Prospective Randomized Evaluation of the Watchman Left Atrial Appendage Closure Device in Patients With Atrial Fibrillation Versus Long-Term Warfarin Therapy : The PREVAIL Trial

Background

In the PROTECT AF (Watchman Left Atrial Appendage Closure Technology for Embolic Protection in Patients With Atrial Fibrillation) trial that evaluated patients with nonvalvular atrial fibrillation (NVAF), left atrial appendage (LAA) occlusion was noninferior to warfarin for stroke prevention, but a periprocedural safety hazard was identified.

Objectives

The goal of this study was to assess the safety and efficacy of LAA occlusion for stroke prevention in patients with NVAF compared with long-term warfarin therapy.

Methods

This randomized trial further assessed the efficacy and safety of the Watchman device. Patients with NVAF who had a CHADS₂ (congestive heart failure, hypertension, age >75 years, diabetes mellitus, and previous stroke/transient ischemic attack) score ≥2 or 1 and another risk factor were eligible. Patients were randomly assigned (in a 2:1 ratio) to undergo LAA occlusion and subsequent discontinuation of warfarin (intervention group, n = 269) or receive chronic warfarin therapy (control group, n = 138). Two efficacy and 1 safety coprimary endpoints were assessed.

Results

At 18 months, the rate of the first coprimary efficacy endpoint (composite of stroke, systemic embolism [SE], and cardiovascular/unexplained death) was 0.064 in the device group versus 0.063 in the control group (rate ratio 1.07 [95% credible interval (CrI): 0.57 to 1.89]) and did not achieve the prespecified criteria noninferiority (upper boundary of 95% CrI ≥1.75). The rate for the second coprimary efficacy endpoint (stroke or SE >7 days’ postrandomization) was 0.0253 versus 0.0200 (risk difference 0.0053 [95% CrI: –0.0190 to 0.0273]), achieving noninferiority. Early safety events occurred in 2.2% of the Watchman arm, significantly lower than in PROTECT AF, satisfying the pre-specified safety performance goal. Using a broader, more inclusive definition of adverse effects, these still were lower in PREVAIL (Watchman LAA Closure Device in Patients With Atrial Fibrillation Versus Long Term Warfarin Therapy) trial than in PROTECT AF (4.2% vs. 8.7%; p = 0.004). Pericardial effusions requiring surgical repair decreased from 1.6% to 0.4% (p = 0.027), and those requiring pericardiocentesis decreased from 2.9% to 1.5% (p = 0.36), although the number of events was small.

Conclusions

In this trial, LAA occlusion was noninferior to warfarin for ischemic stroke prevention or SE >7 days’ post-procedure. Although noninferiority was not achieved for overall efficacy, event rates were low and numerically comparable in both arms. Procedural safety has significantly improved. This trial provides additional data that LAA occlusion is a reasonable alternative to warfarin therapy for stroke prevention in patients with NVAF who do not have an absolute contraindication to short-term warfarin therapy.     

Transcatheter left atrial appendage occlusion with Amplatzer devices to obviate anticoagulation in patients with atrial fibrillation.

It is assumed that over 90% of clinically apparent embolisms in atrial fibrillation originate from the left atrial appendage. Recently, a percutaneous method (PLAATO technique) to occlude the left atrial appendage to the end of preventing thromboembolic complications of atrial fibrillation has been introduced into clinical practice. This technique is quite intricate and requires general anesthesia. The Amplatzer atrial septal occluder lends itself for a more simple approach to this intervention. The first 16 patients treated at four centers are described. Their age varied from 58 to 83 years. All suffered from atrial fibrillation but eight of them were in sinus rhythm at the time of implantation. All but two procedures were done under local anesthesia of the groin only. There was one technical failure (device embolization) requiring surgery. All other patients left the hospital a day after the procedure without complications. There were no problems or embolic events during an overall follow-up of 5 patient-years and all left atrial appendages were completely occluded without evidence of thrombosis at the atrial side of the device at the latest follow-up echocardiography. With the Amplatzer technique, the left atrial appendage can be percutaneously occluded with a venous puncture under local anesthesia, without echocardiographic guidance, and at a reasonable risk. It remains to be evaluated in larger series or randomized trials how the simpler Amplatzer technique compares with the complex PLAATO technique, and whether left atrial appendage closure is competitive with oral anticoagulation with warfarin or the novel ximelagatran to prevent thromboembolism in atrial fibrillation.     

