Elisabeth Mahla

Consensus and Update on the Definition of On-Treatment Platelet Reactivity to Adenosine Diphosphate Associated With Ischemia and Bleeding

Dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker is a key strategy to reduce platelet reactivity and to prevent thrombotic events in patients treated with percutaneous coronary intervention. In an earlier consensus document, we proposed cutoff values for high on-treatment platelet reactivity to adenosine diphosphate (ADP) associated with post-percutaneous coronary intervention ischemic events for various platelet function tests (PFTs). Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y12 receptor inhibitor in selected high-risk patients treated with percutaneous coronary intervention, although routine testing is not recommended (Class III). Accumulated data from large studies underscore the importance of high on-treatment platelet reactivity to ADP as a prognostic risk factor. Recent prospective randomized trials of PFT did not demonstrate clinical benefit, thus questioning whether treatment modification based on the results of current PFT platforms can actually influence outcomes. However, there are major limitations associated with these randomized trials. In addition, recent data suggest that low on-treatment platelet reactivity to ADP is associated with a higher risk of bleeding. Therefore, a therapeutic window concept has been proposed for P2Y12 inhibitor therapy. In this updated consensus document, we review the available evidence addressing the relation of platelet reactivity to thrombotic and bleeding events. In addition, we propose cutoff values for high and low on-treatment platelet reactivity to ADP that might be used in future investigations of personalized antiplatelet therapy.

Platelet Function Measurement–Based Strategy to Reduce Bleeding and Waiting Time in Clopidogrel-Treated Patients Undergoing Coronary Artery Bypass Graft Surgery The Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG (TARGET-CABG) Study

Background— Aspirin and clopidogrel therapy is associated with a variable bleeding risk in patients undergoing coronary artery bypass graft surgery (CABG). We evaluated the role of platelet function testing in clopidogrel-treated patients undergoing CABG. Methods and Results— One hundred eighty patients on background aspirin with/without clopidogrel therapy undergoing elective first time isolated on-pump CABG were enrolled in a prospective single-center, nonrandomized, unblinded investigation (Timing Based on Platelet Function Strategy to Reduce Clopidogrel-Associated Bleeding Related to CABG [TARGET-CABG] study) between September 2008 and January 2011. Clopidogrel responsiveness (ADP-induced platelet-fibrin clot strength [MAADP]) was determined by thrombelastography; CABG was done within 1 day, 3–5 days, and >5 days in patients with an MAADP >50 mm, 35–50 mm, and <35 mm, respectively. The primary end point was 24-hour chest tube drainage and key secondary end point was total number of transfused red blood cells. Equivalence was defined as ⩽25% difference between groups. ANCOVA was used to adjust for confounders. Mean 24-hour chest tube drainage in clopidogrel-treated patients was 93% (95% confidence interval, 81–107%) of the amount observed in clopidogrel-naive patients, and the total amount of red blood cells transfused did not differ between groups (1.80 U versus 2.08 U, respectively, P=0.540). The total waiting period in clopidogrel-treated patients was 233 days (mean, 2.7 days per patient). Conclusions— A strategy based on preoperative platelet function testing to determine the timing of CABG in clopidogrel-treated patients was associated with the same amount of bleeding observed in clopidogrel-naive patients and ≈50% shorter waiting time than recommended in the current guidelines. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00857155.

Thromboelastography for monitoring prolonged hypercoagulability after major abdominal surgery

Despite clinical and laboratory evidence of perioperative hypercoagulability, there are no consistent data evaluating the extent, duration, and specific contribution of platelets and procoagulatory proteins by in vitro testing. We tested the hypothesis that the parallel use of standard and abciximab-cytochalasin D-modified thromboelastography (TEG®) can assess 7 days’ postoperative hypercoagulability and can estimate the independent contribution of procoagulatory proteins and platelets. Thromboelastograms were performed before surgery, at the end of surgery, 6 h after surgery, and on postoperative days 1, 2, 3, and 7; they were analyzed for the reaction time and the maximal amplitude (MA). We calculated the elastic shear modulus of standard MA (Gt) and modified MA (Gc), which reflect total clot strength and procoagulatory protein component, respectively. The difference was an estimate of the platelet component (Gp). There was a 10% perioperative increase of standard MA, corresponding to a 50% increase of Gt (P < 0.0001) and an 86%–90% contribution of the calculated Gp to Gt. We conclude that serial standard and modified thromboelastography may reveal prolonged postoperative hypercoagulability and the independent contribution of platelets and procoagulatory proteins to clot strength.

