Recombinant factor VIIa (Eptacog Alfa): a review of its use in congenital or acquired haemophilia and other congenital bleeding disorders

Recombinant factor VIIa (NovoSeven) [also known as recombinant activated factor VII or eptacog alfa] is a vitamin K-dependent glycoprotein that is structurally similar to human plasma-derived factor VIIa. It is a recombinant product, manufactured using DNA biotechnology. Intravenous recombinant factor VIIa has been evaluated in the treatment of bleeding episodes and for providing haemostasis cover during surgery in patients with certain bleeding disorders. Large, well controlled trials of recombinant factor VIIa have not been performed because of the rarity of these bleeding disorders. However, the efficacy of recombinant factor VIIa has been investigated in these patients in double-blind dose-finding or noncomparative clinical trials and worldwide compassionate-use programmes. Recombinant factor VIIa is effective and generally well tolerated in patients with haemophilia A or B with inhibitors, those with acquired haemophilia or Glanzmann's thrombasthenia. Also, recombinant factor VIIa is a treatment of choice in patients with haemophilia B with high-responding inhibitors and those with factor VII deficiency. Direct head-to-head comparisons and robust pharmacoeconomic data are required to fully determine the position of recombinant factor VIIa in relation to other therapies. Importantly though, the product appears to be relatively free of antigenicity, thrombogenicity and risk of viral transmission that, in the past, have limited the utility of blood products. Given that these characteristics are important determinants of the place of a treatment in bleeding disorders, recombinant factor VIIa provides a valuable treatment alternative in patients with haemophilia with inhibitors, platelet-refractory Glanzmann's thrombasthenia or congenital factor VII deficiency.     

Recombinant factor VIIa (eptacog alfa): a pharmacoeconomic review of its use in haemophilia in patients with inhibitors to clotting factors VIII or IX

Recombinant factor VIIa (NovoSeven; also known as recombinant activated factor VII or eptacog alfa) is indicated as an intravenous haemostatic agent in haemophilia patients with inhibitors to clotting factors VIII or IX. In noncomparative trials in haemophilia patients with inhibitors, on-demand home treatment with recombinant factor VIIa was effective in controlling episodes of mild to moderate bleeding and well tolerated, with early treatment being associated with a greater rate of success and the need for fewer doses than delayed treatment. Prophylactic treatment with recombinant factor VIIa was also effective in maintaining haemostasis in patients with this indication undergoing surgery. Relative to prior treatment with plasma-derived agents, treatment with recombinant factor VIIa was associated with improvements in health-related quality of life in a cost-utility study in haemophilia patients with inhibitors in Australia. In well designed decision-model cost analyses conducted from a healthcare payer perspective in several countries, on-demand treatment with recombinant factor VIIa to control mild to moderate bleeding episodes in this patient population was predicted to be cost saving or cost neutral relative to on-demand treatment with intravenous activated prothrombin complex concentrate (aPCC). Although the acquisition cost of recombinant factor VIIa was greater than that of aPCC in some studies, the greater initial efficacy of recombinant factor VIIa than aPCC resulted in lower predicted total medical costs. Results were generally robust to plausible changes in key parameters. Orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients undergoing or not undergoing surgery was predicted to decline over time, as savings were realised from the decrease in the number of bleeding episodes requiring treatment in patients who underwent surgery. In haemophilia patients with inhibitors, recombinant factor VIIa is clinically effective in controlling mild to moderate bleeds, and in maintaining haemostasis in patients undergoing orthopaedic surgery. Available pharmacoeconomic data from several countries, despite inherent limitations, support the use of recombinant factor VIIa as a treatment option that is at least cost neutral relative to aPCC in treating mild to moderate bleeds in this patient population. In addition, orthopaedic surgery with recombinant factor VIIa to maintain haemostasis in haemophilia patients with inhibitors is generally cost saving relative to not having surgery over the medium to long term, as the acquisition costs of recombinant factor VIIa are offset by cost savings resulting from the decrease in the number of joint-related bleeds.     

