Abstract
Background
In the POISE-2 (PeriOperative ISchemic Evaluation 2) trial, perioperative aspirin did not reduce cardiovascular events, but increased major bleeding. There remains uncertainty regarding the effect of perioperative aspirin in patients undergoing vascular surgery. The aim of this substudy was to determine whether there is a subgroup effect of initiating or continuing aspirin in patients undergoing vascular surgery.
Methods
POISE-2 was a blinded, randomized trial of patients having non-cardiac surgery. Patients were assigned to perioperative aspirin or placebo. The primary outcome was a composite of death or myocardial infarction at 30 days. Secondary outcomes included: vascular occlusive complications (a composite of amputation and peripheral arterial thrombosis) and major or life-threatening bleeding.
Results
Of 10 010 patients in POISE-2, 603 underwent vascular surgery, 319 in the continuation and 284 in the initiation stratum. Some 272 patients had vascular surgery for occlusive disease and 265 had aneurysm surgery. The primary outcome occurred in 13·7 per cent of patients having aneurysm repair allocated to aspirin and 9·0 per cent who had placebo (hazard ratio (HR) 1·48, 95 per cent c.i. 0·71 to 3·09). Among patients who had surgery for occlusive vascular disease, 15·8 per cent allocated to aspirin and 13·6 per cent on placebo had the primary outcome (HR 1·16, 0·62 to 2·17). There was no interaction with the primary outcome for type of surgery (P = 0·294) or aspirin stratum (P = 0·623). There was no interaction for vascular occlusive complications (P = 0·413) or bleeding (P = 0·900) for vascular compared with non-vascular surgery.
Conclusion
This study suggests that the overall POISE-2 results apply to vascular surgery. Perioperative withdrawal of chronic aspirin therapy did not increase cardiovascular or vascular occlusive complications. Registration number: NCT01082874 (http://www.clinicaltrials.gov).
No evidence to start or stop aspirin
Introduction
The POISE-2 trial randomized 10 010 patients undergoing non-cardiac surgery who were either already taking aspirin (continuation stratum) or not (initiation stratum) to receive aspirin or placebo during the perioperative phase1. The trial demonstrated no benefit from low-dose perioperative aspirin in reducing cardiovascular events within 30 days of surgery, but an increased risk of major bleeding, in both the initiation and continuation strata2.
Despite these results, there remains uncertainty whether low-dose aspirin therapy should be discontinued (or initiated) in patients undergoing vascular surgery3. In POISE-2, 603 patients underwent vascular surgery. An a priori subgroup analysis showed no interaction for the primary outcome (a composite of death or non-fatal myocardial infarction) between the vascular and non-vascular surgery subgroups2; however, no other outcomes were evaluated. Moreover, the thrombotic and haemorrhagic risks may differ between patients with occlusive peripheral vascular disease and those with aneurysms. Low-dose aspirin may decrease vascular occlusive complications (amputation and peripheral arterial thrombosis) in occlusive peripheral vascular disease, but may increase the risk of bleeding in patients with an aneurysm. These data could be important for vascular surgeons as they consider whether to continue or start aspirin during the perioperative phase in their patients4.
It is important to understand whether there are important differences in the secondary outcomes or safety outcomes among patients undergoing vascular surgery compared with those treated by other specialties. Therefore, the aim of this POISE-2 substudy was to determine whether there were any interactions in the treatment effects based on whether patients underwent vascular versus non-vascular surgery. Furthermore, differences in outcomes between the subgroups of patients undergoing occlusive vascular surgery (who may be at increased thrombotic risk) and aneurysm vascular surgery (who may be at increased risk of bleeding) were examined.
The primary objective was to determine whether there was a subgroup effect with aspirin therapy for the primary outcome of mortality or non-fatal myocardial infarction by 30 days after surgery among patients who underwent vascular surgery for occlusive or aneurysm disease.
Methods
The POISE-2 trial was an investigator-initiated, global, multicentre, 2 × 2 factorial RCT of low-dose aspirin versus placebo and low-dose clonidine versus placebo in patients at risk of a perioperative cardiovascular event who were undergoing non-cardiac surgery. Details of the trial objectives, design and methods were published previously and have been reported at ClinicalTrials.gov (NCT01082874)1,2,5. All patients were recruited after giving informed consent with full local ethics board approval. An external safety and efficacy and monitoring committee monitored the trial results during its conduct. Blinded adjudicators assessed outcome events.
