CABG-related Bleeding Research Articles

The impact of ticagrelor therapy on CABG-related bleeding in patients with STEMI managed with pPCI and following on-pump CABG.

Patients on double antiplatelet treatment who need early in-hospital coronary artery bypass grafting (CABG) are at high risk of major bleeding. In this study, we aimed to investigate the impact of ticagrelor preloading on CABG related bleeding in patients with ST-segment elevation myocardial infarction (STEMI) initially managed with primary percutaneous coronary intervention (pPCI). Patients with the diagnosis of STEMI who were managed with pPCI and underwent subsequent early (4-7days following pPCI) or delayed (> 7days following pPCI) on-pump CABG surgery were included. All study patients were preloaded with ticagrelor 180mg prior to pPCI procedure. Patients' demographics, clinical variables, and short-term cardiovascular outcomes were recorded. This is a retrospective study which included 98 patients. Fifty-four (54%) patients underwent early and 44 (45%) patients underwent delayed CABG surgery. CABG-related bleeding occurred in 22 (22.4%) patients. There was no significant difference with respect to total ticagrelor dose and timing of the surgery between patients with or without CABG-related bleeding (p: 0.165 and p: 0.142). Multivariate analyses demonstrated that only preoperative hemoglobin level < 10.9 and use of mechanical cardiac support devices were independent predictors of CABG-related bleeding [OR: 3719, p: 0.009 and OR: 11,698, p: 0.004, respectively].There were three deaths within the 30days of surgery, all occurring in patients with CABG-related bleeding. However, CABG-related bleeding was not associated with long-term cardiovascular events during the follow-up. Our results indicated that discontinuation of ticagrelor therapy 3days prior to surgery is sufficient to avoid CABG-related bleeding. Moreover, early CABG following STEMI does not increase the risk of long-term cardiovascular events.

The impact of ticagrelor therapy on CABG-related bleeding in patients with STEMI managed with pPCI

Abstract Background Patients on double antiplatelet treatment who need early in-hospital coronary artery bypass grafting (CABG) are at high risk of major bleeding. However, recent studies have demonstrated that early CABG surgery within 7 days of discontinuation of p2Y12 inhibitors are safe with respect to bleeding events in patients with acute coronary syndrome. Purpose In this study, we aimed to investigate the impact of ticagrelor preloading on CABG related bleeding in patients with ST-segment elevation myocardial infarction (STEMI) initially managed with primary percutaneous coronary intervention (pPCI). Methods Patients with the diagnosis of STEMI who were managed with pPCI and underwent subsequent early (4-7 days following pPCI) or delayed (&amp;gt; 7 days following pPCI) CABG surgery were included. All study patients were preloaded with ticagrelor 180 mg prior to pPCI procedure. Patients’ demographics, clinical variables and short-term cardiovascular outcomes were recorded. Results The study cohort included 98 patients. Fifty-four (54%) patients underwent early and 44(45%) patients underwent delayed CABG surgery. Left main coronary artery involvement and presence of chronic total occlusion in the non-infarct related artery were 26.5% and 25.5%. CABG-related bleeding occurred in 22 (22.4%) patients. There was no significant difference with respect to total ticagrelor dose and timing of the surgery between patients with or without CABG-related bleeding (p: 0.165 and p:0.142). Multivariate analyses demonstrated that only preoperative hemoglobin level was an independent predictor of CABG-related bleeding (OR:0.720, p: 0.034).There were three deaths within the 30 days of surgery, all occurring in patients with CABG-related bleeding. However, CABG-related bleeding was not associated with long-term cardiovascular events during the follow-up. Conclusion Our results indicated that discontinuation of ticagrelor therapy 3 days prior to surgery is sufficient to avoid CABG-related bleeding. Moreover, early CABG following STEMI does not increase the risk of long-term cardiovascular events.

How do type of preoperative P2Y12 receptor inhibitor and withdrawal time affect bleeding? Protocol of a systematic review and individual patient data meta-analysis

IntroductionIn order to reduce the risk of bleeding in patients on P2Y12 receptor inhibitors presenting for non-emergent coronary artery bypass grafting (CABG), current guidelines recommend a preoperative discontinuation period of...

Adenosine Diphosphate Receptor Inhibitors: Balancing Perioperative Bleeding and Protection From Adverse Coronary Events

In this issue of The Annals of Thoracic Surgery, Voetsch and colleagues1 describe an observational study of the relationship between preoperative withdrawal time of 3 adenosine diphosphate-platelet receptor (P2Y12 receptor) antagonists (prasugrel, ticagrelor, and clopidogrel) and bleeding outcomes after cardiac operations. They studied 299 coronary artery bypass grafting ± valve patients whose dual-antiplatelet therapy was discontinued within 7 days of operation and measured red blood cell loss and Bleeding Academic Research Consortium type 4 (CABG-related bleeding within 48 hours) bleeding outcomes in these patients.

Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes: effects on platelet function and cellular adenosine uptake

Ticagrelor is an antagonist of both platelet adenosine diphosphate (ADP) receptor P2Y12 and equilibrative nucleoside transporter-1. Optimal timing of ticagrelor cessation prior to coronary artery bypass grafting (CABG) remains unclear. We characterized the offset of ticagrelor’s effects on platelets and cellular adenosine uptake in ticagrelor-treated patients (n = 13) awaiting CABG. Blood was drawn prior to CABG at multiple timepoints 2 to 120 (h) after the last dose of ticagrelor. Platelet function (n = 13) was assessed with multiple electrode aggregometry (MEA), expressed as arbitrary units (U) derived from area-under-the-curve (AUC) in response to ADP, and inhibition of adenosine uptake by high-performance liquid chromatography (n = 7). Mean±SD AUC was 20.3 ± 8.2 U (2 h post-ticagrelor), 33.0 ± 18.3U (24 h), 56.6 ± 30.6U (48 h), 61.4 ± 20.2U (72 h), 82.8 ± 24.2U (96 h) and 96.0 ± 15.3U (120 h). There was a significant difference between 72 h and 120 h (p = .007), but not between 96 h and 120 h (p > .99). By 96 h, all patients had AUC >31U, an accepted cutoff below which surgical bleeding risk is increased. Adenosine uptake showed no significant differences between the timepoints. These data suggest it takes 4 days for platelet reactivity to recover sufficiently after cessation of ticagrelor to avoid the excess risk of CABG-related bleeding. Discontinuing ticagrelor had no measurable effect on cellular adenosine uptake.

Monitoring platelet reactivity during prasugrel or ticagrelor washout before urgent coronary artery bypass grafting

Patients with acute myocardial infarction pretreated with prasugrel or ticagrelor may require urgent coronary artery bypass grafting (CABG). However, prasugrel and ticagrelor withdrawal period is recommended for 5-7 days before planned CABG to enable full platelet recovery. We hypothesized that monitoring sequential platelet reactivity (PR) could identify patients with early platelet recovery who may benefit from earlier surgery before the guideline-recommended 5-7 day delay. We performed preoperative PR assays in 35 patients with acute myocardial infarction who received prasugrel (60%) or ticagrelor (40%) and required an urgent CABG. When platelet inhibition levels were favorable, on the basis of the VerifyNow assay, surgery was endorsed. CABG-related bleeding parameters were collected and compared with two matched control groups composed of patients who received fewer potent antiplatelet regimens. On the basis of platelet function monitoring, we identified 21 (56.7%) patients with a relatively earlier platelet recovery who underwent CABG before the end of the conventional washout period (5-7 days). For these patients, the washout periods were shortened to an average time of 2.6±1.0 days for ticagrelor and 3.8±1.5 days for prasugrel. CABG-related bleeding parameters were comparable with the two matched control groups. A strategy of performing preoperative PR assays can identify patients who recover platelet function in less than 5-7 days after ticagrelor or prasugrel discontinuation. This strategy may provide the basis for performing urgent CABGs earlier than the currently recommended delay. Future, larger studies are required to establish these preliminary findings.

Does Platelet Reactivity Predict Bleeding in Patients Needing Urgent Coronary Artery Bypass Grafting During Dual Antiplatelet Therapy?

Up to 15% of patients require coronary artery bypass grafting (CABG) during dual antiplatelet therapy. Available evidence suggests an association between platelet reactivity and CABG-related bleeding. However, platelet reactivity cutoffs for bleeding remain elusive. We sought to explore the association between platelet reactivity and bleeding. Patients on aspirin and a P2Y12 receptor inhibitor within 48 hours before isolated CABG (n= 149) were enrolled in this prospective study. Blood was drawn2 to 4 hours preoperatively and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator-stimulated phosphoprotein (VASP) assay, Multiplate analyzer and Innovance PFA2Y. The primary endpoint was calculated red blood cell loss computed asfollows: (blood volume× preoperative hematocrit× 0.91) - (blood volume× hematocrit× 0.91 on postoperative day 5)+ (mL of transfused red blood cells×0.59). Preoperative platelet reactivity was low [median (interquartile range): LTA: 20 (9-28)%; VASP-PRI: 39 (15-73)%; Multiplate adenosine phosphate test: 16 (12-22) U∗min]. Innovance PFA2Y ≥300 seconds, 72%. Median (IQR) red blood cell loss in patients in first the LTA tertile was 1,449 (1,020 to 1,754) mL compared with 1,107 (858to 1,512) mL and 1,075 (811 to 1,269) mL in those inthe second and third tertiles, respectively (p < 0.004). Bleeding Academic Research Consortium (BARC)-4 bleeding differed between tertiles (62% versus 46% versus 36%; p= 0.037). In a multivariable linear regression model, aspirin dose ≥300 mg, cardiopulmonary bypass time, EuroSCORE, and tertile distribution of platelet reactivity were significantly associated with red blood cell loss. A gradual decrease in red blood cell loss and BARC-4 bleeding occurs with increasing platelet reactivity in patients on antiplatelet therapy undergoing CABG. Our findings support current guidelines to determine time of surgery based on an objective measurement of platelet function (Platelet Inhibition and Bleeding in Patients Undergoing Emergent Cardiac Surgery; clinicaltrials.gov NCT01468597).

