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To determine major adverse outcomes, including the risk of mediastinal reexploration, death, stroke and myocardial infarction, associated with continuing antiplatelet therapy in patients undergoing surgery with cardiopulmonary bypass.
Design
A meta-analysis of parallel randomized, controlled trials published in English.
Setting
A university-based electronic search.
Participants
Patients undergoing surgery with cardiopulmonary bypass (CPB).
Intervention
Continuing antiplatelet therapy versus stopping antiplatelet therapy before the surgery.
Measurements and Main Results
A search was conducted in PubMed, EMBASE, MEDLINE(R), and the Cochrane Central Register of Controlled Trials. Twelve studies were retained for analysis. Continuing antiplatelet drugs for CPB increases the rate of reexploration by a standardized mean difference (SMD) 0.22, 95% confidence interval (CI) 0.06, 0.39; I-square 0%; p value 0.01; classical fail-safe number 5. The number needed to harm (NNTH) is 87 (95% CI 390, 44). There was no statistical difference for death at 30 days and 1 year, myocardial infarction at 30 days, and stroke at 30 days. Continuing antiplatelet drugs increases blood loss, SMD 0.27 (95% CI 0.09, 0.45), I-square 73.1%; p = 0.003.
Conclusions
Continuing antiplatelet therapy for patients undergoing surgery with CPB is associated with a low risk for reexploration.
DUAL ANTIPLATELET THERAPY is recommended for 4 to 6 weeks after the insertion of a bare metal coronary artery stent and for 6 to 12 months after a drug-eluting one. Premature cessation of this antiplatelet therapy increases the risk of stent thrombosis, a highly lethal condition.
Bridging therapy has been proposed as a solution to decrease both the time when the patient is at increased risk for thrombosis when oral antiplatelet drugs are stopped prior to surgery and to minimize surgical blood loss by allowing timed perioperative cessation of antiplatelet activity. Oral drugs are stopped 5 to 7 days prior to surgery, and the bridge therapy with a short-acting drug is introduced 2 to 3 days prior to surgery and stopped shortly (usually a few hours) before the surgery. Results with bridging therapy have, however, been disappointing. Heparin usually is not considered an optimal bridging agent as it does not offer protection against stent thrombosis equivalent to antiplatelet drugs.
Potent short-acting antiplatelet drugs such as the small molecule glycoprotein IIb/IIIa inhibitors (tirofiban and eptifibatide) or a reversible P2Y12 platelet inhibitor (cangrelor) have been identified as the most promising solutions for bridging therapy. The inhibition of tirofiban and eptifibatide wears off in 4 to 6 hours, and the inhibition of cangrelor wears off within 1 hour.
Unfortunately, a recent randomized controlled trial (RCT) evaluating cangrelor as a bridging agent to prevent preoperative thrombotic events did not demonstrate the expected benefit of short-acting antiplatelet drugs.
In this trial, 210 patients with either an acute coronary syndrome or treated with a coronary stent and receiving a thienopyridine (ticlopidine, clopidogrel or prasugrel) were randomized to either cangrelor, 0.75 μg/kg/min (a dose determined as being capable of maintaining the level of platelet reactivity identical to the one expected if the thienopyridine drugs had not been discontinued), or a placebo while awaiting coronary artery bypass graft (CABG) surgery. Aspirin therapy was maintained as per routine local practice. In this trial, the pre-procedural achievement of composite endpoints (death/myocardial infarction/need for urgent revascularization) was similar for both groups: 3/106 and 4/101 for cangrelor and placebo, respectively. Therefore, the extra cost associated with bridging therapy that requires hospitalization for IV administration of the short-acting antiplatelet drugs may not be justified in view of the lack of benefit.
The simple option of continuing the dual antiplatelet therapy through surgery usually is not adopted in patients scheduled for CABG with cardiopulmonary bypass (CPB) in view of the increased risk of surgical bleeding associated with it. Continuation may be an acceptable solution in patients at high risk for stent thrombosis if it does not increase the risk of death or permanent injury because, on the other hand, a stent thrombosis may do so. The present meta-analysis was undertaken to quantify the risk of the need for reexploration for bleeding associated with continuing antiplatelet therapy in patients undergoing CABG with CPB.
