PATENT FORAMEN OVALE: RISK FACTORS FOR STROKE

Patent Foramen Ovale Overview

The foramen ovale is vital for fetal circulation, when blood returning to the right atrium is shunted through to the left atrium. Postnatally the foramen ovale closes spontaneously in most people, but patent foramen ovale (PFO) occurs in about 25% of the population.1

Most people with PFO are asymptomatic. But an atrial septal aneurysm may open the PFO with every heartbeat, thereby increasing the possibility for thrombus to pass from the venous to arterial system, which can cause stroke.2

Frequency of PFO in Cryptogenic Stroke

1/3

ABOUT ONE-THIRD OF ISCHEMIC STROKES ARE CRYPTOGENIC3,4

That translates into annual figures of:

200,000

200,000 CRYPTOGENIC
STROKES IN THE U.S.5

400,000

400,000 CRYPTOGENIC STROKES
AND TRANSIENT ISCHEMIC ATTACKS (TIAs)
IN WESTERN EUROPE ALONE4

50%

Nearly 50% of patients with
cryptogenic stroke have a PFO2

20.4%

Moreover, patients with PFO and a prior cryptogenic ischemic stroke are at risk for recurrent stroke6—a 20.4% rate of a recurrent embolic event at 2 years7

WHAT DO ACCUMULATING DATA REVEAL

The dilemma of whether to percutaneously close PFOs in selected patients in order to reduce the risk of recurrent embolism has been a matter of ongoing debate for more than a decade.

But now the long-term data from the RESPECT trial,8 as well as data from the CLOSE and REDUCE trials,9,10 have clarified the issue. These studies have revealed that with attentive patient selection, transcatheter PFO closure significantly reduces the risk of recurrent stroke compared with medical therapy in patients with cryptogenic stroke—with no increased risk of serious adverse events or influence on major bleeding.2

DISCREPANCIES AMONG PRACTICE GUIDELINES

For patients who have had a cryptogenic stroke and have PFO, these are the typical options for prevention of recurrent stroke:11

  • Antiplatelet therapy alone
  • Anticoagulant therapy alone
  • PFO closure with antiplatelet therapy

Unfortunately, guidelines differ on which option is preferable.

Following the 2016 FDA approval of the AmplatzerTM PFO occluder used in the RESPECT trial, specialty organizations in the U.S. have not yet responded to these data with updated recommendations.2

  • PRIOR RECOMMENDATIONS

    American Academy of Neurology 201612

    • The effectiveness of PFO closure to lower stroke risk is uncertain
    • If there is no other indication for anticoagulation, clinicians may prescribe antiplatelets

    American Heart Association/American Stroke Association 20146

    • Among patients with an ischemic stroke or TIA and a PFO:
      • In the absence of deep vein thrombosis (DVT), there is not supporting data showing a benefit for PFO closure
      • If they are not on anticoagulation therapy, antiplatelet therapy is recommended
      • If they have a venous source of embolism, anticoagulation is indicated and, when contraindicated, an inferior vena cava filter is reasonable
    • Among patients with a PFO and DVT, transcatheter PFO closure might be considered

    Netherlands Society of Cardiology 201613
    Among patients with cryptogenic stroke or TIA and a persistent PFO, PFO closure may be considered in patients with a RoPE score > 6* and at least 1 clinical risk factor

  • NEWER RECOMMENDATIONS

    BMJ Rapid Recommendation 201811

    Among patients younger than age 60 who have had a cryptogenic ischemic stroke thought to be secondary to PFO (due to absence of other etiologies):

    • Strong recommendation—among patients in whom anticoagulation is contraindicated or declined—to provide PFO closure + antiplatelet therapy, vs antiplatelet therapy alone
    • Weak recommendation—among patients who are open to all options—to provide PFO closure + antiplatelet therapy vs anticoagulant therapy
    • Weak recommendation—among patients in whom closure is contraindicated or declined—to provide anticoagulant therapy vs antiplatelet therapy

    European Position Paper 201814
    Among patients age 18-65 who have had a cryptogenic ischemic stroke cryptogenic stroke, TIA, or systemic embolism thought to be secondary to PFO due to absence of other etiologies:

    • Recommend percutaneous PFO closure

* RoPE = risk of paradoxical embolism

BMJ PANEL CLINICAL PRACTICE GUIDELINES11

The British Medical Journal published on this topic in a BMJ Rapid Recommendation, which informs clinicians about potentially practice-changing evidence.