Validation of BARC Bleeding Criteria in Patients With Acute Coronary Syndromes: The TRACER Trial

BackgroundThe Bleeding Academic Research Consortium (BARC) scale has been proposed to standardize bleeding endpoint definitions and reporting in cardiovascular trials. Validation in large cohorts of patients is needed. ObjectivesThis study sought to investigate the relationship between BARC-classified bleeding and mortality and compared its prognostic value against 2 validated bleeding scales: TIMI (Thrombolysis In Myocardial Infarction) and GUSTO (Global Use of Strategies to Open Occluded Arteries). MethodsWe analyzed bleeding in 12,944 patients with acute coronary syndromes without ST-segment elevation, with or without early invasive strategy. The main outcome measure was all-cause death. ResultsDuring follow-up (median: 502 days), noncoronary artery bypass graft (CABG) bleeding occurred in 1,998 (15.4%) patients according to BARC (grades 2, 3, or 5), 484 (3.7%) patients according to TIMI minor/major, and 514 (4.0%) patients according to GUSTO moderate/severe criteria. CABG-related bleeding (BARC 4) occurred in 155 (1.2%) patients. Patients with BARC (2, 3, or 4) bleeding had a significant increase in risk of death versus patients without bleeding (BARC 0 or 1); the hazard was highest in the 30 days after bleeding (hazard ratio: 7.35; 95% confidence interval: 5.59 to 9.68; p < 0.0001) and remained significant up to 1 year. The hazard of mortality increased progressively with non-CABG BARC grades. BARC 4 bleeds were significantly associated with mortality within 30 days (hazard ratio: 10.05; 95% confidence interval: 5.41 to 18.69; p < 0.0001), but not thereafter. Inclusion of BARC (2, 3, or 4) bleeding in the 1-year mortality model with baseline characteristics improved it to an extent comparable to TIMI minor/major and GUSTO moderate/severe bleeding. ConclusionsIn patients with acute coronary syndromes without ST-segment elevation, bleeding assessed with the BARC scale was significantly associated with risk of subsequent death up to 1 year after the event and risk of mortality increased gradually with higher BARC grades. Our results support adoption of the BARC bleeding scale in ACS clinical trials. (Trial to Assess the Effects of Vorapaxar [SCH 530348; MK-5348] in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome [TRACER] [Study P04736]; NCT00527943)

The predictive value of multiple electrode platelet aggregometry for postoperative bleeding complications in patients undergoing coronary artery bypass graft surgery.

IntroductionPostoperative bleeding is one of the most serious complications of cardiac surgery and requires transfusion of blood or blood products. Acetylsalicylic acid (ASA) and clopidogrel (CLO) are the two most commonly used antiplatelet agents; when used in combination (i.e., as dual antiplatelet therapy [DAPT]), they exert a synergistic effect. Dual antiplatelet therapy, however, significantly increases the risk of postoperative bleeding. The effect of antiplatelet therapy can be monitored by platelet aggregation testing. One of the most commonly methods used for assessing platelet reactivity is multiple electrode aggregometry (MEA) which can be performed with the use of Multiplate analyzer. Although the method has long been used in interventional cardiology to assess the effect of antiplatelet therapy, it is not available at cardiac surgery departments as a standard diagnostic procedure. The aim of the study was to establish the frequency of bleeding complications following coronary artery bypass graft (CABG) surgery in patients on single antiplatelet therapy (SAPT) and patients on DAPT and to determine the usefulness of routine measurement of platelet responsiveness before CABG surgery in patients receiving antiplatelet therapy.Material and methodsA consecutive cohort of 200 patients referred for elective surgical treatment of stable coronary artery disease was enrolled (100 consecutive patients on SAPT [ASA 75 mg/day] and 100 consecutive patients on DAPT [ASA 75 mg/day + CLO 75 mg/day]). All subjects continued their antiplatelet therapy until the day before surgery. For each subject, platelet aggregation testing in the form of an ASPI test and an ADP test was performed on the Multiplate analyzer. Each subject underwent coronary artery bypass grafting surgery. For the primary and secondary endpoints in our study we adopted the definition provided in ‘Standardised Bleeding Definitions for Cardiovascular Clinical Trials: A Consensus Report from the Bleeding Academic Research Consortium’ (‘Circulation’, 2011) for BARC type 4 bleeding (i.e. CABG-related bleeding).ResultsAn ROC curve was constructed for the ASPI test and ADP test for a total of 200 patients. No significant correlations were demonstrated between the ASPI test results and either the primary endpoint or the secondary endpoints. A correlation was found between the ADP test results and the composite primary endpoint and each of the secondary endpoints. The primary endpoint of major postoperative bleeding occurred in 16 subjects. From the ROC curve, we established the optimal cut-off value for the ADP test of 26 U at sensitivity of 72%, specificity of 69%, positive predictive value of 69.90%, and negative predictive value of 71.13%.ConclusionsIn patients on antiplatelet therapy, an ADP test result of < 26 U is strongly predictive of serious bleeding complications after CABG surgery. The MEA ADP test allows to identify the group of patients at an increased risk of postoperative bleeding.

