Author
Year
No. of patients
Findings
Mugge [19]
1995
195
Patients with ASA and shunt showed a high frequency of previous clinical events (65 %)
Bogousslavsky [20]
1996
140
The stroke or death rate was 2.4 % per year, but only eight patients had a recurrent infarct of 1.9 % per year
Cujec [21]
1999
90
Patients with PFO had a significantly higher rate of recurrent cerebral ischemic events than those without PFO. The attributable risk of PFO in recurrent neurological events was 7 %/patient/year
Mas [22]
2001
581
The risk of recurrent stroke was 2.3 % among the patients with patent foramen ovale alone, 15.2 % among the patients with both patent foramen ovale and atrial septal aneurysm, and 4.2 % among the patients with neither of these cardiac abnormalities
Mattioli [23]
2001
606
Atrial septal aneurysm predicted the presence of a patent foramen ovale. Multivariate analysis showed that atrial septal aneurysm was an independent predictor of an embolic event. A PFO was present in 95 % of patients with atrial septal aneurysm and cerebral ischemia aged less than 45 years
Lamy [24]
2002
581 (267 with PFO)
Patients with PFO were younger (OR, 0.95; 95 % CI, 0.93–0.97) and less likely to have traditional risk factors such as hypertension, hypercholesterolemia, or current smoking. Features suggestive of paradoxical embolism, such as Valsalva-provoking activities or deep vein thrombosis, were not more frequent in patients with PFO
Unfortunately in the late 2000s, the studies aimed to confirm the superiority of mechanical device closure over medical therapy with antiplatelet and anticoagulant agents, in particular the CLOSURE I and MIST [25, 26], failed to demonstrate even an equivalence, turning back the question about a real increase of risk of stroke related to the presence of PFO, despite large non-randomized series from different authors in different parts of the world have suggested a net benefit of mechanical closure over medical therapy.
Although many reasons have been claimed to be confounding factors in the design and enrollment process of these negative or inconsistent trials, and despite the results of some studies raised subsequently, such as the CODICIA study [27], TACET study [28], and the PC trial [29], which again suggested that PFO with or without septal aneurysm confers risk factor for stroke, and closure is ineffective, very recently, the RESPECT trial seems to shed light on.
The Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment (RESPECT) trial [30]) evaluated patients 18–60 years old affected by nonfatal stroke randomized 499 to device closure using the Amplatzer device and 481 to medical therapy (aspirin 46.5 %, warfarin 25 %) over a period of follow-up of 8 years with a mean of 3 years. Despite the raw count, the intent to treat resulted in a nonsignificant difference between the two-arm, the per-protocol, and the as-treated analysis demonstrating for the first time a reduction of recurrence of stroke of 63.4 and 72.7 % with an immediate, procedural, and effective closure rates very high (>93 %). The analysis of the number needed to treat (NNT) demonstrated that 24 patients would need to be treated with the device in order to prevent one stroke over a 5-year period of time.
Although the results are not widely accepted, the most recent meta-analysis including this last trial, differently from the past, demonstrated a net benefit of closure over medical therapy (Tables 20.2 and 20.3).
Table 20.2
Results of the most recent meta-analysis about PFO/stroke, device closure/medical therapy
Author | Year | Studies considered or number of pts. | Findings |
|---|---|---|---|
Ma [31] | 2014 | 12 case control + 6 cohort | Case-control studies showed strong association between PFO and CS, but cohort studies failed to demonstrate a significant association |
Khan [33] | 2013 | 3 trials | PFO closure is beneficial as compared to medical therapy in the prevention of recurrent neurological events |
Capodanno [32] | 2014 | 2,231 | Pooling trials of the Amplatzer PFO Occluder device resulted in a significant reduction of stroke (HR 0.44, 95 % CI: 0.20–0.95; p = 0.04) |
Pickett [34] | 2014 | 2,303 | Pooled hazard ratio was 0.67 in favor of closure. The use of the Amplatzer™ PFO Occluder resulted in significant stroke prevention benefit over medical therapy alone: hazard ratio = 0.44 |
Stortecky [35] | 2015 | 2,963 | The probability to be best in preventing strokes was 77.1 % for Amplatzer, 20.9 % for Helex, 1.7 % for Starflex, and 0.4 % for medical therapy |
Patti [36] | 2015 | 3,311 | Patent foramen ovale closure was associated over the long term with significant net clinical benefit versus both antiplatelet and anticoagulant therapies; such benefit was driven by 50 % relative reduction of stroke and/or transient ischemic attack versus antiplatelet therapy and by 82 % relative reduction of major bleeding versus anticoagulant therapy |
Table 20.3
Extra-cerebral PFO-related conditions
Conditions |
|---|
Platypnea-orthodeoxia |
Unexplainable hypoxemia |
Extra-cerebral embolization |
Hypoxemia in OSAS |
Migraine with aura |
It appears clear that this trial helped at least to identify patients who may benefit from PFO closure: patients with recurrent stroke or stroke at first appearance in the absence of all other causes of stroke have been included nowadays in most advance protocols, even driven by some cost-effectiveness studies which suggest a cost-effective positive balance for device closure [37].
