[Goal-directed hemodynamic therapy: Concepts, indications and risks]. / Zielorientierte Volumen- und Kreislauftherapie : Konzepte, Indikationen und Risiken.

Goal-directed hemodynamic therapy is becoming increasingly more interesting for anesthesiologists and intensive care physicians. Meta-analyses of studies evaluating perioperative therapy algorithms demonstrated a reduction of postoperative morbidity compared to the previous clinical practices. In this review article the basic concepts of goal-directed hemodynamic therapy and the principles of previously employed therapy algorithms are described and discussed. Furthermore, the questions of how these therapy strategies can be transferred into daily clinical practice and whether these therapeutic approaches might even bear risks for patients are elucidated.

[New direct oral anticoagulants : Many advantages, but open questions]. / Neue orale direkte Antikoagulanzien : Viele Vorteile, aber offene Fragen.

In the past few years, the clinical field of anticoagulation has undergone dramatic changes due to the introduction of the new class of direct oral anticoagulants. All these agents share common features such as stable oral bioavailability, short half-life compared to vitamin K antagonists, paucity of drug-drug interactions, and fixed dosing without laboratory monitoring. However, the new agents differ regarding metabolism pathways, impact on routine clotting tests, availability of test systems for plasma concentration, and-of utmost clinical importance-dose regimens, clinical evidence, and approved indications.The present review outlines pharmacologic properties, clinical indications, different dose regimens, and preliminary clinical experience from their use in daily practice. Each of the four topics will be complemented by a compilation and in-depth discussion of open questions and lessons still to learn. The well-documented benefits of the direct oral anticoagulants as documented in clinical trials will translate to routine clinical practice only if all the rules regarding dosing and indications are obeyed, and if the experience with these agents is captured and communicated in a controlled manner.

Impact of sex on the efficacy and safety of panitumumab plus fluorouracil and folinic acid versus fluorouracil and folinic acid alone as maintenance therapy in RAS WT metastatic colorectal cancer (mCRC). Subgroup analysis of the PanaMa-study (AIO-KRK-0212).

BACKGROUND: Clinical trials in metastatic colorectal cancer (mCRC) are usually conducted irrespective of sex. Sex-associated differences relating to safety and efficacy in the treatment of mCRC, however, are gaining interest. METHODS: PanaMa investigated the efficacy of panitumumab (Pmab) plus fluorouracil and folinic acid (FU/FA) versus FU/FA alone after induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab in patients with RAS wild-type mCRC. In this post hoc analysis, the study population was stratified for sex. Evaluated efficacy endpoints during maintenance treatment were progression-free survival (PFS, primary endpoint of the trial), overall survival (OS) and objective response rate during maintenance therapy. Safety endpoints were rates of any grade and grade 3/4 adverse events during maintenance therapy. RESULTS: In total, 165 male and 83 female patients were randomized and treated. Male and female patients showed numerically better objective response rates with Pmab, without reaching statistical significance. Male patients derived a significant benefit from the addition of Pmab to maintenance treatment with regard to PFS [hazard ratio (HR) 0.63; 95% confidence interval (CI) 0.45-0.88; P = 0.006] that was not observed in female patients (HR 0.85; 95% CI 0.53-1.35; P = 0.491). The better PFS for male patients treated with Pmab did not translate into improved OS (HR 0.85; 95% CI 0.55-1.30; P = 0.452). Female patients showed numerically improved OS when treated with Pmab. There was no difference in the total of grade ≥3 adverse events during maintenance regarding sex (P = 0.791). Female patients, however, had a higher rate of any grade nausea, diarrhea and stomatitis. CONCLUSIONS: In the PanaMa trial, the addition of Pmab to maintenance treatment of RAS wild-type mCRC with FU/FA improved the outcome in terms of the primary endpoint (PFS) particularly in male patients. Female patients did not show the same benefit while experiencing higher rates of adverse events. Our results support the development of sex-specific protocols.

Recommendations for the diagnosis and management of vaccine-induced immune thrombotic thrombocytopenia.