The Left Atrial Appendage: Target for Stroke Reduction in Atrial Fibrillation

A patient with atrial fibrillation (AF) has a greater than 5% annual risk of major stroke, a 5-fold increase compared to the general population. While anticoagulation remains the standard stroke prevention strategy, the nature of lifelong anticoagulation inevitably carries an increased risk of bleeding, increased stroke during periods of interruption, increased cost, and significant lifestyle modification. Many patients with atrial fibrillation have had their left atrial appendage (LAA) ligated or excised by surgeons during cardiac surgery, a decision based largely on intuition and with no clear evidence of efficacy in stroke risk reduction. The observation that 90% of the thrombi found in nonvalvular AF patients and 57% found in valvular AF are in the LAA, triggered significant interest in the LAA as a potential therapeutic target. Until recently, the results were inconsistent, and high rates of incomplete occlusions precluded the medical community from confirming a definite relationship between LAA and stroke. As a result, anticoagulation is still the recommended first-line stroke risk reduction in AF, and the American College of Cardiology/American Heart Association guidelines recommend LAA exclusion only with surgical ablation of AF or in the context of concomitant mitral valve surgery.A handful of devices have been developed for LAA exclusion. This includes percutaneous options such as WATCHMAN™ Left Atrial Appendage Closure Device (Boston Scientific Corporation, Marlborough, MA), hybrid epicardial devices such as the LARIAT Suture Delivery Device (SentreHEART, Inc., Redwood City, CA), and epicardial surgical devices such as AtriClip® LAA Occlusion System (AtriCure, Inc., West Chester, OH). Studies of the Watchman device have shown noninferiority to Warfarin in stroke prevention and this device has recently gained approval from the U.S. Food and Drug Administration (FDA) following lengthy delays due to safety concerns. The Lariat device, which received 510K clearance by the FDA for tissue approximation but not LAA exclusion, has been the target of significant criticism due to serious procedural safety concerns and high incomplete closure rates. The surgical AtriClip has been FDA approved since 2009 and is currently the most widely used LAA exclusion device placed through an epicardial approach. Small studies have shown excellent reliability and success of complete LAA closure with the AtriClip device, which is implanted through an epicardial approach. Currently, we are conducting a multicenter trial to demonstrate the stroke prevention potential of this epicardial device through a short (45 minute), stand-alone, minimally invasive procedure in lieu of lifelong anticoagulation in patients at high risk of bleeding.     

Effect of non‐recommended doses versus recommended doses of direct oral anticoagulants in atrial fibrillation patients: A meta‐analysis

BackgroundSeveral observational studies have shown that the inappropriate dosing use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) that does not conform to recommendations is becoming a widespread phenomenon. Therefore, we performed a meta‐analysis and systematic review to assess the effect of non‐recommended doses versus recommended doses of DOACs on the effectiveness and safety outcomes among AF patients.MethodsThe PubMed and Ovid databases were systematically searched to identify the relevant studies until December 2020. The effect estimates were hazard ratios (HRs) and 95% confidence intervals (CIs), which were pooled using a fixed‐effects model (I² ≤ 50%) or a random‐effects model (I² > 50%).ResultsA total of 11 studies were included in this meta‐analysis. Compared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of stroke or systemic embolism (SSE, HR = 1.29, 95% CI 1.12–1.49) and all‐cause death (HR = 1.37, 95% CI 1.15–1.62), but not the ischemic stroke, myocardial infarction, gastrointestinal bleeding, intracranial bleeding, and major bleeding. Compared with recommended dosing of DOACs, non‐recommended high dosing of DOACs was associated with increased risks of SSE (HR = 1.44, 95% CI 1.01–2.04), major bleeding (HR = 1.99, 95% CI 1.48–2.68), and all‐cause death(HR = 1.38, 95% CI 1.02–1.87).ConclusionCompared with recommended dosing of DOACs, non‐recommended low dosing of DOACs was associated with increased risks of SSE and all‐cause death. Further study should confirm the findings of non‐recommended high dosing versus recommended dosing of DOACs.     

