Supplemental fibrinogen restores thrombus formation in cardiopulmonary bypass-induced platelet dysfunction ex vivo.

BACKGROUND: Major cardiac surgery related blood loss is associated with increased postoperative morbidity and mortality. Platelet dysfunction is believed to contribute to post-cardiopulmonary bypass (CPB)-induced microvascular bleeding. We hypothesised that moderately hypothermic CPB induces platelet dysfunction and that supplemental fibrinogen can restore in vitro thrombus formation. METHODS: Blood from 18 patients, undergoing first-time elective isolated aortic valve surgery was drawn before CPB, 30 min after initiation of CPB, and after CPB and protamine administration, respectively. Platelet aggregation was quantified by optical aggregometry, platelet activation by flow-cytometric detection of platelet surface expression of P-selectin, annexin V, and activated glycoprotein IIb/IIIa, thrombus formation under flow and effect of supplemental fibrinogen (4 mg ml-1) on in vitro thrombogenesis. RESULTS: Post-CPB adenosine-diphosphate and TRAP-6-induced aggregation decreased by 40% and 10% of pre-CPB levels, respectively (P<0.0001). Although CPB did not change glycoprotein IIb/IIIa receptor expression, it increased the percentage of unstimulated P-selectin (1.2% vs 7%, P<0.01) positive cells and annexin V mean fluorescence intensity (15.5 vs 17.2, P<0.05), but decreased percentage of stimulated P-selectin (52% vs 26%, P<0.01) positive cells and annexin V mean fluorescence intensity (508 vs 325, P<0.05). Thrombus area decreased from 6820 before CPB to 5230 after CPB (P<0.05, arbitrary units [a.u.]). Supplemental fibrinogen increased thrombus formation to 20 324 and 11 367 a.u. before CPB and after CPB, respectively (P<0.001), thereby restoring post-CPB thrombus area to levels comparable with or higher than pre-CPB baseline. CONCLUSIONS: Single valve surgery using moderately hypothermic CPB induces partial platelet dysfunction. Thrombus formation was restored in an experimental study design by ex vivo supplementation of fibrinogen.

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

INTRODUCTION: In 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 at least three, five and seven days for ticagrelor, clopidogrel and prasugrel, respectively, to allow for recovery of platelet function. However, there is still substantial interinstitutional variation in preoperative management and relevant covariates of CABG-related bleeding are largely elusive so far. METHODS AND ANALYSIS: We will search PubMed (July 2013 to November 2021) and EMBASE (January 2014 to November 2021) using the following terms, MeSH terms and their synonyms: clopidogrel, prasugrel, ticagrelor, dual antiplatelet, P2Y12 receptor inhibitor, CABG, bleeding, haemorrhage. Two independent reviewers will screen all abstracts and full papers for eligibility. Disagreements will be solved by consulting with a third reviewer.The primary outcome is the incidence of Bleeding Academic Research Consortium type-4 bleeding depending on type of P2Y12 receptor inhibitor and preoperative withdrawal period. The secondary outcomes are mortality and ischaemic events according to the Academic Research Consortium 2 Consensus Document. We will perform an individual patient data meta-analysis (IPD-MA) with drug-specific preoperative withdrawal time and adjust for demographic and procedural variables. Subgroup analyses will be performed for anaemic patients and patients undergoing non-emergent versus urgent/emergent surgery. ETHICS AND DISSEMINATION: This IPD-MA consists of secondary analyses of existing non-identifiable data and meets the criteria for waiver of ethics review by the local Research Ethics Committee. Data sharing and transfer will be subject to a confidentiality agreement and a data use agreement. Findings will be disseminated through peer-reviewed publication and conference presentation. PROSPERO REGISTRATION NUMBER: CRD42022291946.

The role of viscoelastic testing in assessing peri-interventional platelet function and coagulation.

