Use of topical tranexamic acid or aminocaproic acid to prevent bleeding after major surgical procedures.

OBJECTIVE: To evaluate the literature describing topical use of tranexamic acid or aminocaproic acid for prevention of postoperative bleeding after major surgical procedures. DATA SOURCES: Literature was retrieved through MEDLINE (1946-September 2011) and International Pharmaceutical Abstracts (1970-September 2011) using the terms tranexamic acid, aminocaproic acid, antifibrinolytic, topical, and surgical. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All identified articles in English were evaluated. Clinical trials, case reports, and meta-analyses describing topical use of tranexamic acid or aminocaproic acid to prevent postoperative bleeding were included. DATA SYNTHESIS: A total of 16 publications in the setting of major surgical procedures were included; the majority of data were for tranexamic acid. For cardiac surgery, 4 trials used solutions containing tranexamic acid (1-2.5 g in 100-250 mL of 0.9% NaCl), and 1 trial assessed a solution containing aminocaproic acid (24 g in 250 mL of 0.9% NaCl). These solutions were poured into the chest cavity before sternotomy closure. For orthopedic procedures, all of the data were for topical irrigation solutions containing tranexamic acid (500 mg-3 g in 50-100 mL of 0.9% NaCl) or for intraarticular injections of tranexamic acid (250 mg to 2 g in 20-50 mL of 0.9% sodium chloride, with or without carbazochrome sodium sulfate). Overall, use of topical tranexamic acid or aminocaproic acid reduced postoperative blood loss; however, few studies reported a significant reduction in the number of packed red blood cell transfusions or units given, intensive care unit stay, or length of hospitalization. CONCLUSIONS: Topical application of tranexamic acid and aminocaproic acid to decrease postsurgical bleeding after major surgical procedures is a promising strategy. Further data are needed regarding the safety of this hemostatic approach.

A comparison of aprotinin and lysine analogues in high-risk cardiac surgery.

BACKGROUND: Antifibrinolytic agents are commonly used during cardiac surgery to minimize bleeding and to reduce exposure to blood products. We sought to determine whether aprotinin was superior to either tranexamic acid or aminocaproic acid in decreasing massive postoperative bleeding and other clinically important consequences. METHODS: In this multicenter, blinded trial, we randomly assigned 2331 high-risk cardiac surgical patients to one of three groups: 781 received aprotinin, 770 received tranexamic acid, and 780 received aminocaproic acid. The primary outcome was massive postoperative bleeding. Secondary outcomes included death from any cause at 30 days. RESULTS: The trial was terminated early because of a higher rate of death in patients receiving aprotinin. A total of 74 patients (9.5%) in the aprotinin group had massive bleeding, as compared with 93 (12.1%) in the tranexamic acid group and 94 (12.1%) in the aminocaproic acid group (relative risk in the aprotinin group for both comparisons, 0.79; 95% confidence interval [CI], 0.59 to 1.05). At 30 days, the rate of death from any cause was 6.0% in the aprotinin group, as compared with 3.9% in the tranexamic acid group (relative risk, 1.55; 95% CI, 0.99 to 2.42) and 4.0% in the aminocaproic acid group (relative risk, 1.52; 95% CI, 0.98 to 2.36). The relative risk of death in the aprotinin group, as compared with that in both groups receiving lysine analogues, was 1.53 (95% CI, 1.06 to 2.22). CONCLUSIONS: Despite the possibility of a modest reduction in the risk of massive bleeding, the strong and consistent negative mortality trend associated with aprotinin, as compared with the lysine analogues, precludes its use in high-risk cardiac surgery. (Current Controlled Trials number, ISRCTN15166455 [controlled-trials.com].).

The effect of aprotinin on outcome after coronary-artery bypass grafting.

BACKGROUND: Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center. METHODS: We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels. RESULTS: A total of 1343 patients (13.2%) received aprotinin, 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001) but not with a greater risk-adjusted incidence of dialysis (P=0.56). CONCLUSIONS: Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

[Aprotinin in cardiac surgery: more risks than usefulness?]. / Aprotinin in der Kardiochirurgie: Mehr Risiko als Nutzen?

