新型口服抗凝药在经导管主动脉瓣膜植入术中应用的研究进展

经导管主动脉瓣膜植入术(TAVI)已经被广泛应用于具有临床症状的主动脉瓣严重狭窄且无法手术或手术风险较高的患者。目前,各指南推荐TAVI术后以抗血小板为主的抗血栓治疗方案,抗凝治疗尤其是新型口服抗凝药(NOACs)在TAVI中应用的有效性及安全性有待进一步研究。本文旨在探讨近年来NOACs在TAVI中应用的最新研究进展。     

Adherence to guidelines and mortality in atrial fibrillation

Objective

Determining the adherence to ACC/AHA/ESC 2006 guidelines and its influence on the survival of patients with atrial fibrillation.

Methods

Prospective observational study of patients discharged during 2007 from an Internal Medicine department with a main or secondary diagnose of atrial fibrillation. The stroke risk was estimated with the CHADS₂ score. The follow-up was carried out in outpatient medical office or via telephone.

Results

We included 259 patients (mean age 80.9 years); 73% of them had a high risk of stroke. Oral anticoagulants were administered to 134 (51.7%), and antiplatelet drugs to 71 (27%) patients. A rate control strategy was chosen for 155 (59.8%) patients and a rhythm control one for 28 (10.8%). In 100 (38.6%) patients, treatment was adherent to the guidelines. Adherence to the guidelines was associated with age (0.95 95%CI 0.92–0.99; p = 0.03), contraindication to the use of oral anticoagulants (0.38 95%CI 0.18–0.81; p = 0.01) and mitral valve heart disease/valvular prosthesis (2.10 95%CI 1.04–4.25; p = 0.04). The median follow-up was 727 days, and 191 patients died. Patients treated according to the guidelines had a higher rate of survival during the first three years (0.47 vs. 0.36; p = 0.049). The use of oral anticoagulants was associated with a higher probability of survival over a 5 year period (0.34 vs 0.21; p = 0.001) and the rate control strategy during the first year (0.69 vs 0.57; p = 0.04).

Conclusions

In the real world, the treatment of atrial fibrillation according to the guidelines is associated with improved survival for up to three years during follow-up.     

Transition of Patients From Blinded Study Drug to Open-Label Anticoagulation : The ENGAGE AF–TIMI 48 Trial

Background

At the end of 2 previous trials, an excess of stroke and bleeding was observed in patients with AF randomized to a new oral anticoagulant (NOAC) who transitioned to a vitamin K antagonist (VKA).

Objectives

The ENGAGE AF–TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation—Thrombolysis in Myocardial Infarction 48) trial compared once-daily edoxaban to warfarin for stroke prevention in patients with AF. An end-of-trial transition plan was developed to minimize the risks of stroke due to inadequate anticoagulation and bleeding from excessive anticoagulation during this critical period.

Methods

All patients on the blinded study drug at the trial’s conclusion were included in this analysis. In pre-specified analyses, stroke, bleeding, and death that occurred through 30 days after the end-of-trial visit were stratified by randomized treatment allocation and open-label anticoagulant selected post-trial.

Results

Of the 13,642 patients taking the blinded study drug at the end of the trial, 9,304 (68.2%) were transitioned to open-label VKA and 4,258 patients (31.2%) to an NOAC. There were 21 strokes evenly distributed across the 3 randomized treatment arms: warfarin 7 (1.90%/year), edoxaban high dose 7 (1.89%/year), edoxaban low dose 7 (1.85%/year). Major bleeding was also similar across the 3 treatment arms: warfarin 11 (2.98%/year), edoxaban high dose 10 (2.69%/year), edoxaban low dose 18 (4.76%/year). In patients transitioned to VKA, 85% of patients had at least 1 INR ≥2 by day 14 after the transition and 99% by day 30.

Conclusions

The ENGAGE AF–TIMI 48 transition plan protected patients from an excess of thrombotic and bleeding events and should be helpful in clinical practice when patients are transitioned between oral anticoagulants. (Global Study to Assess the Safety and Effectiveness of Edoxaban [DU-176b] vs Standard Practice of Dosing With Warfarin in Patients With Atrial Fibrillation [EngageAFTIMI48]; NCT00781391)     

Safety and Efficacy of Apixaban Following Bioprosthetic Valve Replacements: A Retrospective Evaluation