Methods
The intervention was defined as continuing antiplatelet therapy until the surgery (versus stopping). A search was conducted in PubMed (up to November 13, 2012), EMBASE (1974-2012 Week 45), MEDLINE(R) (1946-November Week 1 2012) and the Cochrane Central Register of Controlled Trials (November 2012) for all RCTs that compared the intervention to no intervention for adult cardiac surgery with CPB. The reference lists of all studies retained and the ones of the recent (≥2009) previous meta-analyses on the topic also were checked. The exact search strategy is provided in Figure 1. When data were published in more than 1 report, available reports were consulted, but the study (not the report) was considered the unit; therefore, no study was considered more than once. As recommended by the Cochrane Collaboration, the RCTs were judged on the information contained in the reports without any assumption of the following: (1) adequate sequence generation (quasi-randomized studies were rejected), (2) allocation concealment (inability of the person who was recruiting the patient to know in advance to which group the patient would be assigned), (3) blinding of patients, the personnel, and the assessor for the outcomes of interest, (4) incomplete outcome data addressed (clear description of the fate of all patients included in the study), (5) free of selective reporting (outcomes of interest specified in the methods of the study clearly available for all patients included in the study or acceptable number of patients lost to follow-up, similar for all groups and with acceptable reasons mentioned in the report), and (6) free of other bias (any other possible factor that could have influenced the results). Outcomes were defined as reexploration for bleeding, blood loss and blood product administration, death (all causes) at 30 days and at 1 year (cumulative), myocardial infarction at 30 days, stroke at 30 days, and renal insufficiency at 30 days. At least 1 of these outcomes had to be among the primary objectives of the original study. Post hoc analyses from RCTs designed for another purpose were not retained. A priori defined factors for heterogeneity exploration were permanent versus transient inhibition of platelet function, age, ASA physical status, type of surgery (redo versus primary surgery, CPB type and duration, duration of surgery, acuity of surgery), anticoagulants, antifibrinolytics (single versus dual therapy, bridging, gender), and race. Data were extracted in duplicate from texts, tables, figures, or from previously published meta-analysis as required. For continuous data, the authors kept only the studies in which results were available as mean and standard deviations or sample size and exact p values. Only real data (no estimated figure) were considered. Data were analyzed with RevMan 5 (for the risk of bias assessment) (Version 5.0; The Nordic Cochrane Centre, Copenhagen, Denmark) and Comprehensive Meta Analysis version 2.2.044 (http://www.Meta-Analysis.com). Random effects models were used for all the analyses. Heterogeneity was assessed by the I2 value, and 25% was chosen as the cut-off limit for heterogeneity exploration. Heterogeneity exploration was performed by visual inspection of the forest plots followed by the Egger’s intercept, meta-regressions, subgroupings, and/or sensitivity analysis as required. Numbers needed to treat (NNT) or harm (NNTH) were calculated on the odds ratios (OR) (http://www.nntonline.net/visualrx/).
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Details of the study selection can be found in Figure 1. The quality of the studies retained for analysis is in Figure 2 and the details of those studies can be found in Table 1. Continuing antiplatelet drugs up to the surgery in patients undergoing CPB increases the rate of reexploration: standardized mean difference (SMD) 0.22, 95% confidence interval (CI) 0.06, 0.39; I-square 0%; p value 0.01; classic fail-safe number 5 (Fig 3, Table 2).
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends, and outcomes.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
There were no data available for renal insufficiency. Continuing antiplatelet drugs increases blood loss: SMD 0.27 (95% CI 0.09, 0.45), I-square 73.1%; p = 0.003.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
The lack of appropriate clinical information such as use of positive end-expiratory pressure, prophylactic administration of anti-fibrinolytic agents, type of oxygenator, duration of CPB, and surgery in many studies impede clinicians from performing an adequate heterogeneity exploration. There was no statistical difference for administration of red blood cells,
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
It is important to note, however, that a high amount of heterogeneity was found for these last three results (Table 2). Only 2 studies mentioned a priori trigger point for administration of blood products.
