RESPECT 2013.
| Methods | Prospective, multicenter, controlled, randomized, open label clinical trial with blinded adjudication of endpoint events | |
| Participants | Multicenter: 69 sites (USA and Canada) 980 participants between 18 and 60 years of age: 499 randomly assigned to closure and 481 to medical therapy All participants had a cryptogenic ischemic stroke within the last 270 days and a PFO which was defined as transesophageal echocardiographic evidence of infused microbubbles in the left atrium within 3 cardiac cycles after their appearance in the right atrium, at rest or during Valsalva release Exclusion criteria: a mechanism for the index stroke other than paradoxical embolization could be identified; stroke with poor outcome at time of enrolment (mRS > 3); contraindication to medical or device therapy; limited life expectancy less than 2 years; inability to attend follow‐up |
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| Interventions | Closure of the PFO with the Amplatzer PFO Occluder plus antiplatelet therapy versus medical therapy alone Participants in the closure group underwent the closure within 21 days after randomization and continued their pre‐randomization antithrombotic regimen until placement of the device. After placement of the device, participants received 81 to 325 mg of aspirin plus clopidogrel for 1 month, followed by aspirin monotherapy for 5 months. Subsequent antiplatelet therapy was administered at the discretion of the site investigator In the medical therapy group, aspirin, warfarin, clopidogrel, aspirin with clopidogrel, and aspirin combined with extended‐release dipyridamole were allowed (aspirin with clopidogrel was also permitted initially but was eliminated in 2006 to conform to a change in AHA/ASA stroke guidelines) Mean follow up: 2.6 ± 2.0 years |
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| Outcomes | All participants were evaluated at 1, 6, 12, 18, and 24 months and annually thereafter Primary endpoint: composite of recurrent non‐fatal ischemic stroke, fatal ischemic stroke, or early death after randomization Secondary endpoint: the absence of recurrent symptomatic non‐fatal ischemic stroke or cardiovascular death, and the absence of a TIA; complete closure of the PFO on the 6‐month follow‐up TEE; and serious adverse events |
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| Notes | The trial was sponsored by St Jude Medical, who selected and monitored the sites and was responsible for data management | |
| Risk of bias | ||
| Bias | Authors' judgement | Support for judgement |
| Random sequence generation (selection bias) | Unclear risk | Not reported |
| Allocation concealment (selection bias) | Unclear risk | Participants were randomly assigned, in a 1:1 ratio, to medical therapy alone or to closure of the PFO Randomisation was stratified according to site, recommended medical treatment before randomization, and presence or absence of an atrial septal aneurysm |
| Blinding of participants and personnel (performance bias) All outcomes | High risk | Not blinded |
| Blinding of outcome assessment (detection bias) All outcomes | Low risk | An independent clinical events committee, whose members were unaware of the identities of the participants, the treatment assignments, and the site at which the participants were enrolled, adjudicated endpoint events |
| Incomplete outcome data (attrition bias) All outcomes | High risk | Although the study clearly reported the number of participants who withdrew from the study and were lost to follow‐up (46 (9.2%) participants in the closure group and 83 (17.2%) participants in the medical therapy group) and performed the ITT analysis, the high dropout rate compared with event rate and the difference in the dropout rate between the closure and medical therapy groups could still lead to high risk of attrition bias |
| Selective reporting (reporting bias) | Unclear risk | Not reported |
| Other bias | Low risk | Not reported |
INR: International Normalized Ratio ITT: intention‐to‐treat mRS: modified Rankin Scale PFO: patent foramen ovale TEE: transesophageal echocardiography TIA: transient ischemic attack