or discontinuation of therapy
21.7% in the ASA group and 6.7% discontinued treatment
NR
No ITT Independent panel of blinded experts NR
Sample size calculation Patency I/C (%) Major bleeding I/C (%) Death I/C (%)
NR 83/68 p ¼ NR NR 10/5; p ¼ NS
NR 74/51; p ¼ .04 8/NR 45.3/49.5; p ¼ NS
Yes 85.7/79.7 HR 0.69 (95% CI 0.54e0.88) 1/0.3 15.9/16.7; p ¼ NS
Amputation I/C (%)
NR
Limb salvage rate 81/31; p ¼ .02
6.6/9.3 HR 0.72 (95% CI 0.5e1.01)
Excluded studies Publication Arfvidsson et al. (1990)28
Intervention Warfarin vs. control
Reason(s) for exclusion Control was no treatment
Investigators contacted? Yes
Intervention/control Year Country Centers Was analysis of vein bypass graft prespecified? Intervention/control (n) VKA target range Days from surgery to intervention Duration of follow up Inclusion criteria
a
Yes Graft occlusion NR NR NR NR Computer generated blocked sequences, stratified by center
No ITT NR 14 lost to follow up (4 I/10 C); 41% were off warfarin by the end of the study Yes 25.1/24.7 RR 1.04 (95% CI 0.72e1.51) 10.5/4.6; p ¼ .01 13.2/12.9; p ¼ NS 5.4/3.5; p ¼ NS
Comment e
E. Gándara et al.
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Table 2. Studies comparing vitamin K antagonists (VKAs) with antiplatelet agents.
In this study, the combination of warfarin þ clopidogrel was superior to ASA þ clopidogrel Note. ASA ¼ aspirin; NR ¼ not reported; NA ¼ not applicable; INR ¼ International Normalized Ratio; I ¼ Intervention; C ¼ Control; ITT ¼ intention to treat; HR ¼ hazard ratio; CI ¼ confidence interval; RR ¼ relative risk; NS ¼ nonsignificant. a The venous conduit was considered suboptimal if it was < 3.0 mm in diameter with pre-operative duplex ultrasound mapping, if the vein was sclerotic with intra-operative angioscopy, or if insufficient saphenous vein was available, which would necessitate the use of arm, vein, or a composite saphenous vein bypass graft. Runoff was considered poor if the distal anastomotic site of the bypass graft was in the distal third of the tibial or peroneal arteries, if there was runoff to the foot only through collateral vessels, if the anastomotic site was located in any portion of the tibial or peroneal arteries and the entire runoff bed was diffusely diseased with multiple sites of >50% stenoses, or if selection of the distal target was compromised as a result of inadequate vein length such that the anastomosis could not be placed beyond all significant disease. b Axillofemoral, femoralefemoral, femoralepopliteal, or femoraledistal. Yes
Warfarin INR 2e3 þ clopidogrel vs. ASA þ clopidogrel
Warfarin Antiplatelet Vascular Evaluation Trial Investigators et al. (2007)29 Monaco et al. (2012)27
Warfarin INR 2e3 plus ASA vs. ASA alone
Unable to isolate data of subpopulation that underwent infrainguinal venous bypass Unable to obtain data for those with venous bypasses
Yes
e
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compared VKAs plus ASA versus ASA alone.19,21 The Dutch By-pass Oral anticoagulants or Aspirin study (BOA) was the largest and best designed study.18 This was an open label multicenter trial in which all outcomes were independently adjudicated, thereby reducing the risk for potential bias. Although they did not stratify the randomization to the type of material used, they reported on the outcomes of 1,546 patients with an infrainguinal venous bypass as a prespecified subgroup analysis. In this trial, VKAs with a target INR range of 3.0e4.5 were compared with ASA (80 mg). The trial showed not only that VKAs were superior to ASA in the prevention of graft occlusion (hazard ratio [HR] 0.69, 95% CI 0.54e0.88), but also increased the risk of major bleeding. Although it did not reach statistical significance, the rate of amputations appeared to be lower in patients receiving VKAs after a venous bypass (6.6% vs. 9.3%; HR 0.72, 95% CI 0.5e1.01, as reported by the study authors), and the composite outcome of vascular death, myocardial infarction (MI), stroke, or amputation (HR 0.89, 95% CI 0.75e1.06) was also reduced. A recent re-analysis of the BOA trial suggested that using ASA instead of a VKAs in patients with a high risk of bleeding would result in fewer nonfatal hemorrhages but would increase ischemic events and graft occlusions.22 One limitation of the BOA trial was that evidence supporting the use of VKAs in venous bypass came from a prespecified subgroup analysis,23,24 thereby reducing its validity. However, this argument is more relevant for subgroup analyses that were not prespecified or were derived on the basis of observed results.25,26 In a low-quality trial conducted in 1980 and with a sample of 90 patients, Bollinger suggested that using VKAs after bypass resulted in higher rates of primary patency at 2 years compared with 1 g ASA alone (or combined with dipyridamole).20 The aforementioned study was a single center, open label trial in which adjudication of outcomes was open, with high a probability of bias. The two studies that reported on the combined use of VKAs þ concomitant ASA versus ASA alone showed opposite results.19,21 In 1998, Sarac et al. suggested that VKAs significantly improved patency and limb salvage rates in patients with suboptimal conduits.19 In this trial, the authors compared VKAs (target INR 2e3) þ ASA 325 mg with ASA 325 mg alone. Despite showing a significant improvement in patency with VKAs (74% vs. 51%; p ¼ .04) the results of this study should be interpreted carefully as it was open label, conducted at two centers with open adjudication, and had a sample of 64 patients. However, in 2002 Johnson and Williford found no difference in the outcomes of patients requiring venous bypass treated with VKAs (target INR 1.4e 2.8) þ ASA 325 mg versus ASA 325 mg alone.21 This was a multicenter trial with open adjudication and a large number of patients with poor VKA compliance during follow up. The present systematic review identified other relevant RCTs that were not included (Table 2).27e29 The most recent compared the outcome of any bypass (venous or prosthetic) treated with clopidogrel/VKAs (INR 2e3) versus clopidogrel/ ASA. The graft patency rate was significantly higher in the VKA group.27
