Influence of Direct Oral Anticoagulant Levels and Thrombin Generation on Postoperative Bleeding [SONAR]: A Nested Case–Control Study

Abstract

Background

A direct oral anticoagulant (DOAC) concentration threshold above which an impact on surgical hemostasis starts to occur is unknown. Thrombin generation assays (TGAs) provide a measure of the coagulation phenotype. This study aimed to determine whether preoperative TGA parameters are associated with postoperative bleeding, and whether this is partly due to residual DOAC levels.

Materials and Methods

We conducted a nested case–control study using samples from apixaban/rivaroxaban-treated patients with atrial fibrillation from the PAUSE (Perioperative Anticoagulation Use for Surgery Evaluation) perioperative study. Cases were participants with postoperative major or clinically relevant nonmajor bleeding; controls were participants without bleeding. DOAC levels were measured using a chromogenic anti-Xa assay (BIOPHEN DiXaI; rivaroxaban/apixaban calibrators). TGA parameters were measured using calibrated automated thrombography.

Generalized linear mixed models and causal mediation analyses were used to evaluate the relationship between DOAC levels, TGA parameters, and bleeding.

Results

Forty eight cases were matched to 474 controls. Residual DOAC levels were higher in cases than controls (p = 0.03) and each TGA parameter was correlated with residual DOAC levels (p<0.05). A longer lag time (LT; odds ratio [OR] = 1.319 per minute [95% confidence interval [CI]: 1.077–1.617]) and time-to-peak (TTP; OR = 1.154 per minute [95% CI: 1.028–1.296]) were associated with an increased odds of bleeding; higher peak (OR = 0.994 per nM [95% CI: 0.989–0.998]) and mean velocity rate index (mVRI; OR = 0.986 per nM/min [95% CI: 0.976–0.996]) were associated with a lower odds of bleeding. The effect of apixaban/rivaroxaban levels on bleeding was mediated by altered TGA parameters (LT, TTP, peak, mVRI).

Conclusion

These findings support a measurable effect from low residual DOAC levels on thrombin generation and suggest a causal contribution of both toward bleeding.

Keywords

anticoagulants - thrombin generation - perioperative medicine - atrial fibrillation - hemostasis

