Percutaneous closure of patent foramen ovale for cryptogenic stroke: A meta-analysis of randomized controlled trials,☆☆

https://doi.org/10.1016/j.ijcard.2013.07.077Get rights and content

Abstract

Background

There is an ongoing debate on the role of percutaneous closure of patent foramen ovale (PFO) in preventing recurrent ischemic events in patients with cryptogenic stroke and PFO. We systematically reviewed the latest randomized data on the efficacy and safety of percutaneous PFO closure in patients with cryptogenic stroke and PFO.

Methods

MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched in April 2013 for eligible randomized controlled trials (RCTs). Primary outcome measures included: (i) stroke; (ii) transient ischemic attack (TIA); and (iii) all-cause mortality. Secondary outcomes were new-onset atrial fibrillation (AF) and bleeding.

Results

We included a total of three RCTs randomizing 2303 participants. The intervention groups used either the STARFlex® Septal Closure System (one trial, n = 447) or the AMPLATZER™ PFO Occluder (two trials, n = 703). Control arms (n = 1153) used medical treatment composing of antiplatelet or anticoagulation therapy. There were no significant differences between groups in the analyses of stroke (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.36–1.20, P = 0.17), TIA (hazard ratio (HR) 0.77, 95% CI 0.45–1.32, P = 0.35), all-cause mortality (OR 0.65, 95% CI 0.23–1.85, P = 0.42) or bleeding (OR 1.43, 95% CI 0.47–4.42, P = 0.53). Percutaneous PFO closure was associated with a significantly higher incidence of new-onset AF as compared to medical therapy (OR 3.77, 95% CI 1.44–9.87, P = 0.007).

Conclusions

Currently-available randomized data do not support the use of percutaneous PFO closure for secondary stroke prevention in patients with cryptogenic stroke and PFO. An updated meta-analysis including further data from ongoing RCTs is warranted.

Introduction

Stroke is a leading cause of mortality in the world and ranked as the fourth leading cause in the United States in 2010 [1]. 87% of all strokes are ischemic and it has been found that causes of up to 40% of infarcts in ischemic strokes were classified as undetermined [1], [2]. Such strokes are referred to as cryptogenic strokes [3]. Foramen ovale is formed during fetal development of the atrial septum as an unfused partition between the septum secundum and septum primum [4], [5], [6]. The flap-like structure of the foramen ovale allows right-to-left shunting of blood for fetal circulation and is usually fused against the septum secundum by age two due to increased left atrial pressure and decreased pulmonary resistance; however, patency occurs in approximately 25% of the population, resulting in patent foramen ovale (PFO) [4], [6]. Venous thromboembolism with right-to-left transit via PFO has been proposed as the major mechanism for cryptogenic stroke [7], and a higher prevalence of PFO was identified in patients with cryptogenic stroke [8], [9], [10], [11]. This has prompted a paradigm shift of research interest from medical therapy with antiplatelets or anticoagulants to percutaneous closure of PFO for secondary stroke prevention in patients with cryptogenic stroke and PFO [12], [13]. Previous efforts in exploring the relative effectiveness of percutaneous PFO closure versus medical therapy relied heavily on data from single-arm or non-randomized comparative studies [14]. Existing meta-analyses of non-randomized studies demonstrated that percutaneous closure of PFO was associated with a significantly lower incidence of recurrent stroke or transient ischemic attack (TIA) as compared with medical therapy (incidence rate ratio 0.22, 95% confidence interval (CI) 0.07–0.64 [15]; relative risk (RR) 0.25, 95% CI 0.11–0.58 [16]). Randomized data have since become available and consequently, we conducted this meta-analysis to systematically review the latest evidence on the efficacy and safety of percutaneous PFO closure compared to medical therapy for cryptogenic stroke.

Section snippets

Study selection and data extraction

MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched in April 2013 to identify eligible randomized controlled trials (RCTs) evaluating the efficacy and safety of percutaneous closure of PFO in patients with cryptogenic stroke or TIA using the keywords: “Foramen Ovale, Patent”, “Stroke” and “Embolism”. No language restrictions were applied. Reference lists of retrieved records and relevant reviews were also screened. Ongoing studies were identified from

Description of included studies

Our study selection process is illustrated in Fig. 1 [18]. A total 1439 records were identified from our literature search. Of these, full-texts of 20 were retrieved for further assessment. Three RCTs were eventually included in our meta-analysis and three ongoing studies were also identified (Table 1, Table 2) [19], [20], [21], [22], [23], [24], [25], [26]. The three included studies were all multicenter studies and randomized a total of 2303 participants, of whom 1150 were allocated to

Discussion

To our knowledge, this is the first attempt to pool data from the three available randomized studies in the field of percutaneous PFO closure for secondary stroke prevention in patients with cryptogenic stroke. Our meta-analysis indicates that, when compared to medical therapy, percutaneous closure of PFO does not differ from medical therapy in terms of secondary stroke prevention, there are no apparent benefits in reducing the incidence of TIA or mortality, and percutaneous closure of PFO is

Conclusions

Our meta-analysis of three randomized studies indicates that there is currently insufficient evidence to support the use of percutaneous PFO closure for secondary stroke prevention in patients with cryptogenic stroke and PFO. Due to unique pathophysiology and low event rates, the quest for further randomized studies to expand on the body of evidence of the efficacy and safety of percutaneous PFO closure in cryptogenic stroke remains challenging. Despite the modest statistical power of the

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      For instance, in the CLOSE trial, patients were enrolled only if they had an atrial septal aneurysm, defined by a septal primum excursion of greater than 10 milimeters present on transesophageal echocardiography, as well as a large shunt, which was defined as the appearance of more than 30 microbubbles in the left atrium within three cardiac cycles of opacification of right atrium. Secondly, the historical trials used a liberal definition criteria for stroke, which may have led to inclusion of the events that were mechanistically distinct from the strokes that occur in patients with PFO (although unclear, the two commonly believed mechanisms are paradoxical embolism traveling via PFO or clot formation within the PFO tract).14-16 This was illustrated in the CLOSURE I trial, which included patients with lacunar strokes that were unlikely to be explained by PFO.6

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    All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

    ☆☆

    Grant support: None.

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