Effects of low-dose warfarin and aspirin versus no treatment on stroke in a medium-risk patient population with atrial fibrillation

OBJECTIVES: To assess the optimal stroke prevention treatment for patients with atrial fibrillation (AF) and a low-medium risk (< or =4%) of stroke. DESIGN: A total of 668 patients with persistent or permanent AF, without an indication for full dose and with adequate rate control on sotalol, were randomized to warfarin 1.25 mg + aspirin 75 mg daily (W/A, 334 patients) or no anticoagulation (C, 334 patients). The mean follow-up period was 33 months. The protocol intended to verify a 37% relative risk reduction provided a 4% stroke incidence in the C group. RESULTS: The stroke incidence was less in the W/A group, although the reduction was not statistically significant (W/A 9.6% versus C 12.3%). Four haemorrhagic strokes were identified, two in each group. Secondary end-points were transient ischaemic attacks (TIA) (W/A 3.3% versus C 4.5%), all cause mortality (W/A 9.3% versus C 10.8%), cardiovascular morbidity (W/A 17.7% versus C 22.2%) and the combination of stroke + TIA (W/A 11.7% versus C 16.5%). Bleedings were documented in 19 versus four patients (W/A 5.7% versus C 1.2%) (P = 0.003), although none fatal. Sinus rhythm (SR) was recorded occasionally in 68 patients (W/A 9.6% versus C 10.8%). The stroke incidence tended to be higher in those with SR than without, 16.2% versus 10.4%. CONCLUSIONS: Our results were inconclusive, but consistent with a small beneficial effect of W/A for reduction of stroke and major vascular events in AF patients at moderate risk. The low-dose regiment produced, however, a significantly increased risk of bleedings. Documented SR occasionally recorded may represent a subpopulation that warrants full dose warfarin.     

射频消融联合左心耳封堵术治疗心房纤颤17例回顾性分析

目的探讨心房颤动"一站式"手术的有效性和安全性。方法回顾性分析临床17例心房纤颤患者通过射频消融联合左心耳封堵"一站式"手术治疗后的临床资料。结果手术后出现肺部感染2例(11.76%),一过性交界性逸搏心律2例(11.76%),食管瘘1例(5.89%),术后3个月经食道超声心动图复查发现,封堵器表面血栓形成1例(5.89%),术后6个月随访无卒中、出血及死亡患者,1例患者心房颤动复发,继续抗凝治疗,其他患者均改为阿司匹林或氯吡格雷单联抗栓治疗。结论对于卒中高危且有抗凝禁忌的非瓣膜性心房颤动患者,射频消融联合左心耳封堵"一站式"手术是可行的、安全的、有效的。     

Left atrial appendage occlusion with the Watchman device in a patient with paroxysmal atrial fibrillation and intolerance of all forms of anticoagulation due to hereditary haemorrhagic telangiectasia

An elderly woman presented to our attention because of paroxysmal atrial fibrillation and cerebrovascular events requiring systemic anticoagulation and a concomitant, serious bleeding diathesis (the Osler‐Weber‐Rendu syndrome, or hereditary haemorrhagic telangiectasia). Her risk of suffering a major stroke was significant given a CHA₂DS₂VASc score of 6. However, she was unable to tolerate any form of anticoagulation because of torrential epistaxis and previous gastrointestinal haemorrhage on antiplatelet therapy. We proceeded with percutaneous occlusion of the left atrial appendage with a Watchman device. Ten months post‐procedure she is well, without recurrence of neurological symptoms, and off all forms of anticoagulation. The current internationally accepted practice post‐deployment of the Watchman device mandates warfarin transition for 6 months to allow for endothelialisation of the device. However, there is no evidence in the literature to support left atrial appendage occlusion without any peri‐procedural antiplatelet and anticoagulation therapy and therefore our case represents novel and important anecdotal evidence that secondary stroke prevention with left atrial appendage occlusion may be effective and safe even in patients who cannot tolerate any form of anticoagulation at all.