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
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Table 3. Quality assessment. Study
Random sequence generation Unclear Unclear Low
Bollinger20 Sarac et al.19 The Dutch Bypass Oral anticoagulants or Aspirin study18 Johnson and Williford21 Unclear
Allocation concealment Unclear Low Low
Blinding of participants/personnel High High High
Blinding of outcome assessment High High Low
Incomplete outcome data Unclear Unclear Low
Selective reporting Low Low Low
Low
High
Low
Low
Low
DISCUSSION Antithrombotic agents play a fundamental role in secondary prevention of vascular events in patients with PAD (e.g., stroke or MI)10 and in improving graft patency following venous bypass. Despite its convenience (e.g., no need for monitoring and limited interaction with other drugs) and established benefit following prosthetic grafts, there is conflicting evidence regarding the benefit of ASA and other antiplatelet agents following venous grafts.30 Evidence supporting the combined use of VKAs and ASA is also unclear. The present systematic review suggests that VKAs confer the greatest patency following venous bypass but increase the risk of major bleeding. RCTs showing superiority of venous bypass over synthetic grafts have commonly used VKAs (target INR 2e4) for at least 6 months, followed by ASA daily (Table 4).2e5 As indicated in the BOA trial,18 if VKAs are effective for venous but not for prosthetic grafts, the superiority seen for venous bypass could be explained, in part, by the initial antithrombotic regimen. Interestingly, to date, no study has compared the outcome of venous bypass using VKAs with synthetic grafts treated with antiplatelet agents alone. To the authors’ knowledge, two other systematic reviews have suggested a benefit of VKAs after venous bypass based on an analysis comparing the use of VKAs ASA versus no treatment, or studies comparing VKAs alone with ASA dipyridamole.6,7 To avoid bias (i.e., INR range is an important determinant of outcomes),16 this approach was not used in this review. For now, multiple questions remain unanswered. For instance: (i) What is the best INR range? (ii) What is an appropriate duration of treatment? (iii) Is concomitant ASA needed when treating with VKAs? Unfortunately, VKAs are associated with an increased risk of major bleeding and require frequent monitoring, making them less appealing than ASA.31 Future studies should evaluate and compare
new direct oral anticoagulants (such as apixaban),32 which have a better safety profile than warfarin, against ASA or new antiplatelet agents.33 This systematic review has limitations. First, owing to different strategies across studies, results could not be pooled. Second, the populations and outcomes varied significantly. Third, the best evidence comes from a prespecified subgroup analysis of a trial using high intensity anticoagulation. Finally, some of the studies are old and not representative of the current population. Management of the initial clinical case As shown in Table 1, current guidelines vary significantly,8e15 but ASA remains the most commonly recommended drug for improving patency and preventing future vascular events. When deliberating between VKAs or aspirin, physicians should remember that although amputation is the most severe outcome of graft failure, improved graft patency does not directly translate into reduced risk of amputation.34 Furthermore, it should be remembered that major bleeding is associated with significant mortality.35 For the present case study, it is believed that the current available evidence suggests a benefit of VKAs over ASA for patency limb salvage (HR 0.72, 95% CI 0.5e1.01). VKAs targeting an INR between 2 and 4 (ideally between 3 and 4)2e 5,36 should be given for a minimum of 6 months, as indicated in studies showing a benefit of venous bypass over prosthetic bypass. A target INR similar to that specified in the BOA trial has been shown to be effective in preventing recurrent vascular events following an acute coronary syndrome without the need for concomitant aspirin.37,38 The ideal target INR range for the venous bypass population is higher than that used for populations with other medical conditions.39,40 Therefore, the use of VKAs over ASA could be justified in patients: (i) having a high risk of bypass failure; (ii) having a low bleeding risk (i.e., low HAS-BLED score)41;
Table 4. Antithrombotic strategies in studies comparing venous and prosthetic bypass. Trial Ballota et al.4
Intervention Above-knee SV vs. PTFE
Burger et al.5
Above-knee SV vs. PTFE
Tilanus et al.2 Mohammadi Tofigh et al.3
Above-knee SV vs. PTFE Above-knee SV vs. PTFE
Note. SV ¼ saphenous vein; PTFE ¼ polytetrafluoroethylene; VKA ASA ¼ aspirin.
