In Nordic countries 30-day mortality rate is half that estimated with EuroSCORE II in high-risk adult patients given aprotinin and undergoing mainly complex cardiac procedures.

Objectives. To describe current on- (isolated coronary arterty bypass grafting, iCABG) and off-label (non-iCABG) use of aprotinin and associated safety endpoints in adult patients undergoing high-risk cardiac surgery in Nordic countries. Design. Data come from 10 cardiac surgery centres in Finland, Norway and Sweden participating in the European Nordic aprotinin patient registry (NAPaR). Results. 486 patients were given aprotinin between 2016 and 2020. 59 patients (12.1%) underwent iCABG and 427 (87.9%) non-iCABG, including surgery for aortic dissection (16.7%) and endocarditis (36.0%). 89.9% were administered a full aprotinin dosage and 37.0% were re-sternotomies. Dual antiplatelet treatment affected 72.9% of iCABG and 7.0% of non-iCABG patients. 0.6% of patients had anaphylactic reactions associated with aprotinin. 6.4% (95 CI% 4.2%-8.6%) of patients were reoperated for bleeding. Rate of postoperative thromboembolic events, day 1 rise in creatinine >44µmol/L and new dialysis for any reason was 4.7% (95%CI 2.8%-6.6%), 16.7% (95%CI 13.4%-20.0%) and 14.0% (95%CI 10.9%-17.1%), respectively. In-hospital mortality and 30-day mortality was 4.9% (95%CI 2.8%-6.9%) and 6.3% (95%CI 3.7%-7.8%) in all patients versus mean EuroSCORE II 11.4% (95%CI 8.4%-14.0%, p < .01). 30-day mortality in patients undergoing surgery for aortic dissection and endocarditis was 6.2% (95%CI 0.9%-11.4%) and 6.3% (95%CI 2.7%-9.9%) versus mean EuroSCORE II 13.2% (95%CI 6.1%-21.0%, p = .11) and 14.5% (95%CI 12.1%-16.8%, p = .01), respectively. Conclusions. NAPaR data from Nordic countries suggest a favourable safety profile of aprotinin in adult cardiac surgery.

Use of Aprotinin versus Tranexamic Acid in Cardiac Surgery Patients with High-Risk for Excessive Bleeding (APACHE) trial: a multicentre retrospective comparative non-randomized historical study.

OBJECTIVES: Following the reintroduction of aprotinin into the European market, the French Society of Cardiovascular and Thoracic Anaesthesiologists recommended its prophylactic use at half-dose for high-risk cardiac surgery patients. We examined whether the use of aprotinin instead of tranexamic acid could significantly reduce severe perioperative bleeding. METHODS: This multicentre, retrospective, historical study included cardiac surgery patients treated with aprotinin or tranexamic acid between December 2017 and September 2020. The primary efficacy end point was the severe or massive perioperative bleeding (class 3-4 of the universal definition of perioperative bleeding). The safety secondary end points included the occurrence of thromboembolic events and all-cause mortality within 30 days after surgery. RESULTS: Among the 693 patients included in the study, 347 received aprotinin and 346 took tranexamic acid. The percentage of patients with severe or massive bleeding was similar in the 2 groups (42.1% vs 43.6%, Adjusted odds ratio [ORadj] = 0.87, 95% confidence interval: 0.62-1.23, P = 0.44), as was the perioperative need for blood products (81.0% vs 83.2%, ORadj = 0.75, 95% confidence interval: 0.48-1.17, P = 0.20). However, the median (Interquartile range) 12 h postoperative blood loss was significantly lower in the aprotinin group (383 ml [241-625] vs 450 ml [290-730], P < 0.01). Compared to tranexamic acid, the intraoperative use of aprotinin was associated with increased risk for thromboembolic events (adjusted Hazard ratio 2.30 [95% Cl: 1.06-5.30]; P = 0.04). CONCLUSIONS: Given the modest reduction in blood loss at the expense of a significant increase in thromboembolic adverse events, aprotinin use in high-risk cardiac surgery patients should be based on a carefully considered benefit-risk assessment.