Antifibrinolytic therapy with the serine protease inhibitor Aprotinin or the lysine analogues epsilon-aminocapronic acid or tranexamic acid is a therapeutic measure to reduce perioperative blood loss during cardiac surgery. In an international, prospective, non-randomised phase 4 observation study, Mangano et al. investigated the effectiveness and side-effects of Aprotinin, epsilon-aminocapronic acid and tranexamic acid in comparison to no antifibrinolytic therapy in a total of 4,374 patients who underwent cardiac surgery with extracorporeal circulation. In the opinion of Mangano et al. the results of this study question the safety and effectiveness of Aprotinin for reduction of perioperative blood loss by cardiac surgery patients. Despite a critical review of the study and results reported by Mangano et al., the authors of the present paper come to the conclusion that, in view of the availability of more reasonably priced alternatives in Germany, it appears to be sensible to give preference to tranexamic acid instead of aprotinin.

The risk associated with aprotinin in cardiac surgery.

BACKGROUND: The majority of patients undergoing surgical treatment for ST-elevation myocardial infarction receive antifibrinolytic therapy to limit blood loss. This approach appears counterintuitive to the accepted medical treatment of the same condition--namely, fibrinolysis to limit thrombosis. Despite this concern, no independent, large-scale safety assessment has been undertaken. METHODS: In this observational study involving 4374 patients undergoing revascularization, we prospectively assessed three agents (aprotinin [1295 patients], aminocaproic acid [883], and tranexamic acid [822]) as compared with no agent (1374 patients) with regard to serious outcomes by propensity and multivariable methods. (Although aprotinin is a serine protease inhibitor, here we use the term antifibrinolytic therapy to include all three agents.) RESULTS: In propensity-adjusted, multivariable logistic regression (C-index, 0.72), use of aprotinin was associated with a doubling in the risk of renal failure requiring dialysis among patients undergoing complex coronary-artery surgery (odds ratio, 2.59; 95 percent confidence interval, 1.36 to 4.95) or primary surgery (odds ratio, 2.34; 95 percent confidence interval, 1.27 to 4.31). Similarly, use of aprotinin in the latter group was associated with a 55 percent increase in the risk of myocardial infarction or heart failure (P<0.001) and a 181 percent increase in the risk of stroke or encephalopathy (P=0.001). Neither aminocaproic acid nor tranexamic acid was associated with an increased risk of renal, cardiac, or cerebral events. Adjustment according to propensity score for the use of any one of the three agents as compared with no agent yielded nearly identical findings. All the agents reduced blood loss. CONCLUSIONS: The association between aprotinin and serious end-organ damage indicates that continued use is not prudent. In contrast, the less expensive generic medications aminocaproic acid and tranexamic acid are safe alternatives.

Predictors of pericardial effusion after orthotopic heart transplantation.

OBJECTIVES: Pericardial effusion occurs frequently after orthotopic heart transplantation, but the causes of this complication have not been well described. This study was designed to identify factors predisposing toward the development of significant postoperative pericardial effusions in a large, single-institution population of orthotopic heart transplant recipients. METHODS: A retrospective review of more than 90 preoperative, intraoperative, and postoperative variables was conducted for 241 patients undergoing orthotopic heart transplantation from September 1988 to December 1999. Patients who had significant postoperative pericardial effusions develop were identified from postoperative echocardiograms by standard criteria. Factors associated with the development of significant pericardial effusions were determined by multivariate logistic regression analysis. RESULTS: Echocardiographic data were available for 203 of 241 transplant recipients. Forty-two patients (21%) had significant effusions develop. According to multivariate analysis, pericardial effusions were less likely to occur in recipients with a history of previous cardiac surgery (odds ratio 0.13, 95% confidence interval 0.05-0.36, P <.0001) and with greater weight (odds ratio 0.96, 95% confidence interval 0.94-0.99, P <.0048). Pericardial effusions were more likely to occur in patients who had received aminocaproic acid during the operation (odds ratio 5.92, 95% confidence interval 2.23-15.72, P <.0008). Patient survival and hospital length of stay did not differ between patients with and without postoperative pericardial effusions. CONCLUSIONS: Postoperative pericardial effusions develop in approximately 20% of patients undergoing orthotopic cardiac transplantation. On the basis of the risk factors identified in this study, prevention may prove difficult, although avoidance of the intraoperative use of aminocaproic acid may be helpful.

Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints.

