Migraine intervention with starflex technology mist trial

In addition, about half the people with migraine with aura have no shunt. They presumable have a different mechanism, unrelated to right-to-left shunting, as the cause. It follows that some people that have a right-to-left shunt will have migraine with aura as a result of the other mechanism unrelated to a right-to-left shunt. The data suggest that such coincidence is most likely when the shunt size is small. People with migraine with aura have high incidences of shunt related events.

They have an incidence of stroke that is 2. Women with migraine with aura on the combined oral contraceptive pill have a risk of stroke that is increased 8. The majority of episodes of neurological, cardiovascular and cutaneous decompression illness are the result of paradoxical gas embolism—venous bubbles that form during decompression circumventing the lung filter by crossing a PFO or other right-to-left shunt.

It is important to appreciate that the size of the shunt across a PFO is related to diameter of the defect. Migraine often appears to run in families. In many families, the presence of a large PFO is dominantly inherited and co-segregates with affected individuals having migraine with aura. Prevalence and size of PFOs are equal in men and women, but migraine is three times more frequent in women than men.

In some women, migraine attacks appear to be influenced by hormone changes: often starting or increasing at puberty and being influenced by the menstrual cycle, pregnancy and the menopause. Pulmonary shunts are more frequent in women and their size can change with the levels of female hormones. It is not known whether the variability of pulmonary shunts influences migraine incidence in women, or whether different levels of trigger substances or tissue susceptibility to the triggers have a role in the observed excess incidence in women.

If a trigger substance is bypassing the lungs, what is it? One possibility is 5-hydroxytryptamine 5HT or serotonin. There is evidence that 5HT has a role in migraine and drugs that act on 5HT receptors are used to treat migraine. If 5HT is the trigger substance in some migraineurs, high venous concentrations may arise as a result of platelet activation. In a randomised study of UK doctors prophylactic dose aspirin, which has an antiplatelet action, reduced migraine compared with controls.

Interventions that activate platelet downstream from the lungs, such as implanting a prosthetic aortic or mitral valve, can trigger migraine with aura for the first time in people who have no shunt. Closure of a PFO or an atrial septal defect can also precipitate or exacerbate migraine with aura. So, at the end of the procedure there is a disc in the left atrium, which can active platelets downstream from the lungs.

The increased propensity to migraine with aura after PFO closure lasts a few weeks and ceases about the time when the occlusion device is covered with endothelial growth and is no longer a site for platelet activation.

Migraine with aura soon after PFO closure is virtually abolished if the patient is given clopidogrel 75 mg daily for the first 4 weeks after the closure procedure. Those that were eligible were referred to one of two centres for an initial contrast echocardiogram to determine whether they had a moderate or large shunt across a PFO. Those that did were eligible for the next stage of the trial and were referred to one of six interventional cardiology centres where they were randomised when under general anaesthetic to either implantation of a STARFlex device, with the intention of closing their PFO or to a sham procedure.

The aim was to randomise 75 patients to each arm of the trial. The first 3 months after the procedure were the healing period when migraine might be expected to increase.

The second 3 months were the analysis period and were used to compare the two arms of the trial using an intention to treat analysis. I strongly advised NMT before the protocol was finalised that only patients with large shunts across a PFO should be included, because prevalence of migraine with aura is related to shunt size. Inclusion of patients with smaller shunts increased the chance that migraine with aura and a PFO were coincidental rather than causal.

I had also strongly advised that the trial needed a single echocardiography core laboratory. My advice was rejected. The results of the initial contrast echocardiograms at the two hospitals are shown in Table 1.

Three patients found to have atrial septal defects had those closed outside the trial. There were important differences between the findings at the two hospitals that have relevance to the outcome of the trial.

RSH and RBH each referred patients for randomisation procedures at three interventional cardiac centres six centres in total.

At the end of the trial the patients with an implant had a repeat contrast echocardiogram. Against the advice of the steering committee, NMT insisted that the implanting cardiologists should perform the final contrast echocardiograms.

The steering committee objected that the implanting cardiologists were interventionists and not experts on echocardiography and that they had operator bias and would be assessing their own handiwork. Also, that performance of the initial and final echocardiograms at the same sites would insure that the performance techniques were identical and so make comparisons in individual patients before and after STARFlex implantation reliable.

The primary outcome, freedom from attacks of migraine during the analysis period, was identical in the two arms. Only three patients in each arm were migraine free. Patients in the trial were identified outside the treating hospitals only by an alphanumeric code. There were no statements from the three migraine-free patients who had sham procedures or the patients whose migraine was not improved or was worse after the implantation.

Even more surprising was that one of the three patients who were migraine free after the STARFlex implant was pictured on the NHS website of the Royal Brompton Hospital with her testimonial to the treatment and the statement 'This is significant news for migraine sufferers.

For the first time this study has shown that closing a PFO can have a substantial effect in reducing the symptoms for patients with severe migraine. A paper reporting results of the MIST Trial was published in Circulation, but it was so inaccurate that another member of the steering committee, Dr Simon Nightingale, and I refused to be authors of the paper. They did not serve the claim on Dr Nightingale, but sued me four times.