Use and safety of aprotinin in routine clinical practice: A European postauthorisation safety study conducted in patients undergoing cardiac surgery.

BACKGROUND: Aprotinin has been used to reduce blood loss and blood product transfusions in patients at high risk of major blood loss during cardiac surgery. Approval by the European Medicines Agency (EMA) for its current indication is limited to patients at high risk of major blood loss undergoing isolated coronary artery bypass graft surgery (iCABG). OBJECTIVE: To report current real-world data on the use and certain endpoints related to the safety of aprotinin in adult patients. DESIGN: The Nordic aprotinin patient registry (NAPaR) received data from 83 European centres in a noninterventional, postauthorisation safety study (PASS) performed at the request of the EMA. SETTING: Cardiac surgical centres committed to enrolling patients in the NAPaR. PATIENTS: Patients receiving aprotinin agreeing to participate. INTERVENTION: The decision to administer aprotinin was made by the treating physicians. MAIN OUTCOME MEASURES: Aprotinin safety endpoints were in-hospital death, thrombo-embolic events (TEEs), specifically stroke, renal impairment, re-exploration for bleeding/tamponade. RESULTS: From 2016 to 2020, 5309 patients (male 71.5%; >75 years 18.9%) were treated with aprotinin; 1363 (25.7%) underwent iCABG and 3946 (74.3%) another procedure, including a surgical treatment for aortic dissection ( n  = 660, 16.7%); 54.5% of patients received the full-dose regimen. In-hospital mortality in iCABG patients was 1.3% (95% CI, 0.66 to 1.84%) vs. 8.3% (7.21 to 8.91%) in non-iCABG patients; incidence of TEEs and postoperative rise in creatinine level greater than 44 µmol l -1 2.3% (1.48 to 3.07%) and 2.7% (1.79 to 3.49%) vs. 7.2% (6.20 to 7.79%) and 15.5% (13.84 to 16.06%); patients undergoing re-exploration for bleeding 1.4% (0.71 to 1.93%) vs. 3.0% (2.39 to 3.44%). Twelve cases of hypersensitivity/anaphylactic reaction (0.2%) were reported as Adverse Drug Reactions. CONCLUSION: The data in the NApaR indicated that in this patient population, at high risk of death or blood loss undergoing cardiac surgery, including complex cardiac surgeries other than iCABG, the incidence of adverse events is in line with data from current literature, where aprotinin was not used. TRIAL REGISTRATION: EU PAS register number: EUPAS11384.

Perioperative anaphylaxis to fibrin sealants in children with Noonan Syndrome: A retrospective study.

BACKGROUND: In the diagnosis of perioperative anaphylaxis, it is essential to define its cause to prevent future reexposures, especially in children with Noonan Syndrome who are characterized by a large number of systemic features and wide-ranging dysmorphia. From an oral surgeon's point of view, apart from an increased risk of tumor incidence, diverse hematologic anomalies are of high concern. OBJECTIVE: Perioperative management of such patients often requires the use of fibrin sealants, which contain aprotinin. A certain number of anaphylaxis cases have been observed in our daily practice during such treatment, which was the reason for this evaluation. METHODS: The study was conducted to retrospectively review perioperative anaphylaxis grade II and above in children with Noonan Syndrome who underwent surgeries in the Department of Oral Surgery, Medical University of Lodz, between 2006 and 2021. RESULTS: Out of the 16 cases of suspected anaphylaxis to aprotinin, 14 were observed in children with Noonan Syndrome. The postoperative serologic screening revealed positive results for qualitative aprotinin-specific immunoglobulin (Ig) G, highly elevated quantitative aprotinin-specific IgG, and slightly elevated aprotinin-specific IgE antibodies. Interestingly, previous aprotinin administration or contact in the past 12 months was excluded. CONCLUSION: Given that fibrin sealants are typically used in various surgical practices and although the anaphylaxis reactions in such cases are rare, it is essential to be cautious in patients with RASopathies who are at a high risk of developing anaphylaxis.

Efficacy and safety of aprotinin in paediatric cardiac surgery: A systematic review and meta-analysis.

