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In this clinical trial involving patients undergoing high-risk cardiac surgery, aprotinin was somewhat more effective than either aminocaproic acid or tranexamic acid in reducing massive perioperative bleeding but at the expense of a higher rate of death, mainly from cardiac causes. Aprotinin cannot be recommended to control blood loss in this clinical setting. In patients undergoing high-risk cardiac surgery, aprotinin was somewhat more effective than either aminocaproic acid or tranexamic acid in reducing massive perioperative bleeding but at the expense of a higher rate of death, mainly from cardiac causes. Every year an estimated 1 million to 1.25 million patients worldwide undergo cardiac surgery, including high-risk procedures such as repeat coronary-artery bypass grafting (CABG), valve replacements, and combined procedures. 1 High-risk procedures present an increased risk of death, massive bleeding, renal failure, and thrombotic complications, as compared with first-time isolated CABG. 2 – 4 Three antifibrinolytic agents have been used in cardiac surgery to minimize bleeding and reduce the need for transfusion: aprotinin, a naturally occurring serine protease inhibitor, and two lysine analogues, tranexamic acid and aminocaproic acid. 5 In clinical trials, all three drugs have been shown to be effective in reducing the . . .

Background The peak of the global COVID-19 pandemic has not yet been reached, and many countries face the prospect of a second wave of infections before effective vaccinations will be available. After an initial phase of viral replication, some patients develop a second illness phase in which the host thrombotic and inflammatory responses seem to drive complications. Severe COVID-19 disease is linked to high mortality, hyperinflammation, and a remarkably high incidence of thrombotic events. We hypothesize a crucial pathophysiological role for the contact pathway of coagulation and the kallikrein-bradykinin pathway. Therefore, drugs that modulate this excessive thromboinflammatory response should be investigated in severe COVID-19. Methods In this adaptive, open-label multicenter randomized clinical trial, we compare low molecular weight heparins at 50 IU anti-Xa/kg twice daily—or 75 IU anti-Xa twice daily for intensive care (ICU) patients—in combination with aprotinin to standard thromboprophylaxis in hospitalized COVID-19 patients. In the case of hyperinflammation, the interleukin-1 receptor antagonist anakinra will be added on top of the drugs in the interventional arm. In a pilot phase, the effect of the intervention on thrombotic markers (D-dimer) will be assessed. In the full trial, the primary outcome is defined as the effect of the interventional drugs on clinical status as defined by the WHO ordinal scale for clinical improvement. Discussion In this trial, we target the thromboinflammatory response at multiple levels. We intensify the dose of low molecular weight heparins to reduce thrombotic complications. Aprotinin is a potent kallikrein pathway inhibitor that reduces fibrinolysis, activation of the contact pathway of coagulation, and local inflammatory response. Additionally, aprotinin has shown in vitro inhibitory effects on SARS-CoV-2 cellular entry. Because the excessive thromboinflammatory response is one of the most adverse prognostic factors in COVID-19, we will add anakinra, a recombinant interleukin-1 receptor antagonist, to the regimen in case of severely increased inflammatory parameters. This way, we hope to modulate the systemic response to SARS-CoV-2 and avoid disease progressions with a potentially fatal outcome. Trial registration The EU Clinical Trials Register 2020-001739-28 . Registered on April 10, 2020.

BackgroundThis study aimed to demonstrate the noninferior efficacy of TachoSil vs. TachoComb in Japanese patients undergoing liver resection and to assess the safety of TachoSil vs. TachoComb in these patients.MethodsThis randomized, double-blind, noninferiority study (JapicCTI-090684) involved participants scheduled for liver resection/living donors (age ≥ 20 years). TachoSil or TachoComb (1:1 allocation ratio) was applied to control persistent exudative bleeding after primary hemostasis during liver resection/removal for donation. The primary outcome was hemostasis 5 min after study treatment application. The 95% confidence interval (CI) for the difference in the proportion of participants with hemostasis 5 min after application of TachoSil/TachoComb was determined; noninferiority of TachoSil was indicated if the lower limit of the CI was ≥−14%. Adverse events (AEs) were recorded.ResultsAll participants in the efficacy analysis (TachoSil: 54/54, 100%; TachoComb: 54/54, 100%) achieved hemostasis 5 min after study treatment application. Therefore, TachoSil was noninferior to TachoComb. All participants experienced ≥1 AE; however, none discontinued because of an AE. Most (≥97.8%) AEs were mild or moderate in severity.ConclusionsThese findings confirm the safety profile and noninferior hemostatic efficacy of TachoSil compared with TachoComb.