20.4.2 PFO and Other Conditions
Paradoxical embolism has been suggested as cause or mediator of a variety of different syndromes (Table 20.4), of whom migraine with aura and PFO causing life-threatening hypoxemia in patients with left ventricular assist device or heart transplantation deserve a separated brief discussion.
Table 20.4
RoPE score calculation
Characteristic | Points | Score |
|---|---|---|
No history of hypertension | 1 | Maximum score 10 |
No history of diabetes | 1 | Minimum score 0 |
No history of stroke or TIA | 1 | |
Nonsmoker | 1 | |
Cortical infarct on imaging | 1 | |
Age | ||
18–29 | 5 | |
30–39 | 4 | |
40–49 | 3 | |
50–59 | 2 | |
60–69 | 1 | |
≥70 | 0 | |
Different speculations have been argued on the causality of PFO and migraine attacks. Two main hypotheses have been put forward: first the shunt could allow microemboli or substances such as serotonin and norepinephrine to bypass filtration by the lungs and circulate through the brain and provoke migraine [38]. Second, the inheritance of PFO and migraine as lateralization defect: during embryonic development, any pineal gland displacement in respect to the medial line due to a deviation from the optimal serotonin levels may promote both migraine and incomplete closure of the fossa ovalis [39].
Recently, a certain degree of LA dysfunction, such as impairment of active or passive emptying or perhaps conduit function, has been suggested to be present in patients with PFO, especially those with atrial septal aneurysm [40], contributing to create the hemodynamic conditions for fibrin deposit or microthrombus formation just inside the left atrium, on the atrial aneurysm surface, or within the tunnel. Cortical spreading depression, a slow propagating wave of neuronal depolarization followed by neural suppression, has been suggested to be the main substrate for migraine, but its pathobiology is not completely understood. Most series of migrainous patients submitted to PFO closure reporting a certain amount of improvement faced to patients with severe disabling and refractory migraine and included patients with previous paradoxical embolism or at high-risk or paradoxical embolism. This might suggests that future studies should be probably conceived keeping in mind that not all patients with PFO have the same risk of paradoxical embolism and not all the patients with PFO suffered from significant migraine. Indeed, it is likely that the same factors influencing the risk of paradoxical embolism may play a role in the genesis of migraine and in particular in migraine with aura, a form of migraine particularly linked with cortical spreading depression. Although actually there is no fully clear evidence to include migraine with aura patients in the selection process, however, in case of very severe migraine refractory to medical optimal therapy and permanent right-to-left shunt, there might be space for device-based therapy [41].
Complications relating to left ventricular assist devices (LVAD) are prone to cause hemodynamic instability. In particular, patients may experience life-threatening hypoxemia despite adequate pulmonary function. Right-to-left shunting may occur across the interatrial septum via unrecognized patent foramen ovale (PFO) or even atrial septal defects. Shunting may be insignificant before LVAD placement, whereas device implantation may decrease left atrial pressure sufficiently to cause considerable conduction of venous blood into the left atrium [42].
LVAD, however, presents a dangerous context for interatrial septal shunts. With the existing devices, the inflow cannula is placed within the left atrium or left ventricle and fills the device by gravity. In this way, left atrial pressure is reduced, creating a gradient that may result in considerable shunting and hypoxemia when interatrial communications are present. Factors that increase right atrium pressure may compound this effect. The degree of shunting across interatrial septal shunts may be aggravated by chest closure or pleural suction. Commonly, hypoxemia after orthotopic heart transplantation is due to pulmonary hypertension, pulmonary complications, and acute allograft rejection; rarely, it can be caused by structural defects either in the donor or recipient heart. In such case, similarly to post LVAD implantation period, hypoxemia is caused by an increased right-to-left shunt produced by volume overload of the donor right ventricle during the period of early postoperative myocardial depression [43].
Preimplantation transcranial Doppler thanks to its high sensitivity was able to correctly detect a right-to-left shunt in all patients scheduled for LVAD, whereas transesophageal echocardiography with bubble test was used to assess the type of shunt in those patients with positive transcranial Doppler (PFO versus an extracardiac fistula) [44].