We carried out a literature search in MEDLINE (PubMed) and EMBASE literature databases to provide a concise review of the role of viscoelastic testing in assessing peri-interventional platelet function and coagulation. The search identified 130 articles that were relevant for the review, covering the basic science of VHA and VHA in clinical settings including cardiac surgery, cardiology, neurology, trauma, non-cardiac surgery, obstetrics, liver disease, and COVID-19. Evidence from these articles is used to describe the important role of VHAs and platelet function testing in various peri-interventional setups. VHAs can help us to comprehensively assess the contribution of platelets and coagulation dynamics to clotting at the site-of-care much faster than standard laboratory measures. In addition to standard coagulation tests, VHAs are beneficial in reducing allogeneic transfusion requirements and bleeding, in predicting ischemic events, and improving outcomes in several peri-interventional care settings. Further focused studies are needed to confirm their utility in the peri-interventional case.

How Do Type of Preoperative P2Y12 Receptor Inhibitor and Withdrawal Time Affect Bleeding?

BACKGROUND: Despite recommendations for standardized preoperative waiting of at least 3, 5, and 7 days for ticagrelor, clopidogrel, and prasugrel, respectively, there is still substantial interinstitutional variation in preoperative discontinuation of dual antiplatelet therapy in patients needing coronary artery bypass grafting (CABG). METHODS: In 299 patients undergoing CABG with or without valve intervention less than 7 days after last P2Y12 receptor inhibition, this study evaluated calculated red blood cell loss and Bleeding Academic Research Consortium type 4 (BARC-4) bleeding. RESULTS: A total of 83% of patients underwent CABG less than 48 hours after last drug intake. Calculated blood loss was lower in patients taking clopidogrel as compared with prasugrel or ticagrelor (1063 mL [690 to 1394 mL] vs 1351 mL [876 to 1829 mL] vs 1330 mL [994 to 1691 mL]; P < .001). Overall, 135 (45%) patients sustained BARC-4 bleeding; the incidence differed among the groups (P = .015) and was significantly higher in prasugrel-treated patients, as compared with clopidogrel-treated patients. In multivariable linear regression analysis, European System for Cardiac Operative Risk Evaluation II (EuroSCORE II), aspirin dose, cardiopulmonary bypass time, drug withdrawal time, and type of P2Y12 receptor inhibitor were significantly associated with red blood cell loss. Compared with 0 to 24 hours, a period of more than 48 hours of preoperative discontinuation substantially reduced calculated blood loss by 37% to 48% and BARC-4 bleeding by 58% to 71%, depending on the P2Y12 receptor inhibitor. CONCLUSIONS: Exposure to prasugrel and ticagrelor 24 hours or less before CABG increases both calculated blood loss and BARC-4 bleeding as compared with clopidogrel. Although discontinuation for longer than 48 hours substantially reduced calculated blood loss and BARC-4 bleeding across all P2Y12 receptor inhibitors, our single-center data further support strict adherence to the 2017 guidelines whenever justified by stable hemodynamics and nonjeopardized myocardium.

Supplemental Fibrinogen Restores Platelet Inhibitor-Induced Reduction in Thrombus Formation without Altering Platelet Function: An In Vitro Study.

BACKGROUND: For patients treated with dual antiplatelet therapy, standardized drug-specific 3-to-7 day cessation is recommended prior to major surgery to reach sufficient platelet function recovery. Here we investigated the hypothesis that supplemental fibrinogen might mitigate the inhibitory effects of antiplatelet therapy. METHODS AND RESULTS: To this end blood from healthy donors was treated in vitro with platelet inhibitors, and in vitro thrombus formation and platelet activation were assessed. Ticagrelor, acetylsalicylic acid, the combination of both, and tirofiban all markedly attenuated the formation of adherent thrombi, when whole blood was perfused through collagen-coated microchannels at physiological shear rates. Addition of fibrinogen restored in vitro thrombus formation in the presence of antiplatelet drugs and heparin. However, platelet activation, as investigated in assays of P-selectin expression and calcium flux, was not altered by fibrinogen supplementation. Most importantly, fibrinogen was able to restore in vitro thrombogenesis in patients on maintenance dual antiplatelet therapy after percutaneous coronary intervention. CONCLUSION: Thus, our in vitro data support the notion that supplementation of fibrinogen influences the perioperative hemostasis in patients undergoing surgery during antiplatelet therapy by promoting thrombogenesis without significantly interfering with platelet activation.

