Efficacy and safety of left atrial appendage closure procedure in patients with non-valvular atrial fibrillation with contraindication and/or failure for oral anticoagulants: A systematic review and meta-analysis

Simões, Ricardo dos Santos; Bortoluzzi, Aline Frossard Ribeiro; Marinho, Janaina Cardoso Nunes; Galendi, Julia Simões Corrêa; Bernardo, Wanderley Marques

doi:10.1016/j.clinsp.2024.100465

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Review articles • Clinics 79 • 2024 • https://doi.org/10.1016/j.clinsp.2024.100465 copy

Efficacy and safety of left atrial appendage closure procedure in patients with non-valvular atrial fibrillation with contraindication and/or failure for oral anticoagulants: A systematic review and meta-analysis

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Background:

With the aim of reducing the risk of Cerebrovascular Accident (CVA) in patients with Non-Valvular Atrial Fibrillation (NVAF), Left Atrial Appendage Occlusion (LAAO) devices are emerging as an alternative to oral anticoagulants.

Objective:

To analyze the efficacy and safety of the LAAO procedure in patients with NVAF and contraindications and/or failure for oral anticoagulants.

Method:

The search for evidence was carried out in the electronic databases Medline and Embase till January 2024. Additional searches were conducted on Google Scholar. The clinical trials registry database was also consulted. Two blinded investigators performed the search, study selection, and data collection, and assessed quality and risk of bias using the Cochrane tool for randomized clinical trials. Meta-analyses of eligible trials were performed using RevMan 5.4.1 software. The random effects model was used for all analyses.

Results:

Five articles were selected, among which three were non-inferiority randomized clinical trials that analyzed the performance and safety of LAAO devices compared to the use of Vitamin K Antagonists (AVKs) or Novel Oral Anticoagulants (NOACs). No randomized clinical trials were found that analyzed populations with absolute contraindications to oral anticoagulants. Having as primary outcomes analyzed the occurrence of stroke (ischemic or hemorrhagic), cardiovascular or unexplained death and systemic embolism, the non-inferiority of the LAAO procedure compared to the use of oral anticoagulants was verified.

Conclusions:

For patients with an absolute contraindication to anticoagulation and/or failure to use oral anticoagulants, evidence for the use of LAAO devices is scarce.

Keywords:
Atrial fibrillation; Left atrial appendage closure; Systematic review; Meta-analysis

HIGHLIGHTS

Left atrial appendage occlusion is a surgical procedure considered as an alternative for populations with contraindications or failure of anticoagulation.

Based on the studies, it was evaluated that, among the consensual metrics (CHADS-VASC and HAS-BLED), the degree of thromboembolic risk and bleeding used was variable, not clarifying the profile of patients who would benefit from the occlusion procedure.

Most of the studies evaluated are non-inferior, comparing the occlusion of the atrial appendage of patients on anticoagulation with vitamin K inhibitors, with no contraindication to the use of this group of drugs. There are ongoing studies, with data to be published with the use of new oral anticoagulants (direct inhibitors), to compare the safety of patients undergoing atrial appendage occlusion.

There is also a lack of evidence related to the occlusion devices, especially regarding long-term use data, since when positioned, it can cause anatomical and physiological changes. Also, there is more than one model of the device with differences between them, suggesting the need for comparative studies.

Medline/PubMed

#1: (Atrial Appendage* OR Atrium Appendage OR Appendage, Atrium OR Appendages, Atrium OR Atrium Appendages OR Auricular Appendage OR Appendage, Auricular OR Appendages, Auricular OR Auricular Appendages OR Heart Atrium Appendage OR Appendage, Heart Atrium OR Appendages, Heart Atrium OR Atrium Appendage, Heart OR Heart Atrium Appendages) n=10.683

#2: (Atrial Fibrillation* OR Persistent Atrial Fibrillation OR Atrial Fibrillation, Persistent OR Atrial Fibrillations, Persistent OR Fibrillation, Persistent Atrial OR Fibrillations, Persistent Atrial OR Fibrillation, Atrial OR Fibrillations, Atrial OR Auricular Fibrillation OR Paroxysmal Atrial Fibrillation OR Atrial Fibrillation, Paroxysmal OR Atrial Fibrillations, Paroxysmal OR Fibrillation, Paroxysmal Atrial OR Fibrillations, Paroxysmal Atrial OR Paroxysmal Atrial Fibrillations) n=110.878

#3: (Cardiac Surgical Procedures* OR Surgical Procedures, Heart OR Cardiac Surgical Procedure OR Heart Surgical Procedures OR Procedure, Heart Surgical OR Procedures, Heart Surgical OR Surgical Procedure, Heart OR Heart Surgical Procedure) n=299.347

#4: Random* n=1.724.478

#1 AND #2 n=6.714

#1 AND #2 AND#3n=1.318

#1 AND #2 AND#3AND #4n=142

#1 AND #2 AND #3 n=1.318 AND ((clinical[Title/Abstract] AND trial[Title/ Abstract]) OR clinical trials as topic[MeSH Terms] OR clinical trial[Publication Type] OR random*[Title/Abstract] OR random allocation[MeSH Terms] OR therapeutic use[MeSH Subheading]) n=609