Patients
Patients were recruited between July 2010 and December 2013. Eligibility criteria for the trial are listed in Table S1 (supporting information). Briefly, patients who had, or were at risk of, coronary artery disease were included who underwent in-hospital non-cardiac surgery. Patients who had taken aspirin within 72 h before surgery, and those who had a clear indication or contraindication to be on aspirin or clonidine in the perioperative phase, were excluded. Previous studies suggested that haemostasis is unimpaired if there are at least 20 per cent of platelets with normal cyclo-oxygenase 1 activity6,7, and 12 per cent of circulating platelets are replaced every 24 h8,9. Therefore, stopping aspirin at least 72 h before surgery was determined to be adequate to minimize the risk of perioperative bleeding in this study. Low-dose aspirin, 100 mg, was chosen, because it has been associated with less gastritis and was non-inferior to high-dose aspirin in preventing vascular complications10–12.
Patients were enrolled in an initiation stratum if they were not taking aspirin chronically, and in a continuation stratum if they were taking aspirin chronically (defined as daily administration for at least 1 month within the 6 weeks before surgery). Patients were randomized in a 1 : 1 : 1 : 1 allocation to receive aspirin/clonidine, aspirin placebo/clonidine, aspirin/clonidine placebo or aspirin placebo/clonidine placebo. Patients started the study drug (200 mg) just before surgery and continued it (100 mg/day) for 30 days in the initiation stratum and for 7 days in the continuation stratum, after which patients resumed their regular aspirin. Patients also started clonidine or placebo (0·2 mg/day) just before surgery and continued for 72 h. All recruited patients were included in this study, with a subgroup analysis of those who underwent vascular surgery, which includes surgery for occlusive vascular disease or aneurysms.
Procedures
After providing written informed consent, patients were randomized before surgery via a 24-h computerized internet system using block randomization stratified by centre and aspirin stratum. Patients, healthcare providers, data collectors and outcome adjudicators were blinded to the treatment allocation.
Patients had routine screening for myocardial infarction with troponin measurements (or creatinine kinase–myocardial band if troponin was not available), using blood drawn 6–12 h after surgery and daily for the first 3 days thereafter. Patients with raised troponin levels had an ECG immediately after detection of the raised level. The diagnosis of myocardial infarction was according to the criteria of the third universal definition of myocardial infarction (Table S2, supporting information)13. Research personnel followed patients during the hospital stay and contacted them 30 days after randomization to determine whether a trial outcome had been experienced.
Substudy outcomes
The primary objective of this substudy was to determine whether there was a subgroup effect with aspirin therapy for the primary outcome of mortality or non-fatal myocardial infarction by 30 days after surgery in patients undergoing vascular surgery for occlusive or aneurysm disease. The secondary objectives were to determine whether there was a subgroup effect for aspirin: for the primary outcome of mortality or non-fatal myocardial infarction by 30 days after vascular surgery, according to initiation or continuation stratum; for vascular occlusive complications (a composite of fatal and non-fatal amputation and peripheral arterial thrombosis) by 30 days after surgery, based on whether patients underwent surgery for occlusive or aneurysm disease versus non-vascular surgery; and for the composite of major and life-threatening bleeding by 30 days after surgery, based on whether patients underwent vascular surgery for occlusive or aneurysm disease versus non-vascular surgery. Tertiary outcomes reported are individual subgroup effects of vascular surgery for occlusive or aneurysm disease in terms of total mortality, vascular mortality, myocardial infarction, peripheral arterial thrombosis, amputation and readmission to hospital for vascular reasons; and the individual safety subgroup effects for life-threatening bleed, other major bleed and stroke, and acute kidney injury with need for dialysis. Definitions of the primary, secondary and tertiary outcomes are reported in Table S2 (supporting information), and the adjudicated outcomes in Appendix S1 (supporting information).
Statistical analysis
Patients were analysed in the treatment group to which they were originally allocated. To evaluate outcome events, research personnel followed patients in hospital and contacted them at 30 days after randomization. All events that centres had reported and the adjudication committee had not refuted were included. An a priori subgroup analysis comparing vascular surgery procedures and non-vascular procedures showed no interaction for the primary outcomes2. The analysis was based on the first occurrence of the outcome up to 30 days after randomization. Patients allocated to aspirin were compared with those allocated to aspirin placebo. Patients lost to follow-up before day 30 after randomization who did not experience the outcome under evaluation were censored at the last day the patient had a complete evaluation.
