凝血因子Xa直接抑制剂的研究现状及应用

抗凝药物在血栓性疾病的预防和治疗中具有重要地位。抗凝治疗是防治静脉血栓栓塞症（VTE）、心房颤动（AF）和急性冠状动脉综合征（ACS）的重点,由于传统药物的局限性,凝血因子Xa抑制剂成为了研究的热点药物并逐步走向临床。本文对凝血因子Xa直接抑制剂的研究现状进行回顾,并对其临床应用及临床试验研究结果进行综述。     

Breakthroughs in anticoagulation: advent of the oral direct factor Xa inhibitors

The oral direct factor Xa inhibitors include rivaroxaban and apixaban that recently have been evaluated comprehensively in multiple randomized clinical trials. Based on the efficacy and safety data from these trials, these novel anticoagulants are disseminating throughout clinical practice for thromboprophylaxis in major lower-extremity joint replacement, acute medical illness, atrial fibrillation, and acute coronary syndromes. The advantages of the xabans over vitamin K antagonists include no requirement for routine anticoagulation monitoring as well as a fast and reliable onset of action. The first perioperative limitation of the xabans is the lack of a routine coagulation test for monitoring their anticoagulant effect in scenarios, such as the timing of surgical procedures, the reversal of xaban-related bleeding, and the conduct of regional anesthesia. A second perioperative limitation is the lack of fully validated clinical reversal agents although prothrombin complex concentrate, recombinant factor VIIa, and factor X concentrate are options for xaban reversal in life-threatening bleeding scenarios. Given their clinical efficacy and advantages, further xabans are in clinical development, with edoxaban already in phase III clinical trials. Although the xabans have ushered in a new paradigm for clinical anticoagulation, further clinical trials are indicated to refine their clinical indications even further, such as anticoagulation for patients with mechanical heart valves.     

Advances in anticoagulation: focus on dabigatran, an oral direct thrombin inhibitor

Dabigatran is an oral direct thrombin inhibitor with a rapid onset. Patients on dabigatran do not require coagulation monitoring. Recent prospective randomized trials have shown the efficacy of dabigatran for the prevention of venous thromboembolism after knee or hip arthroplasty and for the prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. Because dabigatran is cleared principally by the kidneys, dosage adjustments are required in the setting of renal dysfunction. There currently is no reversal agent for dabigatran although hemodialysis can facilitate its rapid removal in life-threatening circumstances. The management of severe bleeding associated with dabigatran also may include the administration of a procoagulant, such as recombinant activated factor VII. Based on recent guidelines, regional anesthesia should be used cautiously in patients taking this novel oral thrombin inhibitor.     

Wound problems following hip arthroplasty before and after the introduction of a direct thrombin inhibitor for thromboprophylaxis

In the United Kingdom, national guidelines have stated that patients undergoing elective hip surgery are at increased risk for venous thromboembolic events (VTE) following surgery and have recommended thromboprophylaxis for 28-35 days (1, 2). Studies of direct thrombin inhibitors have hitherto concentrated on major bleeding. We prospectively assessed wound discharge in patients who underwent hip arthroplasty and who received oral dabigatran postoperatively between March 2010 and April 2010 (n=56). We compared these results to a retrospective matched group of patients who underwent similar operations six months earlier, at which time all patients were given subcutaneous dalteparin routinely postoperatively until discharge, and then discharged home on 150 mg aspirin daily for 6 weeks (n=67). Wound discharge after 5 days was significantly higher in the patients taking dabigatran (32% dabigatran n=18, 10% dalteparin n=17, p=0.003) and our rate of delayed discharges due to wound discharge significantly increased from 7% in the dalteparin group (n=5) to 27% for dabigatran (n=15, p=0.004). Patients who received dabigatran were more than five times as likely to return to theatre with a wound complication compared with those who received dalteparin (7% dabigatran n=4, vs. 1% dalteparin n=1), but this was not statistically significant (p=0.18). We now administer dalteparin until the wound is dry and then start dabigatran. Our study demonstrates the need for further clinical studies regarding wound discharge and direct thrombin inhibitors.     

Surgery and invasive procedures in patients on long-term treatment with oral direct thrombin or factor Xa inhibitors

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24 h before surgery, restart 24 h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1–2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.     

Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration,dose stratification,and antifactor Xa activity

BackgroundMorbidly obese patients undergoing gastric bypass surgery are at risk for postoperative venous thromboembolism. Evidence-based recommendations regarding the dosing and duration of thromboprophylaxis are lacking for morbidly obese surgical patients. The aims of this study were to evaluate the safety and efficacy of an extended duration, body mass index (BMI)–stratified enoxaparin thromboprophylaxis regimen in patients undergoing Roux-en-Y gastric bypass and to determine the resultant antifactor Xa (AFXa) activity in morbidly obese surgical patients.MethodsIn this prospective open trial, 223 patients (75% female, mean BMI 50.4 kg/m²) undergoing Roux-en-Y gastric bypass were assigned to receive enoxaparin 40 mg (BMI ≤50 kg/m², n = 124) or 60 mg (BMI >50 kg/m², n = 99) every 12 hours during hospitalization and once daily for 10 days after discharge. The AFXa levels were monitored serially, and dose adjustments were made for results outside the target prophylactic range (.2–.4 IU/mL ± 10%) after the third dose. The safety and efficacy outcomes were major bleeding and venous thromboembolism.ResultsRoux-en-Y gastric bypass was performed laparoscopically in 208 subjects (93%). The duration of surgery averaged 99.5 ± 31 minutes, and the median length of hospitalization was 3 days. Target prophylactic AFXa concentration was achieved by 74% of patients after the third enoxaparin dose; none reached the full anticoagulation concentration. One patient developed nonfatal venous thromboembolism (.45%). Four patients required transfusion (1.79%). Bleeding was not associated with a high AFXa concentration.ConclusionThis BMI-stratified, extended enoxaparin dosing regimen provided well-tolerated, effective prophylaxis against venous thromboembolism in patients undergoing gastric bypass surgery.     

Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations

The oral direct thrombin inhibitor ximelagatran shows great promise for prevention of venous thromboembolic events following major elective orthopaedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In orthopaedic surgery clinical trials, ximelagatran was effective and well tolerated compared with standard therapy, with dose and timing relative to surgery important factors in determining its optimal profile. In European trials, an initial 3-mg postoperative dose of subcutaneous melagatran, the active form of ximelagatran, followed by oral ximelagatran 24 mg twice daily achieved similar efficacy and safety to enoxaparin. Although the risk of spinal haematoma following neuraxial anaesthesia is rare, it is increased by the concomitant use of anticoagulants. In orthopaedic surgery trials with ximelagatran to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of ximelagatran suggests that concurrent use with neuraxial anaesthesia should require no further precautions than those currently necessary with low-molecular-weight heparin.     

Ponseti casting: a new soft option

We have modified the Ponseti casting technique by using a below-knee Softcast instead of an above-knee plaster of Paris cast. Treatment was initiated as soon as possible after birth and the Pirani score was recorded at each visit. Following the manipulation techniques of Ponseti, a below-knee Softcast was applied directly over a stockinette for a snug fit and particular attention was paid to creating a deep groove above the heel to prevent slippage. If necessary, a percutaneous Achilles tenotomy was performed and casting continued until the child was fitted with Denis Browne abduction boots. Between April 2003 and May 2007 we treated 51 consecutive babies with 80 idiopathic club feet with a mean age at presentation of 4.5 weeks (4 days to 62 weeks). The initial mean Pirani score was 5.5 (3 to 6). It took a mean of 8.5 weeks (4 to 53) of weekly manipulation and casting to reach the stage of percutaneous Achilles tenotomy. A total of 20 feet (25%) did not require a tenotomy and for the 60 that did, the mean Pirani score at time of operation was 2.5 (0.5 to 3). Denis Browne boots were applied at a mean of 10 weeks (4 to 56) after presentation. The mean time from tenotomy to boots was 3.3 weeks (2 to 10). We experienced one case of cast-slippage during a period of non-attendance, which prolonged the casting process. One case of prolonged casting required repeated tenotomy, and three feet required repeated tenotomy and casting after relapsing while in Denis Browne boots. We believe the use of a below-knee Softcast in conjunction with Ponseti manipulation techniques shows promising initial results which are comparable to those using above-knee plaster of Paris casts.     

Retroperitoneoscopic pancreatectomy: a new surgical option for pancreatic disease

Objective

The advantage of retroperitoneoscopy in renal and adrenal gland surgery has been widely acknowledged. Retroperitoneoscopy may also be a useful approach to the pancreas, a retroperitoneal organ. This study aims to evaluate the feasibility of retroperitoneoscopic pancreatectomy performed in an animal model and a small patient cohort.

Methods

This study was divided into two stages. Initially, retroperitoneoscopic distal pancreatectomy was performed in 6-month-old Yorkshire breed piglets (n?=?5; mean weight, 50?±?5 kg). Subsequently, seven patients with suspected diagnosis of distal pancreatic lesions were selected between February 2010 and April 2011 to undergo retroperitoneoscopy. Approval was obtained from both the Animal Ethics Committee and the Institutional Review Board.