Embase

’heart atrium appendage’/exp AND ’atrial fibrillation’/exp AND ’heart surgery’/exp AND ’controlled study’/de n=459

Author/Year	Study type	Patients	Intervention	Comparison	Outcomes	Results	Follow-up (months)
Holmes et al., 2009 (PROTECT AF study)	RCT, multicentric non-inferiority	n = 707 patients ≥ 18-years, persistent or paroxysmal NVAF, CHADS2 risk score ≥ 1 with at least one of the following characteristics: previous stroke or TIA, DM, CHF	Percutaneous LAAO device (n 463 )	Warfarin (n = 244)	Primary outcomes: ischemic stroke, cardiovascular or unexplained death, systemic embolism. The primary composite endpoint for safety consisted of events related to excessive bleeding or procedure-related complications	Efficacy: With the follow-up of 1,065 patients/year, the occurrence rate of primary outcomes was 3 per 100 patients/year (95% CI 1.9‒4.5) and 4.9 per 100 patients/year (95% CI 2.8‒7.1) for the intervention and control groups respectively Adverse events: Occurred more frequently in the intervention group (RR = 1.69 with 95% CI 1.01‒3.19) with the most frequent being severe pericardial effusion, which occurred in n = 22 patients. In the two-year follow-up after randomization, the cumulative rate of adverse events was 10.2% (95% CI 7.4‒13) for the intervention group vs. 6.8% (95% CI 3.0‒ 10.6) for the control group	18
Holmes et al., 2014 (PREVAIL study)	RCT, multicentric non-inferiority	n = 407 patients with a mean age of 74-years and CHADS2 ≥ 2	Percutaneous LAAO device (n = 269)	Warfarin (n = 138)	Primary outcomes: stroke, systemic embolism and cardiovascular or unexplained death	Efficacy: The rate of stroke and death in the 18^th month of follow-up was 0.064 in the intervention group and 0.063 in the warfarin group. The calculated rate ratio was 1.07 with 95% CI 0.57‒1.89. This, however, did not meet the predefined non-inferiority criterion, as the upper limit (1.89) crosses the predefined non-inferiority margin of 1.75. The percentage per patient/year who had a stroke in the intervention group was 2.3% and in the control group 0.7%	12
Reddy et al., 2014	RCT, multicentric non-inferiority	n = 707 patients ≥ 18-years, persistent or paroxysmal NVAF, CHADS2 risk score ≥ 1 with at least one of the following characteristics: previous stroke or TIA, DM	Percutaneous LAAO device (n = 463)	Warfarin (n = 244)	Primary outcomes: ischemic stroke, cardiovascular or unexplained death, systemic embolism. The primary composite endpoint for safety consisted of events related to excessive bleeding or procedure-related complications	Efficacy: With a mean follow-up of 3.8±1.7 years (2,621 patients/year), there were 39 events among 463 patients (8.4%) in the intervention group (2.3 events per 100 patient-years) in compared to 34 events among 244 patients (13.9%) in the control group (3.8 events per 100 patient-years). Patients in the intervention group demonstrated lower rates of cardiovascular mortality (1 event per 100 patient-years for the device group [n = 17/463] vs. 2.4 events per 100 patient-years for warfarin [n = 22/244] and all-cause mortality (3.2 events per 100 patient-years for the device group [n = 57/466] vs. 4.8 events per 100 patient-years for warfarin [n = 44/244]	60
Osmancik et al., 2020 (PRAGUE-17 study NCT02426944)	RCT, multicentric non-inferiority	n = 415 patients with a mean age of 73.3-years and a history of bleeding that required intervention or hospitalization, history of a cardioembolic event while using an anticoagulant agent; or moderate to high risk profile, defined as CHA2DS2-VASc ≥ 3 + HAS-BLED ≥ 2	Percutaneous LAAO device (n = 213)	NOAC (n = 202)	Primary outcomes: ischemic stroke, hemorrhagic stroke or TIA, embolism, clinically significant bleeding, cardiovascular death, bleeding, and procedure/ device-related complications	Efficacy: LAAO was successful in n = 181/201 patients. In the NOAC group, apixaban was used more frequently (n = 192/201). The annual primary outcome rates were 10.99% with OAAE and 13.42% with NOAC. There was no difference between the groups for the components of the outcome consisting of ischemic stroke, hemorrhagic stroke, TIA, clinically significant bleeding and cardiovascular death Adverse events: LAAO device-related complications occurred in n = 9 patients	19
Reddy et al., 2013 (estudo ASAP NCT00851578)	CT, multicentric	n = 150 patients with a mean age of 72.5 ± 7.4 years and NVAF and CHADS2 risk score ≥ 1 ineligible for the	Percutaneous LAAO device	-	Primary outcomes: ischemic stroke, hemorrhagic stroke, systemic embolism, and death car-diovascular/ unexplained	Efficacy: ischemic stroke, hemorrhagic stroke or systemic embolism occurred in n = 4 patients Adverse events: Serious safety events related to the procedure or device occurred in 8.7% of patients (n = 13/150)	14