BACKGROUND: The relicensing of aprotinin in Europe and Canada has stimulated discussions on its usefulness in paediatric cardiac surgery. OBJECTIVE: To systematically evaluate the available evidence on the efficacy and safety of aprotinin in paediatric cardiac surgery. DESIGN: Systematic review of all randomised and observational studies comparing aprotinin with tranexamic acid, epsilon aminocaproic acid, placebo or no drug in paediatric cardiac surgery. Meta-analyses were performed on efficacy and safety outcomes. DATA SOURCES: PubMed, Cochrane Central Register of Controlled Trials, Web of Science and Embase were searched from January 2000 to March 2021. ELIGIBILITY CRITERIA: Studies that enrolled children under 18 years undergoing cardiac surgery with cardiopulmonary bypass. RESULTS: Thirty-two studies enrolling a total of 63 894 paediatric cardiac procedures were included. Aprotinin significantly reduced total blood loss [mean difference -4.70 ml kg-1, 95% confidence interval (CI), -7.88 to -1.53; P = 0.004], postoperative transfusion requirements and the incidence of surgical re-exploration for bleeding [odds ratio (OR) 0.74, 95% CI, 0.56 to 0.97; P = 0.03]. Aprotinin had no effects on 30-day mortality (OR 1.02, 95% CI, 0.93 to 1.11; P = 0.73) and on other safety outcomes, except for the incidence of renal replacement therapy (RRT), which was significantly increased in patients given aprotinin (OR 1.29, 95% CI, 1.08 to 1.54; P = 0.006). Findings from observational and randomised controlled trials did not largely differ. A sub-group analysis in neonates showed that aprotinin significantly reduced packed red blood cell transfusions and the incidence of postoperative surgical re-exploration for bleeding and/or tamponade. When compared with lysine analogues, aprotinin was more effective at reducing bleeding and transfusion without increasing the risk of side effects. CONCLUSION: This meta-analysis suggests that aprotinin is effective and well tolerated in paediatric cardiac surgery. Given the large heterogeneity of the results and the risk of selection bias in observational studies, large randomised controlled trials are warranted.

Antifibrinolytic Drugs for the Prevention of Bleeding in Pediatric Cardiac Surgery on Cardiopulmonary Bypass: A Systematic Review and Meta-analysis.

BACKGROUND: Bleeding is one of the commonest complications affecting children undergoing cardiac surgery on cardiopulmonary bypass. Antifibrinolytic drugs are part of a multifaceted approach aimed at reducing bleeding, though sufficiently sized pediatric studies are sparse, and dosing algorithms are heterogeneous. Our objective was to evaluate the efficacy and safety of antifibrinolytic agents as well as the effectiveness of different dosing regimens in pediatric cardiac surgery using cardiopulmonary bypass. METHODS: We performed a systematic review and meta-analysis evaluating randomized controlled trials published between 1980 and 2019, identified by searching the databases MEDLINE, EMBASE, PubMed, and CENTRAL. All studies investigating patients <18 years of age without underlying hematological disorders were included. The primary outcome was postoperative bleeding; secondary end points included blood product transfusion, mortality, and safety (thromboses, anaphylaxis, renal or neurological dysfunction, and seizures). Different dosing regimens were compared. Studies were dual appraised, outcomes were reported descriptively and, if appropriate, quantitatively using the Review Manager 5 (REVMAN 5) software (The Cochrane Collaboration). RESULTS: Thirty of 209 articles were included, evaluating the following drugs versus control: aprotinin n = 14, tranexamic acid (TXA) n = 12, and epsilon-aminocaproic acid (EACA) n = 4. The number of participants per intervention group ranged from 11 to 100 (median, 25; interquartile range [IQR], 20.5) with a wide age span (mean, 13 days to 5.8 years) and weight range (mean, 3.1-26.3 kg). Methodological quality was low to moderate.All agents reduced mean 24-hour blood loss compared to control: aprotinin by 6.0 mL/kg (95% confidence interval [CI], -9.1 to -3.0; P = .0001), TXA by 9.0 mL/kg (95% CI, -11.3 to -6.8; P < .00001), and EACA by 10.5 mL/kg (95% CI, -21.1 to 0.0; P = .05). Heterogeneity was low for TXA (I2 = 29%; P = .19), moderate for aprotinin (I2 = 41%; P = .11), and high for EACA (I2 = 95%; P < .00001). All agents also reduced 24-hour blood product transfusion. There was no clear dose-response effect for TXA nor aprotinin. Studies were underpowered to detect significant differences in mortality, thromboses, anaphylaxis, and renal or neurological dysfunction. CONCLUSIONS: The available data demonstrate efficacy for all 3 antifibrinolytic drugs. Therefore, the agent with the most favorable safety profile should be used. As sufficient data are lacking, large comparative trials are warranted to assess the relative safety and appropriate dosing regimens in pediatrics.

