Pursuit of Scientific Certainty Versus Patient Care

Migraine is a common, heterogeneous, primary headache disorder with inherited aspects, which burdens 28 million people or 13 percent of the population of the United States.

Migraine diagnosis is characterized by:

  • Absence of objective diagnostic testing or markers
  • Clinical diagnosis by “Chinese menu” criteria scheme (IHS)
  • Aura, focal neurologic symptoms, occur in 30% of patients
  • 29 different ICD-10 subtypes
  • Poorly understood pathophysiology; No longer thought “vascular”

The burden of migraine is substantial.

Financial cost

  • US productivity: $28 Billion per year
  • US Direct/Indirect medical costs: $20 Billion per year

Human cost/suffering

  • Migraine is 7th most disabling disease world-wide (WHO)
  • Quality of Life Measure: worse than most chronic diseases
  • Profound effect on family and co-workers
  • Suicide contemplated: 19%; Suicide attempted 5%

Medical therapy of migraine

  • Over 100 medications: mostly “off-label” as few FDA approved
  • Overall, medical therapy relief and prevention of migraine is poor
  • 44% of American Headache Society members support invasive procedures:
    • Stimulation or PFO closure treatment of refractory migraine

Migraine is not just a disabling headache disorder

Permanent, silent brain injury (MRI)

  • White matter abnormalities (WMA) are more common in migraine patients
  • WMA are more common in migraine patients with aura than without
  • T2/FLAIR sequence WMA are ischemic. WMA is a general term
  • WMA load is exponential to migraine attack frequency and duration
  • WMA lesions are a cause of cognitive decline
  • Grey matter changes also occur in migraine
  • Posterior circulation silent infarct-like lesions are likely embolic

Migraine and stroke

  • 45% of cryptogenic stroke patients have migraine
  • Migraine is an independent risk for stroke
  • Stroke risk in migraine/aura patients is increased 2-3 fold
  • Stroke risk increases: contraception 10 X; Pregnancy 15 X; smoking 15 X
  • 85% of patients with stroke/migraine/aura have a PFO (or RL Shunt)
  • PFO is the most likely cause of stroke in migraine patients
  • Migraine is a significant risk for recurrent PFO related stroke

Migraine and PFO

  • PFO prevalence in migraine w/aura is 40-85 percent
  • Conversely, PFO patients are 5 X more likely to have migraine
  • TCD shunt severity increases from no migraine to migraine/no aura to migraine with aura
  • PFO atrial septal aneurysm is 4 x higher in aura than non-aura patients
  • 35 observational and 3 meta-analyses show migraine improvement with percutaneous shunt correction (ASDII, PFO, pAVM)
  • MIST (corrected), PRIMA, and PREMIUM all show statistically significant migraine improvement or complete resolution with PFO closure for secondary end-point analysis
  • Ten percent of CLOSURE 1 investigators (Stroke 2005; 65:172) reported closing
  • PFO for migraine as indication

MIST: A randomized trial of percutaneous closure of PFO for migraine “cure”

“As information surfaced on the potential link between migraines and PFO, some cardiologists became involved in the care of patients with migraine and were quickly humbled by the often debilitating nature of the disease process. Personally witnessing such intense suffering, the inconsistent effect of rescue medications, and the subsequent reliance on powerful narcotics to achieve some means of comfort….has been a sobering experience.

With the development of implantable devices used to close potentially enabling PFOs came a new-found hope in our ability to help these suffering people.” John D Carroll, MD, MIST Editorial, Circulation 2008; 117:1358

MIST failed to meet primary or secondary end-points. The breadth and depth of the failings of this controversial study should challenge the very basis of the randomized trial process. Yet, refusal to disregard it, solely because it was a randomized trial, has adversely impacted PFO/migraine study moving forward. The collapse of MIST II and ESCAPE, the early stopping of PRIMA due to slow enrollment, and the prolonged duration of PREMIUM all underscore the limitations for randomized trials in the current environment of opposition to PFO closure.

The Controversies in Interventional Cardiology Pro/Con debate, “Is Patent Foramen Ovale Closure Indicated for Migraine?” published in 2009 as a MIST post-mortem is well worth reading. (Reisman M and Fuller CJ; Carroll JD and Carroll EP, Circ Cardiovasc Intervent 2009; 2:468-481).

Reisman and Fuller (PFO Closure for Migraine) provide review of the complexities of migraine pathophysiology and genetics, brain imaging and stroke in migraine, and PFO/migraine studies which support a broad range of potential benefits of PFO closure for migraine.