  • Ton Kuijpers, MD, et al.

    PFO Closure: Likely Substantial Benefits

    “The panel believes that there is probably substantial benefit in stroke reduction after PFO closure, which will be very important to all or almost all patients. This is likely to outweigh important undesirable consequences, like procedure or device-related events and persistent atrial fibrillation.”

     

The panel conducted a network meta-analysis combining direct evidence with indirect evidence (inferred benefits and harms of alternatives) to obtain informative estimates of effect. However, the authors noted a paucity of data regarding anticoagulation, with low-certainty evidence.

Nonetheless the panel stated that anticoagulants are likely to be substantially more effective in preventing such clots from initially arising compared to antiplatelet agents.

EUROPEAN POSITION PAPER14

In 2018, 8 scientific societies, including cardiac and stroke societies, published recommendations regarding PFO therapy to aid clinicians in decision making.

Physicians who propose PFO closure for a patient must also evaluate the individual probability of benefit while assessing both the role of the PFO in the thromboembolic event and the expected results and risks of a lifelong medical therapy. Ideally the patient’s role should be proactive.

Using the same shared decision-making approach, PFO closure can also be considered in patients older than 65 or younger than 18, while taking into account the risks of intervention and/or drug therapies.

There are no current indications for surgical PFO closure as first-line treatment, though it may be performed during valvular surgery.

Prioritizing Prevention

There are challenges in determining causation and treatment for cryptogenic stroke. Yet nearly half of patients with cryptogenic stroke have PFO.2 Neurologists and other referring physicians, who represent the primary point of care for recurrent stroke prevention, may consider these factors in treatment planning:

IS THE STROKE CRYPTOGENIC?

Rule out known causes

Is the patient eligible for alternative therapy?

Consider age and medical history

Is there a possibility of PFO?

Determine the likelihood of paradoxical embolism

A cardiologist can then determine if the patient has a PFO and can help determine treatment options.

DETERMINING PFO CAUSATION OF STROKE

Characteristics that are strongly associated with a causal role of PFO in cryptogenic stroke are:14

  • Atrial septal aneurysm and/or a moderate-to-severe shunt
  • Atrial septal hypermobility
  • PFO size

The presence of other risk factors does not exclude PFO as the causative factor, but PFO is more likely when patients are young and lack other risk factors. Determining whether a patient’s stroke is related to a PFO should involve a multidisciplinary team including a neurologist, a cardiologist, and other health professionals trained in the care of patients with stroke.2

RULING OUT LEFT ATRIAL APPENDAGE (LAA) INVOLVEMENT

It is important to identify whether atrial fibrillation is present, since recurrences of left circulation embolism are often due to LAA thrombosis. In certain patients at high risk for atrial fibrillation, insertable cardiac monitor use for 6 months can reasonably rule out LAA involvement before proceeding with PFO closure.14

RESPECT TRIAL LONG-TERM DATA8

The RESPECT trial was conducted at 69 centers across the U.S. and Canada. Alone among PFO closure studies, RESPECT included patients on anticoagulation therapy, providing a real-world cross section of patients. This trial has the most extensive follow-up data among all PFO closure studies; it spanned 13 years overall with 5,810 patient years of safety follow-up. The RESPECT trial also revealed low rates of serious atrial fibrillation with the closure device, consistent with medical therapy.

LOOKING TO FUTURE GUIDELINES

Practitioners are anticipating updated guidelines about device closure and medical therapy for cryptogenic stroke caused by PFO. From the perspective of Mojadidi et al., the relative safety and simplicity of percutaneous PFO closure and the proven protection against stroke open an avenue of further indications for PFO closure.2

Treatment for PATENT FORAMEN OVALE

Treatment for Patent Foramen Ovale

Abbott offers effective treatment for PFO.
 

AmplatzerTM PFO Occluder


The information provided is not intended for medical diagnosis or treatment as a substitute for professional advice.  Consult with a physician or qualified healthcare provider for appropriate medical advices.

