Proof that percutaneous closure of the patent foramen ovale (PFO) is superior to medical treatment is still incomplete. Paradoxical embolism is a rare event occurring over decades rather than years. None of the 4 randomized trials published carried enough patients or was followed up for long enough to reach superiority endpoints. All data, however, point to a benefit of PFO closure. Free wall erosion (exceedingly rare) and triggering of atrial fibrillation (in about 1% of patients) are the only noteworthy complications. They are outweighed by the supposedly prevented events of paradoxical embolisms, such as stroke, transient ischemic attacks, myocardial infarctions, or other systemic embolisms. Medical treatment with perhaps the exception of lifelong oral anticoagulation provides less protection. During a 10-year follow-up of a comparative study the annual mortality was significantly lower in the patients with PFO closure (0.4%) than in those with medical treatment (1.1%,
The patent foramen ovale (PFO) has been recognized for over a century as a plausible cause of stroke permitting paradoxical embolism of a per se rather innocuous small venous clot that would go clinically unnoticed if it embolized to the lungs where it would be lysed by intrinsic fibrinogen activators in a day or two [
While the initial devices were far from perfect, the clinical introduction of the Amplatzer PFO occluder (APO) in 1997 by Kurt Amplatz and the author on September 10, 1997 (Figure
Kurt Amplatz (left) and Bernhard Meier (right) on the occasion of the world’s first closure of a patent foramen ovale using an Amplatzer PFO occluder (insert) on September 10, 1997, in Switzerland.
The technique developed by the inventor and the author is very straightforward and stripped to the bare essential. In particular, there is no intraprocedural echocardiography involved in contrast to the policy of most centers. While additional imaging has a potential to enhance safety and quality, it also harbors additional risks, for example, by prolonging the procedure which my engender clot-forming in the indwelling gear.
All that is required is a set consisting of a TorqVue sheath with its obturator, a pusher cable, a short loader sheath, and a Y-connector with adjustable fitting. The 9 French (F) size sheath fits all APOs except for the 40/40 mm cribriform ASD occluder which is the largest member of the Amplatzer device families predestined for PFO occlusion (Figure
Family of Amplatzer PFO occluders. The right/left numbers indicate the diameters of the left and right disk, respectively (different in some devices). The French size indicates the minimal inner lumen of the required sheath (1F = 0.3 mm). The double (cribriform) occluders are also predestined for cribriform atrial septal defects.
The patient does not usually need sedation. A bolus of 5,000 units of heparin is given. After local anesthesia of the groin a regular 0.035 inch U-shape tip guidewire is introduced through a puncture needle. In about half of the cases the wire will readily pass through the PFO into the left atrium. If not, a curved catheter (ideally multipurpose shape) placed at the level of the diaphragm will direct the wire medially. If the PFO still cannot be passed, it is negotiated with the catheter alone and if that fails with the leading wire after straightening the U-tip. Occasionally it will be necessary to inject contrast medium to the direction where the PFO is suspected to learn more about anatomy before passing the PFO. A typical situation for that would be a PFO that consists only of a small hole in one of the corners of the initial foramen. In this case it will be necessary to guide the wire to a sharp turn once it has entered the PFO tunnel.
Next the device is prepared by screwing it loosely onto the pusher cable and retracting it in a water bath into the short loading sheath to avoid trapped air bubbles. It is wise to push it out of the loading sheath just once and retract it back while staying under water. Repeated loading maneuvers may temporarily impede the formation of flat disks.
The device is now introduced into the TorqVue sheath which was advanced into the left atrium where the obturator was slowly withdrawn allowing for back bleeding while holding the outer end of the sheath as low as possible (usually on the right side of the patient’s thigh). For this, the short loading sheath is connected to the TorqVue sheath and the device is advanced close to the tip of the sheath. Air that is entering the sheath behind the device is of no concern at that point. Before exiting the sheath the safe but slightly loosened attachment of the screw is checked on fluoroscopy. If there is no gap between the screw and its female counterpart on the device, the pusher cable is turned leftward until it is felt that the apparently too tightly fit screw is now freely turning. The gap mentioned before will now appear on fluoroscopy.