Safety and Efficacy of Cangrelor, an Intravenous, Short-Acting Platelet Inhibitor in Patients Requiring Coronary Artery Bypass Surgery

Oral P2Y₁₂ platelet receptor inhibitors are a cornerstone of reducing complications in patients with acute coronary syndromes or coronary stents. Guidelines advocate discontinuing treatment with P2Y₁₂ platelet receptor inhibitors before surgery. Cangrelor, a short-acting, reversible, intravenously administered P2Y₁₂ platelet inhibitor is effective in achieving appropriate platelet inhibition in patients who are awaiting coronary artery bypass grafting (CABG) and require P2Y₁₂ inhibition. The objective of this study was to assess the effects of preoperative cangrelor on the incidence of perioperative complications, which are currently unknown. Patients (n = 210) requiring preoperative clinical administration of thienopyridine therapy were randomized in a multicenter, double-blinded study to receive cangrelor or placebo while awaiting CABG after discontinuation of the thienopyridine. Optimal platelet reactivity, which was defined as <240 P2Y₁₂ platelet reaction units, was measured with serial point-of-care testing (VerifyNow). Pre- and postoperative outcomes, bleeding values, and transfusion rates were compared. To quantify potential risk factors for bleeding, we developed a multivariate logistic model. The differences between the groups in bleeding and perioperative transfusion rates were not significantly different. The rate of CABG-related bleeding was 11.8% (12/102) in cangrelor-treated patients and 10.4% (10/96) in the placebo group (P = .763). Transfusion rates for the groups were similar. Serious postoperative adverse events for the cangrelor and placebo groups were 7.8% (8/102) and 5.2% (5/96), respectively (P = .454). Compared with placebo, bridging patients with cangrelor prior to CABG effectively maintains platelet inhibition without increasing post-CABG complications, including bleeding and the need for transfusions. These data suggest cangrelor treatment is a potential strategy for bridging patients requiring P2Y₁₂ receptor inhibition while they await surgery.

Antiplatelet agents and heart surgery: new drugs, new challenges?

In this issue of the European Journal of Cardiothoracic Surgery, Schotola and associates present the result of an interesting study. They analysed the outcomes of patients undergoing isolated or associated coronary operations without discontinuation of double antiplatelet therapy, comparing patients under clopidogrel vs ticagrelor treatment. They could demonstrate that patients pretreated with ticagrelor had a higher postoperative blood loss, required more red blood cell and platelet transfusions and more prothrombin complex concentrate and fibrinogen concentrate and had a tendency towards a higher rate of surgical re-exploration [1]. The problem of double antiplatelet therapy discontinuation before cardiac surgery and the risks associated with surgery in patients with ongoing double antiplatelet therapy (bleeding, transfusion, surgical re-exploration) is not new, but is recently becoming multifaceted, due to the availability of new-generation drugs. The existing guidelines suggest discontinuation of clopidogrel, prasugrel and ticagrelor before heart surgery. However, the exact timing of discontinuation is still a matter of debate, with suggestions that range from 3 to 7 days in different documents released in different years [2–5]. As a matter of fact, this changing scenario depends on the different nature of the different antiplatelet agents. Clopidogrel and prasugrel are thienopyridines and share the same mechanism of action (irreversible inhibition of the platelet receptor P2Y12). However, clopidogrel is a prodrug that requires hepatic conversion into its active form, and many studies have highlighted the variable and unpredictable response of platelet to clopidogrel treatment, with rates of non-responsiveness around 20%. Prasugrel is not affected by genetic variations of the CYP2C19 enzyme and its use has been suggested in clopidogrel non-responsive patients. However, high on-treatment platelet reactivity has been reported in prasugrel-treated patients, even if at a lower rate (around 5%) [6]. Getting rid of thienopyridines effects requires new platelet generation, and the time to recovery of platelet function depends on the rate of platelet turn-over. Even if acting on the P2Y12 receptor, ticagrelor is not a thienopyridine; the inhibition of the P2Y12 is reversible, faster and more effective than with clopidogrel [7]. Offset of ticagrelor effects after discontinuation is faster than after clopidogrel discontinuation, but given the higher efficacy while on-treatment, 3 days of discontinuation are required to obtain a platelet function recovery significantly higher in ticagrelor vs clopidogrel-treated patients [7]. Recently, a novel antiplatelet agent has been tested in clinical practice. Vorapaxar inhibits the protease-activated receptor and therefore acts against the powerful thrombin-induced platelet aggregation [8]. Coronary artery bypass graft (CABG) surgery in patients under the effects of the above-mentioned drugs is a matter of concern. CABGrelated major bleeding in prasugrel vs clopidogrel-treated patients has a hazard ratio of 4.73 [9]; the study of Schotola and associates reports a 50% higher use of red blood cell transfusions in ticagrelortreated vs clopidogrel-treated patients undergoing CABG; comparative studies of vorapaxar vs clopidogrel or prasugrel in terms of CABG-related bleeding are presently lacking. However, the present scenario, not surprisingly, highlights that the more these antiplatelet agents are effective in terms of platelet inhibition, the higher is the major bleeding risk in case of CABG surgery in patients with ongoing therapy or residual effects of the drug after discontinuation. In a recent study [10], we investigated the recovery of platelet function after discontinuation from P2Y12 inhibitors in patients undergoing CABG surgery. We used multiple electrode aggregometry to assess platelet function before the operation (adenosine diphosphate test) in 344 patients. According to our definition, 28% of the patients were thienopyridine-resistant, and the remaining patients demonstrated a huge individual variation in the rate of platelet function recovery, with a daily percentage recovery ranging from 10 to 200% of the platelet function. We could not identify any predictor of this pattern, but the analysis of the whole population led us to establish that at least 3 days of discontinuation are required to reach an acceptable level of platelet function (60% of the lower limit of normal range) and up to 8 days may be required to reach a full recovery of platelet function. Finally, values of platelet function below 60% of the lower limit of normal range were associated with a significant higher postoperative bleeding. In summary, it is very difficult to provide universal suggestions about the timing of major antiplatelet discontinuation in patients undergoing CABG surgery. There is a consistent rate of patients under clopidogrel or prasugrel treatment that are actually poorresponsive: in this patient population, postponing the operation for 3–5 days is probably an unnecessary measure. Within responsive patients, the rate of recovery of platelet function is highly unpredictable. Finally, ticagrelor-treated patients form a different patient population, where the recovery of platelet function after discontinuation is faster and more predictable, but where the high effectiveness of the drug places the patient at high risk of major

