Closure of a patent foramen ovale with a device does not offer a greater benefit than medical therapy alone for the prevention of recurrent cerebrovascular events
- Correspondence to: Professor Heinrich Mattle
Department of Neurology, Freiburgstrasse, 3010 Bern, Switzerland;
Stroke can rarely be caused by paradoxical emboli passing from the right side of the circulatory system to the left side. Case reports have shown that the most common site of right to left shunt is the patent foramen ovale (PFO), and case control studies have shown a higher prevalence of PFO in patients with cryptogenic stroke as compared to stroke victims with a known cause or non-stroke controls. Therefore, the question arises as to whether closure of the PFO is useful in preventing recurrent stroke in patients with cryptogenic stroke and PFO.
CLOSURE is a multicentre, randomised, open-label trial of PFO closure with STARFlex, a percutaneous device, as compared with medical therapy alone in patients aged 18–60 years who presented with a cryptogenic stroke or transient ischaemic attack (TIA) and had a PFO. The primary endpoint was a composite of stroke or transient ischaemic attack during 2 years of follow-up, death from any cause during the first 30 days or death from neurological causes between 31 days and 2 years.
A total of 909 patients were randomised. The cumulative incidence (Kaplan-Meier estimate) of the primary endpoint was 5.5% in the closure group (447 patients) as compared with 6.8% in the medical therapy group (462 patients) (adjusted HR, 0.78, 95%, CI 0.45 to 1.35, p=0.37). The respective rates were 2.9% and 3.1% for stroke (p=0.79) and 3.1% and 4.1% for TIA (p=0.44). No deaths occurred by 30 days in either group, and there were no deaths from neurological causes during the 2-year follow-up period. A cause other than paradoxical embolism was usually apparent in patients with recurrent neurological events.
Several randomised trials have been initiated to compare device closure of a PFO and medical therapy in patients with cryptogenic stroke or TIA and a PFO. CLOSURE is the first trial to report results. Closure of the PFO with a device did not offer a greater benefit than medical therapy alone for the prevention of recurrent cerebrovascular events. There was only a non-significant trend towards less composite endpoints in the closure group, a result that was mainly driven by less recurrent TIAs and that could be a chance finding. The rate of recurrent stroke was similar in both groups and was lower than expected (ie, around 3% in the two study years in both groups). Surprisingly, recurrent events were, in a high proportion, not cryptogenic but were related to a clearly defined cause other than PFO. This may already indicate that the index stroke or TIA was not related to the PFO and the real cause may have been overlooked. It also speaks of the difficulty of precisely defining paradoxical embolism, especially when one or more traditional risk factors such as smoking, hypertension or hypercholesterolaemia are present in a patient with PFO and some atherosclerotic wall changes but no apparent macroangiopathy.
Overall, device closure was a safe procedure and adverse events were rare. It was also effective with a PFO closure rate of 86%. Nevertheless, adverse events such as major vascular complications occurred only in the closure group and atrial fibrillation, although transient, was more common in the closure arm of the trial. This leaves us with the open question of whether the device closure caused the atrial fibrillation or whether the atrial septal anomaly per se is related to the arrhythmia.
The CLOSURE trial is an excellent trial. Nevertheless, it does not answer the question of whether some patients or a subgroup with an elevated recurrence risk will benefit from device closure. The question of whether there is a place for device closure remains unanswered. The event rate and the risk reduction were lower than expected, and the trial did not have adequate power to find or rule out a meaningful effect. In addition, a follow-up of 2 years in a condition that exposes a patient to a lifetime risk of paradoxical emboli does not seem to be adequate. The PC-Trial, RESPECT, CLOSE and GORE are additional randomised trials to compare device closure and medical therapy that are ongoing or about to be finished. Approximately 4500–5000 patients will eventually be randomised. Potentially the findings of these trials can answer the following questions: (a) which device is the best among several devices on the market and (b) whether there is a benefit from closure of the PFO compared to medical therapy alone. Medical therapy cannot be discontinued after successful device closure, because the diagnosis of a paradoxical embolic stroke mechanism can only be inferred by ruling out other causes and can be assumed as certain only in a very rare patient in whom the embolus is seen on echocardiography passing through the PFO.
Competing interests None.