The left half of the device is pushed out of the sheath up to the middle waist so that the left disk can fully form. The sheath and the pusher are then pulled back as a unit until the left disk gets stopped at the septum. In a left anterior oblique (LAO) projection the left disk will now appear in its profile. From there on only the sheath will be pulled back while gently advancing on the pusher cable. As soon as the tip of the sheath has passed the screw, the entire set is pushed against the septum to put the right disk into its proper place. At this point the typical Pacman sign should be apparent in the LAO projection (Figure
Correct placement of an Amplatzer PFO occluder ascertained by the Pacman sign. The transesophageal echocardiogram at the left is depicted in the projection usually used on fluoroscopy during implantation. The septum secundum (SS) has to be bitten into by the left more cranial parts of the occluder disks. This reminds us of Pacman biting into a dot.
The stability of the position is checked with a strong wiggle on the pusher cable and a dye injection delineating the right atrial septal border in a projection showing the 2 disks in profile and perfectly separating them (Figure
The patient can well compress the femoral venous puncture himself or herself as there is no risk of hematoma in a supine person. The pressure in the femoral vein is 10 mmHg or less. The patient may even get up immediately but then the pressure on the groin has to be increased to about 60 mmHg because of the weight of the blood column from the top of the head to the groin.
The patient receives a tablet each of acetylsalicylic acid, 100 mg, and clopidogrel, 75 mg, to continue the former daily for 5 and the latter for 1 month. We usually perform a control transesophageal echocardiography (TEE) about 1 month after stopping all medications, that is, at about 6 months.
No restrictions are asked for and even sports are permitted immediately. Usually a transthoracic echocardiogram is performed to document the device in place before the patient leaves the hospital after an hour or so of surveillance.
Antibiotic coverage during the procedure is used in most places, for example, by giving 1 g of a cephalosporin by mouth before the procedure and another one a couple of hours later. Most centers also recommend observing the usual prophylaxis against endocarditis at least for the first 2 months.
Table
Potential indications for PFO closure.
(i) Secondary prevention | |
(a) Stroke | |
(b) Transient ischemic attack | |
(c) Embolic myocardial infarction | |
(d) Peripheral embolism | |
(e) Decompression incident | |
(f) High altitude pulmonary edema | |
(ii) Primary prevention | |
(a) Aggravating PFO attributes | |
(1) Atrial septal aneurysm | |
(2) Eustachian valve | |
(3) Chiari network | |
(b) Prothrombotic state | |
(c) Deep vein thrombosis | |
(d) Pulmonary embolism | |
(e) Pacemaker/defibrillator electrodes | |
(f) Embolism-prone surgery | |
(1) Major orthopedic | |
(2) Cerebral in sitting position | |
(g) Planned pregnancy | |
(h) Carcinoid tumor | |
(i) Special congenital situations | |
(iii) Therapeutic | |
(a) Migraine (with aura) | |
(b) Platypnea orthodeoxia | |
(c) Provoked exercise desaturation | |
(d) Sleep apnea | |
(iv) Vocational or recreational | |
(a) Deep sea diver | |
(b) Mountain climber, highlander | |
(c) Brass musician | |
(d) Glass blower | |
(e) Tile setter | |
(f) Military jet | |
(g) Astronaut or commercial pilot driver | |
(h) Acrobat pilot |
In light of the ease and safety of PFO closure and the compelling evidence of its efficacy in the prevention of several types of events, it appears mandatory to react to the first event already. Even in case that the event was not related to the PFO, the fact that the PFO was closed without any untoward effects (almost invariably the case) prevents the subject from any of the PFO-mediated problems in Table
The indication to close a PFO should not be subject to the absence of other potential stroke causes or stroke facilitators such as the ones listed in Table
Ischemic stroke classification.
(i) Arterial occlusion | |
(a) Lacunar | |
(b) Intracerebral | |
(c) Vertebral | |
(d) Internal carotid | |
(e) Common carotid | |
(f) Brachiocephalic | |
(ii) Arterial embolus | |
(a) Plaque/ulcer/dissection | |
(1) Intracerebral | |
(2) Carotid | |
(3) Vertebral | |
(4) Brachiocephalic | |
(5) Ascending aortic | |
(iii) Cardiac embolus from | |
(a) Left ventricle | |
(b) Left atrium | |
(1) Left atrial appendage (atrial fibrillation) | |
(2) Left atrial foramen pouch | |
(c) Myxoma or other tumors | |
(d) Vegetation (septic embolus) | |
(iv) Paradoxical embolus | |
(a) Patent foramen ovale | |
(b) Atrial septal defect | |
(c) Pulmonary fistula | |
(v) Pulmonary venous bed embolus | |
(vi) Cryptogenic |
Prothrombotic predisposition is common in the general population and should be a reason to close the PFO rather than not to. Even if the predisposition is considered severe enough to warrant lifelong oral anticoagulation, the thrombotic risk with the possibility of paradoxical embolism should still be considered high enough to warrant PFO closure.
