Aprotinin to Reduce Bleeding in Cardiac Surgery - An Update Back

Bleeding and transfusion in cardiac surgery

Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are at risk for excessive intra- and postoperative bleeding as a result of many factors, including CPB-related alterations in the haemostatic system and exposure to long-acting antithrombotic agents. The pathophysiology of acquired haemostatic system abnormalities as related to the use of extracorporeal circulation includes haemodilution, activation of the haemostatic system and coagulation factor consumption mediated by thrombin, plasmin, inflammation and the mechanics of CPB.1

Excessive bleeding following cardiac surgery with CPB often results in the need for allogeneic blood transfusion. Blood transfusions are associated with serious postoperative complications, such as infections, renal failure, stroke and transfusion-related acute lung injury (TRALI), and with increased intensive care unit and hospital lengths of stay.2-5 There is also evidence that red blood cell (RBC) transfusion is associated with reduced short- and long-term survival after cardiac surgery.3,4,6,7

In the TRACS (Transfusion Requirements After Cardiac Surgery) randomised controlled trial, the number of transfused RBC units was an independent risk factor for clinical complications or death at 30 days, with a hazard ratio of 1.2 (95% CI, 1.1-1.4; P<0.002) for each additional unit transfused.8

Pharmacological strategies to reduce perioperative bleeding

Numerous pharmacologic strategies have been proposed as means to attenuate the alterations in the haemostatic system during CPB, thereby reducing excessive bleeding and transfusion requirements.9 The prophylactic use of antifibrinolytics such as epsilon-aminocaproic acid and tranexamic acid, which preserve haemostasis through plasmin inhibition, and of aprotinin, a broad-spectrum serine protease inhibitor, has been studied extensively in cardiac surgery.10

Aprotinin inhibits a broad spectrum of proteases including plasmin, trypsin, kallikrein, chymotrypsin, activated protein C, and thrombin; it acts in a number of interrelated ways to provide an antifibrinolytic effect, inhibit contact activation, reduce platelet dysfunction and attenuate the inflammatory response to CPB.11 A meta-analysis of 35 trials involving 3879 patients undergoing coronary artery bypass graft (CABG) surgery found that aprotinin reduced the number of patients requiring any blood transfusion (relative risk [RR], 0.61; 95% CI, 0.58-0.66) and was associated with a reduced risk of stroke (RR, 0.53; 95% CI, 0.31-0.90) (Figure 1).12 Another meta-analysis reported that treatment with aprotinin decreased the frequency of surgical reexploration (odds ratio [OR], 0.37; 95% CI, 0.25-0.55) after cardiac surgery.13

A 2011 Cochrane review assessed the comparative effects of aprotinin, tranexamic acid and epsilonaminocaproic acid on blood loss during surgery.10

A total of 252 randomised controlled trials involving over 25,000 participants were identified, and cardiac surgery accounted for 69% of the data. When the pooled estimates from the head-to-head trials of the two lysine analogues were combined and compared with aprotinin alone, aprotinin appeared more effective in reducing the need for RBC transfusion (RR, 0.90; 95% CI, 0.81-0.99) and reduced the need for reoperation due to bleeding by 54% (RR, 0.46; 95% CI, 0.34-0.62).

Identifying cardiac surgery patients at risk of major transfusion

There is currently no expert consensus on the definition of the ‘high-risk patient’ likely to benefit from a blood-saving agent such as aprotinin. Using a prospective database, Stevens et al. performed a retrospective study of consecutive patients that underwent cardiac surgery at the Centre hospitalier de l’Université de Montréal (CHUM) since 2012 in order to identify the incidence of — and the variables associated with — major transfusion, as well as possible associations between major transfusion and morbidity/mortality outcomes.14 Major transfusion was defined as the administration of >4 RBC units and/or haemostatic products (>2 units of fresh frozen plasma, platelets, cryoprecipitate, or recombinant factor VIIa). Stratified multivariate logistic regression analysis was used to identify associated variables. The results of this study were presented for the first time at the 15th Annual NATA Symposium on Patient Blood Management, Haemostasis and Thrombosis.