Background: Data on the use of direct oral anticoagulants in the setting of bioprosthetic valve replacements is limited. Objective: The purpose of this study was to describe outcomes among patients who underwent a bioprosthetic valve replacement and were subsequently prescribed apixaban. Methods: A retrospective cohort study was completed for inpatients at a community hospital who were prescribed apixaban following a bioprosthetic valve replacement from 2015 to 2020. Endpoints assessed included incidence of all-cause readmission and emergency visits within 3 months following valvular surgery, incidence of mortality, and all-cause major and minor bleeding. A post hoc analysis was conducted comparing outcomes among patients who underwent mitral versus aortic valve replacement, as well as patients with and without atrial fibrillation. The study was deemed exempt by hospital and university institutional review boards. Results: A total of 54 patients were included for analysis. All-cause readmission or emergency visit occurred in 33% (n = 18) of patients and the mortality rate was 6% (n = 3). A minor bleeding event was reported in 6% (n = 3) of patients and a major bleeding event was reported in 2% (n = 1) of patients. A thrombotic event was reported in 2% (n = 1) of patients. Conclusion: Within this cohort of patients requiring anticoagulation following bioprosthetic valve replacement, apixaban was safe and well-tolerated. However, more prospective data are needed to further correlate the safety and efficacy of apixaban, particularly in the setting of mitral valve replacement.     

Safety of switching from vitamin K antagonists to dabigatran or rivaroxaban in daily care – results from the Dresden NOAC registry

Aim

Vitamin-K antagonists (VKA) and non-vitamin-K dependent oral anticoagulants (NOAC) have been approved for anticoagulation in venous thromboembolism (VTE) and atrial fibrillation and patients previously treated with VKA are switched to NOAC therapy. Safety data for this switching are urgently needed.

Methods

Using data from a large regional prospective registry of daily care NOAC patients, we evaluated the safety of switching anticoagulation from VKA to dabigatran or rivaroxaban. Switching procedures and cardiovascular and bleeding events occurring within 30 days after switching were centrally adjudicated.

Results

Between 1 October 2011 and 18 June 2013, 2231 patients were enrolled. Of these, 716 patients were switched from VKA to NOAC. Only 410 of the 546 evaluable patients (75.1%) had a recorded INR measurement within the 10 days preceding or following the end of VKA treatment (mean INR 2.4). As of day 30, major bleeding complications were rare (0.3%; 95% CI 0.0, 1.0) with an overall bleeding rate of 12.2% (95% CI 9.8, 14.8). Major cardiovascular events occurred in 0.8% (95% CI 0.3, 1.8). There was no significant difference in outcome event rates between the subgroups of patients with or without INR testing.

Conclusion

In daily care, only 75% of VKA patients have an INR measurement documented before NOAC are started. On average, NOAC are started within 2 to 5 days after the last intake of VKA. However, at 30 days follow-up cardiovascular events or major bleedings were rare both in patients with and without INR testing. However, switching procedures need to be further evaluated in larger cohorts of patients.     

新型口服抗凝药临床一览

随着新型口服抗凝药物相继批准上市,血栓疾病的治疗又有了新的有效途径。已经通过美国FDA批准的口服抗凝药有达比加群酯、利伐沙班、阿哌沙班。本文综述了以上3个药物的主要临床研究,间接对比了其有效性和安全性。     

Prior use of antithrombotic agents and neurological functional outcome at discharge in patients with ischemic stroke

Summary.  Background:  Studies in experimental animals have suggested that antithrombotic agents may have a neuroprotective effect after an ischemic injury. The aim of this study was to analyze the effect of prior use of antithrombotic agents (antiplatelets or anticoagulants) on neurological functional outcome in patients with acute ischemic stroke. Subjects and methods:  Consecutive patients included in the Perugia Stroke Registry were considered for this analysis. Neurological functional outcome was evaluated at discharge using the modified Rankin Scale (mRS ≥ 3 disabling stroke). Results:  Of the 1921 patients included in the analysis (mean age 76.3 ± 12.5 years; 53% males), 662 (34.5%) were on antithrombotic treatment (581 antiplatelets, 71 anticoagulants and 10 antiplatelets associated with anticoagulants). One hundred and twenty-two patients (6.4%) died in hospital; at discharge 712 patients (37.1%) were disabled and 1087 patients (56.6%) were non-disabled. Fifty-four (44.3%) of the deceased patients and 270 (37.9%) of disabled patients were on antithrombotic treatment, while 338 (31.1%) non-disabled patients were taking antithrombotic agents. From multivariate analysis, age and stroke severity were associated with an adverse outcome. Male gender, dyslipidemia, stroke due to small vessel disease and no history of previous stroke were associated with an improved outcome, while no correlation was found between prior use of antithrombotic agents and outcome (mortality odds ratio; OR = 1.32, 95% confidence interval; CI 0.85–2.04; P  = 0.20, mortality or disability OR = 0.95, 95% CI 0.72–1.25; P  = 0.80). Conclusion:  Prior use of antithrombotic agents does not improve the functional outcome in patients with acute ischemic stroke.     