Vorapaxar in Acute Coronary Syndrome Patients Undergoing Coronary Artery Bypass Graft Surgery: Subgroup Analysis From the TRACER Trial (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome)

This study evaluated effects of protease-activated receptor-1 antagonist vorapaxar (Merck, Whitehouse Station, New Jersey) versus placebo among the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) study patients with non-ST-segment elevation acute coronary syndromes undergoing coronary artery bypass grafting (CABG). Platelet activation may play a key role in graft occlusion, and antiplatelet therapies may reduce ischemic events, but perioperative bleeding risk remains a major concern. Although the TRACER study did not meet the primary quintuple composite outcome in the overall population with increased bleeding, an efficacy signal with vorapaxar was noted on major ischemic outcomes, and preliminary data suggest an acceptable surgical bleeding profile. We aimed to assess efficacy and safety of vorapaxar among CABG patients. Associations between treatment and ischemic and bleeding outcomes were assessed using time-to-event analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the Cox hazards model. Event rates were estimated using the Kaplan-Meier method. Among 12,944 patients, 1,312 (10.1%) underwent CABG during index hospitalization, with 78% on the study drug at the time of surgery. Compared with placebo CABG patients, vorapaxar-treated patients had a 45% lower rate of the primary endpoint (i.e., a composite of death, myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent coronary revascularization during index hospitalization) (HR: 0.55; 95% CI: 0.36 to 0.83; p= 0.005), with a significant interaction (p= 0.012). The CABG-related Thrombolysis In Myocardial Infarction major bleeding was numerically higher with vorapaxar, but not significantly different between vorapaxar and placebo (9.7% vs. 7.3%; HR: 1.36; 95% CI: 0.92 to 2.02; p= 0.12), with no excess in fatal bleeding (0% vs. 0.3%) or need for reoperation (4.7% vs. 4.6%). In non-ST-segment elevation acute coronary syndrome patients undergoing CABG, vorapaxar was associated with a significant reduction in ischemic events and no significant increase in major CABG-related bleeding. These data show promise for protease-activated receptor 1 antagonism in patients undergoing CABG and warrant confirmatory evidence in randomized trials. (Trial to Assess the Effects of SCH 530348 in Preventing Heart Attack and Stroke in Patients With Acute Coronary Syndrome [TRA·CER] [Study P04736AM3]; NCT00527943).

Bleeding outcomes in patients given clopidogrel within 5 days of robotic coronary artery bypass graft procedure.

Current guidelines recommend that clopidogrel should be held for 5 days prior to coronary artery bypass graft (CABG) procedure. However, it is unknown if this recommendation should apply to robotic-assisted (rCABG), which is less invasive because it does not involve sternotomy and thus reduces the risk of bleeding. To compare postoperative bleeding for rCABG patients who were taking clopidogrel within 5 days of the procedure with those who were not taking clopidogrel. This was a retrospective cohort study conducted between January 1, 2012 and December 31, 2012 of consecutive patients undergoing rCABG. Patients were categorized into 2 groups based on whether or not clopidogrel was administered within 5 days prior to the date of surgery. The primary outcome measure was the occurrence of the Bleeding Academic Research Consortium (BARC) definition for CABG-related bleeding. The secondary outcome measure was a comparison of chest tube output during the first 24-hour postoperative period. A total of 136 rCABG patients were included in the final analyses. Of these, 39 (29%) received clopidogrel within 5 days of surgery. CABG-related bleeding using the BARC definition occurred in 26% of patients who received clopidogrel and 8% of patients who did not (P = .011). Median chest tube output during the first 24-hour postoperative period was also greater in patients who received clopidogrel (900 vs 735 mL, P = .002). The use of clopidogrel within 5 days of rCABG is associated with greater postoperative bleeding and chest tube output, as defined by the BARC criteria.