Minimally invasive versus conventional aortic valve operations: a prospective study in 120 patients

BACKGROUND Risk evaluation comparing the minimally invasive and standard aortic valve operations has not been studied. METHODS Four surgeons were randomly assigned to perform the minimally invasive (L-shaped sternotomy) (group 1) or the conventional (group 2) operation in 120 patients exclusively. RESULTS In both groups (n = 60) a CarboMedics prothesis was implanted in 90% of patients. There was no significant difference in the cross-clamping period (group 1, 60 minutes; range, 35 to 116 minutes), in the duration of extracorporal circulation (group 1, 84 minutes; range, 51 to 179 minutes) or in the time from skin-to-skin (group 1, 195 minutes; range, 145 to 466 minutes). Patients in group 1 were extubated earlier (p<0.001), the postoperative blood loss was less (p<0.001), and the need for analgesics was reduced (p<0.05). In 5 patients in group 1 a redo operation was required for bleeding (p>0.05), 3 patients in group 1 required a redo operation because of paravalvular leakage or endocarditis (p>0.05), the 30-day mortality rate was 1.6%. Overall the survival rate was 95% in group 1 and 97% in group 2 (mean follow-up, 294 days; range, 30 to 745 days). CONCLUSION The advantages of minimally invasive aortic valve operation include reduced trauma from incision and duration of ventilation, decreased blood loss and postoperative pain, the avoidance of groin cannulation, and a cosmetically attractive result. Simple equipment is used with a high degree of effectiveness and with no sacrifice of safety. Our study demonstrated the practicability and reliability of this new method.

Different effects of abciximab and cytochalasin D on clot strength in thrombelastography.

Summary.  Maximum amplitude (MA) in thrombelastography (TEG) consists of a plasmatic and a platelet component. To assess the magnitude of the plasmatic component, pharmacological approaches have been proposed to eliminate the platelet component. We evaluated the individual and combined effects of abciximab and cytochalasin D on the MA of TEG. Whole blood, platelet‐rich plasma (PRP) and homologous platelet‐poor plasma (PPP) from 20 healthy volunteers were spiked with abciximab or cytochalasin D or a combination of both and TEGs performed. Abciximab and cytochalasin D decreased MA in all samples. MA of whole blood (18.6 ± 3.1 mm) and PRP (33.7 ± 3.5 mm) spiked with abciximab or cytochalasin D alone (15.0 ± 2.9 mm and 25.0 ± 4.0 mm) were significantly higher when compared with abciximab and cytochalasin D combined (10.4 ± 3.0 and 20.2 ± 3.5 mm). While MA of PRP and homologous PPP were significantly (P < 0.001) different after individual administration of abciximab and cytochalasin D, combination of both abolished this difference (20.2 ± 3.5 mm and 20.4 ± 3.7 mm, P = 0.372). In whole blood of critically ill patients or patients undergoing major surgery there was also a significant difference of MA between abciximab alone and in combination with cytochalasin D (16.5 ± 11.3 mm and 11.3 ± 7.7 mm, P < 0.001). This indicates that in contrast to individual administration of abciximab or cytochalasin D, a combination of both compounds eliminates the platelet‐specific effect on MA of TEG tracings.

The prognostic value of pre-operative and post-operative B-type natriuretic peptides in patients undergoing noncardiac surgery: B-type natriuretic peptide and N-terminal fragment of pro-B-type natriuretic peptide: A systematic review and individual patient data meta-analysis

OBJECTIVES The objective of this study was to determine whether measuring post-operative B-type natriuretic peptides (NPs) (i.e., B-type natriuretic peptide [BNP] and N-terminal fragment of proBNP [NT-proBNP]) enhances risk stratification in adult patients undergoing noncardiac surgery, in whom a pre-operative NP has been measured. BACKGROUND Pre-operative NP concentrations are powerful independent predictors of perioperative cardiovascular complications, but recent studies have reported that elevated post-operative NP concentrations are independently associated with these complications. It is not clear whether there is value in measuring post-operative NP when a pre-operative measurement has been done. METHODS We conducted a systematic review and individual patient data meta-analysis to determine whether the addition of post-operative NP levels enhanced the prediction of the composite of death and nonfatal myocardial infarction at 30 and ≥180 days after surgery. RESULTS Eighteen eligible studies provided individual patient data (n = 2,179). Adding post-operative NP to a risk prediction model containing pre-operative NP improved model fit and risk classification at both 30 days (corrected quasi-likelihood under the independence model criterion: 1,280 to 1,204; net reclassification index: 20%; p < 0.001) and ≥180 days (corrected quasi-likelihood under the independence model criterion: 1,320 to 1,300; net reclassification index: 11%; p = 0.003). Elevated post-operative NP was the strongest independent predictor of the primary outcome at 30 days (odds ratio: 3.7; 95% confidence interval: 2.2 to 6.2; p < 0.001) and ≥180 days (odds ratio: 2.2; 95% confidence interval: 1.9 to 2.7; p < 0.001) after surgery. CONCLUSIONS Additional post-operative NP measurement enhanced risk stratification for the composite outcomes of death or nonfatal myocardial infarction at 30 days and ≥180 days after noncardiac surgery compared with a pre-operative NP measurement alone.