Role of aprotinin in the management of patients during and after cardiac surgery

Management of patients undergoing cardiac surgery has evolved in recent years as more is understood about the physiological changes and responses that occur during and after cardiopulmonary bypass (CPB). In particular, our understanding of the mechanisms involved in haemostasis and in the inflammatory response to bypass surgery, has allowed significant refinements in patient management. Improvements in the pharmacological conservation of blood loss have been striking, particularly with the development of the serine protease inhibitor, aprotinin (Trasylol, Bayer). Aprotinin represents a significant improvement, especially for patients at high risk, since it reduces the need for allogeneic and (sometimes scarce) blood products. However, in view of its cost, making an appropriate selection of patients most at risk of serious blood loss is a major consideration in the use of aprotinin. While its mechanisms of action are not well understood, the use of aprotinin also appears to reduce inflammatory response to CPB.     

Role of aprotinin in the management of patients during and after cardiac surgery

Management of patients undergoing cardiac surgery has evolved in recent years as more is understood about the physiological changes and responses that occur during and after cardiopulmonary bypass (CPB). In particular, our understanding of the mechanisms involved in haemostasis and in the inflammatory response to bypass surgery, has allowed significant refinements in patient management. Improvements in the pharmacological conservation of blood loss have been striking, particularly with the development of the serine protease inhibitor, aprotinin (Trasylol^®, Bayer). Aprotinin represents a significant improvement, especially for patients at high risk, since it reduces the need for allogeneic and (sometimes scarce) blood products. However, in view of its cost, making an appropriate selection of patients most at risk of serious blood loss is a major consideration in the use of aprotinin. While its mechanisms of action are not well understood, the use of aprotinin also appears to reduce inflammatory response to CPB.     

A benefit-risk review of systemic haemostatic agents: part 1: in major surgery

Systemic haemostatic agents play an important role in the management of blood loss during major surgery where significant blood loss is likely and their use has increased in recent times as a consequence of demand for blood products outstripping supply and the risks associated with transfusions. Their main application is as prophylaxis to reduce bleeding in major surgery, including cardiac and orthopaedic surgery and orthotopic liver transplantation. Aprotinin has been the predominant agent used in this setting; of the other antifibrinolytic agents that have been studied, tranexamic acid is the most effective and epsilon-aminocaproic acid may also have a role. Eptacog alfa (recombinant factor VIIa) has also shown promise. Tranexamic acid, epsilon-aminocaproic acid and eptacog alfa are generally well tolerated; however, when considering the methods to reduce or prevent blood loss intra- and postoperatively, the benefits of these agents need to be weighed against the risk of adverse events. Recently, concerns have been raised about the safety of aprotinin after an association between increased renal dysfunction and mortality was shown in retrospective observational studies and an increase in all-cause mortality with aprotinin relative to tranexamic acid or epsilon-aminocaproic acid was seen after a pre-planned periodic analysis of the large BART (Blood conservation using Antifibrinolytics in a Randomized Trial) study. The latter finding resulted in the trial being halted, and aprotinin has subsequently been withdrawn from the market pending detailed analysis of efficacy and safety results from the study. Part 1 of this benefit-risk review examines the efficacy and adverse effect profiles of systemic haemostatic agents commonly used in surgery, and provides individual benefit-risk profiles that may assist clinicians in selecting appropriate pharmacological therapy in this setting.     

Tranexamic acid: a review of its use in surgery and other indications.