Clopidogrel is safer than ticagrelor in regard to bleeds: A closer look at the PLATO trial

To compare hemorrhagic events between clopidogrel and ticagrelor in the Platelet Inhibition and Patient Outcomes (PLATO) trial. We examined the FDA Medical Review. Compared to clopidogrel, ticagrelor significantly increased spontaneous bleeds, major bleeds, major plus minor bleeds, and major plus minor plus minimal bleeds. Ticagrelor also increased both major and fatal/life-threatening bleeds versus clopidogrel when CABG was performed between 24 and 96 h after stopping medication, which was also accompanied by a larger volume of chest tube drainage and transfusions. Moreover, ticagrelor increased CABG-related bleeding versus clopidogrel in those patients who did not wait until day 5 after stopping treatment to have CABG. Additionally, compared to clopidogrel, ticagrelor increased the risk of hematuria (RR=1.91; 95% CI: 0.95-3.83), intracranial hemorrhage or subdural or other hematoma (RR 1.87; 95% CI: 1.02-3.42), subcutaneous hemorrhage, ecchymosis, hematoma (RR=1.63; 95% CI: 0.84-3.17), epistaxis (RR=1.49; 95% CI: 0.67-3.32), retroperitoneal hematoma or hemorrhage (RR=1.49; 95% CI: 0.53-4.19), gastrointestinal/anal bleed (RR=1.23; 95% CI: 0.93-1.64) and bleed/hematoma (RR=1.21, 95% CI: 1.02-1.43). Clopidogrel is safer than ticagrelor in regard to bleeding. Additionally, ticagrelor's purported faster antiplatelet 'offset' is substantially longer than its pharmacokinetics indicate. Considering the fact that the mortality, stent thrombosis and myocardial infarction 'benefit' of ticagrelor have recently been challenged, and that the increase in stroke on ticagrelor has recently been shown to be worse than originally published, the decision to use ticagrelor over clopidogrel in the face of a higher risk for bleeds is not advised.

Impact of major bleeding and blood transfusions after cardiac surgery: Analysis from the Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial

Prior retrospective studies have identified a relationship between bleeding after cardiac surgery and subsequent mortality. Whether this is attributable to bleeding, anemia, or transfusions is undetermined. ACUITY was an international prospective trial of patients with acute coronary syndromes. Coronary artery bypass grafting (CABG) before hospital discharge was performed in 1,491 patients. Major bleeding was adjudicated as CABG- or non-CABG related. The relationship between CABG-related bleeding and 1-year mortality was determined using a time-updated covariate-adjusted Cox model. Coronary artery bypass grafting-related major bleeding after surgery occurred in 789 patients (52.9%); allogeneic blood product transfusions were administered in 612 patients (41.0%), including red blood cell (RBC) transfusions in 570 (38.2%, range 1-53 U), platelet transfusions in 180 (12.1%), and fresh-frozen plasma in 195 (13.1%). One-year mortality occurred in 95 patients (6.4%). Red blood cell transfusion (but not transfusion of platelets or fresh-frozen plasma, CABG-related major bleeding per se, or nadir hemoglobin) was an independent predictor of 1-year mortality, but only after transfusion of ≥4 U (adjusted hazard ratio for death after transfusion of 1-3, 4-6, and ≥7 RBC units = 0.74, 2.01, and 5.22, respectively). Of the 95 deaths after CABG, 23 (24.2%) were attributable to CABG-related RBC transfusions. In patients with acute coronary syndromes, RBC transfusion of ≥4 U after CABG is strongly associated with subsequent mortality. Future strategies should focus on reducing major hemorrhagic complications and RBC transfusions after CABG.

Role of ticagrelor in the treatment of coronary artery disease

Ticagrelor is a reversibly binding, noncompetitive, direct-acting, orally administered P2Y12-receptor antagonist and is a credible alternative to clopidogrel in the treatment of patients with acute coronary syndrome. Ticagrelor therapy has been associated with rapid onset and faster offset of actions and greater and consistent platelet inhibition. In the Study of Platelet Inhibition and Patient Outcomes (PLATO) trial, ticagrelor significantly reduced the rate of the combined end point of cardiovascular death, myocardial infarction or stroke in acute coronary syndrome patients compared with clopidogrel. A major potential benefit of ticagrelor is the unprecedented reduction in mortality among acute coronary syndrome patients. An additional important observation was similar CABG-related bleeding events in ticagrelor (vs clopidogrel)-treated patients despite the fact that ticagrelor provides more potent P2Y12-receptor blockade.

