Left atrial appendage occlusion plus oral anticoagulation in stroke patients despite ongoing anticoagulation: rationale and design of the ADD-LAAO clinical trial

INTRODUCTION

Atrial fibrillation (AF) increases with age and raises the risk of ischemic stroke, systemic embolism, and death, with stroke or transient ischemic attack (TIA) often being the initial presentation. 1,2 Oral anticoagulation (OAC) with direct OAC (DOAC) or vitamin K antagonists (VKA) is effective in reducing these risks.1,2 However, recent randomized clinical trials suggest a 1.0%–1.5% annual stroke rate in AF patients on OAC.3-5 Up to one-third of AF patients who develop ischemic stroke are on OAC at stroke onset, with 8.8% up to 20% being on DOAC,6-9 which poses a significant challenge for secondary prevention purpose. Additionally, these patients tend to be older and have more comorbidities, sometimes requiring off-label low-dose DOAC.7 The use of off-label low-dose DOAC, atrial enlargement, and increased AF burden further raises the risk of stroke despite OAC therapy, suggesting a possible association with advanced cardiac disease or inadequate anticoagulation.10,11

After an ischemic stroke—despite OAC—there are no clear guidelines on the management of OAC, such as switching drugs, targeting a higher international normalized ratio (INR) with AVK, or adding antiplatelet agents. Network meta-analyses show no differences in stroke risk across different DOAC. Observational studies also found no benefits in changing OAC, suggesting additional stroke mechanisms.7 Stroke workups should identify alternative embolisms or sources of thrombosis, such as large-vessel atherosclerosis or small-vessel disease, which may need specific antithrombotic strategies.7,9,10,12 Although adding antiplatelets may reduce platelet activation, it is associated with a higher bleeding risk.13 Therefore, the best secondary prevention for AF patients after stroke despite OAC remains unclear, highlighting the need for new treatments, including novel non-pharmacological approaches such as left atrial appendage occlusion (LAAO).

Recent data from the STR-OAC cohort—an international LAAO registry—showed promising findings in AF patients with stroke despite OAC. In this study, the LAAO cohort had a 2.2% per patient-year stroke rate vs the 9.8% reported in the non-LAAO cohort (HR, 0.33; 95%CI, 0.19-0.59).14 Despite this positive outcome, no RCTs have assessed the feasibility, safety and efficacy profile of using OAC plus LAAO as adjuvant therapy in this complex population. Herein, we propose oral anticoagulation alone vs oral anticoagulation plus left atrial appendage occlusion in stroke patients despite ongoing anticoagulation (ADD-LAAO trial). This is a pragmatic randomized controlled trial (RCT) designed to evaluate the superiority of a hybrid strategy combining transcatheter left atrial appendage occlusion (LAAO) and long-term continued oral anticoagulation (OAC)—either direct oral anticoagulants (DOAC) or VKA when clinically appropriate—vs medical management with OAC alone. The trial aims to assess the effectiveness of this approach in reducing recurrent ischemic stroke in patients with atrial fibrillation (AF) who have experienced an AF-related acute ischemic stroke despite being anticoagulated at the time of stroke onset.

METHODS

Study design

We conducted a multicenter randomized controlled trial with patients with a past medical history of ischemic stroke within the past 6 months despite OAC. A total of 6 teaching hospital centers are involved in this study. Eligible patients will be screened and included based on specific criteria (figure 1 illustrates the inclusion and exclusion criteria). In general, patients with stroke despite OAC will include the following data: those with VKA with correct or labile INR and those with DOAC with poor compliance. Poor compliance will be defined as missing a maximum of 1 day dose (1 pill for VKA and 2 for DOAC) over the past week before the index stroke. Poor compliant patients will be included as the risk of non-compliance is an inherent characteristic of OAC. In contrast, patients missing > 1 day dose over the past week before the index procedure will not be included as these patients cannot be considered anticoagulated. A crucial inclusion criterion for randomization purposes will be the absence of an absolute contraindication to OAC, as this population is considered a high-risk cohort for thrombotic events, and post-LAAO OAC discontinuation has been reported to increase thrombotic risk.15 The study flow diagram is shown in figure 2.