AP2947066-WBU Rev. A

References
  1. Homma S, et al. Patent foramen ovale and stroke. Circulation. 2005;112:1063-1072. doi: 10.1161/CIRCULATIONAHA.104.524371.
  2. Mojadidi MK, et al. Cryptogenic stroke and patent foramen ovale. J Am Coll Cardiol. 2018;71(9):1035-1043. doi: 10.1016/j.jacc.2017.12.059.
  3. Shah R, et al. Device closure versus medical therapy alone for patent foramen ovale in patients with cryptogenic stroke. Ann Intern Med. 2018;168:335-342. doi:10.7326/M17-2679.
  4. Li L, et al. Incidence, outcome, risk factors, and long-term prognosis of cryptogenic transient ischaemic attack and ischaemic stroke: a population-based study. Lancet Neurol. 2015;14:903–913. doi.org/10.1016/S1474-4422(15)00132-5.
  5. American Heart Association/American Stroke Association. Understanding Diagnosis and Treatment of Cryptogenic Stroke. 2015.
  6. Kernan WN, et al. AHA/ASA guidelines for the prevention of stroke in patients with stroke and transient ischemic attack. Stroke. 2014;45:2160-2236.
  7. Homma S, et al. Effect of medical treatment in stroke patients with patent foramen ovale: Patent foramen ovale In Cryptogenic Stroke Study (PICSS). Circulation. 2002;105:2625-2631. doi: 10.1161/01.CIR.0000017498.88393.44.
  8. Saver JL, et al. Long-term outcomes of patent foramen ovale closure or medical therapy after stroke. N Engl J Med. 2017; 377:1022-1032. doi: 10.1056/NEJMoa1610057.
  9. Mas J-L, et al. Patent foramen ovale closure or anticoagulation vs. antiplatelets after stroke. N Engl J Med. 2017;377:1011- 1021 and supplementary appendix. doi: 10.1056/NEJMoa1705915.
  10. Søndergaard L, et al. Patent foramen ovale closure or antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017; 377: 1033-1042. doi: 10.1056/NEJMoa1707404.
  11. Kuijpers T, et al. Patent foramen ovale closure, antiplatelet therapy or anticoagulation therapy alone for management of cryptogenic stroke? A clinical practice guideline. BMJ. 2018;362:k2515. doi: 10.1136/bmj.k2515.
  12. Messé SR, et al. Practice advisory: Recurrent stroke with patent foramen ovale (update of practice parameter): report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology.  Neurology.® 2016;87:815–821.
  13. Netherlands Society of Cardiology (NVVC). Guideline for the closure of patent foramen ovale. 2016. www.nvvc.nl/media/richtlijn/208/2017_ Leidraad_PFO-sluiting.pdf. Accessed September 18, 2018.
  14. Pristipino C, et al. European position paper on the management of patients with patent foramen ovale. EuroIntervention. 2018. doi: 10.4244/EIJ-D-18-00622.
     
Important safety information

AMPLATZERTM PFO OCCLUDER
INDICATION FOR USE


The AMPLATZERTM PFO Occluder is indicated for percutaneous transcatheter closure of a patent foramen ovale (PFO) to reduce the risk of recurrent ischemic stroke in patients, predominantly between the ages of 18 and 60 years, who have had a cryptogenic stroke due to a presumed paradoxical embolism, as determined by a neurologist and cardiologist following an evaluation to exclude known causes of ischemic stroke.

CONTRAINDICATIONS

  • Patients with intra-cardiac mass, vegetation, tumor or thrombus at the intended site of implant, or documented evidence of venous thrombus in the vessels through which access to the PFO is gained.
  • Patients whose vasculature, through which access to the PFO is gained, is inadequate to accommodate the appropriate sheath size.
  • Patients with anatomy in which the AMPLATZERTM PFO device size required would interfere with other intracardiac or intravascular structures, such as valves or pulmonary veins.
  • Patients with other source of right-to-left shunts, including an atrial septal defect and/or fenestrated septum.
  • Patients with active endocarditis or other untreated infections.

WARNINGS

  • Patients who are at increased risk for venous thromboembolic events should be managed with thromboembolic risk reduction regimen after the PFO Closure following standard of care.
  • Do not use this device if the sterile package is open or damaged.
  • Prepare for situations that require percutaneous or surgical removal of this device. This includes availability of a surgeon.
  • Embolized devices must be removed as they may disrupt critical cardiac functions. Do not remove an embolized occluder through intracardiac structures unless the occluder is fully recaptured inside a catheter or sheath.
  • Patients who are allergic to nickel can have an allergic reaction to this device.
  •  This device should be used only by physicians who are trained in standard transcatheter techniques. 
  •  Transient hemodynamic compromise may be encountered during device placement, which may require fluid replacement or other medications as determined by the physician.
  • Do not release the device from the delivery cable if the device does not conform to its original configuration, or if the device position is unstable or if the device interferes with any adjacent cardiac structure (such as Superior Vena Cava (SVC), Pulmonary Vein (PV), Mitral Valve (MV), Coronary Sinus (CS), aorta (AO)). If the device interferes with an adjacent cardiac structure, recapture the device and redeploy. If still unsatisfactory, recapture the device and either replace with a new device or refer the patient for alternative treatment.
  • Ensure there is sufficient distance from the PFO to the aortic root or SVC (typically defined as 9 mm or greater as measured by echo). See Figure 6. and Figure 7. 