Antithrombotic strategy VKA started the day before the operation and was continued for 6 mo (INR 2 and 4), then 325 mg ASA VKA for the first 6 mo (INR between 2 and 4), then 38 mg ASA All patients were kept on anticoagulation therapy VKA during the first 6 mo (INR 2 and 4), then 38 mg ASA ¼ vitamin K antagonist; INR ¼ International Normalized Ratio;
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Role of Vitamin K Antagonists
and (iii) expected to achieve and stay within the therapeutic INR range when treated with VKAs (i.e., low SAMe-TT2R2 score).42 When using VKAs, concomitant use of ASA should be avoided because it increases the risk of bleeding without providing significant benefits.37,38,43,44 Finally, when VKAs are used, management should ideally be provided by specialized centers that have expertise in keeping patients in a therapeutic INR range.45
7
9
10
CONCLUSION Current evidence suggests that guidelines should consider oral anticoagulation with VKAs (targeting an INR > 2, but likely ranging between 3 and 4) to be a superior alternative to ASA for the prevention of infrainguinal autologous venous graft thrombosis. For the present patient population, the use of VKAs is recommended to preserve patency, assuming that the bleeding risk is acceptable.
11
12
ACKNOWLEDGMENTS Ms. Alexandra Davis for helping with the literature search. CONFLICT OF INTEREST
13
None. FUNDING None. 14
APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2016.03.026.
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Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
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32
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E. Gándara et al. consequences? The Dutch BOA (Bypass Oral Anticoagulants or Aspirin) Study. Eur J Vasc Endovasc Surg 2005;30:154e9. Moyé L. What can we do about exploratory analyses in clinical trials? Contemp Clin Trials 2015;45:302e10. Lindblad B. Antithrombotic drug therapy after infrainguinal vascular surgery. Lancet 2000;355:334. Davis CE. Secondary endpoints can be validly analyzed, even if the primary endpoint does not provide clear statistical significance. Control Clin Trials 1997;18:557e60. Freemantle N. Interpreting the results of secondary end points and subgroup analyses in clinical trials: should we lock the crazy aunt in the attic? BMJ 2001;322:989e91. Monaco M, Di Tommaso L, Pinna GB, Lillo S, Schiavone V, Stassano P. Combination therapy with warfarin plus clopidogrel improves outcomes in femoropopliteal bypass surgery patients. J Vasc Surg 2012;56:96e105. Arfvidsson B, Lundgren F, Drott C, Scherstén T, Lundholm K. Influence of coumarin treatment on patency and limb salvage after peripheral arterial reconstructive surgery. Am J Surg 1990;159:556e60. Warfarin Antiplatelet Vascular Evaluation Trial Investigators, Anand S, Yusuf S, Xie C, Pogue J, Eikelboom J, et al. Oral anticoagulant and antiplatelet therapy and peripheral arterial disease. N Engl J Med 2007;357:217e27. Bedenis R, Lethaby A, Maxwell H, Acosta S, Prins MH. Antiplatelet agents for preventing thrombosis after peripheral arterial bypass surgery. Cochrane Database Syst Rev 2015;2: CD000535. Warkentin AE, Donadini MP, Spencer FA, Lim W, Crowther M. Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta-analysis. J Thromb Haemost 2012;10:512e20. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981e92. Vandvik PO, Lincoff AM, Gore JM, Gutterman DD, Sonnenberg FA, Alonso-Coello P, et al. Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl.):e637Se68S. Davies AH, Hawdon AJ, Sydes MR, Thompson SG, VGST Participants. Is duplex surveillance of value after leg vein bypass grafting? Principal results of the Vein Graft Surveillance Randomised Trial (VGST). Circulation 2005;112:1985e91.
35 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152:578e89. 36 Tangelder MJD, Algra A, Lawson JA, Hennekes S, Eikelboom BC. Optimal oral anticoagulant intensity to prevent secondary ischemic and hemorrhagic events in patients after infrainguinal bypass graft surgery. J Vasc Surg 2001;33:522e7. 37 Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969e74. 38 van Es RF, Jonker JJC, Verheugt FWA, Deckers JW, Grobbee DE. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial. Lancet 2002;360:109e13. 39 Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719e47. 40 Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of chest physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl.):e419Se94S. 41 Lane DA, Lip GYH. Use of the CHA2DS2-VASc and HAS-BLED scores to aid decision making for thromboprophylaxis in nonvalvular atrial fibrillation. Circulation 2012;126:860e5. 42 Abumuaileq RR-Y, Abu-Assi E, Raposeiras-Roubin S, LópezLópez A, Redondo-Diéguez A, Álvarez-Iglesias D, et al. Evaluation of SAMe-TT2R2 risk score for predicting the quality of anticoagulation control in a real-world cohort of patients with non-valvular atrial fibrillation on vitamin-K antagonists. Europace 2015;17:711e7. 43 Thrombosis prevention trial. Randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Lancet 1998;351:233e41. 44 Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003;41:S62e9. 45 Wilson SJ-A, Wells PS, Kovacs MJ, Lewis GM, Martin J, Burton E, et al. Comparing the quality of oral anticoagulant management by anticoagulation clinics and by family physicians: a randomized controlled trial. CMAJ 2003;169:293e8.