Figure 1. Inclusion and exclusion criteria. AF, atrial fibrillation; CT, computed tomography; DOAC, direct oral anticoagulant; Hb, hemoglobin; LAAO, left atrial appendage occlusion; NYHA, New York Heart Association; OAC, oral anticoagulation; PFO, patent foramen ovale; TEE, transesophageal echocardiogram; TIA, transient ischemic attack.
^a Cardioembolic ischemic stroke definition: AF-related stroke after ruling out symptomatic ipsilateral great vessel/intracranial vascular disease, and small vessel disease and active endocarditis or neoplasm.
^b > 1 dose per antagonist of vitamin K and > 2 doses per DOAC.
^c > 50% lumen diameter narrowing on CT, magnetic resonance imaging, or transcranial Doppler with symptoms of ipsilateral transient or visual TIA.
^d If general anesthesia is planned for the study procedure.
^e If the patient needs CCTA and cannot undergo TEE.
^f The active treatment group may confound the results of this trial.

Figure 2. Central illustration. Study protocol. CT, computed tomography; DOAC, direct oral anticoagulant; LAAO, left atrial appendage occlusion; OAC, oral anticoagulation; TEE, transesophageal echocardiogram.

Subject screening, enrollment, and randomization

Patients meeting all inclusion and no exclusion criteria will be approached for the study. Prior to inclusion, transesophageal echocardiography (TEE) or coronary computed computed tomography will rule out the presence intra-cardiac thrombus and assess the LAA anatomy. If suitable for LAAO, the study will be explained, and informed consent from the patients will be obtained. Upon consent, patients will be randomized on a 1:1 ratio to the interventional group—receiving LAAO and long-term OAC—or the control group, receiving the optimal medical therapy as decided by neurologists. The interventional procedure will occur within 2 weeks post-randomization. The optimal medical therapy may involve intensified antithrombotic therapy, switching OAC regimens, reinforcing drug compliance, or a combination of these strategies. Randomization will be managed online, allocating patients in groups of 10 to ensure balanced inclusion across both groups.

OAC strategies

The treating neurologist team will decide on the OAC strategy and dosage for the interventional and control groups. Any DOAC (apixaban, dabigatran, rivaroxaban, or edoxaban) will be accepted. DOAC dosages will be down titrated if the patient’s bleeding risk is high or per product label recommendations. In the interventional group, although DOAC is preferred to minimize bleeding risk,16 VKA will be allowed if necessary, such as for patients with mechanical cardiac valves. The protocol does not restrict other concomitant drugs; each will be assessed for additional hemorrhagic risk by the physician. The OAC duration will be indefinite in the 2 groups unless a new formal contraindication emerges, such as in cases of major bleeding. Furthermore, each situation will be managed individually by investigators at each center.

Interventional group

Patients from the interventional group will undergo LAAO following standard practice. ACO will be discontinued prior to the procedure per product label recommendations for DOAC, and with bridging therapy using low-molecular-weight heparin in patients with an indication for VKA. A prophylactic antibiotic—cephalosporin or vancomycin for beta-lactam allergy—will be administered 2 hour prior. Procedure will be performed under general anesthesia or deep sedation with TEE or intracardiac echocardiography guidance. The femoral vein will be used for vascular acces, followed by a transseptal puncture. A 100 IU/kg bolus of IV heparin will be administered to achieve an activated clotting time ≥ 250 seconds. Fluoroscopy and TEE or intracardiac echocardiography will guide the procedure, allowing for LAA measurement, catheter and device positioning, and early complication detection. Approved LAAO devices include Amulet (Abbott Medical, United States), Watchman FLX (Boston Scientific, United States), and LAmbre (Lifetech Scientific [Shenzhen] Co. Ltd., China). Six to 24 hours after the intervention, transthoracic echocardiography will check for any pericardial effusions or device embolizations that may have occurred. If no complications are found, the patient will be discharged the same or the next day (institution protocol). Anticoagulation therapy (DOAC at the same dose as before LAAO or VKA with the initial dose determined by the thrombosis clinic assessment) will be resumed the day after the procedure. No antiplatelet therapy will be added to anticoagulation therapy in the LAAO group.