Of 1439 included patients, 550 (38.2%) required major transfusion. The proportion of redo, urgent and complex procedures was higher among patients with major transfusion. A total of 1042 patients underwent cardiac surgery with CPB, and of these 1040 (99.8%) received tranexamic acid. Preoperative variables associated with an increased risk of major transfusion included a low or borderline platelet count, clopidogrel administration within 5 days of surgery, chronic kidney disease, prior cardiac surgery and low left ventricular ejection fraction (Figure 2). Urgency status (need to operate within 6 hours) and CPB time (especially above 90 minutes) were also significantly associated with major transfusion. Using propensity-score matching, the authors found that major transfusion was associated with increased 30-day mortality (6.0 vs. 1.4%; P<0.002) as well as an increased risk of cardiac reoperation, ventilation for >24 hours and hospital length of stay >14 days (all P<0.001).

This study confirms that major transfusion is associated with poor outcomes including increased mortality, and that it is possible to predict which patients are likely to receive a major transfusion. It is also noteworthy that despite advances in surgical and perfusion techniques and the routine use of tranexamic acid, 38% of cardiac surgical patients required major transfusion, which clearly underlines an unmet clinical need.

Preoperative management of antiplatelet therapy: the delicate balance between bleeding and thrombosis

CABG-related bleeding complications and perioperative coronary events are strongly influenced by the management of antithrombotic therapy before and after CABG.15 A number of observational studies have found clopidogrel exposure within 5-7 days prior to CABG to be associated with an increased risk of major bleeding, reoperation and blood component transfusion.16 While patients on dual antiplatelet therapy undergoing urgent CABG are at risk for increased bleeding, withholding antiplatelet therapy prior to CABG puts the patient at increased risk of thrombotic events. A multidisciplinary approach is therefore needed in order to determine the best strategy.

European guidelines for myocardial revascularisation state that “in patients on P2Y12 inhibitors who need to undergo non-emergency major surgery (including CABG), it should be considered to postpone surgery for at least 5 days after cessation of ticagrelor or clopidogrel, and for 7 days for prasugrel, if clinically feasible and unless the patient is at high risk for ischaemic events (Class IIa recommendation, level C evidence)”.17 Low-dose aspirin should generally be maintained, but may be interrupted 3-5 days before surgery in patients with increased bleeding risk.15

Antifibrinolytics in patients on antiplatelet therapy undergoing CABG surgery

The effects of antifibrinolytic agents in patients undergoing cardiac surgery and maintained on aspirin therapy throughout the preoperative period were assessed in a meta-analysis.18 Antifibrinolytics were found to reduce the risk of receiving any allogeneic blood product (OR, 0.37; 95% CI, 0.27-0.49; P<0.00001).

The difference was statistically significant for aprotinin (10 studies; OR, 0.34; 95% CI, 0.25-0.46; P<0.00001) but not for lysine analogues (1 study; OR, 0.97; 95% CI, 0.32-2.90; P<0.95).

The benefits of aprotinin have also been evaluated in patients receiving dual antiplatelet therapy before cardiac surgery. Akowuah et al. compared two
strategies in 50 patients requiring urgent surgical coronary revascularisation: the treatment group remained on aspirin and clopidogrel therapy for five days before surgery and received intraoperative aprotinin, whereas the placebo group was given placebo capsules instead of aspirin and clopidogrel for five days and placebo infusions intraoperatively.19 In the aprotinin group, the number of RBC concentrates transfused was significantly reduced (0.3 ± 1.2 vs. 1.0 ± 1.7 units; P=0.03). Furthermore, three patients in the placebo group, compared with none in the treatment group, had a myocardial infarction (P=0.07).