Tranexamic acid is a synthetic derivative of the amino acid lysine that exerts its antifibrinolytic effect through the reversible blockade of lysine binding sites on plasminogen molecules. Intravenously administered tranexamic acid (most commonly 10 mg/kg followed by infusion of 1 mg/kg/hour) caused reductions relative to placebo of 29 to 54% in postoperative blood losses in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), with statistically significant reductions in transfusion requirements in some studies. Tranexamic acid had similar efficacy to aprotinin 2 x 10(6) kallikrein inhibitory units (KIU) and was superior to dipyridamole in the reduction of postoperative blood losses. Transfusion requirements were reduced significantly by 43% with tranexamic acid and by 60% with aprotinin in 1 study. Meta-analysis of 60 trials showed tranexamic acid and aprotinin, unlike epsilon-aminocaproic acid (EACA) and desmopressin, to reduce significantly the number of patients requiring allogeneic blood transfusions after cardiac surgery with CPB. Tranexamic acid was associated with reductions relative to placebo in mortality of 5 to 54% in patients with upper gastrointestinal bleeding. Meta-analysis indicated a reduction of 40%. Reductions of 34 to 57.9% versus placebo or control in mean menstrual blood loss occurred during tranexamic acid therapy in women with menorrhagia; the drug has also been used to good effect in placental bleeding, postpartum haemorrhage and conisation of the cervix. Tranexamic acid significantly reduced mean blood losses after oral surgery in patients with haemophilia and was effective as a mouthwash in dental patients receiving oral anticoagulants. Reductions in blood loss were also obtained with the use of the drug in patients undergoing orthotopic liver transplantation or transurethral prostatic surgery, and rates of rebleeding were reduced in patients with traumatic hyphaema. Clinical benefit has also been reported with tranexamic acid in patients with hereditary angioneurotic oedema. Tranexamic acid is well tolerated; nausea and diarrhoea are the most common adverse events. Increased risk of thrombosis with the drug has not been demonstrated in clinical trials. CONCLUSIONS: Tranexamic acid is useful in a wide range of haemorrhagic conditions. The drug reduces postoperative blood losses and transfusion requirements in a number of types of surgery, with potential cost and tolerability advantages over aprotinin, and appears to reduce rates of mortality and urgent surgery in patients with upper gastrointestinal haemorrhage. Tranexamic acid reduces menstrual blood loss and is a possible alternative to surgery in menorrhagia, and has been used successfully to control bleeding in pregnancy.     

Aprotinin: an update of its pharmacology and therapeutic use in open heart surgery and coronary artery bypass surgery

Cardiopulmonary bypass (CPB) is associated with defective haemostasis which results in bleeding and the requirement for allogenic blood product transfusions in many patients undergoing open heart surgery (OHS) and/or coronary artery bypass graft surgery (CABG) with CPB. Conservation of blood has become a priority during surgery because of shortages of donor blood, the risks associated with the use of allogenic blood products and the costs of these products. Aprotinin is a serine protease inhibitor isolated from bovine lung tissue which 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. It is used to reduce blood loss and transfusion requirements in patients with a risk of haemorrhage and has clear advantages over placebo or no treatment. High dose aprotinin significantly reduces postoperative blood loss compared with aminocaproic acid and desmopressin, and decreases transfusion requirements compared with desmopressin. Results are less consistent with tranexamic acid: high dose aprotinin either reduces blood loss significantly more than, or to an equivalent level to, tranexamic acid. A variety of other lower aprotinin dosage regimens consistently result in similar reductions in blood loss to aminocaproic acid or tranexamic acid. Data from clinical trials indicate that aprotinin is generally well tolerated, and the adverse events seen are those expected in patients undergoing OHS and/or CABG with CPB. Hypersensitivity reactions occur in <0.1 to 0.6% of patients receiving aprotinin for the first time. The results of original reports indicating that aprotinin therapy may increase myocardial infarction rates or mortality have not been supported by more recent studies specifically designed to investigate this outcome. However, a tendency to early vein graft occlusion with aprotinin has been shown and care with anticoagulation and vessel grafts is required. No comparative tolerability data between aprotinin and the lysine analogues, aminocaproic acid and tranexamic acid, are available. CONCLUSION: Comparative tolerability and cost-effectiveness data for aprotinin and the lysine analogues are required to more fully assess their individual roles in reducing blood loss and transfusion requirements in patients undergoing CPB during OHS and/or CABG. However, clinical evidence to date supports the use of aprotinin over its competitors in patients at high risk of haemorrhage, in those for whom transfusion is unavailable or in patients who refuse allogenic transfusions.     

Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin-releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high-dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.     

Safety of low-dose aprotinin in coronary artery bypass graft surgery: a single-centre investigation in 2,436 patients in Germany

BACKGROUND: The antifibrinolytic agent aprotinin is used to limit blood loss in cardiac surgery. In a recently performed multicentre observational study, the use of aprotinin was dose-dependently associated with a higher risk of renal failure and cardiovascular events. OBJECTIVE: Therefore, the aim of this study was to evaluate the impact of low-dose aprotinin (2 million kallikrein-inhibitor units) on safety variables in a large single-centre investigation in patients who underwent coronary artery bypass graft (CABG) surgery. METHODS: Clinical outcome variables such as renal failure, myocardial infarction, gastrointestinal failure, neurological complications and in-hospital mortality were assessed in 2,436 CABG surgery patients, whereof 1,162 patients received low-dose aprotinin perioperatively and 1,274 patients did not receive aprotinin. Statistical analysis was performed using multivariable logistic regression. RESULTS: In patients receiving aprotinin, the odds ratios of experiencing one of the aforementioned adverse events were not significantly different from the patients who did not receive aprotinin (p = 0.136-0.288). Moreover, the need for rethoracotomy did not differ between the two groups (p = 0.129). However, the use of low-dose aprotinin reduced the risk of peri- and postoperative use of packed red blood cells by 39% and was associated with a mean reduction in postoperative blood loss of 201 mL compared with patients who did not receive aprotinin (p < 0.001). Mean total blood loss in the aprotinin group and the control group was 875 mL (standard deviation [SD]: 757 mL) and 1,105 mL (SD: 867 mL), respectively (p < 0.001). In a sub-analysis in 2,049 patients undergoing their first cardiac surgery and undergoing CABG using the internal mammary artery, efficacy and safety data of aprotinin were similar to the results of the entire study cohort of 2,436 patients. CONCLUSIONS: Our data indicate that low-dose aprotinin efficiently reduces blood loss and does not adversely affect relevant safety variables in CABG surgery.     

Transfusion Medicine

There is still no alternative that is as effective or as well tolerated as blood; nevertheless, the search for ways to conserve, and even eliminate blood transfusion, continues. Based on hemoglobin levels, practice guidelines for the use of perioperative transfusion of red blood cells in patients undergoing coronary artery bypass grafting have been formulated by the National Institutes of Health and the American Society of Anesthesiologists. However, it has been argued that more physiologic indicators of adequacy of oxygen delivery should be used to assess the need for blood transfusion. Methods used for conserving blood during surgery include autologous blood donation, acute normovolemic hemodilution and intra- and postoperative blood recovery and reinfusion. The guidelines for the use of autologous blood transfusion are controversial and it does not appear to be cost effective compared with allogeneic blood transfusion in patients undergoing cardiac surgery. Similarly, the cost effectiveness of intra- and postoperative blood recovery and reinfusion need further evaluation. Treatment with recombinant human erythropoietin (rhEPO) remains unapproved in the US for patients undergoing cardiac or vascular surgery, but it is a valuable adjunct in Jehovah’s Witness patients, for whom blood is unacceptable. The characterization of darbepoetin alfa, a novel erythropoiesis stimulating protein with a 3-fold greater plasma elimination half-life compared with rhEPO, is an important advance in this field. Darbepoetin alfa appears to be effective in treating the anemia in patients with renal failure or cancer and trials in patients with surgical anemia are planned. Desmopressin has been used to effectively reduce intraoperative blood loss. Topical agents to prevent blood loss, such as fibrin glue and fibrin gel, and agents that alter platelet function, such as aspirin (acetylsalicylic acid) or dipyridamole, need further evaluation in patients undergoing cardiac surgery. Aprotinin has been shown to preserve hemostasis and reduce allogeneic blood exposure to a greater extent than the antifibrinolytic agents tranexamic acid and aminocaproic acid. Controlled clinical trials comparing the costs of these agents with clinical outcomes, along with tolerability profiles in patients at risk for substantial perioperative bleeding are needed.     