There have recently been safety concerns regarding an increased risk of vaccine-induced immune thrombotic thrombocytopenia (VITT) following administration of SARS-CoV-2 adenoviral vector vaccines. The Southern African Society of Thrombosis and Haemostasis reviewed the emerging literature on this idiosyncratic complication. A draft document was produced and revised by consensus agreement by a panel of professionals from various specialties. The recommendations were adjudicated by independent international experts to avoid local bias. We present concise, practical guidelines for the clinical management of VITT.

[New oral anticoagulants from the perspective of trauma surgery]. / Neue orale Antikoagulanzien aus unfallchirurgischer Sicht.

Heparins and vitamin K antagonists have been the cornerstones of anticoagulation therapy for several decades. While these compounds have proven to be effective at inhibiting the coagulation process, they have inherent limitations. This has spurred efforts to develop therapies that will overcome these drawbacks while matching the efficacy of the conventional anticoagulants. Significant advances have been made in the development of more specific treatments targeting factor Xa or thrombin and providing more predictable anticoagulant responses. They also offer the convenience of oral administration with fixed dose regimens not requiring routine monitoring which may have an impact on compliance. The factor Xa inhibitor rivaroxaban and the thrombin inhibitor dabigatran etexilate have become available for prevention of venous thromboembolism after elective hip and knee replacement surgery and registration of the factor Xa inhibitor apixaban is expected to occur soon. Furthermore, first clinical evidence has become available for all of these compounds in patients requiring long-term anticoagulation. It is to be expected that these results will lead to improvements in prevention of stroke in patients with atrial fibrillation and in treatment of venous thromboembolism.

[Bridging, interruption and switching of anticoagulants in trauma surgery]. / Überbrückung, Pausieren und Wechsel von Antikoagulanzien in der Unfallchirurgie.

Patients under long-term administration of vitamin K antagonists may require temporary interruption of anticoagulation therapy for invasive procedures or trauma surgery. Due to the long half-life of these substances bridging therapy with anticoagulants having a shorter half-life may become necessary. In this situation the risk of bleeding due to the intervention and the risk of thromboembolism due the underlying disease must be assessed. Low molecular weight heparins (LMWHs) are considered to be the medication of choice for bridging anticoagulation, mainly due to practical reasons and as they do not require coagulation monitoring and dose adjustment out of hospital treatment is feasible. Low molecular weight heparins are not authorized for the indication of bridging anticoagulation, however, on the basis of recent studies on large patient cohorts, the evidence of efficacy and safety is significantly better for LMWHs than for unfractionated heparin. New oral anticoagulants will soon become available for stroke prevention in patients with atrial fibrillation and for treatment of venous thromboembolism. Due to the shorter half-lives these compounds will no longer require bridging anticoagulation. However, the trauma surgeon should be familiar with the dosing regimens for different indications in order to adequately decide about the preoperative cessation and the perioperative pause of these anticoagulants.

[Thromboembolism prophylaxis in trauma surgery: S3 guidelines and significance of the amendment for trauma surgeons]. / Thromboembolieprophylaxe in der Unfallchirurgie: S3-Leitlinie und Bedeutung des Amendments für den Unfallchirurgen.

Prevention of venous thromboembolism has become an integral component of trauma surgery treatment and consists of physical and pharmacological measures. The indications and choice of prophylaxis modalities depend on the patient's individual risk profile which is determined by the combination of exposing and predisposing risk factors. The exposing risk is characterized by the type and extent of surgery or trauma, whereas the predisposing risk relates to patient inherent risk factors. This has also been considered in the compilation of the guidelines. This review summarizes the recommendations of the German S3 guidelines relating to trauma surgery and also discusses the amendment referring to the registration of the new oral anticoagulants rivaroxaban and dabigatran etexilate. The availability of these new compounds increases the spectrum of prophylaxis modalities thereby creating a need for new information in trauma surgery.

[Prophylaxis for thromboembolism in internal medicine and family practice]. / Thromboembolieprophylaxe in der Inneren Medizin und der hausärztlichen Versorgung.