Renal effects of the serine protease inhibitor aprotinin in healthy conscious mice.

Treatment with aprotinin, a broad-spectrum serine protease inhibitor with a molecular weight of 6512 Da, was associated with acute kidney injury, which was one of the reasons for withdrawal from the market in 2007. Inhibition of renal serine proteases regulating the epithelial sodium channel ENaC could be a possible mechanism. Herein, we studied the effect of aprotinin in wild-type 129S1/SvImJ mice on sodium handling, tubular function, and integrity under a control and low-salt diet. Mice were studied in metabolic cages, and aprotinin was delivered by subcutaneously implanted sustained release pellets (2 mg/day over 10 days). Mean urinary aprotinin concentration ranged between 642 ± 135 (day 2) and 127 ± 16 (day 8) µg/mL . Aprotinin caused impaired sodium preservation under a low-salt diet while stimulating excessive hyperaldosteronism and unexpectedly, proteolytic activation of ENaC. Aprotinin inhibited proximal tubular function leading to glucosuria and proteinuria. Plasma urea and cystatin C concentration increased significantly under aprotinin treatment. Kidney tissues from aprotinin-treated mice showed accumulation of intracellular aprotinin and expression of the kidney injury molecule 1 (KIM-1). In electron microscopy, electron-dense deposits were observed. There was no evidence for kidney injury in mice treated with a lower aprotinin dose (0.5 mg/day). In conclusion, high doses of aprotinin exert nephrotoxic effects by accumulation in the tubular system of healthy mice, leading to inhibition of proximal tubular function and counterregulatory stimulation of ENaC-mediated sodium transport.

Comparison of TachoComb and TissuDura in Terms of Adverse Effects and Complications in Duraplasty in Rats.

AIM: To compare two synthetic graft materials, TachoComb®, a fibrin sealant composed of collagen, fibrinogen, thrombin and aprotinin and TissuDura®, a collagen-based biomatrix. MATERIAL AND METHODS: Thirty Sprague?Dawley rats were randomly divided into three groups with 10 animals in each group. A dural defect was created on the left parietal bone of each animal, and the dural defect was repaired using either TachoComb® (TachoComb group) or TissuDura® (TissuDura group). Sham animals did not receive any dural graft. After 21 days of follow-up, the brain was dissected, and inflammation, oedema, gliosis and foreign body reaction in the bone and parenchymal tissue were investigated histopathologically. RESULTS: The TachoComb group showed significantly greater inflammation, gliosis and parenchymal foreign body reaction compared with the sham group. By contrast, the TissuDura group had significantly lower gliosis and insignificantly less inflammation in the bone and parenchymal foreign body reaction compared with the TachoComb group. CONCLUSION: In conclusion, our results suggest that TissuDura® may be considered more biocompatible than TachoComb® in duraplasty.

Three consecutive cases of fatal intraoperative intracardiac thrombosis associated with the initiation of venoarterial extracorporeal membrane oxygenation in the presence of aprotinin.