Certainty assessment							No of patients		Effect		Certainty	Importance
No of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	LAAO	Relative (95% CI)	Absolute (95% CI)		Certainty	Importance
Primary composite outcome (ischemic stroke, hemorrhagic stroke, cardiovascular or unexplained death, systemic embolism) (follow-up: 18 months)
2	Randomised trials	Very serious^a a Due to the interventionist nature of the technology under study, blind allocation or blinding of participants or attending physicians involved in the analyzes was not possible. Domain 3 was judged to have high risk of bias, because in both included studies there was high rates of loss of follow-up, which were unbalanced between groups. There were some concerns regarding domain 5 because neither the PROTECT AF trial nor the PREVAIL trial had their protocols published beforehand.	Serious^b b Heterogeneity was assessed at 73% by Higgins’s test.	Serious^c c No included study assessed patients with contraindication to oral anticoagulation.	Serious^d d Confidence interval included the null effect.	None	35/732 (4.8%)	22/382 (5.8%)	Not estimable	0 fewer per 1,000 (from 50 fewer to 50 more)^e e A risk difference meta-analysis was done.	⨁◯◯◯ Very low	CRITICAL
Ischemic stroke (follow-up: 18 months)
2	Randomised trials	Very serious^a a Due to the interventionist nature of the technology under study, blind allocation or blinding of participants or attending physicians involved in the analyzes was not possible. Domain 3 was judged to have high risk of bias, because in both included studies there was high rates of loss of follow-up, which were unbalanced between groups. There were some concerns regarding domain 5 because neither the PROTECT AF trial nor the PREVAIL trial had their protocols published beforehand.	Not serious	Serious^c c No included study assessed patients with contraindication to oral anticoagulation.	Serious^d d Confidence interval included the null effect.	None	20/732 (2.7%)	7/382 (1.8%)	Not estimable	10 more per 1,000 (from 10 fewer to 30 more)^e e A risk difference meta-analysis was done.	⨁◯◯◯ Very low	CRITICAL
Hemorrhagic stroke (follow-up: 18 months)
2	Randomised trials	Very serious^a a Due to the interventionist nature of the technology under study, blind allocation or blinding of participants or attending physicians involved in the analyzes was not possible. Domain 3 was judged to have high risk of bias, because in both included studies there was high rates of loss of follow-up, which were unbalanced between groups. There were some concerns regarding domain 5 because neither the PROTECT AF trial nor the PREVAIL trial had their protocols published beforehand.	Serious^f f Heterogeneity was assessed at 85% by the Higgins test.	Serious^c c No included study assessed patients with contraindication to oral anticoagulation.	Serious^d d Confidence interval included the null effect.	None	2/732 (0.3%)	6/382 (1.6%)	Not estimable	10 fewer per 1,000 (from 40 fewer to 20 more)^e e A risk difference meta-analysis was done.	⨁◯◯◯ Very low	CRITICAL
Cardiovascular or unexplained death (follow-up: 18 months)
2	Randomised trials	Very serious^a a Due to the interventionist nature of the technology under study, blind allocation or blinding of participants or attending physicians involved in the analyzes was not possible. Domain 3 was judged to have high risk of bias, because in both included studies there was high rates of loss of follow-up, which were unbalanced between groups. There were some concerns regarding domain 5 because neither the PROTECT AF trial nor the PREVAIL trial had their protocols published beforehand.	Serious^g g Heterogeneity was assessed at 64% by the Higgins test.	Serious^c c No included study assessed patients with contraindication to oral anticoagulation.	Serious^d d Confidence interval included the null effect.	None	12/732 (1.6%)	13/382 (3.4%)	Not estimable	10 fewer per 1,000 (from 50 fewer to 20 more)^e e A risk difference meta-analysis was done.	⨁◯◯◯ Very low	CRITICAL
Systemic embolism (follow-up: 18-months)
2	Randomised trials	Very serious^a a Due to the interventionist nature of the technology under study, blind allocation or blinding of participants or attending physicians involved in the analyzes was not possible. Domain 3 was judged to have high risk of bias, because in both included studies there was high rates of loss of follow-up, which were unbalanced between groups. There were some concerns regarding domain 5 because neither the PROTECT AF trial nor the PREVAIL trial had their protocols published beforehand.	Not serious	Serious^c c No included study assessed patients with contraindication to oral anticoagulation.	Serious^d d Confidence interval included the null effect.	None	3/732 (0.4%)	0/382 (0.0%)	Not estimable	0 fewer per 1,000 (from 0 fewer to 10 more)^e e A risk difference meta-analysis was done.	⨁◯◯◯ Very low	CRITICAL

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[1] *Corresponding author. E-mail address:janaina.marinho@unimed.coop.br (J.C.N. Marinho).