Pharmacodynamic, pharmacokinetic and clinical effects of clevidipine, an ultrashort-acting calcium antagonist for rapid blood pressure control

Clevidipine is an ultrashort-acting vasoselective calcium antagonist under development for short-term intravenous control of blood pressure. Studies in animals, healthy volunteers and patients have demonstrated the vascular selectivity and rapid onset and offset of antihypertensive action of clevidipine, a synthetic 1,4-dihydropyridine that inhibits L-type calcium channels. Clevidipine has a high clearance (0.05 L/min/kg) and is rapidly hydrolyzed to inactive metabolites by esterases in arterial blood. Its half-life in patients undergoing cardiac surgery is less than one min. Unlike sodium nitroprusside, a drug commonly used for the short-term control of blood pressure, which dilates both arterioles and veins, clevidipine reduces blood pressure through a selective effect on arterioles. As documented in animals and in cardiac surgical patients, clevidipine reduces peripheral resistance without any undesirable effect on cardiac filling pressure. It increases stroke volume and cardiac output. In anesthetized patients undergoing cardiac surgery clevidipine, unlike sodium nitroprusside, does not increase heart rate. In addition of having a favorable hemodynamic profile, suitable for rapid control of blood pressure, clevidipine protects against ischemia/reperfusion injuries, which are not uncommon during major surgery. In anesthetized pigs, clevidipine reduced infarct size after 45 min-long myocardial ischemia by 40%. In rats, renal function and splanchnic blood flow were better maintained when blood pressure was reduced with clevidipine than with sodium nitroprusside. Clevidipine was well tolerated in Phases I and II of clinical trials that included more than 300 individuals/patients. Since there are no known compounds with similar pharmacodynamic and pharmacokinetic properties in clinical development, it is anticipated that clevidipine, a compound tailored to the needs of anesthesiologists, has the potential to become a drug of choice for controlling blood pressure during surgical procedures.     

Review article: the role of pharmaco-therapy for acute variceal haemorrhage in the era of endoscopic haemostasis

In the last decade, endoscopic haemostasis, including injection sclerotherapy and variceal ligation has become the standard method for the treatment of variceal haemorrhage. While the use of vasopressin has been hampered by severe side effects, the development of new vasoactive agents such as terlipressin, somatostatin and octreotide has opened new indications for these pharmacological therapies. These agents are effective, safe and easy to use. They could be recommended as stop-gap treatment before endoscopy can be arranged. They can also be used as adjunct therapy for endoscopic haemostasis in acute variceal haemorrhage.     

Oxygen therapeutics: oxygen delivery without blood

Nearly 14 million units of packed red blood cells are transfused in the United States each year. According to the U.S. Department of Health and Human Services, in 1999, 6% of hospitals reported a shortage of blood, resulting in the cancellation or postponement of surgical procedures. The many limitations and risks of transfusions of packed red blood cells in critically ill patients have facilitated interest in developing alternative agents for oxygen delivery. Over the past few decades, safe and effective substitutes have been in development. However, no currently approved agent provides both oxygen transport and volume in place of packed red blood cells. Oxygen therapeutic products have several advantages compared with packed red blood cells, including a prolonged shelf-life, lack of a cross-matching requirement, and minimal infectious risks or concerns about immunogenicity. Hemoglobin-based oxygen carriers and perfluorocarbons are being developed. Two products are undergoing clinical trials. Polyheme is undergoing a phase III study in trauma patients, and Hemopure is being evaluated in a phase II study in patients undergoing cardiopulmonary bypass surgery. A third product (Hemolink) was being evaluated in a phase III study in patients undergoing coronary artery bypass grafting surgery; however, the trial was suspended. In addition, several other hemoglobin-based oxygen carriers are in the preclinical stages. Oxygen therapeutics have several potential clinical applications in the management of perioperative blood loss, trauma, acute normovolemic hemodilution, traumatic brain injury, and blood requirements in patients who refuse or have contraindications to transfusions of red blood cells.     