In a study by van der Linden et al., 75 patients with unstable angina treated with clopidogrel less than five days before CABG were randomised to full-dose aprotinin or saline.20 In the aprotinin group, postoperative blood and the volume of transfused RBCs and platelets were significantly reduced (Figure 3). In addition, 53% of patients were exposed to blood products, compared with 79% in the control group (P=0.02). In a subsequent study in 15 clopidogrel-treated patients, the authors showed that administration of aprotinin increased ADP-induced platelet aggregation from 84 to 94% (P<0.001), corresponding to a median decrease in relative platelet inhibition of >50%.21

Safety of aprotinin in cardiac surgery

Potential risks associated with aprotinin administration in patients undergoing cardiac surgery include anaphylactic reactions, inaccurate monitoring of heparin therapy, graft occlusion, renal dysfunction, and increased mortality.

Since aprotinin is a protein derived from bovine lungs and may elicit antibody formation, the possibility of hypersensitivity reactions exists, particularly upon re-exposure to the drug. The incidence of hypersensitivity reactions to aprotinin was evaluated prospectively in over 12,403 cardiac surgical procedures with 801 re-exposures in 697 patients.22 Following primary exposure, the incidence was 0.09% and none of the reactions were severe. In case of repeat exposure, the incidence of hypersensitivity reactions was 4.1%, 1.9%, and 0.4% when reexposure occurred within 6 months, between 6 and 12 months, and more than 12 months, respectively, after the previous exposure.

The use of aprotinin is contraindicated in patients with a known or suspected previous exposure within the last 12 months (European and Canadian labels). The risk of hypersensitivity reactions following aprotinin administration may be balanced against the risk of TRALI, one of the leading causes of acute transfusion-associated morbidity and mortality in countries with a high development index.23 In a cohort of cardiac surgical patients, the incidence of possible TRALI was found to be as high as 2.4% (0.61% per blood product transfused), and TRALI was associated with increased ventilation time, hospital length of stay and in-hospital mortality.5
The largest study reporting on graft occlusion following aprotinin administration was the IMAGE trial, an international multicentre trial evaluating aprotinin in primary CABG surgery.24 Among 703 patients with assessable saphenous vein grafts, occlusions occurred in 15.4% of aprotinin-treated patients and 10.9% of patients receiving placebo (P=0.03). After adjusting for risk factors associated with vein graft occlusion (female gender, lack of prior aspirin therapy, small and poor distal vessel quality), the risk ratio decreased from 1.7 to 1.05 (90% confidence interval, 0.6 to 1.8).   Using an observational database of 4374 patients undergoing surgical revascularisation, Mangano et al. found that aprotinin use, in propensity-adjusted, multivariable logistic regression, doubled the risk of renal failure requiring dialysis among patients undergoing cardiac surgery.25 Another large observational study using data from 11,198 patients in the Merged Cardiac Registry did not confirm these results.26 The authors observed that the number of transfused RBC concentrates was a highly significant risk factor for acute renal failure (P<0.0001; OR, 1.23/transfused unit). Risk adjustment taking blood transfusions into account did not show an independent effect of aprotinin (P=0.231). It is known that after glomerular filtration aprotinin is reabsorbed and metabolised in the proximal tubules. Hence, there may be a competition with other metabolites such as creatinine, and a transient increase in serum creatinine may be observed following aprotinin administration.

In 2008, the results of the Blood Conservation Using Antifibrinolytics in Randomized Trial (BART) were published.27 This multicentre, blinded controlled trial comparing aprotinin, tranexamic acid and epsilon-aminocaproic acid in high-risk cardiac surgical patients was terminated early because of a higher rate of death in patients receiving aprotinin. Among the 2331 patients enrolled in the trial, aprotinin was associated with a reduced rate of massive bleeding compared with both synthetic antifibrinolytics (RR for both comparisons, 0.79; 95% CI, 0.59-1.05). However, 30-day all-cause mortality was significantly increased compared with tranexamic acid (RR, 1.55; 95% CI, 0.99-2.42) and epsilon-aminocaproic acid (RR, 1.52; 95% CI, 0.98-2.36).