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‘EVIDENCE DRIVEN’ CLINICAL SCENARIO
Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass E. Gándara
a,b,*
, D. Hammond c, S. Nagpal
d
a
Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Hospital, Ottawa, Canada Ottawa Hospital Research Institute, Ottawa, Canada c Department of Medicine, University of Toronto, Toronto, Canada d Division of Vascular Surgery, Department of Surgery, University of Ottawa, Ottawa Hospital, Ottawa, Canada b
Clinical vignette: Despite being the most common antithrombotic strategy in trials comparing venous with prosthetic grafts, the use of vitamin K antagonists (VKAs) to improve the outcome of venous bypass remains the subject of debate. In this systematic review, evidence supporting the use of VKAs for improving venous patency following infrainguinal venous bypass is provided. Clinical question: A 67 year old man with lifestyle limiting claudication underwent a successful infrainguinal venous bypass. Can VKAs help preserve patency after venous bypass surgery? Methods: A systematic review of electronic databases, including MEDLINE and Embase, was conducted. Only randomized controlled studies comparing VKAs with aspirin (ASA) were included. The main outcome was bypass patency. Results: Four studies using different intensities of anticoagulation ASA were identified. All but one showed a benefit of VKAs over ASA with respect to primary patency. However, this benefit was also accompanied by an increased risk of bleeding. The Dutch Bypass Oral Anticoagulants, or ASA, study was the largest included and showed that VKAs (without concomitant ASA) were superior to ASA alone for the prevention of graft occlusion (hazard ratio 0.69, 95% confidence interval 0.54e0.88). Conclusion: Current evidence suggests that VKAs are superior to ASA for the prevention of infrainguinal autologous venous graft thrombosis. Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. Article history: Received 14 August 2015, Accepted 23 March 2016, Available online XXX Keywords: Peripheral vasculature, Vein bypass, Vitamin K antagonists
CLINICAL SCENARIO A 67 year old man, who is a former smoker, with lifestyle limiting claudication, develops progressive worsening of his condition, leading to rest pain. He is admitted to hospital where it is determined that he requires a femorotibial bypass. His greater saphenous vein is in good condition and the bypass is successful. Could vitamin K antagonists (VKAs) help preserve patency after venous bypass surgery? BACKGROUND In patients with infrainguinal arterial disease requiring a bypass, the use of autologous venous grafts remains the preferred conduit option given their better patency results.1 Although this continues to be the primary antithrombotic * Corresponding author. Thrombosis Program, Division of Hematology, Department of Medicine, University of Ottawa, Ottawa Hospital, Ottawa, Canada. E-mail address: [email protected] (E. Gándara). 1078-5884/Ó 2016 European Society for Vascular Surgery. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejvs.2016.03.026
strategy in trials comparing venous with prosthetic grafts,2e 5 some systematic reviews suggest that VKAs are superior to aspirin (ASA) at maintaining patency following infrainguinal venous bypass.6,7 In general, guidelines support the use of ASA dipyridamole following any type of surgical intervention for peripheral arterial disease (PAD).8e15 Two guidelines do not support the use of VKAs following bypass,10,13 two recommend VKAs þ ASA for bypass patients at high risk of re-thrombosis,9,11 and three suggest using VKAs after venous bypass when the risk of bleeding is low (see Table 1 for a summary of the recommendations).8,14,15 The aim of this systematic review is to evaluate the evidence supporting the role of VKAs following an infrainguinal venous bypass. METHODS An electronic review of Ovid MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, from 1946 to May 2015 (the search strategies and a Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist are presented in Appendix 1) was performed. Hand searches of relevant articles, abstract books from
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Table 1. Current guideline recommendation for antithrombotic therapy following an infrainguinal venous bypass. Role of VKAs? No role
Guideline ACCP 201210
AHA 201313
Only for high risk bypass
ACCP 200812
CCS 201011
German S39
Consider for venous bypass
ESC 20118
ESVS 201115
TASC 200714
Suggestion