Benefits and risks of aprotinin use during cardiac surgery

Aprotinin is a serine protease inhibitor with antithrombotic, antifibrinolytic, and antiinflammatory effects. It is effective in reducing bleeding and the need for blood transfusions after cardiac surgery with cardiopulmonary bypass. Additional benefits, such as cerebral protection, are hypothesized but not yet thoroughly substantiated. The safety of aprotinin has been questioned based on a phase IV analysis of large data sets, including patients undergoing cardiac surgery. Potential risks including increased occurrences of stroke, myocardial infarction, renal failure, and death are implied by these analyses; however, adequate study group matching is lacking from these nonrandomized, retrospective studies. In October 2007, a large randomized controlled trial comparing antifibrinolytics in patients undergoing cardiac surgery was stopped after a preliminary analysis suggested a trend toward an increase in all-cause 30-day mortality associated with aprotinin. Subsequently, the manufacturer of aprotinin temporarily suspended marketing and halted all shipment of aprotinin on a worldwide basis. Pending a complete analysis of this study, the use of aprotinin could be considered as one component of a blood conservation strategy. After contemplating the benefits and risks of this controversial drug, clinicians should reserve its use for patients at high risk for postoperative blood loss.     

Recent advances in treatment strategies for atopic dermatitis

A wide range of different therapeutic regimens are used for atopic dermatitis. Although many treatment modalities are well established worldwide among clinicians, only the minority of these therapy recommendations are based on results of randomised controlled trials (RCTs). To close the gap between such 'generally' recommended therapies and therapies that are based on data from controlled trials, this review focuses not only on the pharmacological and clinical aspects of the currently proven agents, but also on the advantages and disadvantages of therapies that have not yet been completely tested.A review of the available literature concerning the pharmacological profile and also the level of evidence of therapeutic efficacy of all currently known topical and systemic agents for the treatment of atopic dermatitis reveals a large gap between the knowledge concerning the pharmacological action in vitro and the evidence of clinical efficacy in many cases.We agree with the conclusion of previous reviews that numerous therapies for atopic dermatitis urgently require more independent RCTs and especially comparative trials (e.g. corticosteroids vs calcineurin inhibitors). These are required in order to facilitate the choice of therapeutic strategy for the individual treatment of atopic dermatitis, with its broad spectrum of clinical manifestations and potential complications in adult patients and, particularly, in children.Finally, we also review preclinical trials with several new drugs. Immunomodulators appear to promise a new dimension for the future of therapy for atopic dermatitis, especially for severe and otherwise refractory forms or as alternatives to corticosteroids, that is, to treat facial atopic eczema without the risk of adverse effects.     