Baseline characteristics are described using summary statistics. Differences in continuous variables between groups were analysed using ANOVA, and differences between categorical variables using χ2 test and Fisher's exact test, as appropriate. Only observed values were used; there was no imputation of missing variables.
For the outcomes of this study, subgroup analyses were based on: the type of vascular surgery (aneurysm surgery, which included thoracic aorta reconstruction, open abdominal aortic aneurysm repair, extracranial aneurysm cerebrovascular surgery and endovascular aneurysm repair; and surgery for occlusive disease, which included aortoiliac reconstruction and peripheral vascular reconstruction without aortic cross-clamping) and the aspirin stratum in patients having vascular surgery (initiation stratum and continuation stratum). Patients who underwent mixed vascular surgical procedures (for both aneurysm and occlusive vascular disease) were excluded from analyses of the subgroup effects for aneurysm and occlusive vascular surgery. Patients were categorized into one of four levels based on whether they underwent vascular surgery or not, and whether they were in the initiation or continuation stratum. The interaction effect was sought and presented as a P value for overall subgroup interaction. For the subgroup analyses, outcome variables were analysed using a Cox proportional hazards model stratified by centre that incorporated a test of interaction.
The number of patients with each outcome, estimated hazard ratios (HRs) and associated two-sided 95 per cent confidence intervals were calculated for each of the four subgroups generated by these analyses, as assessed in the main model. The only exception was acute kidney injury receiving dialysis, for which the odds ratio is reported, as the timing of dialysis was unknown, and so a logistic regression analysis was undertaken. A subgroup effect was inferred if the interaction term of treatment and subgroup was statistically significant at P < 0·050. A two-sided significance level of 5 per cent was applied. All analyses were conducted using SAS® software version 9.4 (SAS Institute, Cary, North Carolina, USA).
Results
POISE-2 randomized 10 010 patients from 130 centres in 23 countries; data were missing for 77 patients and 9933 were included in the analysis. Among 9330 patients who had non-vascular surgery, there were 4024 in the aspirin continuation stratum and 5306 in the aspirin initiation stratum. A total of 603 patients underwent vascular surgery: 265 had aneurysm repair and 272 had surgery for occlusive disease. Sixty-six patients had surgery for mixed aneurysm and occlusive vascular disease.
The vascular surgery subgroups had significantly more men than the non-vascular subgroup (aneurysm surgery 226 men, 85·3 per cent; occlusive vascular surgery 204, 75·0 per cent; non-vascular surgery 4759, 51·0 per cent; P < 0·001) (Table 1). Patients who underwent aneurysm repair were significantly older, with a mean age of 71·6 years. Patients undergoing aneurysm repair received significantly more prophylactic anticoagulants among the medications taken within 24 h before operation (P < 0·001) (Table S3, supporting information). Patients in the vascular surgery subgroups received significantly more statin therapy before and after operation, and more anticoagulation after surgery than those undergoing non-vascular procedures (P < 0·001). Patients with occlusive vascular disease received significantly more P2Y inhibitors in the first 3 days after surgery than patients having aneurysm repair and those having non-vascular surgery (P < 0·001) (Table S3, supporting information).
Table 1.