Although up to 80% of fatal pulmonary emboli occur in nonsurgical patients, conclusive studies on the prevention of thrombosis have only become available in the last 10 years. Bedridden inpatients with acute medical diseases require pharmacologic prophylaxis for thrombosis with unfractionated or low molecular weight heparin or with fondaparinux. This also holds true for patients with underlying malignancies or those suffering from acute ischemic stroke or paretic leg. The challenges to thrombosis prophylaxis are posed by ensuring that uninterrupted prophylaxis is continued after hospital discharge in cases of persisting risk, determining the indications and applying thrombosis prophylaxis on an outpatient basis as well as the multimorbidity and often advanced age of the internal medicine patients. The last factor not only entails an elevated risk of thromboembolism but also an increased risk of hemorrhage, especially in patients with renal insufficiency or platelet inhibitors. Product-specific recommendations and restrictions on pharmacologic prophylaxis need to be considered. Thromboprophylaxis as applied in internal medicine and family practice represents an effective measure to prevent symptomatic and fatal thromboembolisms, but due to multimorbidity and polytherapy of medical patients it requires careful monitoring.

Difference in triptan effect in patients with migraine and early allodynia.

The aim of this study was to determine whether in migraine patients with and without aura early treatment with various triptans leads to differences in pain reduction after 1 h and in modulating cutaneous allodynia. Thirty-six patients with early manifestation of a clinically recognizable allodynia of the face and non-responders to earlier treatment with sumatriptan 100 mg were included. Patients were randomized to six triptan treatment groups. Significant pain reduction was seen only in the group receiving zolmitriptan nasal spray 5 mg with a mean visual analogue scale (VAS) score of 3.8 (s.d. 1.2) at baseline and 2.4 (s.d. 1.3; P = 0.015) at 1 h after using the triptan and was thus a predictor of a VAS score 3 within 1 h. The study results indicate that migraine headache intensity can be reduced within 1 h by using zolmitriptan 5 mg nasal spray in spite of the presence of early cutaneous allodynia.

A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement.

BACKGROUND: LY517717 is an oral direct inhibitor of activated factor X that is currently under clinical development. OBJECTIVES: The aims of this proof-of-concept study in patients undergoing total knee replacement (TKR) or total hip replacement (THR) were to determine whether LY517717 can safely reduce the risk of venous thromboembolism (VTE) and to identify at least one dose of LY517717 that is non-inferior to enoxaparin. METHODS: In a double-blind, parallel-arm, dose-ranging study, patients undergoing TKR or THR were randomly allocated to receive once-daily oral LY517717 (25, 50, 75, 100, 125 or 150 mg), started 6-8 h after wound closure, or s.c. enoxaparin, 40 mg, started in the evening before surgery. The primary efficacy endpoint was the composite of deep venous thrombosis (DVT), detected by mandatory bilateral venography performed at the end of the study treatment (between days 5 and 9), and objectively confirmed symptomatic DVT and/or pulmonary embolism (PE), occurring during the treatment period. The combination of major and minor bleeding was the primary safety endpoint. RESULTS: Five hundred and seven patients received at least one dose of LY517717 or enoxaparin (safety population). Three hundred and ninety-one patients had evaluable bilateral venography or experienced a clinical DVT and/or PE (primary efficacy population). LY517717 treatment resulted in a dose-dependent decrease in the incidence of thromboembolic events (P = 0.0001). The incidences of VTE with 100, 125, and 150 mg of LY517717 were 19%, 19% and 16%, respectively, compared to 21% with enoxaparin. The efficacies of 100-mg, 125-mg and 150-mg doses of LY517717 were non-inferior to that of enoxaparin according to prespecified criteria. Bleeding events were uncommon in both LY517717 and enoxaparin patients. CONCLUSIONS: Doses of 100, 125 and 150 mg of LY517717 are non-inferior to enoxaparin for the prevention of VTE after TKR or THR, and are associated with similar low rates of bleeding.

Compliance with recommended prophylaxis for venous thromboembolism: improving the use and rate of uptake of clinical practice guidelines.

Although several authoritative, evidence-based, guidelines for the prevention of venous thromboembolism (VTE) have been published, the use of VTE prophylaxis in routine clinical practice varies markedly. Even in orthopedic surgery, the indication for which prophylaxis is used most often, a significant proportion of surgeons do not use routine prophylaxis. When prophylaxis is used, guideline recommendations are often not followed. A number of factors may contribute to the under-use of guidelines. Physician-related factors include: a lack of awareness of, or familiarity with, the guidelines; a perception that VTE is not a significant problem or that VTE prophylaxis is ineffective; and concern about potential bleeding risks. The guidelines may also be perceived to be too complicated or difficult to apply in a routine manner. In addition, a lack of facilities or resources may also present a barrier to implementation of the guidelines. A number of strategies are being investigated in an attempt to improve compliance with guidelines for VTE prophylaxis. For example, the Investigators Against Thromboembolism (INATE) initiative has developed a simplified pocket guideline on VTE prophylaxis in orthopedic and trauma surgery in order to raise awareness of the current guideline recommendations.