Is There a Role for Preoperative Platelet Function Testing in Patients Undergoing Cardiac Surgery During Antiplatelet Therapy?

Up to 11% of patients presenting with acute coronary syndromes undergo coronary artery bypass grafting. Guidelines largely recommend a one-size-fits-all preoperative discontinuation period for P2Y12 receptor blockers to avoid bleeding. These recommendations do not account for highly variable pharmacodynamic responsiveness and for variable recovery of platelet reactivity following discontinuation of P2Y12 receptor blockers. Several observational studies have demonstrated that an objective measurement of platelet function among these patients may reduce the waiting period while mitigating the risk of bleeding. Based on these findings, 2 recent guidelines included a Class IIa and IIb recommendation for platelet function testing in patients undergoing cardiac surgery. The following review article describes the rationale for discontinuation of dual antiplatelet therapy before cardiac surgery and the limitations with this approach, available platelet function assays to assess pharmacodynamic effects, and the association between platelet inhibition and other clinical factors with surgery-related bleeding. The information will assist the reader in determining which patients undergoing cardiac surgery might benefit from preoperative platelet function monitoring.

Platelet Inhibition and Bleeding in Patients Undergoing Non-Cardiac Surgery-The BIANCA Observational Study.

Nearly 20% of patients will need non-cardiac surgery within 1 year of coronary stenting and their management is complicated by concomitant antiplatelet therapy. Platelet function testing may optimize the timing of surgery in these patients. In this prospective observational study, we explored the association between platelet reactivity and bleeding in patients undergoing non-cardiac surgery treated with clopidogrel with or without aspirin within 7 days before surgery. The timing of surgery was at the surgeon's discretion. Blood was drawn at induction of anaesthesia and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator stimulated phosphoprotein (VASP) assay, Multiplate Analyzer and Innovance PFA-200. The primary endpoint was surgery-related thrombolysis in myocardial infarction (TIMI) bleeding. Among 197 patients enrolled, 72 and 12% underwent surgery within 24 and 48 hours of the last dose of clopidogrel, respectively. The median (interquartile range [IQR]) for pre-operative maximal adenosine diphosphate (ADP)-induced aggregation was 33.0% (21.0-57.5%), for VASP-platelet reactivity index was 61.5% (40.1-75.4%), for Multiplate was 22.0 (14.5-36.0) U*min and for Innovance PFA-200 was 224 (101.0-300.0) seconds. TIMI bleeding, observed in 25% of patients, decreased with increasing tertiles of platelet reactivity to ADP assessed by LTA (p = 0.031). Additionally, in a multivariable logistic regression analysis, platelet reactivity to ADP assessed by LTA was significantly associated with TIMI bleeding, as were age and urgency of surgery. These results demonstrate that in clopidogrel-treated patients, pre-operative platelet reactivity to ADP is associated with surgical bleeding risk. An objective assessment of pre-operative platelet function may optimize the timing of non-cardiac surgery in these patients.

Pneumatic tube system transport does not alter platelet function in optical and whole blood aggregometry, prothrombin time, activated partial thromboplastin time, platelet count and fibrinogen in patients on anti-platelet drug therapy.

INTRODUCTION: The aim of this study was to assess pneumatic tube system (PTS) alteration on platelet function by the light transmission aggregometry (LTA) and whole blood aggregometry (WBA) method, and on the results of platelet count, prothrombin time (PT), activated partial thromboplastin time (APTT), and fibrinogen. MATERIALS AND METHODS: Venous blood was collected into six 4.5 mL VACUETTE® 9NC coagulation sodium citrate 3.8% tubes (Greiner Bio-One International GmbH, Kremsmünster, Austria) from 49 intensive care unit (ICU) patients on dual anti-platelet therapy and immediately hand carried to the central laboratory. Blood samples were divided into 2 Groups: Group 1 samples (N = 49) underwent PTS (4 m/s) transport from the central laboratory to the distant laboratory and back to the central laboratory, whereas Group 2 samples (N = 49) were excluded from PTS forces. In both groups, LTA and WBA stimulated with collagen, adenosine-5'-diphosphate (ADP), arachidonic acid (AA) and thrombin-receptor-activated-peptide 6 (TRAP-6) as well as platelet count, PT, APTT, and fibrinogen were performed. RESULTS: No statistically significant differences were observed between blood samples with (Group 1) and without (Group 2) PTS transport (P values from 0.064 - 0.968). The AA-induced LTA (bias: 68.57%) exceeded the bias acceptance limit of ≤ 25%. CONCLUSIONS: Blood sample transportation with computer controlled PTS in our hospital had no statistically significant effects on platelet aggregation determined in patients with anti-platelet therapy. Although AA induced LTA showed a significant bias, the diagnostic accuracy was not influenced.