Clinical outcomes with unfractionated heparin or low-molecular-weight heparin as bridging therapy in patients on long-term oral anticoagulants: the REGIMEN registry.

BACKGROUND: Patients who receive long-term oral anticoagulant (OAC) therapy often require interruption of OAC for an elective surgical or an invasive procedure. Heparin bridging therapy has been used in these situations, although the optimal method has not been established. No large prospective studies have compared unfractionated heparin (UFH) with low-molecular-weight heparin (LMWH) for the perioperative management of patients at risk of thromboembolism requiring temporary interruption of long-term OAC therapy. PATIENTS/METHODS: This multicenter, observational, prospective registry conducted in North America enrolled 901 eligible patients on long-term OAC who required heparin bridging therapy for an elective surgical or invasive procedure. Practice patterns and clinical outcomes were compared between patients who received either UFH alone (n = 180) or LMWH alone (n = 721). RESULTS: Overall, the majority of patients (74.5%) requiring heparin bridging therapy had arterial indications for OAC. LMWH, in mostly twice-daily treatment doses, represented approximately 80% of the study population. LMWH-bridged patients had significantly fewer arterial indications for OAC, a lower mean Charlson comorbidity score, and were less likely to undergo major or cardiothoracic surgery, receive intraprocedural anticoagulants or thrombolytics, or receive general anesthesia than UFH-bridged patients (all P < 0.05). The LMWH group had significantly more bridging therapy completed in an outpatient setting or with a < 24-h hospital stay vs. the UFH group (63.6% vs. 6.1%, P < 0.001). In the LMWH and UFH groups, similar rates of overall adverse events (16.2% vs. 17.1%, respectively, P = 0.81), major composite adverse events (arterial/venous thromboembolism, major bleed, and death; 4.2% vs. 7.9%, respectively, P = 0.07) and major bleeds (3.3% vs. 5.5%, respectively, P = 0.25) were observed. The thromboembolic event rates were 2.4% for UFH and 0.9% for LMWH. Logistic regression analysis revealed that for postoperative heparin use a Charlson comorbidity score > 1 was an independent predictor of a major bleed and that vascular, general, and major surgery were associated with non-significant trends towards an increased risk of major bleed. CONCLUSIONS: Treatment-dose LMWH, mostly in the outpatient setting, is used substantially more often than UFH as bridging therapy in patients with predominately arterial indications for OAC. Overall adverse events, including thromboembolism and bleeding, are similar for patients treated with LMWH or UFH. Postoperative heparin bridging should be used with caution in patients with multiple comorbidities and those undergoing vascular, general, and major surgery. These findings need to be confirmed using large randomized trials for specific patient groups undergoing specific procedures.     

Activated protein C resistance determined with a thrombin generation-based test is associated with thrombotic events in patients with lupus anticoagulants

BACKGROUND: Several studies suggest that antiphospholipid antibodies interfere with the activity of activated protein C (APC). This acquired form of APC resistance has been proposed as a possible pathogenic mechanism underlying hypercoagulability associated with the antiphospholipid syndrome (APS). OBJECTIVES: We wanted to investigate the inhibitory effect of recombinant APC (rAPC) on ex vivo thrombin generation in plasma and the modification of this effect by the presence of lupus anticoagulants (LA). PATIENTS/METHODS: We analyzed plasmas from 81 patients with LA (52 patients fulfilling the criteria for the APS) and 91 controls. Percent inhibition of the endogenous thrombin potential (ETP) as a parameter of APC sensitivity was determined in plasmas using a thrombin generation-based APC resistance test probed with rAPC. All results were normalized using pooled normal plasma (PNP) as a reference. RESULTS: Normalized percent inhibition of ETP by APC was lower in patients with LA [61.4%, 95% confidence interval (CI) 45.8-74.5%] compared to controls (107.8%, 95% CI: 107.1-109.3%). In patients with LA and APS, median inhibition was lower than in patients with LA without APS (44.6%, 95% CI: 30.1-55.7% vs. 78.8%, 95% CI: 73.9-95.8%). This difference also persisted when patients on warfarin therapy were excluded from the APS subgroup. CONCLUSIONS: APC resistance can be demonstrated with a thrombin generation-based test in a majority of patients with the LA laboratory phenotype. A history of thrombotic events in patients with LA is associated with a stronger resistance to the anticoagulant effect of APC.