Limitations of established antithrombotic strategies.

The incidence of venous thromboembolism has declined in recent years, probably due to the successful use of prophylactic strategies. However, pulmonary embolism remains the most common preventable cause of hospital death in industrialized countries. A number of clinical studies have shown that when used appropriately current antithrombotic therapies, such as unfractionated heparin, oral anticoagulants and low-molecular-weight heparins, are effective in preventing thromboembolic events in the majority of patients. However, surveillance data indicate that in certain high-risk clinical settings a significant proportion of patients still develop deep vein thrombosis despite use of the most effective prophylaxis methods currently available. Currently available antithrombotic therapies are also associated with a risk of treatment-specific adverse effects and various practical limitations which restrict their clinical benefit and influence cost-effectiveness. Risk of bleeding, heparin-induced thrombocytopenia, and drug interactions are the most important safety concerns. The need for inconvenient and costly dose adjustment and laboratory monitoring, intravenous or subcutaneous administration, and restrictions on methods of anaesthesia are key practical drawbacks. This paper reviews clinical and practical aspects of existing therapeutic options and develops a profile for the ideal thromboprophylactic agent. The direction of current research into the development of improved prophylactic modalities designed to overcome existing limitations is briefly discussed.

A comparison of four root canal filling techniques.

This study compared the apical seal produced by four obturation techniques. Sixty-four extracted human teeth were prepared and obturated using lateral condensation of gutta-percha that was either unmodified or was dipped in chloroform, eucalyptol, or eucapercha paste. After storage in normal saline and 0.02% azide solution at 37 degrees C for 200 days, the teeth were immersed in India ink for 48 h. The most coronal extent of leakage of India ink into the canal was then determined. Significantly more apical leakage occurred in the eucapercha group than in the other three groups. All other comparisons were equivalent. The results suggest that modification of the gutta-percha master cone with solvent does not improve the apical seal in vitro. If modification is desired, then dipping the master cone in either eucalyptol or chloroform produces an apical seal superior to that achieved with eucapercha.

The significance of calf thrombi after total knee arthroplasty.

We reviewed the records of 1257 patients having 1625 total knee arthroplasties; all had pre-operative and postoperative perfusion lung scans and postoperative venograms which were classified as showing no thrombi, calf thrombi or proximal thrombi. Patients with calf thrombi were found to have a significantly greater risk for both symptomatic and asymptomatic pulmonary embolism compared with patients with no venographic thrombi. There were positive lung scans in 6.9% of patients with calf thrombi compared with 2.0% of patients with negative venograms (p < 0.001). Symptomatic pulmonary embolism occurred in 1.6% of patients with calf thrombi compared with 0.2% of patients with negative venograms (p = 0.034). The risk of pulmonary embolism was not significantly different between patients with treated proximal thrombi, and those with calf thrombi. Patients who develop deep-vein thrombosis despite prophylaxis are at increased risk for pulmonary embolism; these patients should receive treatment, or undergo follow-up studies to detect proximal propagation.

[Home treatment for deep vein thrombosis: pros and cons]. / Ambulante Thrombosebehandlung: Pro und Kontra.

There is sound evidence, that low molecular weight heparin (LMWH) administered subcutaneously is at least as effective and safe as an i.v. infusion of unfractionated heparin. Thus, with LMWH out-patient treatment of deep vein thrombosis (DVT) becomes feasible. According to the current guidelines, an objective diagnosis of DVT is required before the anticoagulation with heparin is initiated. Close monitoring is also required during the subsequent initiation of treatment with vitamin K antagonist. Contraindications and comorbid conditions need to be identified and may necessitate hospital treatment. A checklist may assist in the decision for or against out-patient treatment, but an individual assessment for the individual patient is always a requisite.