One of the following antithrombotic regimens is recommended to be continued long term in most patients following peripheral artery bypass graft surgery over no antithrombotic treatment: ASA 75e100 mg daily or clopidogrel 75 mg daily (all recommendation grade 1A) Single antiplatelet therapy over antiplatelet therapy and warfarin is recommended (recommendation grade 1B) ASA, typically in daily doses of 75e325 mg, or clopidogrel, is recommended as a safe and effective antiplatelet therapy to reduce the risk of MI, stroke, and vascular death in individuals with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia (level of evidence II) The combination of ASA and clopidogrel may be considered to reduce the risk of cardiovascular events in patients with symptomatic atherosclerotic lower extremity PAD, including those with intermittent claudication or CLI, prior lower extremity revascularization (endovascular or surgical), or prior amputation for lower extremity ischemia, and who are not at increased risk of bleeding and who have a high perceived cardiovascular risk (level of evidence II) For patients receiving routine autogenous vein infrainguinal bypass, ASA (75e100 mg, begun pre-operatively) is recommended (recommendation grade 1A) It is suggested that VKAs not be used routinely in patients undergoing infrainguinal vein bypass (recommendation grade 2B) For those at high risk of bypass occlusion and limb loss, VKA þ ASA is suggested (recommendation grade 2B) For those undergoing infrainguinal reconstruction with venous conduits, low-dose ASA is recommended (recommendation grade 1A). Anticoagulation with VKAs is not recommended for routine post-operative use (recommendation grade 2A) In those with infrainguinal grafts with a high risk of thrombosis and limb loss, combination VKA þ ASA therapy may be of benefit in select cases (recommendation grade 2B) In patients with infrainguinal, femoropopliteal, or distal venous bypass, oral anticoagulants should not be used routinely given that the risk of bleeding is significantly increased (recommendation grade A, level of evidence II) In individuals at a very high risk for a bypass closure, oral anticoagulants or oral anticoagulants combined with ASA should be considered (recommendation grade 0, level of evidence V) Antiplatelet treatment with ASA or a combination of ASA and dipyridamole is recommended after infrainguinal bypass surgery Antithrombotic treatment with VKAs may be considered after autogenous vein infrainguinal bypass (level of evidence IIb) Following vein bypass surgery for CLI, ASA or ASA þ dipyridamole is efficient in lowering the incidence of thrombotic occlusions (level of evidence IIb; Grade B) VKAs are superior when closely monitored and should be preferred in suitable patients during early follow up, particularly for below-the-knee bypass (level of evidence Ib; Grade B) Antiplatelet therapy should be started pre-operatively and continued as adjuvant pharmacotherapy after an endovascular or surgical procedure [A]. Unless subsequently contraindicated, this should be continued indefinitely [A] Autogenous grafts may be treated with warfarin, but this is accompanied by a risk of hemorrhage and this decision must be made on an individual patient basis
Note. VKA ¼ vitamin K antagonist; ACCP ¼ American College of Chest Physicians; AHA ¼ American Heart Association; MI ¼ myocardial infarction; PAD ¼ peripheral arterial disease; CLI ¼ critical limb ischemia; CCS ¼ Canadian Cardiovascular Society; ESC ¼ European Society of Cardiology; ESVS ¼ European Society of Vascular Surgery; TASC ¼ Inter-Society Consensus for the Management of Peripheral Arterial Disease.
international meetings, and published reviews were also conducted. Randomized controlled trials (RCTs) were included if they reported outcomes for patients with infrainguinal disease who were treated with venous bypass, and compared VKAs
( ASA) with ASA alone for the prevention of graft occlusion. Trials using other forms of anticoagulation (i.e., low molecular weight heparin) or an antiplatelet other than ASA were excluded. In order to provide a more relevant answer, we analyzed outcomes according to International
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Role of Vitamin K Antagonists
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Normalized Ratio (INR) targets and by the use of concomitant ASA in patients treated with VKAs. The rationale for this approach is based on the different degrees of efficacy/ safety associated with different INR ranges,16 and with the use of concomitant ASA in patients treated with VKAs.17
Data extraction and quality assessment All potentially relevant articles were reviewed in full text to ensure that they satisfied the inclusion criteria. Two reviewers (D.H. and E.G.) independently assessed the eligibility of all articles identified in the initial search strategy. A third reviewer adjudicated all discrepancies if needed. Data regarding VKA strategy (drug, target range, and use of concomitant ASA), ASA strategy (dose), patients enrolled, indication, bypass outcomes, vascular outcomes, deaths, bleeding outcomes, and follow up were collected.
Outcome measure
IdenƟficaƟon
The primary outcome was bypass patency. Secondary outcome measures included major bleeding, death, and amputation.