Fig 2Risk of bias assessment of the included studies. Each item is rated as green (the report contains enough information to say that this specific point was addressed adequately by the authors [example participants and personnel were blinded to the treatment allocation with an adequate placebo]); red (this specific item is at high risk of introducing a bias in the results [example participants and personnel were not blinded to the treatment allocation]); or yellow (the report does not contain enough information to say yes or no).
CABG for acute coronary syndrome (unstable angina or non-ST-segment elevation myocardial infarction [enzymes only])
Aspirin 150 mg + clopidogrel 75 mg + intraoperative aprotinin or cessation of both drugs 5 days before the surgery and placebo intraoperatively. Bridging with IV heparin stopped 0.5 hours before the surgery
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
Dipyridamole 100 mg QID started 2 days before + aspirin 325 mg started after the surgery. All other antiplatelet drugs stopped 7 days before the surgery
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Aspirin 325 mg/d (n = 154) or TID (n = 155) or aspirin 325 mg + dypyridamole 75 mg [started 48 hours before the surgery] (n = 162) or placebo (n = 153). Aspirin was started 12 hours before the surgery. All other antiplatelets stopped 9 days before the surgery
Aspirin 325 mg started 12 hours before surgery versus placebo and aspirin 6 hours after the surgery for all patients. All other antiplatelets stopped 5 days before the surgery
Oral dipyridamole (n = 19) 100 mg QID started 36 hours before the surgery or IV dipyridamole 0.24 mg/kg/h [400 mg/d in a 70-kg patient] started 22 hours before the surgery (n = 21) and changed to dipyridamole 75 mg PO TID + aspirin 325 mg TID for all patients at postoperative day 1. All other antiplatelet drugs stopped 7 days before the surgery
No systematic antifibrinolytic mentioned/nonpulsatile blood flow with membrane (n = 33) or bubble (n = 25) equal number in each treatment groups
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Fig 3Forest plot of the effects of continuing or stopping antiplatelet drugs on the need for reexploration. The squares indicate the effect size (standardized mean difference) for each individual study. The diamond is the sum of the studies. The diamond is located on the right side (stopping antiplatelet drugs). Therefore, it can be said that continuing antiplatelet drugs will increase the need for reexploration. The I-square value of 0% indicates that the effect is consistent through the studies; the difference from one study to the other does not vary more than what is expected by chance alone.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Although the present meta-analysis confirms that continuing antiplatelet drugs in patients undergoing CABG with CPB increases the need for surgical reexploration and blood loss, this risk seems far less important than that of stent thrombosis.
It is unclear how the risk of reexploration compares to the risk of initiating bridge therapy for patients at high risk of thrombosis. In the placebo group of Angiollilo et al,3 4 patients out of 101 suffered a thrombotic event during the preoperative period. Therefore, an NNTH of 87 (95% CI 390, 44) for the need of reexploration appears as an acceptable risk to the authors of the present meta-analysis when compared to the more catastrophic risk of stent thrombosis. More importantly, there was no statistical difference for death at 30 days (1,061 participants) or myocardial infarction (988 participants) (Table 2). There were not enough data on the risk of stroke (hemorrhage and hypotension may increase the risk for stroke) (2 studies only) and no data on renal insufficiency.
This meta-analysis included studies with different antiplatelet drugs and with a variable number of drugs administered. This, however, did not introduce heterogeneity in the main results: I-square value 0% for reexploration, death at 30 days, and myocardial infarction (Table 2). Therefore, the results indicated that, at least for these 3 outcomes, the risk was not influenced by the type of antiplatelet drug used or the number of antiplatelet drugs administered within the range of the drugs and doses used in the studies included in this analysis (Table 1).
Pooling data from half a million patients who underwent surgery between 2004 and 2007 by Mehta RH et al determined that the rate of reexploration was 2.4%, and they identified various factors associated with a higher risk for reexploration.
Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends, and outcomes.
Those associated with a higher risk of reexploration (odds ratio [OR] ≥1.75 in the logistic regression model) were emergent salvage surgery (2.1 [95% CI 1.7, 2.6]), preoperative dialysis (2.2 [95% CI 1.8, 2.6]), and thienopyridine plus glycoprotein IIb/IIIa receptor antagonists administration within 24 hours before the surgery (1.9 [95% CI 1.7, 2.2]).
Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends, and outcomes.
In their review, reexploration predicted worse final outcomes; increasing the rate of deep sternal wound infection, septicemia, total mortality, and postoperative length of stay.
Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends, and outcomes.
Studies in this meta-analysis did not support the increased risk of total mortality from reexploration; thus, the high NNTH added to the potential beneficial effects of continuing antiplatelet drugs on the risk of thrombosis may explain why no difference was found in the risk for mortality in patients in whom antiplatelet drugs were continued compared to those in whom they were stopped.
Because this meta-analysis involved only patients undergoing CABG it is not possible to say whether this low risk of reexploration would be the same in patients at higher risk of bleeding undergoing either primary extensive procedures or repeated sternotomy. The risks of surgical bleeding of patients receiving antiplatelet drugs undergoing noncardiac surgery have been evaluated by Burger et al.
Low-dose aspirin for secondary cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation - review and meta-analysis.
Availability of high-quality data from RCTs in which antiplatelet drugs were given before the surgery was rather limited. One large trial evaluated the effect of aspirin, 160 mg daily, or a placebo started preoperatively in patients undergoing hip fracture repair or total knee or hip replacement.
Aspirin started before a hip fracture repair increased the rate of transfused bleeding episodes by 12 per 1,000 if subcutaneous heparin is administered simultaneously.
For total hip or knee replacement, 25% of the patients of both groups had received aspirin or other nonsteroidal anti-inflammatory drugs within 48 hours before the surgery, and 35% also received low-molecular-weight subcutaneous heparin in the hospital.
For total knee and hip replacement, there was a trend towards an increased number of hematoma evacuations (16/2047 v 8/2041; p = 0.1) in patients randomized to aspirin.
From 2 small RCTs, continuing aspirin did not increase the risk of bleeding not manageable by local hemostasis for dental extraction (simple or complex)
Low-dose aspirin for secondary cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation - review and meta-analysis.
With 75 mg of aspirin only, started on the evening before surgery, there was no statistical difference in the risk of reexploration for carotid endarterectomy in which drains were used routinely: 9/117 v 8/115 for all reexplorations or 7/117 v 5/115 reexplorations for bleeding for aspirin and placebo, respectively.
A trend towards a higher rate of reexploration for bleeding was found with aspirin, 300 mg, plus dipyridamole, 150 mg, started 2 days before a femoral-popliteal bypass (18/286 versus 9/262)
or when clopidogrel, 75 mg, started 12 hours before a carotid endarterectomy was added to aspirin, 150 mg, started 4 weeks previously compared to aspirin plus placebo (5/46 v 3/54).
Finally, fatal intracerebral hemorrhage has been reported with antiplatelet drugs in 7 patients with recent cerebral ischemic events undergoing neurointerventional procedures. All of them had received abciximab plus heparin and clopidogrel. Six of them also had aspirin.
The authors chose to present the results in standardized mean difference. Binary data (an event had occurred or not [the patient had a myocardial infarction or not]) are most often given as risk ratio (the effect size most easily understood by the clinician) or as odds ratio. Continuous data (blood loss in mL) are most often presented as mean difference (previously called weighted mean difference). By converting binary data through the log odds ratio, both types of data can be expressed as standardized mean difference.
Standardized mean difference offers the advantage of being able to combine binary data, continuous data from different scales, correlation data, or even results when the authors gave only the p value, number of tails, and total number of patients. Therefore, the number of studies that can be included in the analysis usually is higher when the standardized mean difference is used. Standardized mean difference has no unit; it is an absolute number. Some authors quantify standardized mean differences by saying that 0.2 is a small effect size, 0.5 is a medium one, and 0.8 a large one.
In their 2011 update of blood conservation clinical practice guidelines, the Society of Thoracic Surgeons (STS) and the Society of Cardiovascular Anesthesiologists (SCA) recommended the administration of lysine analogs (epsilon-aminocaproic acid [EACA] or tranexamic acid [TA] to reduce total blood loss and decrease the number of patients who require blood transfusion during cardiac procedures (Class I [Benefit greatly exceeds the risk and the procedure/treatment, should be performed/administered or is effective]; Level of evidence A [Evidence from multiple randomized trials or meta-analyses]).