Impact of preoperative use of P2Y12 receptor inhibitors on clinical outcomes in cardiac and non-cardiac surgery: A systematic review and meta-analysis.

OBJECTIVE: To review systematically the evidence and perform a meta-analysis of benefits and risks associated with use of P2Y12 receptor inhibitors in coronary artery bypass graft-, non-cardiac- and device surgery. Data selection and analysis: We performed a meta-analysis of published studies. Patients with preoperative use of clopidogrel, ticagrelor or prasugrel (late discontinuation: <5 days before surgery or no discontinuation) were compared with patients without preoperative use of the respective drug (early discontinuation: ⩾5 days before surgery or no users of P2Y12 receptor inhibitors). Outcomes evaluated were re-operation for major bleeding, death, myocardial infarction, combined major adverse cardiac events (MACEs) and major haematoma. Using a random effect model, relative risks (RRs) and 95% confidence intervals (CI) were calculated for each outcome. RESULTS: Fifty-four studies met the selection criteria and included 50,048 patients. Preoperative use of clopidogrel on top of aspirin in patients undergoing coronary artery bypass graft was associated with a 2.5-fold increased risk of re-operation for bleeding (95% CI: 1.92-3.25; p<0.001) and a 1.47-fold increased risk of death (95% CI: 1.25-1.72; p<0.001), but did not diminish the risk for myocardial infarction (RR: 0.96; 95% CI: 0.75-1.25; p=0.18) or MACE (RR: 1.16; 95% CI: 0.90--1.50; p=0.30). In patients undergoing non-cardiac surgery, preoperative use of clopidogrel increased the RR of re-operation for major bleeding by 2.05-fold (95% CI: 1.13-3.73; p=0.002) but did not reduce the RR for MACE or death. Clopidogrel use during cardiac device implantation raised the RR for procedure-related haematoma by 3.0-fold (95% CI: 1.30--6.94; p=0.001). Whereas preoperative ticagrelor use did not increase the risk for mortality (RR: 1.03; 95% CI: 0.49-2.14), preoperative prasugrel use tended to increase the risk for death (RR: 5.06; 95% CI: 0.54-47.65). CONCLUSION: Preoperative exposure to clopidogrel on top of aspirin did not reduce the risk of MACE but was associated with increased risk of bleeding and mortality.

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

BACKGROUND: 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. METHODS: Patients on aspirin and a P2Y12 receptor inhibitor within 48 hours before isolated CABG (n = 149) were enrolled in this prospective study. Blood was drawn 2 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 as follows: (blood volume × preoperative hematocrit × 0.91) - (blood volume × hematocrit × 0.91 on postoperative day 5) + (mL of transfused red blood cells × 0.59). RESULTS: 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 (858 to 1,512) mL and 1,075 (811 to 1,269) mL in those in the 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. CONCLUSIONS: 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).

Predicting the occurrence of major adverse cardiac events within 30 days of a vascular surgery: an empirical comparison of the minimum p value method and ROC curve approach using individual patient data meta-analysis.