Central venoarterial extracorporeal membrane oxygenation has been used since the 1970s to support patients with cardiogenic shock following cardiac surgery. Despite this, in-hospital mortality is still high, and although rare, thrombus within the cardiac chambers or within the extracorporeal membrane oxygenation circuit is often fatal. Aprotinin is an antifibrinolytic available in Europe and Canada, though not currently in the United States. Due to historical safety concerns, use of aprotinin is generally limited and is commonly reserved for patients with the highest bleeding risk. Given the limited availability of aprotinin over the last decade, it is not surprising to find a complete absence of literature describing the use of venoarterial extracorporeal membrane oxygenation in the presence of aprotinin. We present three consecutive cases of rapid fatal intraoperative intracardiac thrombosis associated with post-cardiotomy central venoarterial extracorporeal membrane oxygenation in patients receiving aprotinin.

Safety of Perioperative Aprotinin Administration During Isolated Coronary Artery Bypass Graft Surgery: Insights From the ART (Arterial Revascularization Trial).

BACKGROUND: There is still uncertainty about the safety of aprotinin for coronary artery bypass graft surgery. The ART (Arterial Revascularization Trial) was designed to compare survival after bilateral versus single internal thoracic artery grafting. Many of the ART patients (≈30%) received perioperative aprotinin. We investigated the association between perioperative aprotinin administration and short-term (in-hospital) and long-term outcomes by performing a post hoc analysis of the ART. METHODS AND RESULTS: Among patients enrolled in the ART (n=3102) from 2004 to 2007, we excluded those who did not undergo surgery (n=18) and those with no information about use of perioperative aprotinin (n=9). Finally, 836 of 3076 patients (27%) received aprotinin. Propensity matching was used to select 536 pairs for final comparison. Aprotinin was also associated with an increased risk of hospital mortality (9 [1.7%] versus 1 [0.2%]; odds ratio, 9.12; 95% confidence interval [CI], 1.15-72.2; P=0.03), intra-aortic balloon pump insertion (37 [6.9%] versus 17 [3.2%]; odds ratio, 2.26; 95% CI, 1.26-4.07; P=0.006), and acute kidney injury (102 [19.0%] versus 76 [14.2%]; odds ratio, 1.42; 95% CI, 1.03-1.97; P=0.03). Aprotinin was not associated with a lower incidence of transfusion (37 [6.9%] versus 28 [5.2%]; odds ratio, 1.34; 95% CI, 0.81-2.23; P=0.25) and reexploration (26 [4.9%] versus 19 [3.5%]; hazard ratio, 1.39; 95% CI, 0.76-2.53; P=0.28). At 5 years, all-cause mortality was significantly increased in the aprotinin group (56 [10.6%] versus 38 [7.3%]; hazard ratio, 1.51; 95% CI, 1.0-2.28; P=0.045). CONCLUSIONS: In the present post hoc ART analysis, aprotinin was associated with a significantly increased risk of early and late mortality. CLINICAL TRIAL REGISTRATION: URL: http://www.isrctn.com. Unique identifier: ISRCTN46552265.

Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient.

In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues.

The safety and efficacy of antifibrinolytic therapy in neonatal cardiac surgery.

BACKGROUND: Neonates undergoing open-heart surgery are particularly at risk of postoperative bleeding requiring blood transfusion. Aprotinin has attained high efficacy in reducing the requirement for a blood transfusion following a cardiopulmonary bypass, but is seldom studied in the neonatal age group. The aim of this study was to compare the efficacy and adverse effects of aprotinin and tranexamic acid in neonates undergoing open-heart surgery at a single centre. METHODS: Between October 2003 and March 2008, perioperative data of 552 consecutive neonatal patients undergoing open-heart surgery in Children's Hospital Boston were reviewed. Among them, 177 did not receive antifibrinolytic therapy (Group A); 100 were treated with tranexamic acid only (Group B); and 275 patients received aprotinin with or without tranexamic acid (Group C). Except for antifibrinolytic therapy, the anaesthesiological and surgical protocols remained identical. Postoperative complications and in-hospital mortality were the primary study endpoints. RESULTS: Body weight and Risk Adjustment for Congenital Heart Surgery (RACHS-1) scores were statistically comparable among the three groups. No statistically significant differences were observed between the duration of hospitalization, chest tube drainage, reexploration for bleeding, and kidney function impairment. In Group C, less blood was transfused within 24 hours than in GroupB. Operative mortality was similar among the three groups. CONCLUSION: No further risk and kidney injury were observed in the use of aprotinin in neonatal cardiac surgery, aprotinin demonstrated a reduced requirement for blood transfusion compared with tranexamic acid. Our data provide reasonable evidence that aprotinin and tranexamic acid are safe and efficacious as antifibrinolytic modalities in neonatal patients undergoing cardiac surgery.