Baseline characteristics of patients undergoing non-vascular or vascular surgery
| Non-vascular surgery | Aneurysm surgery | Surgery for occlusive disease | |
|---|---|---|---|
| (n = 9330) | (n = 265) | (n = 272) | |
| Age (years)* | 68·6(10·4) | 71·6(8·4) | 65·1(9·6) |
| Sex ratio (M : F) | 4759 : 4571 | 226 : 39 | 204 : 68 |
| Eligibility criteria met | |||
| History of coronary artery disease | 2090 (22·4) | 77 (29·1) | 55 (20·2) |
| History of peripheral arterial disease | 502 (5·4) | 82 (30·9) | 244 (89·7) |
| History of stroke | 498 (5·3) | 14 (5·3) | 16 (5·9) |
| History of vascular disease | 2799 (30·0) | 144 (54·3) | 251 (92·3) |
| Undergoing major vascular surgery | 0 (0) | 191 (72·1) | 245 (90·1) |
| Any 3 of 9 risk criteria | 8000 (85·7) | 112 (42·3) | 111 (40·8) |
| Undergoing major surgery† | 7638 (81·9) | 70 (26·4) | 31 (11·4) |
| History of congestive heart failure | 312 (3·3) | 7 (2·6) | 10 (3·7) |
| History of TIA | 335 (3·6) | 14 (5·3) | 7 (2·6) |
| Current treatment for diabetes | 3611 (38·7) | 44 (16·6) | 94 (34·6) |
| Age ≥ 70 years | 4921 (52·7) | 156 (58·9) | 85 (31·3) |
| Hypertension | 8150 (87·3) | 187 (70·6) | 185 (68·0) |
| Preoperative creatinine >175 μmol/l | 288 (3·1) | 12 (4·5) | 13 (4·8) |
| History of smoking within 2 years | 2240 (24·0) | 115 (43·4) | 160 (58·8) |
| Emergency/urgent surgery‡ | 701 (7·5) | 3 (1·1) | 9 (3·3) |
| Aspirin stratum | |||
| Continuation | 4024 (43·1) | 142 (53·6) | 133 (48·9) |
| Initiation | 5306 (56·9) | 123 (46·4) | 139 (51·1) |
| Other medical history | |||
| Coronary artery bypass graft surgery | 433 (4·6) | 23 (8·7) | 12 (4·4) |
| Percutaneous coronary intervention | 432 (4·6) | 20 (7·5) | 11 (4·0) |
| Bare-metal stent | 235 (2·5) | 11 (4·2) | 6 (2·2) |
| Drug-eluting stent | 109 (1·2) | 4 (1·5) | 4 (1·5) |
| Stent, type unknown | 52 (0·6) | 1 (0·4) | 0 (0) |
| Dialysis in week before randomization | 114 (1·2) | 3 (1·1) | 9 (3·3) |
Values in parentheses are percentages unless indicated otherwise;
values are mean(s.d.).
Intraperitoneal, intrathoracic, retroperitoneal or major orthopaedic surgery.
Booked for surgery to occur within 48 h of acute presentation to hospital. TIA, transient ischaemic attack.
Study outcomes
Primary and secondary outcomes are summarized in Table 2. Analysis of the primary outcome showed that the effect of aspirin on the composite of death and non-fatal myocardial infarction was similar across aneurysm surgery (HR for aspirin versus placebo 1·48, 95 per cent c.i. 0·71 to 3·09), occlusive vascular surgery (HR 1·16, 0·62 to 2·17) and non-vascular surgery (HR 0·95, 0·81 to 1·11) (test for interaction P = 0·294).
Table 2.
Effects of aspirin on 30-day outcomes
| Aspirin | Placebo | Hazard ratio* | P ‡ | |
|---|---|---|---|---|
| Primary outcome: mortality or non-fatal myocardial infarction | ||||
| Main trial result (n = 10 010) | 351 (7·0) | 355 (7·1) | 0·99 (0·86, 1·15) | 0·920 |
| Aneurysm surgery (n = 265) | 18 (13·7) | 12 (9·0) | 1·48 (0·71, 3·09) | 0·294 |
| Vascular surgery for occlusive disease (n = 272) | 23 (15·8) | 17 (13·6) | 1·16 (0·62, 2·17) | 0·647 |
| Non-vascular surgery (n = 9330) | 299 (6·4) | 319 (6·8) | 0·95 (0·81, 1·11) | 0·484 |
| Interaction | 0·294 | |||
| Secondary outcomes | ||||
| Mortality or non-fatal myocardial infarction by aspirin stratum | ||||
| Main trial result (n = 10 010) | 351 (7·0) | 355 (7·1) | 0·99 (0·86, 1·15) | 0·920 |
| Non-vascular initiation stratum (n = 5306) | 159 (6·0) | 163 (6·1) | 0·99 (0·80, 1·23) | 0·930 |
| Vascular initiation stratum (n = 284) | 22 (14·3) | 21 (16·2) | 0·87 (0·48, 1·59) | 0·660 |
| Non-vascular continuation stratum (n = 4024) | 140 (7·0) | 156 (7·7) | 0·90 (0·72, 1·13) | 0·358 |
| Vascular continuation stratum (n = 319) | 26 (16·8) | 14 (8·6) | 2·00 (1·04, 3·84) | 0·036 |
| Interaction for non-vascular surgery andvascular surgery by aspirin strata | 0·623 | |||
| Vascular occlusive complications† | ||||
| Main trial result (n = 10 010) | 22 (0·4) | 27 (0·5) | 0·82 (0·46, 1·43) | 0·479 |
| Aneurysm surgery (n = 265) | 1 (0·8) | 4 (3·0) | 0·25 (0·03, 2·27) | 0·219 |
| Occlusive vascular surgery (n = 272) | 8 (5·5) | 11 (8·8) | 0·59 (0·24, 1·48) | 0·263 |
| Non-vascular surgery (n = 9330) | 11 (0·2) | 11 (0·2) | 1·01 (0·44, 2·32) | 0·986 |
| Interaction for vascular surgery and aneurysm or non-occlusive vascular surgery | 0·413 | |||
| Major and life-threatening bleeding | ||||