We aimed to compare the minimum p value method and the area under the receiver operating characteristics (ROC) curve approach to categorize continuous biomarkers for the prediction of postoperative 30-day major adverse cardiac events in noncardiac vascular surgery patients. Individual-patient data from six cohorts reporting B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NTproBNP) were obtained. These biomarkers were dichotomized using the minimum p value method and compared with previously reported ROC curve-derived thresholds using logistic regression analysis. A final prediction model was developed, internally validated, and assessed for its sensitivity to clustering effects. Finally, a preoperative risk score system was proposed. Thresholds identified by the minimum p value method and ROC curve approach were 115.57 pg/ml (p < 0.001) and 116 pg/ml for BNP, and 241.7 pg/ml (p = 0.001) and 277.5 pg/ml for NTproBNP, respectively. The minimum p value thresholds were slightly stronger predictors based on our logistic regression analysis. The final model included a composite predictor of the minimum p value method's BNP and NTproBNP thresholds [odds ratio (OR) = 8.5, p < 0.001], surgery type (OR = 2.5, p = 0.002), and diabetes (OR = 2.1, p = 0.015). Preoperative risks using the scoring system ranged from 2 to 49 %. The minimum p value method and ROC curve approach identify similar optimal thresholds. We propose to replace the revised cardiac risk index with our risk score system for individual-specific preoperative risk stratification after noncardiac nonvascular surgery.

Timing of Coronary Bypass Surgery in Patients Receiving Clopidogrel: The Role of VerifyNow.

We briefly report for the first time the association between a point of care platelet recovery test and the timing of coronary artery bypass grafting after clopidogrel withdrawal. We observe an association between suggested wait days and platelet recovery unit values that might potentially allow for safe shorter wait times before coronary artery bypass grafting without increased bleeding. Our results represent an observation and should prompt further validation.

Comparison of functional fibrinogen (FF/CFF) and FIBTEM in surgical patients - a retrospective study.

BACKGROUND: Fibrinogen-based clot firmness is reported as the maximum amplitude (MA) when using the citrated functional fibrinogen (CFF) assay in thrombelastography (TEG), and as the maximum clot firmness (MCF) together with several clot amplitude parameters when using the FIBTEM assay in thromboelastometry (ROTEM). Concern is currently being raised that these two tests have different platelet inhibiting performance and consequently provide different values. This is relevant for the clinical setting of fibrinogen replacement. We aim herein to compare the parameters of these two fibrinogen-based clot quality tests and their correlation with the plasma fibrinogen level as determined by the Clauss method. METHODS: In total 261 whole blood samples taken from 163 clinical routine surgical patients were analyzed with TEG 5000 and ROTEM tests, and correlation with Clauss fibrinogen level was assessed. RESULTS: Using TEG, the overall fibrin-based clot firmness measured in the CFF assay was significantly higher than the MCF measured by FIBTEM assay. Both assays showed significantly positive correlations with the fibrinogen levels measured using the Clauss method. However, individual values of Clauss fibrinogen concentration corresponded with different values for the two viscoelastometric tests; e.g. within the range of 1.9-2.1 g/L Clauss fibrinogen the median of CFF MA was 16.3 mm whereas FIBTEM MCF was 12.0 mm. CONCLUSIONS: We showed herein by measurements of citrated whole blood samples from surgical patients that CFF MA values were different from FIBTEM MCF values measured in the same sample. Awareness that these whole blood assays provide different clot amplitude results is mandatory, particularly if they are being considered as tools for guiding fibrinogen supplementation. Thromboembolic side effects caused by a potentially too high fibrinogen substitution must also kept in mind in this context.

High Residual Collagen-Induced Platelet Reactivity Predicts Development of Restenosis in the Superficial Femoral Artery After Percutaneous Transluminal Angioplasty in Claudicant Patients.

PURPOSE: Although platelet reactivity is routinely inhibited with aspirin after percutaneous angioplasty (PTA) in peripheral arteries, the restenosis rate in the superficial femoral artery (SFA) is high. Interaction of activated platelets and the endothelium in the region of intervention could be one reason for this as collagen in the subendothelium activates platelets. MATERIALS AND METHODS: A prospective study evaluating on-site platelet reactivity during PTA and its influence on the development of restenosis with a total of 30 patients scheduled for PTA of the SFA. Arterial blood was taken from the PTA site after SFA; platelet function was evaluated with light transmission aggregometry. After 3, 6, 12, and 24 months, duplex sonography was performed and the restenosis rate evaluated. RESULTS: Eight out of 30 patients developed a hemodynamically relevant restenosis (>50 % lumen narrowing) in the PTA region during the 24-month follow-up period. High residual collagen-induced platelet reactivity defined as AUC >30 was a significant predictor for the development of restenosis [adjusted odds ratio 11.8 (9.4, 14.2); P = .04]. CONCLUSIONS: High residual collagen-induced platelet reactivity at the interventional site predicts development of restenosis after PTA of the SFA. Platelet function testing may be useful for identifying patients at risk.