Data synthesis and analysis If two or more studies reported the outcomes of a similar intervention (same INR range and use of ASA), it was planned to pool data using the random-effects model generating odds ratios (ORs), along with the corresponding 95% confidence intervals (CIs). The I2 statistic was used to quantify heterogeneity among the pooled estimates across trials. An I2 value < 25% was considered low level heterogeneity, 25e 50% as moderate level, and > 50% as high level. RESULTS As shown in Fig. 1, the search identified 10,723 relevant abstracts, of which 57 were reviewed in full text. The search identified four trials using different intensities of anticoagulation ASA.18e21 The doses of ASA (81 mge1 g) and target INR varied significantly. The methodological quality, inclusion criteria, design, main outcome, adjudication, and number of patients lost to follow up also varied significantly across studies (see Tables 2 and 3), precluding any pooling of information. Most of the studies showed a significant benefit of VKAs.18e20 Two studies compared VKAs without concomitant ASA versus ASA alone,18,20 and another two studies
Records idenƟfied through database searching (n = 10,723)
Eligibility
Screening
Records aŌer duplicates removed (n = 10,723 )
Records screened (n = 10,723)
Records excluded (n = 10,666)
Full-text arƟcles assessed for eligibility (n = 57)
Excluded (n =53): - Review papers (n = 5) - Endovascular intervenƟon (n = 7) - Overlapping paƟents from another study (n = 2) - Not able to translate to English (n = 3) - Lacks primary outcome at relevant Ɵme points (n = 36)
Included
Studies included in qualitaƟve synthesis (n = 4 )
Studies included in quanƟtaƟve synthesis (meta-analysis) (n = 0)
Figure 1. Flow diagram. Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Bollinger20
Sarac et al.19
Acenocoumarol vs. ASA 1g vs. ASA 1 g/dipyridamole 225 mg 1980 Austria NR Yes
4
Jonhson and Williford21
WafarineASA 325 mg vs. ASA 325 mg 1998 USA Single center NA; only veins
The Dutch Bypass Oral anticoagulants or Aspirin study18 Phenprocoumon or acenocoumarol vs. ASA 80 mg 2000 The Netherlands 77 Yes
WafarineASA 325 mg vs. ASA 325 mg 2002 USA 17 Yes
30/60 30e34% of the Quick value NR
37/27 INR 2e3 2; bridged with heparin
784/762 INR 3.0e4.5 5 from procedure
231/227 INR 1.4e2.8 As soon as fluids were tolerated
2y Angiographically proven patent artery postprocedure
3y Suboptimal venous conduits
Mean of 21 mo Patients who required an infrainguinal bypass graft
Exclusion criteria reported Main outcome Mean age (y) Claudicants I/C% Female I/C N(%) Diabetes (%) Randomization
Yes Patency at 2 y 63.9 All 37% NR NR NR
Blinding Type of analysis Adjudication of events
No ITT Open label
Yes Patent but failing graft 69/66 NR 18/25 53/79 Computer-assisted random number generator matched for sex No ITT NR
Up to 5 y (mean 39 mo) All patients scheduled for elective bypass b Yes Assisted primary patency 65/64 NR NR 51.5/51.8 Stratified by center and by bypass material
% loss to follow up or discontinuation of therapy
21.7% in the ASA group and 6.7% discontinued treatment
NR
No ITT Independent panel of blinded experts NR
Sample size calculation Patency I/C (%) Major bleeding I/C (%) Death I/C (%)
NR 83/68 p ¼ NR NR 10/5; p ¼ NS
NR 74/51; p ¼ .04 8/NR 45.3/49.5; p ¼ NS
Yes 85.7/79.7 HR 0.69 (95% CI 0.54e0.88) 1/0.3 15.9/16.7; p ¼ NS
Amputation I/C (%)
NR
Limb salvage rate 81/31; p ¼ .02
6.6/9.3 HR 0.72 (95% CI 0.5e1.01)
Excluded studies Publication Arfvidsson et al. (1990)28
Intervention Warfarin vs. control
Reason(s) for exclusion Control was no treatment
Investigators contacted? Yes
Intervention/control Year Country Centers Was analysis of vein bypass graft prespecified? Intervention/control (n) VKA target range Days from surgery to intervention Duration of follow up Inclusion criteria
a
Yes Graft occlusion NR NR NR NR Computer generated blocked sequences, stratified by center
No ITT NR 14 lost to follow up (4 I/10 C); 41% were off warfarin by the end of the study Yes 25.1/24.7 RR 1.04 (95% CI 0.72e1.51) 10.5/4.6; p ¼ .01 13.2/12.9; p ¼ NS 5.4/3.5; p ¼ NS
Comment e
E. Gándara et al.
Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026
Table 2. Studies comparing vitamin K antagonists (VKAs) with antiplatelet agents.