The Predictive Ability of Pre-Operative B-Type Natriuretic Peptide in Vascular Patients for Major Adverse Cardiac Events: An Individual Patient Data Meta-Analysis

OBJECTIVES The aims of this study were to perform an individual patient data meta-analysis of studies using B-type natriuretic peptides (BNPs) to predict the primary composite endpoint of cardiac death and nonfatal myocardial infarction (MI) within 30 days of vascular surgery and to determine: 1) the cut points for a natriuretic peptide (NP) diagnostic, optimal, and screening test; and 2) if pre-operative NPs improve the predictive accuracy of the revised cardiac risk index (RCRI). BACKGROUND NPs are independent predictors of cardiovascular events in noncardiac and vascular surgery. Their addition to clinical risk indexes may improve pre-operative risk stratification. METHODS Studies reporting the association of pre-operative NP concentrations and the primary study endpoint, post-operative major adverse cardiovascular events (defined as cardiovascular death and nonfatal MI) in vascular surgery, were identified by electronic database search. Secondary study endpoints included all-cause mortality, cardiac death, and nonfatal MI. RESULTS Six data sets were obtained, 5 for BNP (n = 632) and 1 for N-terminal pro-BNP (n = 218). An NP level higher than the optimal cut point was an independent predictor for the primary composite endpoint (odds ratio: 7.9; 95% confidence interval: 4.7 to 13.3). BNP cut points were 30 pg/ml for screening (95% sensitivity, 44% specificity), 116 pg/ml for optimal (highest accuracy point; 66% sensitivity, 82% specificity), and 372 pg/ml for diagnostic (32% sensitivity, 95% specificity). Subsequent to revised cardiac risk index stratification, reclassification using the optimal cut point significantly improved risk prediction in all groups (net reclassification improvement 58%, p < 0.000001), particularly in the intermediate-risk group (net reclassification improvement 84%, p < 0.001). CONCLUSIONS Pre-operative NP levels can be used to independently predict cardiovascular events in the first 30 days after vascular surgery and to significantly improve the predictive performance of the revised cardiac risk index.

N-Terminal Pro-brain Natriuretic Peptide Identifies Patients at High Risk for Adverse Cardiac Outcome after Vascular Surgery

Background:Preoperative N-terminal pro-BNP (NT-proBNP) is independently associated with adverse cardiac outcome but does not anticipate the dynamic consequences of anesthesia and surgery. The authors hypothesized that a single postoperative NT-proBNP level provides additional prognostic information for in-hospital and late cardiac events. Methods:Two hundred eighteen patients scheduled to undergo vascular surgery were enrolled and followed up for 24–30 months. Logistic regression and Cox proportional hazards model were performed to evaluate predictors of in-hospital and long-term cardiac outcome. The optimal discriminatory level of preoperative and postoperative NT-proBNP was determined by receiver operating characteristic analysis. Results:During a median follow-up of 826 days, 44 patients (20%) experienced 51 cardiac events. Perioperatively, median NT-proBNP increased from 215 to 557 pg/ml (interquartile range, 83/457 to 221/1178 pg/ml; P < 0.001). The optimum discriminate threshold for preoperative and postoperative NT-proBNP was 280 pg/ml (95% confidence interval, 123–400) and 860 pg/ml (95% confidence interval, 556–1,054), respectively. Adjusted for age, previous myocardial infarction, preoperative fibrinogen, creatinine, high-sensitivity C-reactive protein, type, duration, and surgical complications, only postoperative NT-proBNP remained significantly associated with in-hospital (adjusted hazard ratio, 19.8; 95% confidence interval, 3.4–115) and long-term cardiac outcome (adjusted hazard ratio, 4.88; 95% confidence interval, 2.43–9.81). Conclusion:A single postoperative NT-proBNP determination provides important additional prognostic information to preoperative levels and may support therapeutic decisions to prevent subsequent structural myocardial damage.