Tranexamic acid: a review of its use in the treatment of hyperfibrinolysis

Tranexamic acid, a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent that acts by binding to plasminogen and blocking the interaction of plasmin(ogen) with fibrin, thereby preventing dissolution of the fibrin clot. Tranexamic acid (Transamin?) is indicated in Japan for use in certain conditions with abnormal bleeding or bleeding tendencies in which local or systemic hyperfibrinolysis is considered to be involved. This article reviews the efficacy and tolerability of tranexamic acid in conditions amenable to antifibrinolytic therapy and briefly overviews the pharmacological properties of the drug. In large, randomized controlled trials, tranexamic acid generally significantly reduced perioperative blood loss compared with placebo in a variety of surgical procedures, including cardiac surgery with or without cardiopulmonary bypass, total hip and knee replacement and prostatectomy. In many instances, tranexamic acid also reduced transfusion requirements associated with surgery. It also reduced blood loss in gynaecological bleeding disorders, such as heavy menstrual bleeding, postpartum haemorrhage and bleeding irregularities caused by contraceptive implants. Tranexamic acid significantly reduced all-cause mortality and death due to bleeding in trauma patients with significant bleeding, particularly when administered early after injury. It was also effective in traumatic hyphaema, gastrointestinal bleeding and hereditary angioneurotic oedema. While it reduces rebleeding in subarachnoid haemorrhage, it may increase ischaemic complications. Pharmacoeconomic analyses predicted that tranexamic acid use in surgery and trauma would be very cost effective and potentially life saving. In direct comparisons with other marketed agents, tranexamic acid was at least as effective as ε-aminocaproic acid and more effective than desmopressin in surgical procedures. It was more effective than desmopressin, etamsylate, flurbiprofen, mefenamic acid and norethisterone, but less effective than the levonorgestrel-releasing intra-uterine device in heavy menstrual bleeding and was as effective as prednisolone in traumatic hyphaema. Tranexamic acid was generally well tolerated. Most adverse events in clinical trials were of mild or moderate severity; severe or serious events were rare. Therefore, while high-quality published evidence is limited for some approved indications, tranexamic acid is an effective and well tolerated antifibrinolytic agent.     

Drugs targeting functional bowel disorders: lessons from drug trials

Recent insights in the field of functional gastrointestinal disorders have opened the way for novel pharmacological treatments directed at the central nervous system or peripheral targets. Now, universally accepted guidelines on therapeutic trial design and in the conduct and reporting of results of large clinical trials in these functional disorders are required. Several lessons have been learned from recent clinical and pharmacological trials of novel agents in irritable bowel syndrome and diabetic dyspepsia. Approaches that carefully characterize the pharmacokinetics, mechanism of action and pharmacodynamics of a drug, and that select subgroups of patients after a thorough understanding of the drug's effects, should facilitate and enhance the likelihood of accurate assessment of potential therapies.     

Fibrin sealant (evicel® [quixil®/crosseal™]): a review of its use as supportive treatment for haemostasis in surgery

Evicel? is a fibrin sealant consisting of two components, human clottable protein (predominantly human fibrinogen) and human thrombin. It is indicated as supportive treatment in patients undergoing surgery when control of bleeding by standard surgical techniques is ineffective or impractical. Evicel? is a new formulation of the previously available fibrin sealant Quixil? (in the EU) or Crosseal? (in the US). Evicel? differs from Quixil?/Crosseal? in that its fibrinogen component does not contain the antifibrinolytic agent tranexamic acid, which is potentially neurotoxic, resulting in Quixil?/Crosseal? being contraindicated for use in neurosurgery. The removal of tranexamic acid did not affect the haemostatic efficacy or longevity of Evicel? fibrin clots and allowed the sealant to be granted an expanded indication. Evicel? and Quixil?/Crosseal? are easy to use and, since they do not contain synthetic or bovine aprotinin, have a reduced potential for hypersensitivity reactions. This article reviews the pharmacological properties, clinical efficacy and tolerability of Evicel? and its previous formulation as supportive treatment for haemostasis in surgery. In clinical studies, Evicel? and Quixil?/Crosseal? were generally well tolerated and effective haemostatic agents for adjunctive use in various types of surgeries when conventional methods were impractical or ineffective in controlling bleeding. Two pivotal, randomized studies showed that Evicel? was significantly more effective than manual compression in patients undergoing vascular surgery, and significantly more effective than Surgicel? in patients undergoing retroperitoneal or intra-abdominal surgery, as assessed by the proportion of patients achieving haemostasis. In another similarly designed pivotal study in patients undergoing liver resection, Crosseal? was significantly more effective than standard haemostatic agents (e.g. Surgicel?), as assessed by the mean time to haemostasis. The incidences of treatment-emergent adverse events in these studies were generally similar between the Evicel? or Crosseal? groups and the comparator groups. Quixil? was also generally well tolerated and an effective haemostatic agent in endonasal surgeries, and tonsillectomies and/or adenoidectomies, with some benefit of treatment with Evicel? or Quixil? also observed in orthopaedic surgeries. Although additional comparative studies with other haemostatic agents would help to definitively position Evicel? with respect to these agents, current evidence suggests that Evicel? is useful in surgeries for improving haemostasis where standard surgical techniques are insufficient.     