Potential Benefit of PFO Closure in Migraine

  1. Reduction of migraine headache frequency
  2. Reduction of migraine-related functional disability
  3. Improve quality of life for patients and their families
  4. Prevention of stroke and TIA
  5. Prevention of other paradoxical embolic events
  6. Prevention of decompression illness
  7. Reduction in progression of cognitive dysfunction
  8. Prevention of migraine progression to chronic migraine
  9. Prevention of brain parenchymal injury

From: Reisman and Fuller 2009

Reisman and Fuller state: “The ability to establish a unique fingerprint for the PFO headache that distinguishes it from the spectrum of migraine headache is critical to the evolution of this therapy”. They propose specific, evidence-based criteria for defining “the PFO Headache” to improve future randomized trials. However, in the post PRIMA and post PREMIUM era, such trials seem unlikely. Assuming that the body of observational, meta-analysis, and randomized data obtained to date is not ignored or rejected, such criteria would seem a good option for registry endeavors and implementation of closure as a therapeutic option in selected patients.

“The PFO Headache” Criteria

  1. Migraine with significant, prolonged aura
  2. Migraine with class 3 or class 4 MIDAS
  3. Right-to-left shunt at rest
  4. Large provoked right-to-left shunt
  5. Atrial septal aneurysm, Chiari, Eustacian valve
  6. Coagulation abnormalities
  7. Previous history of stroke or TIA
  8. Abnormal MRI with white matter abnormalities (?T2/FLAIR)

From: Reisman and Fuller 2009

Carroll and Carroll (PFO Closure Is Not Indicated for Migraine. “Don’t Shoot First, Ask Questions Later”) review the weakness and limitations of PFO migraine trials in general and for the MIST trial specifically. They discuss a sweeping view of the broader PFO closure “quagmire” which include: off-label use, equipoise for stroke and migraine indications, difficulties of industry sponsored device research, over-reach and restriction of FDA approved protocols limiting enrollment and completion of trials, and the disconnect between limited understanding of migraine and PFO pathophysiology versus device utilization.

With acknowledgement of the failure of MIST and closure of two other RCT, the authors paint a dismal landscape devoid of any neurological support. “We could find no leading migraine expert who has written in support of the protagonist viewpoint that closure is indicated for migraine.” These observations are at odds with a large body of literature and survey information. 44% OF American Headache Society members would consider stimulation or PFO closure for refractory migraine (Headache 2009; 49:509). In a survey of CLOSURE 1 investigators, 10% of interventionalists had closed PFO for a migraine indication (Stroke 2009).

They propose “Recommendations to Exit from the Quagmire of PFO Closure for Migraine”:

  1. Neurology leadership in design, conduct, promotion and completion of trials
  2. Research on migraine pathophysiology and identification of the “PFO Headache”
  3. Replace industry sponsorship to joint sponsorship with scientific groups
  4. FDA reform to promote timely trial completion
  5. Promote and institute centers of excellence in structural heart disease interventions
  6. Inclusion of patient advocacy in clinical trials

From: Carroll and Carroll 2009

After nearly a decade: Drained “quagmire” or Brea Tar Pit?

The Academic/Industry/FDA Complex is unchanged

Migraine pathophysiology and micro-embolization – some progress:

  • The vascular theory of migraine has been disproven by Olesen, Schoonman and others. “The vascular theory of migraine-a great story wrecked by the facts.” (Goadsby PJ, Brain 2009; 132:6-7)
  • The new neurovascular theory of migraine considers migraine to be primarily a neurogenic disorder with secondary blood flow changes. The brain, particularly the occipital cortex, is in a state of hyper-excitability making the brain susceptible to headache. Cortical spreading depression (CSD) is a wave of gray matter excitation which is thought to result in aura and the subsequent activation of the trigemino-vascular system which in turn results in a sterile inflammatory process.
  • “Microemboli May Link Spreading Depression, Migraine Aura, and Patent Foramen Ovale” (Nozari A, Dilekoz E, Moskowitz MA, Ann Neurol 2010; 67: 221-228) In a series of articles, these authors have proposed a unifying hypothesis to explain the association of migraine, particularly CSD and aura, with inherited vascular disorders, stroke, TIA, MRI abnormalities and patent foramen ovale. “…we suggest that changes in blood vessels, hypo-perfusion disorders, and micro-embolization can cause neurovascular dysfunction and evoke cortical spreading depression..” Further, in discussing PFO: “Thrombosis and micro-embolization could thereby create a transient hypoxic ischemic focus to induce CSD followed by a migraine attack, whereas more prolonged occlusion of larger vessels might cause transient ischemic attack or stroke”. (Lancet Neurol 2010; 9:309-17;)

  • “Paradoxical Air micro-embolization Induces Cerebral Bioelectrical Abnormalities on Migraine Patients with Large PFO but Not in Non-migraine PFO Patients or Normal Controls (Sevgi EB et al, J Am Heart Assoc 2012; 1:e001735). This study in humans supports the unifying hypotheses of Moskowitz: brain micro-embolization evokes an electrical response in migraine patients who have a baseline hyper-excitable brain. Conversely, severe micro-embolization alone does not evoke a CSD type response in patients without migraine.