Risk of bleeding after prehospital administration of high dose tirofiban for ST Elevation Myocardial Infarction

BackgroundIn most patients with ST-elevation myocardial infarction (STEMI), antiplatelet drugs are already administrated in the ambulance, before hospital admission. We investigated the safety of prehospital initiation of a high dose of the glycoprotein IIb/IIIa inhibitor tirofiban on top of aspirin, clopidogrel and heparin. MethodsIt concerns a sub-analysis of the On-TIME 2 trial. 1398 patients were enrolled and 1275 patients (91.2%) had clinical follow up. Non CABG-related bleeding was defined according to the TIMI criteria. Logistic regression was used to determine predictors of 30-day bleeding. The independent association between bleeding and mortality (30-day and 1-year) was evaluated using Cox proportional Hazard models. ResultsBleeding (major or minor) was observed in 47 patients (3.7%), with only 13 patients (1%) with major bleeding. The strongest independent determinants of bleeding were age (OR 1.05, 95% CI 1.01–1.08, p=0.011), Killip class >1 at admission (OR 2.5, 95% CI 1.2–5.3, p=0.020) and intra aortic balloon pump (IABP) use (OR 4.2, 95% CI 1.6–11.1, p=0.003). High dose tirofiban was not an independent predictor of bleeding (OR 1.7, 95% CI 0.9–3.2, p=0.116). Bleeding was associated with an increased risk of 30-day mortality (HR 5.5, 95% CI 1.6–7.8, p<0.001) and one-year mortality (HR 3.2, 95% CI 1.4–7.2, p=0.005). ConclusionPrehospital use of high dose tirofiban is safe and associated with a low risk of bleeding. Age, Killip class >1, IABP use, but not high dose tirofiban are independent determinants of bleeding in STEMI patients. Bleeding is independently associated with 30-day and 1-year mortality.

Ticagrelor Versus Clopidogrel in Patients With Acute Coronary Syndromes Undergoing Coronary Artery Bypass Surgery: Results From the PLATO (Platelet Inhibition and Patient Outcomes) Trial

The purpose of this study is to evaluate the efficacy and safety of ticagrelor and clopidogrel in patients with acute coronary syndrome undergoing coronary artery bypass graft surgery (CABG), as a post-randomization strategy. Ticagrelor is a novel, reversibly binding, oral, direct-acting P2Y(12)-receptor antagonist. In the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized 18,624 patients with acute coronary syndromes, ticagrelor compared with clopidogrel significantly reduced the risk of the primary composite end point of cardiovascular (CV) death, myocardial infarction, or stroke (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.77 to 0.92; p < 0.001). This report investigated the outcomes of patients treated with CABG during the trial. In total, 1,899 patients underwent CABG post-randomization. The protocol recommended ticagrelor/placebo to be withheld for 24 to 72 h and clopidogrel/placebo for 5 days preoperatively. In all, 1,261 patients underwent CABG and were receiving study drug treatment <7 days before surgery. The statistical analysis was based on events occurring from the CABG procedure until the end of the study, excluding 3 patients with CABG after study end. In the 1,261 patient cohort, the relative reduction of primary composite end point at 12 months (10.6% [66 of 629] with ticagrelor versus 13.1% [79 of 629] with clopidogrel; HR: 0.84; 95% CI: 0.60 to 1.16; p = 0.29) was consistent with the results of the whole trial. Total mortality was reduced from 9.7% (58 of 629) to 4.7% (29 of 629; HR: 0.49; 95% CI: 0.32 to 0.77; p < 0.01), CV death from 7.9% (47 of 629) to 4.1% (25 of 629; HR: 0.52; 95% CI: 0.32 to 0.85; p < 0.01), and non-CV death numerically from 2.0% to 0.7% (p = 0.07). There was no significant difference in CABG-related major bleeding between the randomized treatments. In the subgroup of patients undergoing CABG within 7 days after the last study drug intake, ticagrelor compared with clopidogrel was associated with a substantial reduction in total and CV mortality without excess risk of CABG-related bleeding.

Transfusion Requirements and Outcomes In the Cohort of Patients Undergoing Isolated CABG Treated with Prasugrel or Clopidogrel: TRITON-TIMI 38 Data Analysis.