During those 4 years, I convinced the editors of Circulation of errors in the paper and they publish a words correction, a data supplement and a new version of the paper. He was found guilty of misconduct including two counts of dishonesty by a Fitness to Practise Panel in NMT also paid him large sums of money. He disclosed no conflicts of interest in the paper.

The legal fog that engulfed the MIST Trial means that we may never understand why implantation of a STARFlex device in patients with severe migraine did not replicate the observed improvement in migraine seen in patients who had PFO closure following paradoxical embolism.

But there is some evidence of a relatively high prevalence of PFO in persons who experience cryptogenic stroke and that presence of PFO is a risk factor for stroke. Recurrent cryptogenic stroke is the major indication for PFO closure.

Although there is as yet no firm evidence to support the value of PFO closure in recurrent stroke, thousands of stroke patients have undergone this procedure. Some were migraineurs. In the late s, a few cardiologists who had carried out percutaneous PFO closures received reports from patients that after PFO closure, migraine headaches decreased; in some instances they went away completely.

About 12 patients in whom he carried out PFO closure for cryptogenic stroke told him that after the procedure, their migraine headaches improved.

Some patients said that their headaches stopped entirely. It is one of the controlled sham closure trials that just got under way. The spontaneous reports of migraine improvement were followed by a series of systematic studies in which patients who had a history of migraine headache and were undergoing PFO closure for either cryptogenic stroke or decompression sickness were queried about the effect of PFO closure on their headaches.

The published studies have been consistent in showing that most patients with migraine, with or without aura, experience substantial headache re- lief after PFO closure. However, these studies have been uncontrolled and retrospective. Jonathan Tobis, MD, clinical professor of medicine and director of interventional cardiology research at the University of California at Los Angeles has had the same experience as Rhodes. Tobis is among the investigators who have examined migraine changes after percutaneous PFO closure.

Others in the neurology community are still skeptical about the role of percutaneous PFO closure for the treatment of migraine. He had made the same comment in October during a debate at the Cardiovascular Research Foundation's 17th annual Transcatheter Cardiovascular Therapeutics scientific symposium in Washington, DC. To the credit of all those who have a stake in the PFO-migraine connection, no one is yet suggesting that patients with migraine should start lining up for percutaneous PFO closure.

Interventional cardiologists and the medical technology companies that make the closure devices are moving quickly to conduct rigorously controlled studies. In addition to the first MIST trial, at least 6 additional trials are either under way or in the planning stages.

The primary outcome, cessation of migraine, occurred in three patients in each group. Secondary outcomes such as frequency of migraines and headache scores were also similar between the two groups. When the two patient outliers were excluded from analysis, a difference was noted in the reduction of headache days favoring PFO closure; however, this finding should only be hypothesis generating since it was a post-hoc analysis.

Failure to detect a difference between treatment groups may have been at least partly explained by lack of adequate power. It is unknown if a longer duration of follow-up to allow for more complete healing of the defect would have also been beneficial.

Additionally, patients continued prophylactic medications throughout the trial, which may have made it more difficult for the PFO device to show benefit. Factors that predispose to a larger device include PFO tunnel length, the presence of atrial septal aneurysm and male sex.

Once sizing is completed, an appropriate device with delivery sheath can be passed into the left atrium through the PFO. The left atrial disc is deployed, followed by the right disc. Ensuring that the delivery sheath remains de-aired and flushed throughout the procedure minimises the risk of air or thrombotic embolism. After the device is deployed, confirmation of the adequate position with echocardiography and fluoroscopy should be performed prior to device release. If the device is malpositioned after release, a large gooseneck snare can be used to recover the device.

The steps involved in a PFO closure procedure are shown in Figure 2. A wire crossing a patent foramen ovale into the left upper pulmonary vein with a Judkins Right 4 catheter white arrow is shown A.

The delivery sheath blue arrow is advanced through the patent foramen ovale over the stiff wire B , and the device — a Gore Cardioform septal occluder — is deployed C,D with the left atrial disc green arrow deployed first and then apposed to the atrial septum. The right atrial disc black arrow is then deployed, but the device is not released until the operator is happy with the position both fluoroscopically and with echocardiography.

A released device is shown E; yellow arrow using 3D transoesophageal echocardiography F; purple arrow viewed from the left atrium. Evidence for antiplatelet therapy after device deployment remains incomplete. Device thrombosis remains a feared complication of PFO closure.

In our practice, aspirin and clopidogrel are usually given for 6 months, but evidence for this is limited and practice varied markedly between trials. Earlier discontinuation of dual antiplatelet therapy was associated with an increased frequency of minor cerebrovascular events in a study level meta-analysis of PFO closure trials. Some operators preload patients with antiplatelets, but again, the evidence for this is uncertain.

Single antiplatelet therapy, usually clopidogrel 75 mg daily, is continued indefinitely, as the device may take up to 5 years to endothelialise.

The European Association for Percutaneous Cardiovascular Interventions consensus statement recommends this approach at present. Follow-up is important, but uncertainty remains about the appropriate timeframe.