Completed Migraine/PFO Randomized Trials-PRIMA and PREMIUM

  • PRIMA: PRIMA was a randomized migraine trial comparing the Amplatzer™ PFO Occluder with medical management. MIST II and ESCAPE were discontinued due restrictive inclusion criteria. Similarly, PRIMA was stopped prematurely due to slow enrollment. The primary end-point, migraine days per month, was not met. However, secondary end-points were significant: device closure was superior to medical management for reduction of migraine with aura days (P<0.01), reduction of number of migraine with aura days (p<0.01), and 50% responder rate (p<0.02). Notably, 10% vs 0% of patients had complete freedom from migraine (p=0.05) and 40% vs 10% had complete freedom from migraine with aura (p<0.004).
    (Mattie HP et al, European Heart J 2016; 37:2029-36)
  • PREMIUM: PREMIUM was a randomized, sham controlled, double-blind study of the treatment of migraine using the Amplatzer™ PFO Occluder in patents failing medical therapy. 230 patients were randomized. Response to closure was assessed at one year. Patients in the control arm could undergo PFO closure at one year and 87 of 103 chose this option. PREMIUM was also plague by slow enrollment due to restrictive documentation and medical requirements resulting in 8 years to complete the study. The investigator selected primary end-point, reduction of migraine days per month was significant (p=0.025). However, despite three International Headache Society Trial Guidelines to the contrary, the FDA required a 50% responder rate as the primary end-point. The FDA, regulatory required primary end-point, 50% responder rate, was not met. The regulatory secondary end-point, reduction in migraine days was met (p=0.025) and complete cessation of migraine occurred in 8.6 vs 0.9% of patients (p=0.01). PREMIUM has been presented in abstract form (TCT 2015) but remains unpublished.

Are Randomized Migraine/PFO Trials Just a “Shell Game”?

When the PREEMPT 1 randomized trial of migraine treatment with Botox® failed to meet its primary endpoint “A” but the secondary end-point “B” was statistically significant; FDA approval was denied. So PREEMPT 2 simply reversed the end-points: “B” became the primary end-point and “A” became the secondary endpoint.

“B” of course was significant and —presto, academic and FDA approval.

Migraine/PFO trials have been defeated in part due to extremes of inclusion criteria. For example, in PREMIUM written proof of migraine medication use/ failure was required from pharmacies or physician offices. Failure of therapy required failure of FDA approve drugs. Patients failing a beta blocker other than propranolol or timolol were rejected as beta blocker failures: In the Study Group experience, over 1300 patients were screened for PREMIUM to yield only 20 patients. Taylor FR (Headache 2009) reported that for MIST II recruitment, 30,000 website “hits” generated 376 referrals but few patients.

What now for the patients whose voice remains unheard or unheeded?

Those who insist upon the ruthless pursuit of scientific certainty: only accepting primary end-points and intention-to-treat internal validation, will reject PFO closure for migraine and dismiss the large body of favorable observational and randomized data—“let them eat cake!”

Or, as recently stated by Bothwell LW, et al, (Assessing the Gold Standard—Lessons from the History of RCT, NEJM 2016; 374:2175-2181): “We find ourselves at a crucial point in the history of RCTs. Originally designed to reduce bias in research, RCTs have become sites of conflicting interests that merit careful scrutiny.” Further, “The idea that RCTs would be the only arbiter to resolve medical disputes has given way to more pragmatic approaches…..Observational methods are seen as complementary to RCTs, and new forms of surveillance can embed RCTs into the structure of data collection..”

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Migraine Relief with Shunt Resolution: PFO, ASD, Pulmonary AVM References

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1. Dowson A, Mullen MJ, Peatfield R et al. Migraine Intervention with STARFlex technology Trial (MIST). A prospective, multicenter, double blind, sham controlled trial to evaluated the effectiveness of PFO closure with STARFlex septal repair implant to resolve refractory migraine headache. Circulation 2008; 117: 1397-1404

2. Carrol JD. Migraine intervention with STARflex Technology Trial: A controversial trial of Migraine and PFO closure. Circulation 2008; 117 (11): 1397-404

3. MIST CORRECTION / RETRACTION. Dowson A, Mullen MJ, Peatfield R et al, Correction For Dowson et al (Circulation 2008; 117:1397-1404); Circulation 2009; 117:e71-e72

4. Mattie HP et al, Percutaneous closure of patent foramen ovale in migraine with aura. A Randomized clinical trial. .Eur Heart J 2016; 37:2029-36

5. Tobis J, Charles A, Silberstein S, Sorensen SG et al. Results of the PREMIUM Trial. Patent foramen ovale closure with the Amplatzer PFO occlude for the prevention of migraine TCT 2015 (JACC supplement 2015)

6. MIST II: cancelled (NMT Medica, CardioSEAL/STARflex devicel)

7. ESCAPE: cancelled (St Jude Medical; PREMIER device)

8. Carroll JD, Carroll EP, Controversies in interventional cardiology: Is patent foramen ovale closure indicated for migraine? Circulation: Cardiovascular Interventions 2009;2:475-81