Despite the lack of explanation for the observed increase in mortality, these results led to marketing suspension of aprotinin. However, a number of potential, serious limitations were identified in the BART study. 28-30

One of these was the unexplained exclusion of 137 patients from the analysis after randomisation. Among excluded patients, the trend in mortality was opposite to that among included patients, and with their inclusion the statistical significance of the difference in mortality would have disappeared. Another potential, serious limitation was the unusually high number of outcome reclassifications favouring synthetic antifibrinolytics versus aprotinin*. It should also be noted that among 4846 patients screened and found eligible for inclusion in the study, 2220 (46%) did not undergo randomisation because “patients or their surgeon or anaesthesiologist did not provide consent”27; if, as we feel is likely, the main reason for withholding consent was the clinicians’ feeling that the patient should receive aprotinin, this may have represented a significant selection bias. In 2012, after performing a comprehensive review of the available evidence, the European Medicines Agency recommended lifting the marketing suspension of aprotinin subject to the revision of the indication as follows: “prophylactic use to reduce blood loss and blood transfusion in adult patients who are at high risk of major blood loss undergoing isolated cardiopulmonary bypass graft surgery (i.e. coronary artery bypass graft surgery that is not combined with other cardiovascular surgery)”.

Benefits of aprotinin in high-risk patients

In an attempt to delineate the benefit-risk ratios of aprotinin, tranexamic acid and epsilon-aminocaproic acid in cardiac surgical patients according to their risk status, Meybohm et al. performed a meta-analysis of controlled and observational trials, using early (30-day or inhospital) mortality as the primary outcome measure.31 Whereas early mortality was significantly increased with aprotinin versus lysine analogues among low-risk (risk ratio, 1.58; 95% CI, 1.13-2.21; P<0.001) and intermediate-risk patients (risk ratio, 1.42; 95% CI, 1.09-1.84; P<0.001), in high-risk patients (e.g. redo ternotomy or emergency surgery) the risk for mortality did not differ significantly between aprotinin and lysine analogues (risk ratio, 1.03; 95% CI, 0.67-1.58; P=0.90). The authors concluded that aprotinin might be beneficial in high-risk cardiac surgery as it reduces the risk of transfusion and bleeding complications.

Aiming to evaluate the effect of marketing suspension of aprotinin on patient outcomes and to assess the potential risks and benefits of its reintroduction, Walkden et al. performed a nested case-control study of two cohorts of 3578 and 3030 patients, respectively, undergoing adult cardiac surgery in a single tertiary centre before and after aprotinin withdrawal.32 In propensity-matched cohorts, withdrawal of aprotinin from clinical use was associated with more bleeding and transfusions, higher rates of emergency resternotomy and acute kidney injury, and a significant increase in pulmonary, infectious and cardiac morbidity. Among high-risk patients (29% of all patients), the increases in bleeding and acute kidney injury following aprotinin withdrawal were of a greater magnitude, and a significant increase in 30-day mortality (hazard ratio, 2.51; 95% CI, 1.00-6.29) was observed.

Conclusion

In patients undergoing cardiac surgery, aprotinin reduces transfusion requirements and the rate of reoperations for bleeding. It may generate adverse events such as anaphylactic reactions — particularly upon re-exposure within 12 months — and transient renal impairment. Aprotinin should be reserved for patients with a high risk of bleeding, where it is associated with a clear trend towards decreased mortality. Within the approved indication, i.e. in patients undergoing isolated cardiac surgery who are at high risk of major blood loss, potential candidates include patients undergoing redo procedures and patients on dual antiplatelet therapy. Further to a European Medicines Agency requirement, the use of aprotinin will be allowed in centres that perform cardiac surgery with CPB upon the condition that they participate in an online registry aimed at monitoring its use.

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