20.5 Practical Keys for Patient Selection
For all we discussed above, the selection of patients for device-based closure should necessarily still be driven by a meticulous study of the clinical patients’ profile and the evaluation of different biochemistry assays, together with a complete neurological work-up aimed in excluding acquired or genetic neurological syndromes eventually responsible of the clinical symptoms.
20.5.1 Patients’ Clinical Profile
Patients should be evaluated not only for history and site of previous stroke or the other PFO-related conditions but also for classical risk factors, previous history of deep vein thrombosis, hematologic conditions contraindicating antiplatelet agents to be taken after the device-closure procedure, neoplastic disease limiting the life expectance despite the young age, active systemic infectious disease that enables the patients to undergo an invasive procedure, and, finally, any dental pathologies that may act as infectious foci after device implantation.
20.5.2 RoPE Score
Recently, in order to help the clinicians to manage patients with symptomatic PFO, a clinical score has been implemented. The RoPE score [45] calculator is based on some clinical characteristics combined with age classes accounting for a score (Table 20.4).
The RoPE score has been shown to successfully disaggregate stroke patients into a stratum with a PFO prevalence that matches the background population (23 % RoPE score 0–3), which increases linearly to the highest RoPE scores with a very high prevalence of PFO (73 % RoPE score 9–10). This helps to stratify the patients in whom the PFO may be considered not a confounding factor but presumably a causing factor.
By the way, this score is a clinical score and it doesn’t account for anatomical or functional characteristics, which have been suggested to be important for the patient selection and clinical decision-making process, such as the permanent shunt, the large shunt, the presence of atrial septal aneurysm, etc. Nevertheless, it can be used for an initial stratification of patients with PFO and stroke who should be subsequently checked for biochemistry data and obviously shunt grade.
20.5.3 Biochemistry Assay
Complete hematologic assay with platelet count and a complete assessment of coagulation protein abnormalities including protein C and S, antithrombin III, factor V Leiden, factor VII, factor IX, and factor X should be added to the normal biohumoral assay which is active in any center, before the device-based procedure.
20.5.4 Shunt Severity
The proper quantification of the right-to-left shunt remains necessary for any therapeutic decision about management of PFO patients. The TCD with bubble test identifies three shunt patterns under Valsalva maneuver:
Mild (<10 bubbles within three cardiac cycles)
Moderate (>10 bubbles within three cardiac cycles) with shower effect (many bubbles but still countable)
Severe (>10 bubbles within three cardiac cycles) with curtain effect (many bubbles but not countable)
A distinct pattern of shunt occurs when bubbles are identifiable before the Valsalva maneuver (basal or permanent shunt) [46, 47]. In PFO patients, TEE identifies the shunt under Valsalva maneuver in trivial, small, moderate, and severe following current classification. Usually shower or curtain pattern of shunt correlates with moderate to severe shunt on TEE [48]. Severe and permanent shunt seems to correlate to an increased risk of paradoxical embolism [49].
20.5.5 Accepted Indications
Generally most national consensus and in particular the Italian consensus [50], despite some differences, accept as indications:
- 1.
Cryptogenic event in medical treatment – naïve patients with >1 risk factor (patients should be informed that the mechanical closure is alternative to medical therapy). Risk factors include atrial septal aneurysm, large PFO, basal right-to-left shunt, Eustachian valve >10 mm, Chiari network, long PFO tunnel, multiple ischemic lesions on neuroimaging, Valsalva-associated clinical event, ischemic event on arousal, long travel/immobilization event, and simultaneous systemic or pulmonary embolism.
- 2.
Any cryptogenic event (first or recurrent) on antiplatelet or anticoagulant therapy.
Other PFO-related syndromes such as platypnea-orthodeoxia, unexplained hypoxemia, peripheral or coronary paradoxical embolism, and refractory migraine with aura deserve a specific multidisciplinary work-up in order to identify patients who can benefit from PFO device-based closure.
20.6 Preoperative Evaluation
Preoperative cardiovascular assessment (Table 20.5) of patients with PFO is usually aimed to two main reasons:
Table 20.5
Anatomical-functional characteristics of patients with ASD/PFO
Characteristic | Diagnostic tool | Significance |
|---|---|---|
Left-to-right shunt >2 | TEE, MRI | Therapeutic decision-making |
Severe right-to-left shunt | TDC, TEE | Therapeutic decision-making |
Permanent right-to-left shunt | TDC, TEE | Therapeutic decision-making |
ASA | TEE | Management/device selection |
Eustachian valve/Chiari network | TEE | Management/technical challenge |
Long tunnel | TEE | Management/technical challenge |
Left atrial dysfunction | TTE | Therapeutic decision-making
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