Study endpoint and outcome definitions

The primary endpoint of the study is the occurrence of a cardioembolic event—ischemic stroke or peripheral arterial embolism— within the first 12 months after inclusion. Secondary endpoints include evaluating the safety and efficacy profile of the strategies and combining cardioembolic events (efficacy) and major bleeding (safety) within the same period. A stroke is defined as the sudden onset of a focal neurologic deficit consistent with a major cerebral artery territory, categorized as ischemic, hemorrhagic, or unspecified, and confirmed through imaging using computed tomography or magnetic resonance imaging. Systemic cardioembolic events are acute vascular occlusions in an extremity or organ, confirmed by imaging, surgery, or autopsy. Major bleeding will follow the Bleeding Academic Research Consortium (BARC) criteria for types 3 and 5.17

Additional endpoints will assess major and minor bleeding (using the BARC classification), all-cause and cardiovascular death, recurrent stroke severity (using the modified Rankin scale), procedural major adverse events in the interventional group, device-related thrombus, additional hospital admissions, and OAC compliance. All clinical events, including primary and secondary endpoints, will be independently allocated.

The success of the intervention is defined as the implantation of the LAAO device without major complications, such as death, stroke, or those requiring surgical or endovascular treatment.18 Procedural safety will be evaluated by including all clinical events within the first 7 after the intervention. Events will be defined following the Valve Academic Research Consortium (VARC) guidelines, including mortality, myocardial infarction, stroke, systemic embolism, major bleeding, and procedural complications.19 Major bleeding will follow the BARC criteria for types 3 and 5.17 A neurologist will independently grade disabling strokes with an m-RS score of ≥ 3.20 Device-related thrombus will be any thrombus > 1 mm on the LAAO device, and peri-device leaks will be classified by TEE jet width (> 3 mm being significant).21 Complete LAAO is defined as the absence of any leaks > 3 mm on the final TEE.22

Clinical and imaging follow-up

Patients will be followed for 12 months. Clinical visits with neurological assessment and modified Rankin scale evaluation will occur on months 3 and 12. A phone follow-up will be conducted on month 6. The interventional group will undergo post-LAAO additional imaging modalities. Two imaging modalities with TEE or coronary computed tomography angiography will assess device-related thrombus and peri-device leaks 3 (2-4 months) and 12 months (10-12 months) after the intervention. Additionally, standard blood tests, including complete blood count and renal function will be performed on the same day as the imaging modalities to detect hidden hemorrhagic events.

Sample size and statistical analysis

Sample size is determined based on observed event rates in major registries, with an estimated 10% rate of recurrent cardioembolic events in the control group and 2% in the interventional group within the first year. To detect an 8% difference between the 2 groups, with a 5% type I error and 90% power, 183 patients per group are needed for a total of 366. Accounting for potential dropouts (~5%), the study will include 380 patients. The primary analysis will be conducted following the intention-to-treat principle, making sure that all randomized patients are analyzed in the group they have been initially allocated to, regardless of protocol deviations, dropouts, or crossover. This approach will provide an unbiased estimation of the treatment effect under real-world conditions and preserve the benefits of randomization. If a patient from the interventional group experiences a primary endpoint prior to the procedure—as they will be on OAC treatment—they will be allocated to the interventional group. An interim analysis will be performed after including 50% of the population (190 patients), and the study will be stopped if significant differences are detected.

Categorical variables will be expressed as frequencies and compared using the chi-square or Fisher’s exact test. Continuous variables will be expressed as mean ± SD or median (IQR), using the Kolmogorov-Smirnov test for normality. Comparisons will use the Student’s t test or the Mann-Whitney U test. Composite endpoints will be assessed as a time-to-first event. Cumulative incidence will be evaluated using the Kaplan-Meier method and compared using the log-rank test, followed by Cox proportional hazards modeling. Treatment effects will be estimated with hazard ratios and 95% confidence intervals, with 2-sided P-values ≤ .05 considered statistically significant. Analyses will be performed using STATA (Version 14.0 (Stata Corp., United States). The trial has been registered on ClinicalTrials.gov, and the registry No. is pending registration approval.