PurposeThis randomized, controlled, single-blinded multicenter study evaluated the efficacy of latest-generation fibrin sealant containing synthetic aprotinin as fibrinolysis inhibitor as supportive treatment for hemostasis after elective partial hepatectomy.MethodsAdult subjects undergoing resection of at least one liver segment were assigned to treatment with fibrin sealant or manual compression with a surgical gauze swab if persistent oozing necessitated additional hemostatic measures after primary control of arterial and venous bleeding. The primary outcome measure was the proportion of subjects with intraoperative hemostasis at 4 min after start of randomized treatment application. Secondary efficacy outcome measures included intraoperative hemostasis at 6, 8, and 10 min, intra- and postoperative rebleedings, transfusion requirements, and drainage volume.ResultsSeventy subjects were randomized. Hemostasis at 4 min was achieved in 29/35 (82.9 %) fibrin sealant subjects compared with 13/35 (37.1 %) control subjects (p < 0.001). Significantly more fibrin sealant subjects achieved hemostasis at 6 (p < 0.001), 8 (p = 0.028), and 10 min (p = 0.017). The number of rebleedings was low in both study arms. Transfusion requirements and 48-h drainage volumes were similar between the study arms. No adverse events related to study treatment were reported.ConclusionsFibrin sealant was shown to be safe and superior to manual compression in the control of parenchymal bleeding after hepatic resection. The use of synthetic aprotinin as fibrinolysis inhibitor further improves the safety margin of fibrin sealant by eliminating the risk of transmission of bovine spongiform encephalopathy and other bovine pathogens.

Background: Achilles tendinopathy is a common condition, which can become chronic and interfere with athletic performance. The proteinase inhibitor aprotinin (as injection) has been found to improve recovery in patellar tendinopathy1 (evidence level 1b2) and Achilles tendinopathy.3 Internationally this therapy is being used based on this limited knowledge base. Aim: To evaluate whether aprotinin injections decrease time to recovery in Achilles tendinopathy. Method: A prospective, randomised, double blind, placebo controlled trial was performed comparing saline (0.9%) plus local anaesthetic injections and eccentric exercises with aprotinin (30 000 kIU) plus local anaesthetic injection and eccentric exercise. Three injections were given, each a week apart. In total, 26 patients, with 33 affected tendons, were enrolled for this study. Results: At no follow up point (2, 4, 12, or 52 weeks) was there any statistically significant difference between the treatment group and placebo. This included VISA-A scores4 and secondary outcome measures. However, a trend for improvement over placebo was noted. Conclusion: In this study on Achilles tendinopathy, aprotinin was not shown to offer any statistically significant benefit over placebo. Larger multicentre trials are needed to evaluate the efficacy of aprotinin in Achilles tendinopathy.

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. Ultramini Abstract: Coagulopathy has been a major issue in pediatric cardiac surgery, and anti-fibrinolytics have been used fairly regularly in various settings. This study aims to evaluate the efficacy of tranexamic acid as compared against that of aprotinin in a randomized model. Tranexamic acid proves to be equally effective with less toxicity with no added mortality.

Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery. Randomized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987, and systematic reviews were conducted in 1992 and 1997. Methods A systematic search was conducted for all RCTs of aprotinin that used placebo controls or were open-label with no active control treatment. Data collected included the primary outcome, objective of each study, whether a systematic review was cited or conducted as part of the background and/or rationale for the study and the number of previously published RCTs cited. Cumulative meta-analyses were performed. Results Sixty-four randomized, controlled trials of aprotinin were found, conducted between 1987 and 2002, reporting an endpoint of perioperative transfusion. Median trial size was 64 subjects, with a range of 20 to 1784. A cumulative meta-analysis indicated that aprotinin greatly decreased the need for perioperative transfusion, stabilizing at an odds ratio of 0.25 (p, 10 2 6) by the 12th study, published in June of 1992. The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups. Citation of previous RCTs was extremely low, with a median of 20% of prior trials cited. Only 7 of 44 (15%) of subsequent reports referenced the largest trial (N 1/4 1784), which was 28 times larger than the median trial size. Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research, resulting in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered. Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate searches for prior evidence and conducting systematic reviews.