| Main trial result (n = 10 010) | 312 (6·3) | 257 (5·1) | 1·22 (1·03, 1·44) | 0·018 |
| Aneurysm surgery (n = 265) | 9 (6·9) | 7 (5·2) | 1·45 (0·54, 3·93) | 0·462 |
| Occlusive vascular surgery (n = 272) | 13 (8·9) | 10 (8·0) | 1·10 (0·48, 2·52) | 0·814 |
| Non-vascular surgery (n = 9330) | 285 (6·1) | 233 (5·0) | 1·24 (1·04, 1·47) | 0·016 |
| Interaction for non-vascular surgery and aneurysmor occlusive vascular surgery | 0·900 |
Values in parentheses are percentages unless indicated otherwise;
values in parentheses are 95 per cent confidence intervals.
Composite of fatal and non-fatal amputation and peripheral arterial thrombosis at 30 days after surgery.
Cox proportional hazards model.
The composite outcome of death or non-fatal myocardial infarction occurred in 22 patients (14·3 per cent) allocated to aspirin from the vascular surgery initiation stratum and 21 (16·2 per cent) allocated to placebo (HR 0·87, 0·48 to 1·59). Among patients undergoing non-vascular surgery from the initiation stratum, this composite outcome occurred in 159 patients (6·0 per cent) allocated to aspirin and 163 (6·1 per cent) randomized to placebo (HR 0·99, 0·80 to 1·23). The composite outcome occurred in 26 patients (16·8 per cent) from the vascular surgery continuation stratum allocated to aspirin and 14 (8·6 per cent) randomized to placebo (HR 2·00, 1·04 to 3·84). In the non-vascular surgery continuation stratum, the composite outcome occurred in 140 patients (7·0 per cent) allocated to aspirin and 156 (7·7 per cent) randomized to placebo (HR 0·90, 0·72 to 1·13). There was no interaction across these results (P = 0·623).
For vascular occlusive complications, there was no interaction across the subgroups (P = 0·413). For major and life-threatening bleeding, there was no interaction between vascular subgroups and non-vascular surgery, with an overall test for interaction of P = 0·900. Details of the subgroup analyses and safety outcomes are available online (Figs S1 and S2, supporting information). There was no interaction for any of the tertiary subgroups. The effect of aspirin was consistent across subgroups.
Discussion
In this substudy, aspirin therapy showed no significant benefit for the primary outcome of mortality and non-fatal myocardial infarction in patients having vascular surgery. As the main study showed no benefit in the prevention of myocardial infarction (309 aspirin (6·2 per cent) and 315 placebo (6·3 per cent); HR 0·98, 95 per cent c.i. 0·84 to 1·15), a separate analysis of the differences in rates of myocardial infarction was not undertaken in this substudy. There was no subgroup effect for surgery for aneurysm or occlusive disease. Aspirin showed no benefit in either the continuation or initiation stratum. There was no interaction for vascular occlusive complications or major and life-threatening bleeding between patients with aneurysm and those with occlusive vascular disease.
These results are therefore consistent with the overall results of POISE-22, showing a lack of evidence for primary prevention in patients with vascular disease14, and lack of evidence for secondary prevention in patients with peripheral artery disease15. It is not necessary to start aspirin before operation to prevent cardiovascular events in patients having vascular surgery.
Conversely, there has been concern that stopping long-term aspirin therapy before vascular surgery may be associated with an increased risk of thrombotic events. The vascular surgery continuation stratum was the only subgroup to demonstrate a statistically significant adverse effect: the continuation of chronic aspirin resulted in an increase in death and non-fatal myocardial infarction (HR 2·00, 95 per cent c.i. 1·04 to 3·84). However, this result should be viewed with caution, as it was based on a small number of patients (319), and was associated with a fragility index of 2 and non-significance for interaction16. Given that chronic aspirin therapy was stopped for only 7 days, and that there was no interaction associated with cardiovascular complications and the aspirin strata from POISE-2, the data suggest that withholding aspirin therapy before surgery will not increase adverse cardiovascular events2,15 or peripheral artery complications. These data are important as they provide evidence to inform the management of perioperative aspirin therapy in patients with vascular disease, which until now has been limited17–19.