Bivalirudin and Clopidogrel With and Without Eptifibatide for Elective Stenting: Effects on Platelet Function, Thrombelastographic Indexes, and Their Relation to Periprocedural Infarction: Results of the CLEAR PLATELETS-2 (Clopidogrel With Eptifibatide to Arrest the Reactivity of Platelets) Study

OBJECTIVES The primary objective of this study was to compare the effect of therapy with bivalirudin alone versus bivalirudin plus eptifibatide on platelet reactivity measured by turbidometric aggregometry and thrombin-induced platelet-fibrin clot strength (TIP-FCS) measured by thrombelastography in percutaneous coronary intervention (PCI) patients. The secondary aim was to study the relation of platelet aggregation and TIP-FCS to the occurrence of periprocedural infarction. BACKGROUND Bivalirudin is commonly administered alone to clopidogrel naïve (CN) patients and to patients on maintenance clopidogrel therapy (MT) undergoing elective stenting. The effect of adding eptifibatide to bivalirudin on platelet reactivity (PR) and TIP-FCS, and their relation to periprocedural infarction in these patients are unknown. METHODS Patients (n = 200) stratified to clopidogrel treatment status were randomly treated with bivalirudin (n = 102) or bivalirudin plus eptifibatide (n = 98). One hundred twenty-eight CN patients were loaded with 600 mg clopidogrel immediately after stenting, and 72 MT patients were not loaded. The PR, TIP-FCS, and myonecrosis markers were serially determined. RESULTS In CN and MT patients, bivalirudin plus eptifibatide was associated with markedly lower PR at all times (5- and 20-microM adenosine diphosphate-induced, and 15- and 25-microM thrombin receptor activator peptide-induced aggregation; p < 0.001 for all) and reduced mean TIP-FCS (p < 0.05). Patients who had a periprocedural infarction had higher mean 18-h PR (p < 0.0001) and TIP-FCS (p = 0.002). CONCLUSIONS For elective stenting, the addition of eptifibatide to bivalirudin lowered PR to multiple agonists and the tensile strength of the TIP-FCS, 2 measurements strongly associated with periprocedural myonecrosis. Future studies of PR and TIP-FCS for elective stenting may facilitate personalized antiplatelet therapy and enhance the selection of patients for glycoprotein IIb/IIIa blockade. (Peri-Procedural Myocardial Infarction, Platelet Reactivity, Thrombin Generation, and Clot Strength: Differential Effects of Eptifibatide + Bivalirudin Versus Bivalirudin [CLEAR PLATELETS-2]; NCT00370045.

Postoperative B-type Natriuretic Peptide for Prediction of Major Cardiac Events in Patients Undergoing Noncardiac Surgery: Systematic Review and Individual Patient Meta-analysis.

Background:It is unclear whether postoperative B-type natriuretic peptides (i.e., BNP and N-terminal proBNP) can predict cardiovascular complications in noncardiac surgery. Methods:The authors undertook a systematic review and individual patient data meta-analysis to determine whether postoperative BNPs predict postoperative cardiovascular complications at 30 and 180 days or more. Results:The authors identified 18 eligible studies (n = 2,051). For the primary outcome of 30-day mortality or nonfatal myocardial infarction, BNP of 245 pg/ml had an area under the curve of 0.71 (95% CI, 0.64–0.78), and N-terminal proBNP of 718 pg/ml had an area under the curve of 0.80 (95% CI, 0.77–0.84). These thresholds independently predicted 30-day mortality or nonfatal myocardial infarction (adjusted odds ratio [AOR] 4.5; 95% CI, 2.74–7.4; P < 0.001), mortality (AOR, 4.2; 95% CI, 2.29–7.69; P < 0.001), cardiac mortality (AOR, 9.4; 95% CI, 0.32–254.34; P < 0.001), and cardiac failure (AOR, 18.5; 95% CI, 4.55–75.29; P < 0.001). For greater than or equal to 180-day outcomes, natriuretic peptides independently predicted mortality or nonfatal myocardial infarction (AOR, 3.3; 95% CI, 2.58–4.3; P < 0.001), mortality (AOR, 2.2; 95% CI, 1.67–86; P < 0.001), cardiac mortality (AOR, 2.1; 95% CI, 0.05–1,385.17; P < 0.001), and cardiac failure (AOR, 3.5; 95% CI, 1.0–9.34; P = 0.022). Patients with BNP values of 0–250, greater than 250–400, and greater than 400 pg/ml suffered the primary outcome at a rate of 6.6, 15.7, and 29.5%, respectively. Patients with N-terminal proBNP values of 0–300, greater than 300–900, and greater than 900 pg/ml suffered the primary outcome at a rate of 1.8, 8.7, and 27%, respectively. Conclusions:Increased postoperative BNPs are independently associated with adverse cardiac events after noncardiac surgery.