Results

In the animal models, retroperitoneoscopic procedures were accomplished smoothly with short operative time, insignificant blood loss, and only minor complications. In clinical practice, patients with histologically confirmed pancreatic diseases underwent enucleation (n?=?2) or distal pancreatectomy with splenic preservation (n?=?2). Operative times ranged from 30 to 100 min with controllable blood loss of 10–100 ml. One case of intraoperative retroperitoneal perforation and two cases of pancreatic fistula occurred. All four patients were discharged within 7 days postoperatively. The other three patients with nonpancreatic diseases underwent retroperitoneoscopic resection with excellent clinical outcome.

Conclusions

The results of this preliminary study demonstrate that retroperitoneoscopic pancreatectomy, a novel surgical approach, was feasible and effective in selected patients. The advantages of this approach include acceptable operating time, insignificant blood loss, simple manipulations, minor complications, and excellent postoperative recovery time. Additionally, this study suggests that retroperitoneoscopy could also be feasible for treatment of retroperitoneal nonpancreatic diseases.     

Prevention of venous thromboembolism after major orthopedic surgery: update and contribution of a specific synthetic inhibitor of factor Xa

Despite widespread use of antithrombotic agents, major orthopedic surgery (total hip arthroplasty, major knee surgery, fracture of the femoral neck) still raises a high risk of deep vein thrombosis and pulmonary embolism. Proper understanding of thromboprophylaxis in orthopedic surgery requires good knowledge of the mechanisms of coagulation and the point of action of different antithrombotic agents. Sodium fondaparinux is the first synthetic inhibitor selective for factor Xa. It is composed of five saccharide units obtained by chemical synthesis, thus eliminating the risk of contamination by a pathogenic agent of animal origin and batch variability. Clinical trials using sodium fondaparinux for the prevention of venous thromboembolism after major orthopedic surgery have demonstrated its superiority over low-molecular-weight heparin without increased risk of clinically pertinent bleeding if the first injection is given at the proper time. We present the main results of clinical trials.     

Painless extracorporeal shock wave lithotripsy for outpatients: a new option

Extracorporeal shock wave lithotripsy is becoming the most common procedure for the treatment of renal and ureteral stones. The introduction of a new generator and a new hemi-ellipsoid for the Dornier HM-III lithotripter improves patient comfort and requires no general or peridural anesthesia, thus making it easier to perform this procedure on an outpatient basis.     

Oxinium, a new alternative femoral bearing surface option for hip replacement

Because it is difficult to adapt ceramic technology to prevent ceramic fractures, attention has been directed at the development of a new metal alloy, the surface of which can be treated to be made more scratch-resistant than cobalt chromium alloy. A niobium (Nb) alloy of zirconium (Zr–2.5Nb) has recently been introduced as a bearing surface for the femoral component in hip arthroplasty. The advantage is that the surface of the metal can be transformed into a relatively thick (micrometers) zirconium oxide (i.e., zirconia) ceramic-like material, thus combining the benefits of ceramic and metal in one component. The oxide layer is not a coating but rather the surface zone of the metal alloy. The oxide/metal interface is continuous, without pores or voids which might be detrimental to oxide adhesion. The ceramic like zirconia surface layer is highly adherent to the metal alloy and further supported the use of this novel alloy as a scratch-resistant counterface for total joint replacement prostheses. Laboratory studies have demonstrated the superior wear performance of oxidized zirconium against polyethylene in comparison with cobalt–chromium alloy. This paper comments the advantage of this new bearing surface for hip replacement.     

Rivaroxaban and dabigatran etexilate: two new oral anticoagulants for extended postoperative prevention of venous thromboembolism after elective total hip arthroplasty

Extended thromboprophylaxis is vital in patients undergoing total hip arthroplasty (THA) because of the prolonged risk of venous thromboembolism (VTE). Despite evidence that extended prophylaxis can reduce the incidence of symptomatic VTE in this high-risk patient population and the evidence-based guideline recommendations, a large proportion of patients still do not receive an adequate duration of thromboprophylaxis. This is partly due to the limitations of conventional anticoagulants, such as the subcutaneous route of administration or the requirement for routine coagulation monitoring and dose adjustment. New oral anticoagulants (such as the direct thrombin inhibitor dabigatran etexilate and the Factor Xa inhibitor rivaroxaban) could address the current unmet need. Phase III clinical studies in VTE prevention in patients undergoing THA and total knee arthroplasty (TKA) showed that dabigatran etexilate was non-inferior to the EU regimen of enoxaparin, but did not achieve non-inferiority to the US regimen of enoxaparin. In contrast, rivaroxaban demonstrated superiority to both enoxaparin regimens for the prevention of VTE after THA and TKA, without a significant increase in major bleeding rates. Their convenient, once-daily, fixed dosing, with no need for routine coagulation monitoring, could facilitate adherence to evidence-based guideline recommendations of extended thromboprophylaxis after THA.