PRECAUTIONS

  • The safety and effectiveness of the AMPLATZERTM PFO Occluder has not been established in patients (with):
    • Age less than 18 years or greater than 60 years because enrollment in the pivotal study (the RESPECT trial) was limited to patients 18 to 60 years old
    • A hypercoagulable state including those with a positive test for a anticardiolipin antibody (IgG or IgM), Lupus anticoagulant, beta-2 glycoprotein-1 antibodies, or persistently elevated fasting plasma homocysteine despite medical therapy
    • Unable to take antiplatelet therapy
    • Atherosclerosis or other arteriopathy of the intracranial and extracranial vessels associated with a ≥50% luminal stenosis
    • Acute or recent (within 6 months) myocardial infarction or unstable angina
    • Left ventricular aneurysm or akinesis
    • Mitral valve stenosis or severe mitral regurgita- tion irrespective of etiology
    • Aortic valve stenosis (mean gradient greater than 40 mmHg) or severe aortic valve regurgitation 
    • Mitral or aortic valve vegetation or prosthesis
    • Aortic arch plaques protruding greater than 4 mm into the aortic lumen
    • Left ventricular dilated cardiomyopathy with left ventricular ejection fraction (LVEF) less than 35%
    • Chronic, persistent, or paroxysmal atrial fibrillation or atrial flutter
    • Uncontrolled hypertension or uncontrolled diabetes mellitus
    • Diagnosis of lacunar infarct probably due to intrinsic small vessel as qualifying stroke event
    •  Arterial dissection as cause of stroke
    • Index stroke of poor outcome (modified Rankin score greater than 3)
    • Pregnancy at the time of implant
    •  Multi-organ failure
  • Use on or before the last day of the expiration month that is printed on the product packaging label.
  • This device was sterilized with ethylene oxide and is for single use only. Do not reuse or re-sterilize this device. Attempts to re-sterilize this device can cause a malfunction, insufficient sterilization, or harm to the patient.
  • The AMPLATZERTM PFO Occluder device consists of a nickel-titanium alloy, which is generally considered safe. However, in vitro testing has demonstrated that nickel is released from this device for a minimum of 60 days. Patients who are allergic to nickel may have an allergic reaction to this device, especially those with a history of metal allergies. Certain allergic reactions can be serious; patients should be instructed to notify their physicians immediately if they suspect they are experiencing an allergic reaction such as difficulty breathing or inflammation of the face or throat. Some patients may also develop an allergy to nickel if this device is implanted.
  • Store in a dry place.
  • Pregnancy – Minimize radiation exposure to the fetus and the mother.
  • Nursing mothers – There has been no quantitative assessment for the presence of leachables in breast milk.

ADVERSE EVENTS

Potential adverse events that may occur during or after a procedure using this device may include, but are not limited to: Air embolus Allergic drug reaction; Allergic dye reaction; Allergic metal reaction: Nitinol (nickel, titanium), platinum/iridium, stainless steel (chromium, iron, manganese, molybdenum, nickel); Anesthesia reactions; Apnea; Arrhythmia; Bacterial endocarditis; Bleeding ; Brachial plexus injury; Cardiac perforation; Cardiac tamponade; Cardiac thrombus; Chest pain; Device embolization; Device erosion; Deep vein thrombosis; Death; Endocarditis; Esophagus injury; Fever; Headache/migraine; Hypertension/hypotension; Myocardial infarction; Pacemaker placement secondary to PFO device closure; Palpitations; Pericardial effusion; Pericardial tamponade; Pericarditis; Peripheral embolism; Pleural effusion; Pulmonary embolism; Reintervention for residual shunt/device removal; Sepsis; Stroke; Transient ischemic attack; Thrombus; Valvular regurgitation; Vascular access site injury; Vessel perforation

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