Current study status

Study recruitment is set to commence. The study is expected to be completed in 23 months. The projected study timeline is shown in figure 3.

Figure 3. Projected study timeline.

DISCUSSION AND CLINICAL IMPLICATIONS

The current study is expected to have a significant impact on the scientific community, particularly in the fields of cardiology and neurology. As previously mentioned, the prevalence of AF and the number of patients experiencing ischemic strokes despite being OAC are on the rise,3-5 which presents a significant challenge due to the absence of clear and uniform treatment recommendations for these patients. Intensification of antithrombotic regimens in this population often leads to an elevated risk of major bleeding, especially among elderly and frail individuals.13 Therefore, assessing a novel therapeutic strategy that combines LAAO with DOAC is essential. LAAO targets the left atrial appendage, which is responsible for more than 90% of thrombus formation in non-valvular AF,16 potentially enhancing the efficacy of OAC while maintaining a lower bleeding risk with DOAC. Recent registries evaluating the LAAO + DOAC strategy have reported promising outcomes, demonstrating a significantly reduced rate of recurrent strokes and major bleeding vs optimal medical therapy alone.23-25 Given these encouraging preliminary data, the timing is ideal for a randomized controlled trial to evaluate this combined approach rigorously.

As far as we know, the proposed study is one of the first randomized clinical trials to compare LAAO + DOAC and optimal medical therapy, as determined by a neurologist, in patients who have experienced ischemic strokes despite being on OAC. The ELAPSE trial has also started recruitment with a similar design (NCT05976685). Should trial results confirm the superiority of the LAAO + DOAC strategy over current medical management protocols, our findings will contribute to a paradigm shift in the treatment guidelines for this patient cohort. Specifically, the LAAO + DOAC combo could offer a more effective and safer therapeutic option, addressing the unmet need for reducing stroke recurrence while minimizing bleeding risks, which could impact future clinical practice and guideline recommendations, ultimately improving patient outcomes in those with AF and a history of ischemic stroke. This trial successful completion and positive outcomes can potentially establish a new standard of care, thus significantly impacting clinical practice and patient quality of life alike in this high-risk population.

To achieve these goals, the centers participating in this study have been carefully selected based on their annual volume of candidates for LAAO and their expertise in managing these procedures. These centers are recognized as referral centers for both LAAO and stroke code management. Although randomizing 380 patients across 6 hospitals within a reasonable timeframe may appear challenging, we have implemented measures to streamline the process. Dedicated teams for the early identification of eligible patients and standardized follow-up strategies have been established to facilitate recruitment.

We recognize that this is an ambitious undertaking; however, the study design and the cumulative experience of participant centers provide confidence in achieving the goals set within the anticipated timeline. If successful, this trial has the potential to establish a new standard of care, significantly impacting clinical practice and improving the quality of life of this high-risk population.

FUNDING

This work has been funded by a grant from Fundació La Marató de TV3.

ETHICAL CONSIDERATIONS

The study is being conducted following the recommendations outlined in the Declaration of Helsinki on clinical research, has been approved by Hospital Clinic de Barcelona Research Ethics Committee, and endorsed by the remaining ethics committees of all participant centers. Informed consent acceptance and signature are required prior to performing any elective procedures for the study of the non-culprit lesions. Potential sex and gender biases are considered.

STATEMENT ON THE USE OF ARTIFICIAL INTELLIGENCE

No artificial intelligence was used in the drafting of this manuscript.

AUTHORS’ CONTRIBUTIONS

X. Freixa and E. Flores-Umanzor drafted this document. The remaining signatories reviewed the document and made changes at their discretion. All the authors revised and approved the final version of the manuscript.

CONFLICTS OF INTEREST

I. Cruz-Gonzalez and X. Freixa are proctors from Abbott Medical, Boston Scientific and Lifetech. R. Estevez-Loureiro and D. Arzamendi are proctors from Abbott Medical, Boston Scientific. L. Nombela- Franco is a proctor from Abbott Medical. The rest of the authors declared no conflicts of interest whatsoever.

REFERENCES