Background: This study evaluated the safety and hemostatic effectiveness of a tranexamic acid- and aprotinin-free fibrin sealant versus an absorbable hemostat in soft tissue during elective retroperitoneal or intra-abdominal surgery. Materials and Methods: This randomized, active-controlled, multicenter study enrolled patients who were undergoing elective retroperitoneal or intra-abdominal surgery and required adjunctive hemostatic measures at the target bleeding site (TBS). Patients were randomized (time = 0 minutes) to receive fibrin sealant or absorbable hemostat. The primary endpoint was the absence of bleeding at the TBS at 10 minutes. Secondary endpoints included the absence of bleeding at 4 and 7 minutes and the incidence of treatment failure (bleeding at 10 minutes or brisk bleeding requiring additional hemostatic measures), and the incidence of complications potentially related to bleeding. Adverse events were assessed. Results: Patients (N = 124) were randomized to receive fibrin sealant (n = 62) or absorbable hemostat (n = 62). A higher percentage of patients who received fibrin sealant versus absorbable hemostat achieved hemostasis within 10 minutes (95.2% vs 82.3%; 95% CI, 1.02-1.35) and also at 4 (74.2% vs 54.8%; 95% CI, 1.04-1.80) and 7 (90.3% vs 77.4%; 95% CI, 1.00-1.39) minutes. A lower incidence of treatment failure was observed for patients receiving fibrin sealant. Similar incidences of adverse events and complications potentially related to bleeding were observed. Conclusions: This tranexamic acid- and aprotinin-free fibrin sealant is safe and effective for achieving hemostasis in soft tissue during elective retroperitoneal or intra-abdominal surgery.

Objective Inflammation has been shown to trigger microvascular thrombosis. Patients undergoing cardiac surgery sustain significant inflammatory insults to the lungs and in addition are routinely given anti-fibrinolytic agents to promote thrombosis. In view of these risk factors we investigated if evidence of pulmonary microvascular thrombosis occurs following cardiac surgery and, if so, whether a pre-operative heparin infusion may limit this. Design Double-blind randomised controlled trial. Setting Tertiary university affiliated hospital. Patients Twenty patients undergoing elective cardiac surgery. Interventions Patients were randomised to receive a pre-operative heparin infusion or placebo. All patients were administered aprotinin. Measurements and results Pulmonary microvascular obstruction was estimated by measuring the alveolar dead-space fraction. Pulmonary coagulation activation was estimated by measuring the ratio of prothrombin fragment levels in radial and pulmonary arterial blood. Systemic tissue plasminogen activator (t-PA) levels were also assessed. In the placebo group cardiac surgery triggered increased alveolar dead-space fraction levels and the onset of prothrombin fragment production in the pulmonary circulation. Administration of pre-operative heparin was associated with a lower alveolar dead-space fraction ( p  < 0.05) and reduced prothrombin fragment production in the pulmonary circulation ( p  < 0.05). Pre-operative heparin also increased baseline t-PA levels ( p  < 0.05). Conclusion The changes in the alveolar dead-space fraction and pulmonary coagulation activation suggest that pulmonary microvascular thrombosis develops during cardiac surgery and this may be limited by a pre-operative heparin infusion.

Aprotinin (APR) was discovered in 1930. APR is an effective pan-protease inhibitor, a typical “magic shotgun”. Until 2007, APR was widely used as an antithrombotic and anti-inflammatory drug in cardiac and noncardiac surgeries for reduction of bleeding and thus limiting the need for blood transfusion. The ability of APR to inhibit proteolytic activation of some viruses leads to its use as an antiviral drug for the prevention and treatment of acute respiratory virus infections. However, due to incompetent interpretation of several clinical trials followed by incredible controversy in the literature, the usage of APR was nearly stopped for a decade worldwide. In 2015–2020, after re-analysis of these clinical trials’ data the restrictions in APR usage were lifted worldwide. This review discusses antiviral mechanisms of APR action and summarizes current knowledge and prospective regarding the use of APR treatment for diseases caused by RNA-containing viruses, including influenza and SARS-CoV-2 viruses, or as a part of combination antiviral treatment.