Autologous Platelet-Rich Plasma Preparations: Influence of Nonsteroidal Anti-inflammatory Drugs on Platelet Function.

BACKGROUND: Autologous platelet-rich plasma (PRP) has been widely used for the treatment of sports injuries. It has been associated with improved healing and regeneration of soft tissues in elite athletes. Athletes are commonly receiving nonsteroidal anti-inflammatory drugs (NSAIDs). As yet, the effect of these drugs on platelet function in PRP formulations has not been taken into consideration. HYPOTHESIS: The function of platelets in PRP produced under the influence of NSAIDs is inhibited and may lessen a possible healing effect on the site of injury. STUDY DESIGN: Controlled laboratory study. METHODS: PRP was collected from patients receiving NSAIDs after elective orthopaedic surgery, and platelet function was evaluated using light transmission aggregometry (LTA). Results were compared with those obtained from healthy volunteers without a history of NSAID intake during the previous 2 weeks. Two different systems for blood collection and PRP production (Arthrex ACP double-syringe system and standard 4.5-mL sodium citrate blood collection tubes) were used and compared regarding the quality of PRP that was produced. RESULTS: For both groups, the baseline platelet counts of whole blood and the platelet counts of PRP formulations were found to be in the normal range. Both collection systems for PRP produced comparable results without significant differences between the groups. Platelet function testing with LTA revealed significantly impaired platelet aggregation in both PRP preparations, obtained from patients taking NSAIDs, irrespective of the type of NSAID (P < .001). All subjects from the control group showed normal platelet aggregation patterns when tested with LTA. CONCLUSION: Autologous PRP produced from subjects after NSAID medication shows significantly impaired platelet function and may result in lower quality regarding the content of bioactive compounds. CLINICAL RELEVANCE: If required, the administration of NSAIDs should be performed after blood collection for preparation of autologous PRP; otherwise, the therapeutic effect may be limited.

N-terminal pro-B-type Natriuretic Peptides' Prognostic Utility Is Overestimated in Meta-analyses Using Study-specific Optimal Diagnostic Thresholds.

BACKGROUND: N-terminal fragment B-type natriuretic peptide (NT-proBNP) prognostic utility is commonly determined post hoc by identifying a single optimal discrimination threshold tailored to the individual study population. The authors aimed to determine how using these study-specific post hoc thresholds impacts meta-analysis results. METHODS: The authors conducted a systematic review of studies reporting the ability of preoperative NT-proBNP measurements to predict the composite outcome of all-cause mortality and nonfatal myocardial infarction at 30 days after noncardiac surgery. Individual patient-level data NT-proBNP thresholds were determined using two different methodologies. First, a single combined NT-proBNP threshold was determined for the entire cohort of patients, and a meta-analysis conducted using this single threshold. Second, study-specific thresholds were determined for each individual study, with meta-analysis being conducted using these study-specific thresholds. RESULTS: The authors obtained individual patient data from 14 studies (n = 2,196). Using a single NT-proBNP cohort threshold, the odds ratio (OR) associated with an increased NT-proBNP measurement was 3.43 (95% CI, 2.08 to 5.64). Using individual study-specific thresholds, the OR associated with an increased NT-proBNP measurement was 6.45 (95% CI, 3.98 to 10.46). In smaller studies (<100 patients) a single cohort threshold was associated with an OR of 5.4 (95% CI, 2.27 to 12.84) as compared with an OR of 14.38 (95% CI, 6.08 to 34.01) for study-specific thresholds. CONCLUSIONS: Post hoc identification of study-specific prognostic biomarker thresholds artificially maximizes biomarker predictive power, resulting in an amplification or overestimation during meta-analysis of these results. This effect is accentuated in small studies.