BACKGROUND: Excessive bleeding may complicate cardiac surgery, and is associated with increased morbidity and mortality. Pharmacological strategies to decrease perioperative bleeding have been investigated in a large number of controlled trials, most of which have shown a decrease in blood loss. However, most studies lacked sufficient power to detect a beneficial effect on clinically more relevant outcomes. We did a meta-analysis of all randomised, controlled trials of the three most frequently used pharmacological strategies to decrease perioperative blood loss (aprotinin, lysine analogues [aminocaproic acid and tranexamic acid], and desmopressin). METHODS: Studies were included if they reported at least one clinically relevant outcome (mortality, rethoracotomy, proportion of patients receiving a transfusion, or perioperative myocardial infarction) in addition to perioperative blood loss. In addition, a separate meta-analysis was done for studies concerning complicated cardiac surgery. FINDINGS: We identified 72 trials (8409 patients) that met the inclusion criteria. Treatment with aprotinin decreased mortality almost two-fold (odds ratio 0.55 [95% CI 0.34-0.90]) compared with placebo. Treatment with aprotinin and with lysine analogues decreased the frequency of surgical re-exploration (0.37 [0.25-0.55], and 0.44 [0.22-0.90], respectively). These two treatments also significantly decreased the proportion of patients receiving any allogeneic blood transfusion. By contrast, the use of desmopressin resulted in a small decrease in perioperative blood loss, but was not associated with a beneficial effect on other clinical outcomes. Aprotinin and lysine analogues did not increase the risk of perioperative myocardial infarction; however, desmopressin was associated with a 2.4-fold increase in the risk of this complication. Studies in patients undergoing complicated cardiac surgery showed similar results. INTERPRETATION: Pharmacological strategies that decrease perioperative blood loss in cardiac surgery, in particular aprotinin and lysine analogues, also decrease mortality, the need for rethoracotomy, and the proportion of patients receiving a blood transfusion.

Fibrel.

Fibrel is a useful product for the treatment of depressed cutaneous scars, facial lines, and wrinkles. There have been documented increases in collagen production and inflammatory response over time. Adverse reactions seem to be minimal. If a more user-friendly product can be used--no plasma, minimal inflammatory response, 30-gauge needle--Fibrel should be considered in all patients for soft tissue augmentation.

Injectable soft tissue substitutes.

Historical and modern advances in the development of an injectable soft tissue substitute are reviewed. Nonbiologic alloplastic and biologic injectables are described. The authors' experiences, as well as those of others, employing presently available materials in terms of specific indications and special techniques are delineated. The search for a safe, effective, easy-to-use, and long-lasting soft tissue substitute continues.

Vigabatrin (gamma-vinyl-GABA): neuropathologic evaluation in five patients.

We performed neuropathologic examination of cerebral cortex specimens from 4 patients who underwent epilepsy surgery and the brain of 1 patient who died suddenly. All had severe epilepsy and had received gamma-vinyl-GABA (GVG, vigabatrin) for 3-5.5 years. Neither the surgically resected temporal lobe specimens nor the frontal and temporal lobes autopsy specimens showed abnormal white matter vacuolation.

Absence of cortical white matter changes in three patients undergoing long-term vigabatrin therapy.

Chronic administration of the experimental antiepileptic drug vigabatrin (gamma-vinyl GABA) to animals has been shown to cause dose-dependent neuropathological changes characterized by a microvacuolation in specific white matter tracts. This finding has led to some concern as to whether similar pathologic changes might occur in patients taking this medication. Here we report on analysis of tissue specimens taken during neurosurgery from three patients undergoing chronic vigabatrin therapy (4 g/day). The first patient, a 34-year-old woman, had taken vigabatrin for 2 years prior to surgery, the second, a 50-year-old man, had taken the drug for 1 year, and a 34-year-old man had taken the drug for 5.3 years. For comparison, similar specimens were taken from three other patients not taking vigabatrin who were undergoing surgery for intractable epilepsy. Specimens from each subject were prepared in an identical manner and examined with light and electron microscopy. All specimens were examined in a blinded fashion. There was some minor nonspecific myelinic splitting seen in both controls and vigabatrin-treated patients but there was no evidence for any drug-induced lesions similar to that seen in experimental animals.

Vigabatrin in drug-resistant partial epilepsy: a 5-year follow-up study.

We treated 75 patients with drug-resistant complex partial seizures and secondarily generalized seizures with vigabatrin as additional therapy for 6 months. Twenty-one patients either showed no benefit from vigabatrin treatment or had side effects. The remaining 54 patients entered into the long-term study. The median monthly seizure frequency decreased from 12.5 at baseline to 3.3 at the 3-month visit, and was 3.9 after 5 years of therapy in 28 patients who continued using the drug after the 5-year period. During 5 years of therapy with vigabatrin, 26 patients have withdrawn from the study because of various reasons: loss of efficacy (14), suspected side effects (5), noncompliance (3), administrative reasons (2), pregnancy (1), and epilepsy surgery (1). In all, 19 patients had a greater than 50% seizure frequency reduction at 5 years, representing 35% of the 54 patients who entered the long-term study, or 25% of the 75 patients who were initially recruited into the efficacy study.