As most devices endothelialise over a period of approximately 6 months, then a repeat bubble study could be considered at that stage. Timing is of particular relevance where the PFO has been closed for occupational reasons, such as professional diving. A large number of devices with varying shape and size have been marketed.

Many have received CE mark status in the EU. In the US, fewer devices have been approved by the Food and Drug Administration, due to the need for randomised evidence prior to approval. Most devices are of double-disc design, connected by a short waist. The Gore Septal Occluder is constructed from five nitinol wires covered with expanded polytetrafluoroethylene.

This device has been used most commonly in randomised clinical trials. The evidence base for its use is therefore very strong. B: Gore Cardioform Septal Occluder. These devices are approved for patent foramen ovale closure, with the Amplatzer and Gore devices most widely deployed.

There are a number of outstanding research questions regarding PFO closure that need to be answered. First, the optimal antiplatelet or anticoagulation regimen balancing the risk of recurrent stroke or embolism against the risk of bleeding needs to be established. Current guidance is based on consensus statements and the strategies adopted in the clinical trials mentioned earlier.

Meta-analyses have not shown any clear additional benefit for anticoagulation when PFO is not closed after stroke. Simplification of the procedure with the use of non-invasive echocardiography may be attractive, but is not recommended in consensus statements.

Identification of a high risk of PFO-associated stroke prior to the first stroke remains the golden ticket. Some have published studies with scoring systems to identify high-risk PFO, but these have not identified patients prior to cryptogenic stroke, when the PFO is usually silent. Observational studies have suggested that those in this group who have a PFO closure have a reduced incidence of stroke or transient ischaemic attack.

A recent observational study of patients undergoing surgery found a significantly higher incidence of ischemic stroke over a 1-year period in those with PFO.

These observational data are hypothesis generating, but suggest that there may be a population that could be identified to benefit from upfront closure, but further well-designed clinical trials would be required to justify this against the procedural risk.

Furthermore, there are limited data to support differences in treatment by subgroup. The majority of patients treated in these studies were men. Further work is required to identify whether there are meaningful differences in these groups. Similarly, differences between ethnic groups could also be examined. Finally, expansion to other indications, particularly for migraine relief requires a better quality of evidence.

In this review, the main indications for PFO closure have been discussed cryptogenic stroke, paradoxical systemic embolisation, platypnoea—orthodeoxia syndrome and decompression illness , together with the strengthening evidence for closure.

The skills required for this procedure need to be learnt with the assistance of experienced interventional cardiologists who can proctor and advise those starting out with PFO closure.

Attention to detail in the indication for the procedure, and minimising the risks to the patient during the closure are key to an effective PFO closure service. National Center for Biotechnology Information , U. Journal List Interv Cardiol v. Interv Cardiol. Published online Nov Joel P Giblett 1. Lynne K Williams 2. Stephen Kyranis 2. Leonard M Shapiro 2. Patrick A Calvert 2. Author information Article notes Copyright and License information Disclaimer. Corresponding author.

Disclosure : The authors have no conflicts of interest to declare. E: ten. Received Nov 24; Accepted Sep This article has been cited by other articles in PMC. Keywords: Stroke, patent foramen ovale, patent foramen ovale closure, migraine, platypnoea—orthodeoxia syndrome, decompression illness, cryptogenic stroke. The Anatomy of a Patent Foramen Ovale As the heart develops in the foetus, the primum and secundum septa grow and overlap.

Open in a separate window. Figure Indications for Patent Foramen Ovale Closure Cryptogenic Stroke Often, despite extensive investigation, a clear cause cannot be found for stroke. No events in PFO closure arm versus Systemic Embolisation Paradoxical emboli are likely to present with ischaemic stroke, as the brain is exquisitely sensitive to ischaemia and also receives a large proportion of cardiac output.

Decompression Illness Divers and high-altitude pilots, who rapidly transition from high- to low-pressure environments, may suffer from decompression illness. Platypnoea—Orthodeoxia Syndrome Platypnoea—orthodeoxia syndrome is a rare condition characterised by dyspnoea and positional desaturation in individuals with a PFO. Migraine with Aura Migraine is common in young people.

The Patent Foramen Ovale Closure Procedure Pre-procedure Investigations As cryptogenic stroke is the most common indication for closure, an emphasis should be placed on investigation looking for alternative causes of stroke. The Closure Procedure Closure is performed as a day case procedure in many centres.

Closure Devices A large number of devices with varying shape and size have been marketed. Future Directions There are a number of outstanding research questions regarding PFO closure that need to be answered.

Conclusion In this review, the main indications for PFO closure have been discussed cryptogenic stroke, paradoxical systemic embolisation, platypnoea—orthodeoxia syndrome and decompression illness , together with the strengthening evidence for closure.

References 1. Patent foramen ovale: anatomy, outcomes, and closure. Nat Rev Cardiol. Patent foramen ovale and cryptogenic stroke in older patients. N Engl J Med. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. Trial of Org in Acute Stroke Treatment.