A meta-analysis20 suggested that aspirin administration compared with placebo was associated with improved patency of prosthetic grafts, but not venous grafts, at 30 days. The most recent article21 from this meta-analysis of prosthetic graft patency was published in 1987, and therefore may not represent current practice. Indeed, the incidence of graft failure/occlusion has decreased markedly since the 1980s; the event rate was 22 per cent in controls in the 1987 trial compared with 4·8 per cent in the placebo arm of the occlusive vascular surgery cohort in POISE-2 (Fig. S1, supporting information). The reduction in the graft failure rate may in part be due to the increased use of prophylactic anticoagulants, and improved operative techniques and grafts. In the present study, nearly two-thirds of patients received prophylactic anticoagulants in the first 3 days after vascular surgery, and nearly 80 per cent with occlusive vascular disease received either prophylactic or therapeutic anticoagulation in the first 3 postoperative days. Low molecular weight heparins have been associated with improved graft patency at 1 month after operation compared with aspirin22. Current evidence suggests that withholding aspirin in the perioperative phase will not significantly increase the risk of vascular occlusive complications in patients having vascular surgery.
In accordance with the findings of POISE-2, there was no subgroup interaction for major or life-threatening bleeding among patients having vascular surgery. The point estimates also suggested harm in patients undergoing vascular surgery. Given that clinically important bleeding (as defined in Table S2, supporting information) is independently associated with myocardial infarction2, it might be suggested that aspirin should be stopped before vascular surgery. Some 7·9 per cent of patients on aspirin undergoing vascular surgery had life-threatening or major bleeding. However, a limitation of this substudy was the small number of adverse events. Larger studies or meta-analyses of similar studies would be necessary to inform policy and guidelines on this subject. The present substudy was underpowered for the primary and secondary outcomes. It was also underpowered to adjust for co-variables in the analyses.
There are limitations to this study. Patients scheduled for carotid endarterectomy (CEA) were excluded from POISE-2 as perioperative aspirin treatment in these patients showed evidence of benefit in an RCT12. This was further validated in a large observational cohort study23 of over 28 000 patients undergoing CEA, where the risk of thrombotic complications exceeded the risk of bleeding associated with CEA. Based on these data it would be advisable to continue aspirin therapy in patients undergoing CEA.
This study has important messages for vascular surgeons. It found no difference between patients undergoing surgery for aneurysm or occlusive disease. Starting aspirin before a vascular procedure did not reduce death or myocardial infarction rates, but increased the risk of bleeding, and is not recommended. Many patients with vascular disease are already on aspirin. Stopping it before surgery did not increase the risk of cardiovascular morbidity or occlusive complications, but it may decrease perioperative bleeding.
Supplementary Material
Table S1 Eligibility criteria
Table S2 Outcome definitions
Table S3 Baseline characteristics of the non-vascular and vascular surgical patients
Appendix S1 Adjudicated outcomes
Fig. S1 Tertiary outcomes in the POISE-2 vascular surgery substudy
Fig. S2 Safety outcomes in the POISE-2 vascular surgery substudy
Acknowledgements
Boehringer Ingelheim provided clonidine and Bayer provided aspirin for this study.
Sources of funding were: the Canadian Institutes of Health Research (grants 119385, 104026, 116349), the National Health and Medical Research Council of Australia (grant 1004149) and the Spanish Ministry of Health and Social Policy (grant SAS/2481/2009). The POISE-2 trial funding sources had no role in the design and conduct of the study; in collection, management, analysis and interpretation of the data; or in preparation or approval of the manuscript. There was no preregistration of the statistical analysis plan for the substudy reported in this article.
Disclosure: The authors declare no conflict of interest.
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Associated Data
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Supplementary Materials
Table S1 Eligibility criteria
Table S2 Outcome definitions
Table S3 Baseline characteristics of the non-vascular and vascular surgical patients
Appendix S1 Adjudicated outcomes
Fig. S1 Tertiary outcomes in the POISE-2 vascular surgery substudy
Fig. S2 Safety outcomes in the POISE-2 vascular surgery substudy