Amulet IDE: Amplatzer Amulet left atrial appendage occluder randomised controlled trial
Reported from the European Society of Cardiology ESC Congress 2021
A first of its kind
This study is the first of its kind, as it is a head-to-head, randomized controlled trial providing comparative data on safety and efficacy of the Abbott's Amulet left atrial appendage occlusion (LAAO) device tested against the Boston's Watchman LAA occluder.
Following the publication of the PROTECT AF and PREVAIL trials, which demonstrated safety and effectiveness of the Watchman device, the latter has become standard of care treatment for patients eligible to OAC but seeking an alternative, non-pharmacological thromboembolic protection strategy.
So far, accumulated pieces of evidence in favor of Amulet derived from single and multicentre registries mainly focused on high bleeding risk patients, for the most part non-eligible to OAC, whereas no RCT derived data were available for this specific device.
Thus, in order to fill these knowledge gaps, and to test Amulet against the current standard of treatment, the prospective, randomized, multi-center, active-control trial, conducted worldwide, was designed to evaluate the AMPLATZER™ Amulet™ Left Atrial Appendage Occluder in patients with non-valvular atrial fibrillation, eligible for short term OAC.
This non-inferiority trial with a 1:1 randomization ratio between the Amulet (treatment arm) and Watchman (control arm) started enrolment in August 2016, including patients from more than 100 international centers (mainly US sites).
Selection of three primary endpoints
- 'safety' endpoint: a mix of procedure-related complications, all-cause death, major bleeding at 12 months (per-protocol analysis, 5.8 % non-inferiority margin).
- 'effectiveness' endpoint: a composite of ischemic stroke or systemic embolism through 18 months (intention-to-treat approach, 3.2 % non-inferiority margin).
- 'mechanism of action' endpoint: defined as residual jet around the device ≤ 5 mm at the 45-day visit at transesophageal echocardiography (assessed in patients treated by LAAO; for non-inferiority, a - 3 % margin was selected).
- Individual components of the primary endpoints were identified as secondary endpoints.
Events pertaining to the primary and secondary endpoints were adjudicated by an independent, blinded, clinical event committee.
To adequately power the trial, an event rate of 15 % for the primary endpoint was assumed, according to the outcomes observed in the PREVAIL trial. Thus, a sample size of 1,878 patients was calculated to provide at least 90 % power (92 % for safety, 90 % for effectiveness, and 97 % for mechanism of action) to claim non-inferiority for each of the primary endpoints.
Started from August 2016, a total of 1,878 patients (934 from the Amulet arm, 944 from the Watchman arm, with 917 and 916 implants attempted respectively) with documented paroxysmal, persistent, or permanent non-valvular atrial fibrillation at high risk of stroke or systemic embolism (defined as CHADS2 score > 2 or a CHA2DS2-VASc score of ≥ 3) were randomized among 108 international institutions (78 US sites, 30 non-US sites).
Patients were screened with transesophageal echocardiography to ensure they presented suitable LAA anatomy to be implanted either device prior to enrolment. While selecting a high bleeding risk population, patients had however to be suitable for anticoagulation therapy for six weeks post-implantation, according to the Watchman's direction for use.
The mean age of participants was 75 years, with a mean CHA2DS2-VASC score slightly above 4 in both arms. More than 70 % of them had history of minor or major bleedings.
As the Abbott's Amulet obtained FDA approval in August 2021 only, a roll-in phase was required according to study protocol for US implanters, in order to allow adequate familiarization with the investigational device, and to reduce the risk of procedure-related adverse events, a major issue in each prophylactic interventional treatment.
Procedural success was comparable among both arms, achieved in 98.4 % in the Amulet arm vs 96.4 % in the Watchman arm.
Following LAAO procedure, 78.9 % of patients in the investigational arm were discharged with dual antiplatelet therapy, while 95.8 % of patients in the control arm were treated with OAC with Warfarin.
At 45 days and after a follow-up transesophageal echocardiography, patients on OAC were shifted to DAPT (whether absence of device-related thrombosis or residual flow < 5 mm), then, from six months onward, on aspirin alone.
Follow-up was well above 90 % in both treatment arms at all specified time points.
At pre-specified time points, observed outcomes are as follows:
- 'safety' endpoint: Amulet arm 14.5 % vs Watchman arm 14.7 %; difference = -0.14; 95 % CI -3.42–3.13; p < 0.001 for non-inferiority. Nonetheless, procedure-related complications were significantly higher in the Amulet arm (4.5 % vs 2.5 %) driven by pericardial effusion (2.4 % vs 1.2 %) and device embolization (0.7 % vs 0.2 %). All-cause death was higher in the Watchman arm (5.1 % vs 3.9 %).
- 'effectiveness' endpoint: 2.8 % in both arms; difference = 0.00; 95 % CI -1.55–1.55; p < 0.001 for non-inferiority.
- 'mechanism of action' endpoint: a higher closure rate was observed in the Amulet arm as compared to the Watchman arm (residual jet > 5 mm 1 % vs 3 %; difference = 2.03; 95 % CI 0.41–3.66; p < 0.001 for non-inferiority; p = 0.003 for superiority).
Despite differences in discharge therapies among the two groups, the rate of major bleeding (Amulet 11.6 % vs Watchman 12.3 %) and device-related thrombosis or stroke (Amulet 3.3 % vs Watchman 4.5 %) were comparable among the two groups.
Largest RCT on LAAO occlusion
This trial represents the largest RCT on LAAO occlusion that has ever been done so far, with more than 1,800 patients randomized, adding pieces of evidence to the field.
Patients included in this trial are elderly subjects with a moderate to high ischemic risk, according to their baseline CHA2DS2-VASC score, with an associated high rate of previous hemorrhagic events and recurrent bleeding events. The high rate of bleedings at follow-up strengthens the adequate patient selection.
The trial met all primary non-inferiority end-points, showing also superiority for the 'mechanism of action' endpoint. Authors and commenters justified this finding with the dual occlusion mechanism (lobe and disk), typical of the Amulet device, as compared to the single sealing mechanism allowed by the Watchman. While this statistically significant, numerically marginal, difference might in fact translate into any clinical impact remains to be established.
Differences observed in procedural related complications with Amulet were substantially higher as compared to the Watchman, with a learning curve showing a progressive reduction and flattening of procedural complication rate starting from 7 procedures onwards. As specified by the study P.I., despite the pre-specified run-in phase required for US implanters, most of the complications arose from US sites, clearly highlighting the role of operator experience and procedural volume.
Interestingly, despite the significant differences in the rate of antiplatelet therapy vs OAC among the treatment arm vs control arm, no significant differences were observed in terms of ischemic or hemorrhagic events.
A positive outcome but several questions remain to be answered
The results of this trial supported Amulet FDA approval, allowing US implanters to have an alternative, effective device, allowing treatment of a larger patient population. Nonetheless, despite the positive results of the trial, several questions remain to be answered.
As a first, despite significant differences in medical treatment during the first 45 days, haemorrhagic and ischemic events did not differ among treatment arm (DAPT prevalence) and control arm (warfarin plus aspirin), raising the question of whether both regimens truly represent a proper treatment in a population of patients recently treated with LAAO.
In addition, according to the trial selection criteria, patients had to be suitable for short-term anticoagulation with warfarin. This point raises the question of to what extent LAAO really represents an alternative to OAC, in particular in a DOAC era, as no comparative studies exist.
Finally, from a clinical perspective, the threshold for referring patients to LAAO before bleeding events have a real impact on prognosis remains uncertain and left to the discretion of physicians.
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