• References

• 1 Douketis JD, Spyropoulos AC, Murad MH. et al. Perioperative management of antithrombotic therapy: an American College of Chest Physicians Clinical Practice Guideline. Chest 2022; 162 (05) e207-e243
• 2 Spyropoulos AC, Brohi K, Caprini J. et al; SSC Subcommittee on Perioperative and Critical Care Thrombosis and Haemostasis of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee Communication: guidance document on the periprocedural management of patients on chronic oral anticoagulant therapy: recommendations for standardized reporting of procedural/surgical bleed risk and patient-specific thromboembolic risk. J Thromb Haemost 2019; 17 (11) 1966-1972
• 3 Mueck W, Eriksson BI, Bauer KA. et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban–an oral, direct factor Xa inhibitor–in patients undergoing major orthopaedic surgery. Clin Pharmacokinet 2008; 47 (03) 203-216
• 4 Kubitza D, Becka M, Mueck W, Zuehlsdorf M. The Effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban - an oral, direct factor Xa inhibitor. Blood 2006; 108 (11) 905
• 5 Toorop MMA, Lijfering WM, Scheres LJJ. The relationship between DOAC levels and clinical outcomes: the measures tell the tale. J Thromb Haemost 2020; 18 (12) 3163-3168
• 6 Tripodi A. To measure or not to measure direct oral anticoagulants before surgery or invasive procedures. J Thromb Haemost 2016; 14 (07) 1325-1327
• 7 Powell JR. Are new oral anticoagulant dosing recommendations optimal for all patients?. JAMA 2015; 313 (10) 1013-1014
• 8 Douxfils J, Ageno W, Samama CM. et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018; 16 (02) 209-219
• 9 Testa S, Tripodi A, Legnani C. et al; START-Laboratory Register. Plasma levels of direct oral anticoagulants in real life patients with atrial fibrillation: results observed in four anticoagulation clinics. Thromb Res 2016; 137: 178-183
• 10 Reilly PA, Lehr T, Haertter S. et al; RE-LY Investigators. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63 (04) 321-328
• 11 Ruff CT, Giugliano RP, Braunwald E. et al. Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 2015; 385 (9984): 2288-2295
• 12 Testa S, Legnani C, Antonucci E. et al; Coordinator of START2-Register. Drug levels and bleeding complications in atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost 2019; 17 (07) 1064-1072
• 13 Hemker HC, Béguin S. Phenotyping the clotting system. Thromb Haemost 2000; 84 (05) 747-751
• 14 Depasse F, Binder NB, Mueller J. et al. Thrombin generation assays are versatile tools in blood coagulation analysis: a review of technical features, and applications from research to laboratory routine. J Thromb Haemost 2021; 19 (12) 2907-2917
• 15 Shaw JR, Castellucci LA, Siegal D, Carrier M. DOAC-associated bleeding, hemostatic strategies, and thrombin generation assays - a review of the literature. J Thromb Haemost 2023; 21 (03) 433-452
• 16 Levy JH, Ageno W, Chan NC, Crowther M, Verhamme P, Weitz JI. Subcommittee on Control of Anticoagulation. When and how to use antidotes for the reversal of direct oral anticoagulants: guidance from the SSC of the ISTH. J Thromb Haemost 2016; 14 (03) 623-627
• 17 Pernod G, Albaladejo P, Godier A. et al; Working Group on Perioperative Haemostasis. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013. Arch Cardiovasc Dis 2013; 106 (6–7): 382-393
• 18 Evrard J, Hardy M, Dogné JM. et al. Are the DOAC plasma level thresholds appropriate for clinical decision-making? A reappraisal using thrombin generation testing. Int J Lab Hematol 2021; 43 (01) e48-e51
• 19 Douxfils J, Chatelain C, Chatelain B, Dogné JM, Mullier F. Impact of apixaban on routine and specific coagulation assays: a practical laboratory guide. Thromb Haemost 2013; 110 (02) 283-294
• 20 Douxfils J, Mullier F, Loosen C, Chatelain C, Chatelain B, Dogné JM. Assessment of the impact of rivaroxaban on coagulation assays: laboratory recommendations for the monitoring of rivaroxaban and review of the literature. Thromb Res 2012; 130 (06) 956-966
• 21 Douketis JD, Spyropoulos AC, Duncan J. et al. Perioperative management of patients with atrial fibrillation receiving a direct oral anticoagulant. JAMA Intern Med 2019; 179 (11) 1469-1478
• 22 Douketis JD, Spyropoulos AC, Anderson JM. et al. The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study for patients on a direct oral anticoagulant who need an elective surgery or procedure: design and rationale. Thromb Haemost 2017; 117 (12) 2415-2424
• 23 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 (01) 202-204
• 24 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
• 25 Hansen BB, Klopfer SO. Optimal full matching and related designs via network flows. J Comput Graph Stat 2006; 15 (03) 609-627