Efficacy of tranexamic acid as compared to aprotinin in open heart surgery in children.

BACKGROUND: Coagulopathy is a major issue in children undergoing high-risk pediatric cardiac surgery. Use of anti-fibrinolytics is well documented in adults, but recently there are questions raised about safety and effectiveness of their use on routine use. Tranexamic acid is a potent anti-fibrinolytic, but its role is not fully understood in children. This study aims to study the benefits tranexamic acid in controlling postoperative bleeding in pediatric cardiac surgical patients. METHODS AND RESULTS: Fifty consecutive children who underwent cardiac surgery were randomized prospectively to receive either aprotinin (Group A; n = 24) or tranexamic acid (Group B; n = 26) from September 2009 to February 2010 were studied. Primary end points were early mortality, postoperative drainage, reoperation for bleeding and complications. Mean age and body weight was smaller in Group A (Age: 48.55 vs. 64.73 months; weight 10.75 vs. 14.80 kg) respectively. Group A had more cyanotic heart disease than Group B (87.5% vs. 76.92%). Mean cardiopulmonary bypass time (144.33 vs. 84.34 min) and aortic cross-clamp time (78.5 vs. 41.46 min) were significantly higher in group A. While the blood and products usage was significantly higher in Group A, there was no difference in indexed postoperative drainage in first 4, 8 and 12 h and postoperative coagulation parameters. Mean C-reactive protein was less in Group A than B and renal dysfunction was seen more in Group A (25% vs. 7.6%). Mortality in Group A was 16.66% and 7.6% in Group B. CONCLUSION: Anti-fibrinolytics have a definitive role in high-risk children who undergo open-heart surgery. Tranexamic acid is as equally effective as aprotinin with no additional increase in morbidity or mortality.

The current place of aprotinin in the management of bleeding.

There is a considerable difference between the mechanism of action of the lysine analogues, tranexamic acid and epsilon-aminocaproic acid, and the serine protease inhibitor aprotinin. Aprotinin acts to inactivate free plasmin, but with little effect on bound plasmin, whereas the lysine analogues are designed to prevent excessive plasmin formation by fitting into plasminogen's lysine-binding site to prevent the binding of plasminogen to fibrin. Aprotinin is associated with a reduction in bleeding and transfusion requirements following major surgery, and has a dose-response profile, compared with no dose-response effect in the one study investigating tranexamic acid in cardiac surgical patients. Following its withdrawal in 2007, which is explained in detail in this review, the regulators have now licensed aprotinin for myocardial revascularisation only, which is relatively low-risk for bleeding.

The operating surgeon is an independent predictor of chest tube drainage following cardiac surgery.

OBJECTIVES: Bleeding into the chest is a major cause of blood transfusion and adverse outcomes following cardiac surgery. The authors investigated predictors of bleeding following cardiac surgery to identify potentially correctable factors. DESIGN: Data were retrieved from the medical records of patients undergoing cardiac surgery over the period of 2002 to 2008. Multivariate analysis was used to identify the independent predictors of chest tube drainage. SETTING: Tertiary hospital. PARTICIPANTS: Two thousand five hundred seventy-five patients. INTERVENTIONS: Cardiac surgery. RESULTS: The individual operating surgeon was independently associated with the extent of chest tube drainage. Other independent factors included internal mammary artery grafting, cardiopulmonary bypass time, urgency of surgery, tricuspid valve surgery, redo surgery, left ventricular impairment, male gender, lower body mass index and higher preoperative hemoglobin levels. Both a history of diabetes and administration of aprotinin were associated with reduced levels of chest tube drainage. CONCLUSIONS: The individual operating surgeon was an independent predictor of the extent of chest tube drainage. Attention to surgeon-specific factors offers the possibility of reduced bleeding, fewer transfusions, and improved patient outcomes.