Ferraris VA, Brown JR, Despotis GJ, et al: 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 91:944-982, 2011
The safety of using antifibrinolytic agents has been questioned. Henry et al, however, found that TA and EACA would not share the harmful effects attributed to aprotinin and recommended that these 2 agents should be used instead of aprotinin.
In a meta-analysis including 19 trials involving 24 deaths among 1,802 participants in studies on the effects of TA, they found a risk ratio (RR) for death of 0.55 (95% CI 0.24, 1.25). In their meta-analysis on the effects of antifibrinolytics in cardiac surgical patients receiving aspirin, McIlroy et al found 3 studies with lysine analog versus placebo.
The mean difference in blood loss was −247.25 mL (95% CI −322.64, −161.87 mL) for TA (2 studies including 140 patients with TA and 89 for placebo); I-square 0%; p<0.0001 and −122.0 mL (95% CI −164.26, −79.74) for EACA (1 study including 15 patients in each group); p<0.0001. Therefore, if the 2011 STS/SCA recommendations to systematically administer lysine analogs (TA or EACA) are followed, the effects of antiplatelet agents on blood loss (and possibly on the risk of reexploration) in patients undergoing surgery with cardiopulmonary bypass should be even less important than the one reported in their meta-analysis.
The 2011 STS/SCA’s recommendations also say, “Drugs that inhibit the platelet P2Y12 receptor should be discontinued before operative coronary revascularization (either on pump or off pump), if possible. The interval between drug discontinuation and operation varies depending on the drug pharmacodynamics, but may be as short as 3 days for irreversible inhibitors of the P2Y12 platelet receptor (Level of evidence B [Limited evidence from single randomized trials or non- randomized studies with some conflicting evidence of benefit]),”
Ferraris VA, Brown JR, Despotis GJ, et al: 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 91:944-982, 2011
The irreversible inhibitors of the P2Y12 platelet receptor include clopidogrel, prasugrel and ticlopidine. In the search, the authors found only 1 RCT in which the 1 of these 3 agents was continued until the surgery with CPB (Table 1).
In this small RCT, an antifibrinolytic agent was administered only in the group in which dual antiplatelet therapy (aspirin plus clopidrogrel) was continued until the surgery. The authors found that total blood loss (447±287 [mean±SD] versus 702±495), duration of chest tube drainage, and administration of packed red blood cells were all statistically significantly less in the group in which dual antiplatelet therapy was continued (but with the addition of antifibrinolytics) than in the group in which both antiplatelet drugs were stopped 5 days before the surgery (but without antifibrinolytic agents).
This suggests that, if the recommendation of administering an antifibrinolytic agent is followed, continuing dual antiplatelet therapy that includes an irreversible inhibitor of the P2Y12 platelet receptor until the surgery in patients at high risk of thrombosis is reasonable.
In conclusion, continuing antiplatelet therapy for patients undergoing surgery with CPB may be acceptable in patients at high risk of thrombosis as it is associated with a low risk of increased need for reexploration.
References
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Coronary artery stents: II. Perioperative considerations and management.
A platelet-inhibitor-drug trial in coronary-artery bypass operations: Benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein-graft patency.
The effect of preoperative aspirin use on postoperative bleeding and perioperative myocardial infarction in patients undergoing coronary artery bypass surgery.
Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: Results of a Veterans Administration Cooperative Study.
Prevention of one-year vein-graft occlusion after aortocoronary-bypass surgery: A comparison of low-dose aspirin, low-dose aspirin plus dipyridamole, and oral anticoagulants. The CABADAS Research Group of the Interuniversity Cardiology Institute of The Netherlands.
Society of Thoracic Surgeons National Cardiac Surgery Database Investigators. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends, and outcomes.
Low-dose aspirin for secondary cardiovascular prevention - cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation - review and meta-analysis.
Ferraris VA, Brown JR, Despotis GJ, et al: 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 91:944-982, 2011
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