In this study, the combination of warfarin þ clopidogrel was superior to ASA þ clopidogrel Note. ASA ¼ aspirin; NR ¼ not reported; NA ¼ not applicable; INR ¼ International Normalized Ratio; I ¼ Intervention; C ¼ Control; ITT ¼ intention to treat; HR ¼ hazard ratio; CI ¼ confidence interval; RR ¼ relative risk; NS ¼ nonsignificant. a The venous conduit was considered suboptimal if it was < 3.0 mm in diameter with pre-operative duplex ultrasound mapping, if the vein was sclerotic with intra-operative angioscopy, or if insufficient saphenous vein was available, which would necessitate the use of arm, vein, or a composite saphenous vein bypass graft. Runoff was considered poor if the distal anastomotic site of the bypass graft was in the distal third of the tibial or peroneal arteries, if there was runoff to the foot only through collateral vessels, if the anastomotic site was located in any portion of the tibial or peroneal arteries and the entire runoff bed was diffusely diseased with multiple sites of >50% stenoses, or if selection of the distal target was compromised as a result of inadequate vein length such that the anastomosis could not be placed beyond all significant disease. b Axillofemoral, femoralefemoral, femoralepopliteal, or femoraledistal. Yes
Warfarin INR 2e3 þ clopidogrel vs. ASA þ clopidogrel
Warfarin Antiplatelet Vascular Evaluation Trial Investigators et al. (2007)29 Monaco et al. (2012)27
Warfarin INR 2e3 plus ASA vs. ASA alone
Unable to isolate data of subpopulation that underwent infrainguinal venous bypass Unable to obtain data for those with venous bypasses
Yes
e
Role of Vitamin K Antagonists
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compared VKAs plus ASA versus ASA alone.19,21 The Dutch By-pass Oral anticoagulants or Aspirin study (BOA) was the largest and best designed study.18 This was an open label multicenter trial in which all outcomes were independently adjudicated, thereby reducing the risk for potential bias. Although they did not stratify the randomization to the type of material used, they reported on the outcomes of 1,546 patients with an infrainguinal venous bypass as a prespecified subgroup analysis. In this trial, VKAs with a target INR range of 3.0e4.5 were compared with ASA (80 mg). The trial showed not only that VKAs were superior to ASA in the prevention of graft occlusion (hazard ratio [HR] 0.69, 95% CI 0.54e0.88), but also increased the risk of major bleeding. Although it did not reach statistical significance, the rate of amputations appeared to be lower in patients receiving VKAs after a venous bypass (6.6% vs. 9.3%; HR 0.72, 95% CI 0.5e1.01, as reported by the study authors), and the composite outcome of vascular death, myocardial infarction (MI), stroke, or amputation (HR 0.89, 95% CI 0.75e1.06) was also reduced. A recent re-analysis of the BOA trial suggested that using ASA instead of a VKAs in patients with a high risk of bleeding would result in fewer nonfatal hemorrhages but would increase ischemic events and graft occlusions.22 One limitation of the BOA trial was that evidence supporting the use of VKAs in venous bypass came from a prespecified subgroup analysis,23,24 thereby reducing its validity. However, this argument is more relevant for subgroup analyses that were not prespecified or were derived on the basis of observed results.25,26 In a low-quality trial conducted in 1980 and with a sample of 90 patients, Bollinger suggested that using VKAs after bypass resulted in higher rates of primary patency at 2 years compared with 1 g ASA alone (or combined with dipyridamole).20 The aforementioned study was a single center, open label trial in which adjudication of outcomes was open, with high a probability of bias. The two studies that reported on the combined use of VKAs þ concomitant ASA versus ASA alone showed opposite results.19,21 In 1998, Sarac et al. suggested that VKAs significantly improved patency and limb salvage rates in patients with suboptimal conduits.19 In this trial, the authors compared VKAs (target INR 2e3) þ ASA 325 mg with ASA 325 mg alone. Despite showing a significant improvement in patency with VKAs (74% vs. 51%; p ¼ .04) the results of this study should be interpreted carefully as it was open label, conducted at two centers with open adjudication, and had a sample of 64 patients. However, in 2002 Johnson and Williford found no difference in the outcomes of patients requiring venous bypass treated with VKAs (target INR 1.4e 2.8) þ ASA 325 mg versus ASA 325 mg alone.21 This was a multicenter trial with open adjudication and a large number of patients with poor VKA compliance during follow up. The present systematic review identified other relevant RCTs that were not included (Table 2).27e29 The most recent compared the outcome of any bypass (venous or prosthetic) treated with clopidogrel/VKAs (INR 2e3) versus clopidogrel/ ASA. The graft patency rate was significantly higher in the VKA group.27
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Table 3. Quality assessment. Study
Random sequence generation Unclear Unclear Low
Bollinger20 Sarac et al.19 The Dutch Bypass Oral anticoagulants or Aspirin study18 Johnson and Williford21 Unclear
Allocation concealment Unclear Low Low
Blinding of participants/personnel High High High
Blinding of outcome assessment High High Low
Incomplete outcome data Unclear Unclear Low
Selective reporting Low Low Low
Low
High
Low
Low
Low