A 5-year safety and efficacy evaluation with fibrel in the correction of cutaneous scars following one or two treatments.

In a multicenter clinical trial 300 patients were treated with Fibrel, 4 weeks following a negative skin test, for the correction of cutaneous scars. Fibrel treatment was restricted to one or two implants in a maximum of four scars. The scar corrections were evaluated by the physician, the patient, and also via an objective photogrammetric method. At the end of 1 year the percentage of scars with moderate, marked, or complete correction were 65, 63.3, and 85.8% according to physician, patient, and photogrammetric evaluations, respectively. A cohort of 111 patients were followed for up to 2 years and 87 patients were followed up to 5 years postimplantation. The physician and patient evaluations showed 55.1 and 50.6%, respectively, of the scars in the moderate, marked, or complete correction category at the end of 5 years with only one or two treatments. Safety evaluations included tests for antinuclear antibodies, rheumatoid factor, and presence of antibodies to Fibrel and their crossreactivity to human collagen I and III. These tests did not show any causal relationship to Fibrel treatments and the patients did not have any untoward immunologic symptoms. The data from these patients demonstrate that one or two Fibrel treatments are effective in maintaining greater than 50% correction of depressed cutaneous scars up to 5 years with negligible adverse sequelae and no untoward immunologic symptoms.

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Aminocaproic acid (AMICAR) in advanced colorectal carcinoma.

We treated 20 patients with measurable histologically confirmed colorectal adenocarcinoma with aminocaproic acid (AMICAR). There were 11 males and 9 females with a median age of 63 years. All 20 patients had received prior chemotherapy. The majority of monitoring lesions were distributed between lung and liver. We evaluated 12 patients in this series for response. Three patients had stable disease and nine patients had progressive disease. All patients were evaluable for toxic effects, the most common being nausea and vomiting. AMICAR given orally at 210 mg/kg of actual body weight/day is not an effective single agent in the treatment of metastatic colorectal carcinoma. In view of previously published animal data the role of AMICAR in the adjuvant setting for colorectal carcinoma still needs to be determined.

Epsilon amino caproic acid myopathy: additional features.

In a patient with a proximal myopathy due to Epsilon Amino Caproic Acid (EACA) bedrest led to marked improvement even before withdrawal of the drug. A biopsy showed a selective necrosis of type I fibers. Plasma level of EACA was low and plasma level of lysine was normal. A 99mTechnetium-MDP showed marked uptake in the affected muscles, whereas a 67Gallium scan was negative.

Why may epsilon-aminocaproic acid (EACA) induce myopathy in man? Report of a case and literature review.

A case of necrotizing myopathy due to a short epsilon-aminocaproic acid (EACA) treatment in a 72 year-old patient with subarachnoid haemorrhage (SAH) is described. Pathogenetic hypotheses are discussed.

Epsilon-aminocaproic acid-induced myopathy. A case report.

The prolonged administration of epsilon-aminocaproic acid (EACA) resulted in the development of severe proximal myopathy associated with high plasma creatine kinase values, rhabdomyolysis, myoglobinuria, and mild hyperbilirubinaemia. Withdrawal of the drug led to spontaneous resolution of the clinical and biochemical syndrome. Structural and enzyme studies of a biopsy specimen of the involved skeletal muscle supported the presence of subclinical myopathy. The mechanism whereby EACA produces its toxicity in muscle may in part be due to inhibition of cathepsin D, but the possibility that other proteases are involved has not been excluded. The fact that this clinical syndrome is rare despite the widespread use of EACA may be because it only occurs in subjects with a subclinical skeletal muscle disorder which is unmasked by the drug.

Myopathy induced by epsilon-aminocaproic acid. Case report.

The authors present a case of proximal myopathy secondary to epsilon-aminocaproic acid (EACA) administration. This well recognized entity does not occur immediately after institution of therapy, but follows a delay of several days and a cumulative dose. Its consequences include a spectrum of symptoms from myalgias to severe myopathy with rhabdomyolysis, myoglobinuria, and acute tubular necrosis. A presenting symptom of calf pain in a patient receiving EACA should not automatically imply deep vein thrombosis. Serial creatine phosphokinase measurements are essential in monitoring a patient undergoing EACA therapy, especially after 2 weeks of treatment and a total dose of greater than 500 gm.