• 26 Ho D, Imai K, King G, Stuart EA. MatchIt: nonparametric preprocessing for parametric causal inference. J Stat Softw 2011; 42 (08) 1-28
• 27 Shaw JR, Li N, Vanassche T. et al. Predictors of preprocedural direct oral anticoagulant levels in patients having an elective surgery or procedure. Blood Adv 2020; 4 (15) 3520-3527
• 28 Ninivaggi M, de Laat-Kremers R, Tripodi A. et al. Recommendations for the measurement of thrombin generation: communication from the ISTH SSC Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibodies. J Thromb Haemost 2021; 19 (05) 1372-1378
• 29 Åsberg A, Bolann BJ. Calculating the coefficient of variation from duplicate measurements: a new method. J Appl Lab Med 2023; 8 (01) 220-222
• 30 Austin PC. Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity-score matched samples. Stat Med 2009; 28 (25) 3083-3107
• 31 Cohen J. Statistical Power Analysis for the Behavioral Sciences. 2nd ed.. Lawrence Erlbaum Associates; 1988
• 32 Danforth CM, Orfeo T, Everse SJ, Mann KG, Brummel-Ziedins KE. Defining the boundaries of normal thrombin generation: investigations into hemostasis. PLoS One 2012; 7 (02) e30385
• 33 Tafur AJ, Clark NP, Spyropoulos AC. et al. Predictors of bleeding in the perioperative anticoagulant use for surgery evaluation study. J Am Heart Assoc 2020; 9 (19) e017316
• 34 Clark NP, Douketis JD, Hasselblad V, Schulman S, Kindzelski AL, Ortel TL. BRIDGE Investigators. Predictors of perioperative major bleeding in patients who interrupt warfarin for an elective surgery or procedure: analysis of the BRIDGE trial. Am Heart J 2018; 195: 108-114
• 35 Digitale JC, Martin JN, Glymour MM. Tutorial on directed acyclic graphs. J Clin Epidemiol 2022; 142: 264-267
• 36 Schisterman EF, Cole SR, Platt RW. Overadjustment bias and unnecessary adjustment in epidemiologic studies. Epidemiology 2009; 20 (04) 488-495
• 37 Diop A, Lefebvre G, Duchaine CS, Laurin D, Talbot D. The impact of adjusting for pure predictors of exposure, mediator, and outcome on the variance of natural direct and indirect effect estimators. Stat Med 2021; 40 (10) 2339-2354
• 38 Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci 2010; 25 (01) 1-21
• 39 Pearl J. Invited commentary: understanding bias amplification. Am J Epidemiol 2011; 174 (11) 1223-1227 , discussion 1228–1229
• 40 Marchi R, Marcos L, Paradisi I. Comparison by sex between thrombin generation and fibrin network characteristics in a healthy population. Clin Chim Acta 2015; 441: 86-89
• 41 Haidl H, Cimenti C, Leschnik B, Zach D, Muntean W. Age-dependency of thrombin generation measured by means of calibrated automated thrombography (CAT). Thromb Haemost 2006; 95 (05) 772-775
• 42 Hemker HC, Al Dieri R. Age-dependency of thrombin generation. Thromb Haemost 2006; 95 (05) 756-757
• 43 Tingley D, Yamamoto T, Hirose K, Keele L, Imai K. Mediation: R package for causal mediation analysis. J Stat Softw 2014; 59 (05) 1-38
• 44 Imai K, Keele L, Tingley D. A general approach to causal mediation analysis. Psychol Methods 2010; 15 (04) 309-334
• 45 Kim PY, Yeh CH, Dale BJ. et al. Mechanistic basis for the differential effects of rivaroxaban and apixaban on global tests of coagulation. TH Open 2018; 2 (02) e190-e201
• 46 Horlocker TT, Vandermeuelen E, Kopp SL, Gogarten W, Leffert LR, Benzon HT. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine evidence-based guidelines (fourth edition). Reg Anesth Pain Med 2018; 43 (03) 263-309
• 47 Coakley M, Hall JE, Evans C. et al. Assessment of thrombin generation measured before and after cardiopulmonary bypass surgery and its association with postoperative bleeding. J Thromb Haemost 2011; 9 (02) 282-292
• 48 Bosch Y, Al Dieri R, ten Cate H. et al. Preoperative thrombin generation is predictive for the risk of blood loss after cardiac surgery: a research article. J Cardiothorac Surg 2013; 8: 154
• 49 Maag A, van Rein N, Schuijt TJ. et al. Major bleeding during oral anticoagulant therapy associated with factor V activation by factor Xa. J Thromb Haemost 2022; 20 (02) 328-338
• 50 Dielis AW, Castoldi E, Spronk HM. et al. Coagulation factors and the protein C system as determinants of thrombin generation in a normal population. J Thromb Haemost 2008; 6 (01) 125-131
• 51 Zalewski J, Stepien K, Nowak K, Caus S, Butenas S, Undas A. Delayed thrombin generation is associated with minor bleedings in venous thromboembolism patients on rivaroxaban: usefulness of calibrated automated thrombography. J Clin Med 2020; 9 (07) 2018
• 52 Bloemen S, Zwaveling S, Ten Cate H, Ten Cate-Hoek A, de Laat B. Prediction of bleeding risk in patients taking vitamin K antagonists using thrombin generation testing. PLoS One 2017; 12 (05) e0176967
• 53 Woodhams B, Girardot O, Blanco MJ, Colesse G, Gourmelin Y. Stability of coagulation proteins in frozen plasma. Blood Coagul Fibrinolysis 2001; 12 (04) 229-236