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Bleeding after adult cardiac surgery: Clinical and genetic risk factors and effect of prophylactic treatment with tranexamic acid

Greiff, Guri
Doctoral thesis
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URI
http://hdl.handle.net/11250/2364430
Date
2015
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  • Institutt for sirkulasjon og bildediagnostikk [1051]
Abstract
Background: Postoperative excessive bleeding is still one of the most common complications

in cardiac surgery and is associated with increased morbidity and mortality. Major bleeding

is a partially modifiable risk factor, and adequate preventive treatment strategies should be

used to reduce the incidence of this complication. Prophylactic drug treatments can reduce

postoperative bleeding. Prediction modelling strategies can be used for identifying patients

at higher risk of bleeding after cardiac surgery and thereby contribute to implementation of

prophylactic therapies and early interventions. Genetic variation may contribute to

postoperative bleeding after cardiac surgery, and genetic information could make the

prediction of excessive postoperative bleeding more precise.

Aims: The overall aim of the thesis was to contribute to better patient care through

increased knowledge about postoperative bleeding and about the treatment of this

complication in high-risk groups. More specifically, the aim in Study I was to investigate the

effects of tranexamic acid on postoperative blood loss and transfusion requirements in

elderly patients undergoing complex cardiac surgery. In Study II the aims were 1) to

investigate if risk prediction for postoperative bleeding was possible using clinical variables,

by validating the Papworth Bleeding Risk Score and by developing local risk prediction

models, and 2) to compare the usefulness of the universal definition of postoperative

bleeding proposed by Dyke et al with the definition used in the Papworth Bleeding Risk

Score. In Study III the main aim was to validate some earlier identified genetic

polymorphisms associated with bleeding after cardiac surgery, and to explore other

functional polymorphisms central in the coagulation and fibrinolysis systems or in plateletmembrane

receptors related to postoperative bleeding. A secondary aim was to evaluate

the additional predictive ability with inclusion of genetic information in risk prediction

models based only on clinical variables, thereby investigating whether genetic susceptibility

is a clinically relevant factor for further studies.

Methods: A prospective, randomized, double-blind, placebo-controlled, parallel-group trial

was used to investigate the effect of tranexamic acid in patients, 70 years or older,

undergoing aortic valve replacement (AVR) or coronary artery bypass grafting (CABG). For

Study II and III we used a prospectively recorded local database. All patients included in the

studies underwent cardiac surgery with cardiopulmonary bypass at St. Olavs University Hospital, Trondheim, Norway. The predictive ability of the Papworth Bleeding Risk Score was

validated, using the universal definition of perioperative bleeding proposed by Dyke et al

and the definition used to develop the Papworth Bleeding Risk Score. Clinical prediction

models were constructed using multivariate logistic regression analyses, using the two

mentioned endpoints. Genetic associations were performed using allelic association tests

and logistic regression. Multivariate logistic regression was used to evaluate whether the

genetic information could improve the model with clinical variables.

Results: The total number of red cell transfusions given was significantly larger in the

placebo group of elderly patients compared with the tranexamic acid group (5 vs. 3

respectively, p = 0.049). When using both the Papworth Bleeding Risk Score and the locally

developed risk prediction models, the positive predictive value was low (0.15 and 0.12

respectively) in the high-risk group and the negative predictive value was high (0.98 and 0.95

respectively) in the low-risk group. We identified five significant SNPs associated with

postoperative bleeding. Addition of the genetic covariates to a logistic regression model with

clinical variables significantly improved the model (p<0.01).

Conclusions: Tranexamic acid reduced the need for red cell transfusion in elderly patients

undergoing combined AVR and CABG surgery. Neither the Papworth Bleeding Risk Score nor

the locally developed risk prediction models were suitable for identifying the patients at high

risk of severe postoperative bleeding after cardiac surgery, but could more precisely identify

patients at low risk of bleeding. None of the two endpoint definitions for postoperative

bleeding were clearly preferable. We identified five SNPs associated with postoperative

bleeding. Inclusion of genetic information to a risk prediction model with only clinical

variables improved the model, indicating that genetic predisposition is relevant for

postoperative bleeding after cardiac surgery.
Publisher
NTNU
Series
Doctoral thesis at NTNU;2015:162

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