A total of 4 randomized PFO closure trials have been published so far. The first one pertained to the role of the PFO in migraine and is called MIST trial (Migraine Intervention with STARFlex Technology) [
The CLOSURE I trial (Evaluation of the STARFlex Septal Closure System in Patients with a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale) in North America was the first randomized trial to be published on PFO closure for prevention of ischemic cerebral events [
The PC trial (Percutaneous Closure of Patent Foramen Ovale in Cryptogenic Embolism) was the next we published and had been the first to be started, about 12 years before publication by the author and his group [
The RESPECT trial [
Lumping and meta-analyzing these 3 trials, the trend to improved outcome with PFO closure compared to medical therapy becomes stronger [
There are 3 similar randomized trials still ongoing with a projected total cohort of roughly 1,700 patients, that is, the CLOSE trial in France (Closure of Patent Foramen Ovale or Anticoagulants versus Antiplatelet Therapy to Prevent Stroke Recurrence, NCT00562289), the DEFENSE PFO trial in South Korea (Device Closure Versus Medical Therapy for Secondary Prevention in Cryptogenic Stroke Patients with High Risk Patent Foramen Ovale, NCT01550588), and the REDUCE trial in Canada and Denmark (GORE HELEX Septal Occluder and Antiplatelet Medical Management for Reduction of Recurrent Stroke or Imaging-Confirmed TIA in Patients with Patent Foramen Ovale, NCT00738894). However, it is unlikely that any of these trials will be, in itself, significant for the reasons of patient numbers and follow-up duration cited above. They will add to the already sizable amount of data collected. It is close to certain that they will point to the same direction, that is, the advantage of PFO closure. The question even arises whether further randomization of patients with an index event suggesting paradoxical embolism and a proved PFO is ethical still. Recurrent events are more likely to occur in the control group and they may encompass death, debilitating stroke, or myocardial infarction and therefore be difficult to defend considering the fact that they could have been prevented by a simple procedure.
In terms of subjective improvement, 603 consecutive patients with APO PFO closure mainly for reason of secondary prevention after neurological events were assessed as per their migraine status before and long term after PFO closure [
Migraine status in 150 consecutive patients with Amplatzer PFO closure at an average of 5 ± 2 years of follow-up. The average age of the patients was 51 ± 11 years, 61% were males, and 91% had complete closure by 6-month transesophageal echocardiography. Antiplatelet treatment had been stopped at the latest 6 months after the intervention.
The most compelling data recommending PFO closure originate from the author’s group [
Annual event rates during a 10-year follow-up in 308 consecutive patients randomly assigned to PFO closure or medical treatment. PE = peripheral embolism and TI = transient ischemic attack.
Uncontestably, the PFO is a blemish with a small but definite threat to health and even survival. As it is present in about 25% of the population, every PFO cannot be closed. Even if the logistics were created to screen for a PFO and close every PFO detected it might not be economically feasible. Although a prevented stroke may save sufficient money to pay for hundreds of PFO closures, some PFOs may have a lifetime risk of hardly a percent to cause significant damage. Moreover, currently reliable screening for PFO is only possible with TEE combined with a Valsalva maneuver and an intravenous injection of echocardiographic contrast medium (bubble test). If the targeted sensitivity is reduced to large PFOs, such as those with an atrial septal aneurysm, opening the gap with every heartbeat, or those with an Eustachian valve directing the inflow from the inferior vena cava directly on to the PFO, transthoracic echocardiography with a bubble test suffices. Transcranial Doppler techniques to demonstrate right-to-left shunts have been perfected over the past 20 years but they also require an intravenous injection of some media with a gaseous content. They are able to detect even small shunts but they cannot define where the shunt occurs. The same holds true for the most simple of all techniques, the screening for ear lobe oxygen dip after a sustained Valsalva maneuver without using any injection [
The PFO needs not to be looked for in childhood as venous clots are virtually inexistent at very young age. Clots tend to come into existence at middle age (with few exceptions) after which their incidence rises geometrically [
PFO closure is the most straightforward, easy, and perhaps even the most beneficial (net benefit) intervention in today’s cardiology. It has to be in the repertory of every interventional cardiologist. Health authorities should not only ascertain reimbursement but also foster PFO closure. There is still a long way to go to fill the gaps in secondary prevention, not to mention exploiting the potential of PFO closure in primary prevention in terms of a mechanical vaccination.
The author declares that he has received research grants to the institution and speaker fees from St. Jude Medical.