DISCUSSION Antithrombotic agents play a fundamental role in secondary prevention of vascular events in patients with PAD (e.g., stroke or MI)10 and in improving graft patency following venous bypass. Despite its convenience (e.g., no need for monitoring and limited interaction with other drugs) and established benefit following prosthetic grafts, there is conflicting evidence regarding the benefit of ASA and other antiplatelet agents following venous grafts.30 Evidence supporting the combined use of VKAs and ASA is also unclear. The present systematic review suggests that VKAs confer the greatest patency following venous bypass but increase the risk of major bleeding. RCTs showing superiority of venous bypass over synthetic grafts have commonly used VKAs (target INR 2e4) for at least 6 months, followed by ASA daily (Table 4).2e5 As indicated in the BOA trial,18 if VKAs are effective for venous but not for prosthetic grafts, the superiority seen for venous bypass could be explained, in part, by the initial antithrombotic regimen. Interestingly, to date, no study has compared the outcome of venous bypass using VKAs with synthetic grafts treated with antiplatelet agents alone. To the authors’ knowledge, two other systematic reviews have suggested a benefit of VKAs after venous bypass based on an analysis comparing the use of VKAs ASA versus no treatment, or studies comparing VKAs alone with ASA dipyridamole.6,7 To avoid bias (i.e., INR range is an important determinant of outcomes),16 this approach was not used in this review. For now, multiple questions remain unanswered. For instance: (i) What is the best INR range? (ii) What is an appropriate duration of treatment? (iii) Is concomitant ASA needed when treating with VKAs? Unfortunately, VKAs are associated with an increased risk of major bleeding and require frequent monitoring, making them less appealing than ASA.31 Future studies should evaluate and compare
new direct oral anticoagulants (such as apixaban),32 which have a better safety profile than warfarin, against ASA or new antiplatelet agents.33 This systematic review has limitations. First, owing to different strategies across studies, results could not be pooled. Second, the populations and outcomes varied significantly. Third, the best evidence comes from a prespecified subgroup analysis of a trial using high intensity anticoagulation. Finally, some of the studies are old and not representative of the current population. Management of the initial clinical case As shown in Table 1, current guidelines vary significantly,8e15 but ASA remains the most commonly recommended drug for improving patency and preventing future vascular events. When deliberating between VKAs or aspirin, physicians should remember that although amputation is the most severe outcome of graft failure, improved graft patency does not directly translate into reduced risk of amputation.34 Furthermore, it should be remembered that major bleeding is associated with significant mortality.35 For the present case study, it is believed that the current available evidence suggests a benefit of VKAs over ASA for patency limb salvage (HR 0.72, 95% CI 0.5e1.01). VKAs targeting an INR between 2 and 4 (ideally between 3 and 4)2e 5,36 should be given for a minimum of 6 months, as indicated in studies showing a benefit of venous bypass over prosthetic bypass. A target INR similar to that specified in the BOA trial has been shown to be effective in preventing recurrent vascular events following an acute coronary syndrome without the need for concomitant aspirin.37,38 The ideal target INR range for the venous bypass population is higher than that used for populations with other medical conditions.39,40 Therefore, the use of VKAs over ASA could be justified in patients: (i) having a high risk of bypass failure; (ii) having a low bleeding risk (i.e., low HAS-BLED score)41;
Table 4. Antithrombotic strategies in studies comparing venous and prosthetic bypass. Trial Ballota et al.4
Intervention Above-knee SV vs. PTFE
Burger et al.5
Above-knee SV vs. PTFE
Tilanus et al.2 Mohammadi Tofigh et al.3
Above-knee SV vs. PTFE Above-knee SV vs. PTFE
Note. SV ¼ saphenous vein; PTFE ¼ polytetrafluoroethylene; VKA ASA ¼ aspirin.
Antithrombotic strategy VKA started the day before the operation and was continued for 6 mo (INR 2 and 4), then 325 mg ASA VKA for the first 6 mo (INR between 2 and 4), then 38 mg ASA All patients were kept on anticoagulation therapy VKA during the first 6 mo (INR 2 and 4), then 38 mg ASA ¼ vitamin K antagonist; INR ¼ International Normalized Ratio;
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Role of Vitamin K Antagonists
and (iii) expected to achieve and stay within the therapeutic INR range when treated with VKAs (i.e., low SAMe-TT2R2 score).42 When using VKAs, concomitant use of ASA should be avoided because it increases the risk of bleeding without providing significant benefits.37,38,43,44 Finally, when VKAs are used, management should ideally be provided by specialized centers that have expertise in keeping patients in a therapeutic INR range.45
7
9
10
CONCLUSION Current evidence suggests that guidelines should consider oral anticoagulation with VKAs (targeting an INR > 2, but likely ranging between 3 and 4) to be a superior alternative to ASA for the prevention of infrainguinal autologous venous graft thrombosis. For the present patient population, the use of VKAs is recommended to preserve patency, assuming that the bleeding risk is acceptable.
11
12
ACKNOWLEDGMENTS Ms. Alexandra Davis for helping with the literature search. CONFLICT OF INTEREST
13
None. FUNDING None. 14
APPENDIX A. SUPPLEMENTARY DATA Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejvs.2016.03.026.
15
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Please cite this article in press as: Gándara E, et al., Role of Vitamin K Antagonists in the Prevention of Thrombotic Bypass Occlusion After Infrainguinal Venous Bypass, European Journal of Vascular and Endovascular Surgery (2016), http://dx.doi.org/10.1016/j.ejvs.2016.03.026