AbstractAbstract 1108▪Coronary artery bypass grafting (CABG)-related bleeding and associated transfusion support are concerns with dual antiplatelet therapy. The amount and the type of blood products transfused may be influenced by patient characteristics, procedural characteristics, acquired hemostatic defects, regional standard of care, and the amount of perioperative blood loss. Withdrawal of clopidogrel 5 days prior or prasugrel 7 days prior to CABG is suggested by the respective product labels to reduce the potential for CABG-related bleeding. Accordingly, a cohort of 422 patients undergoing isolated CABG in TRITON-TIMI 38 (PRASugrel n=208; CLOPidogrel n=214) was analyzed retrospectively to characterize the risk adjusted (using predicted risk of transfusion - Magovern, et al. Ann Thorac Surg 1996;61:27-32) difference in transfusion requirements between prasugrel and clopidogrel. Seventy-six patients who never received study drug or who received open label thienopyridine treatment prior to CABG were excluded. Packed red blood cells (PRBC) were the most frequently used blood product while platelet transfusions were relatively infrequent and regionally specific. No difference was noted in mean predicted transfusion risk score (TRS) between cohorts (PRAS 2.13 vs. CLOP 2.31; p=0.53; two-sided p value per ANOVA). TRS was associated with the number of units of PRBC transfused (p < 0.0001). Overall, there were significantly higher mean 12 hour chest tube loss (655 ±580 ml vs. 503± 378 ml; Kruskal-Wallis p=0.050) and platelet transfusion rates (18% vs. 9.8%; Pearson's chi-square p=.033) with PRAS. However, there were no statistically significant differences in PRBC transfusion units (mean 2.1±3.0 PRAS vs. 1.7±2.2 CLOP; Kruskal-Wallis p=0.44) or total donor exposure units (PRBC + whole blood + platelets + cryoprecipitate + fresh frozen plasma) (4.4±7.6 PRAS vs. 3.0±4.5 CLOP; Kruskal-Wallis p=0.46), although all of the analyses presented are underpowered. Total donor exposures were correlated with chest tube blood loss at 12 hours and the correlations were similar for both cohorts (PRAS, r=0.42; CLOP, r=0.45) (Figure). Transfusion requirements and blood loss by days from last dose categories are presented in the Table. Fifty-four (54)%, 22%, and 24% of patients went to CABG surgery ≤5 days, 6–7 days, and >7 days from the last dose of study drug, respectively (days from last dose to CABG unknown for 0.6% of patients). A significantly higher number of platelet units were used postoperatively in the PRAS patients going to surgery ≤5 days after withdrawal of drug. There is no suggestion of excess blood loss or excess of total units of blood transfusions after 7 days for PRAS or CLOP. In an analysis adjusted for the predicted risk of mortality (using Society of Thoracic Surgeons mortality score), total donor exposures were not associated with increased mortality risk [all-cause death within 30 days following CABG (odds ratio, 1.05 (0.97- 1.13) p=0.25; logistic regression analysis]. In addition, PRAS was independently associated with a reduction in mortality (PRAS, 1.2%; CLOP, 6.9%; p=0.027). In summary, the amount of blood products transfused is significantly influenced by patient and surgical characteristics, as well as by agents that can inhibit the hemostatic system. However, despite increased blood loss and use of greater numbers of platelets in a higher percentage of patients within the PRAS cohort, use of PRAS was associated with improved outcomes in the isolated CABG cohort of TRITON-TIMI 38. [Display omitted] Disclosures:Goodnough:Eli Lilly and Company: Consultancy. Despotis:Eli Lilly Company: Consultancy. Levy:Eli Lilly Company: Consultancy, Research Funding. Short:Eli Lilly & Company: Employment, Equity Ownership. Weerakkody:Eli Lilly & Company: Employment, Equity Ownership. Lenarz:Eli Lilly & Company: Employment, Equity Ownership.

A Risk Score to Predict Bleeding in Patients With Acute Coronary Syndromes

The aim of this study was to develop a practical risk score to predict the risk and implications of major bleeding in acute coronary syndromes (ACS). Hemorrhagic complications have been strongly linked with subsequent mortality in patients with ACS. A total of 17,421 patients with ACS (including non-ST-segment elevation myocardial infarction [MI], ST-segment elevation MI, and biomarker negative ACS) were studied in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) and the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trials. An integer risk score for major bleeding within 30 days was developed from a multivariable logistic regression model. Non-coronary artery bypass graft surgery (CABG)-related major bleeding within 30 days occurred in 744 patients (7.3%) and had 6 independent baseline predictors (female sex, advanced age, elevated serum creatinine and white blood cell count, anemia, non-ST-segment elevation MI, or ST-segment elevation MI) and 1 treatment-related variable (use of heparin + a glycoprotein IIb/IIIa inhibitor rather than bivalirudin alone) (model c-statistic = 0.74). The integer risk score differentiated patients with a 30-day rate of non-CABG-related major bleeding ranging from 1% to over 40%. In a time-updated covariate-adjusted Cox proportional hazards regression model, major bleeding was an independent predictor of a 3.2-fold increase in mortality. The link to mortality risk was strongest for non-CABG-related Thrombolysis In Myocardial Infarction (TIMI)-defined major bleeding followed by non-TIMI major bleeding with or without blood transfusions, whereas isolated large hematomas and CABG-related bleeding were not significantly associated with subsequent mortality. Patients with ACS have marked variation in their risk of major bleeding. A simple risk score based on 6 baseline measures plus anticoagulation regimen identifies patients at increased risk for non-CABG-related bleeding and subsequent 1-year mortality, for whom appropriate treatment strategies can be implemented.