Pharmacological approaches to regenerative strategies for the treatment of cardiovascular diseases

Cardiovascular diseases are a group of multifactorial and complex debilitating diseases facing limitations in classical pharmacology. Instead of drug-targeting the consequences, the origin of the disease (i.e. cardiomyocytes degeneration) represents a better although challenging target. Indeed, the human heart is not or poorly able to regenerate. The loss of cardiomyocytes, occurring in many ischemic or genetic cardiac diseases, replaced by fibroblasts leads to a lower response of the myocardium to the contractile demand. Following a transient compensatory hypertrophic phase, and despite the intervention of pharmacological agents to limit the contractile demand, including beta-adrenoceptors blockers or inhibitors of the conversion enzyme, the contractile force developed reaches a limitation dropping the myocardium into a failing stage. Thus, myocardial regeneration has been envisioned using 'pharmacological' agents, genes, or stem cells. For the past decade, both gene therapy and more recently cell therapy have been tested in clinical trials to relieve some aspects of heart weakness or to compensate myocardial degeneration. Protein-based and miRNA-based regenerative therapies are also emerging from experimental animal studies. This review brings an update on the most recent research strategies to regenerate the diseased myocardium. The remaining challenges of gene-based, cell-based, or protein-based therapies to relieve heart failure are discussed.     

Clinical and Experimental Experience with Factor Xa Inhibitors

Cardiovascular disease is the major cause of mortality in the industrial world today. We are constantly moving towards new and better ways of fighting this epidemic. Advances have been made in various fields such as patient education, imaging techniques, interventional cardiology, and novel therapeutic agents. In particular, antithrombotics are being studied with great interest and hope. Amid this class of agents, factor Xa inhibitors have already begun to show promising results in trials involving patients with acute coronary syndromes. Whereas DX-9065a is in late stage clinical trials, fondaparinux sodium is available for clinical use. Promising results have been obtained with fondaparinux sodium in patients with coronary artery disease in the PENTUA (Pentasaccharide in Unstable Angina) and PENTALYSE (Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction) trials. Besides having a direct effect on the coagulation cascade, they have shown properties that indirectly influence the remodeling of plaques in the coronary circulation. Available evidence on factor Xa inhibitors does not ensure a remedy to acute coronary syndromes but it gives hope of improving current treatments and reducing the morbidity and mortality of cardiovascular disease.The efficacy and tolerability of fondaparinux sodium in the prevention and treatment of deep vein thrombosis (with or without pulmonary embolism) has been established in several large trials such as PENTATHLON (Pentasaccharide in Total Hip Replacement Surgery), PENTAMAKS (Pentasaccharide in Major Knee Surgery), EPHESUS (European Pentasaccharide Hip Elective Surgery), PENTHIFRA (Pentasaccharide in Hip-Fracture Surgery), and PENTHIFRA-Plus. Whereas fondaparinux sodium offers benefits over low molecular weight heparins and unfractionated heparin, the incidence of bleeding complications was greater with fondaparinux sodium than with unfractionated heparin. Treatment with factor VIIa can reverse the anticoagulant effect of fondaparinux sodium and this may be particularly important in patients who need to undergo emergency surgical procedures. Fondaparinux sodium has been recently approved for use, in conjunction with warfarin, in patients with symptomatic deep vein thrombosis or acute pulmonary embolism based on the results of two large trials conducted by the Matisse investigators. In conclusion, these observations strongly suggest the clinical potential of this class of agents in preventing arterial and venous thrombosis.