Patent Foramen Ovale and Stroke in Intermediate-Risk Pulmonary Embolism

doi:10.1378/chest.14-0100

CHEST

Volume 146, Issue 4, October 2014, Pages 967-973

https://doi.org/10.1378/chest.14-0100 Get rights and content

BACKGROUND

Patent foramen ovale (PFO) in pulmonary embolism (PE) is associated with an increased risk of complications. However, little is known about PFO and ischemic stroke prevalence, particularly in acute intermediate-risk PE. In addition, in this context, the so-called “gold standard” method of PFO diagnosis remains unknown. We aimed to evaluate PFO and ischemic stroke prevalence and determine which of transesophageal echocardiography (TEE) or transthoracic echocardiography (TTE) is the best PFO diagnostic method in this context.

METHODS

We conducted a prospective monocentric study of consecutive patients with intermediate-risk PE in whom a TEE and TTE with contrast were performed. Brain MRI was used to confirm clinically obvious strokes or to diagnose subclinical ones.

RESULTS

Forty-one patients with intermediate-risk PE were identified over a 9-month period. Contrast TEE revealed PFO in 56.1%, whereas contrast TTE showed PFO in only 19.5% (P < .001). Of note, all PFOs observed with TTE were also diagnosed by TEE. Ischemic stroke occurred in 17.1% and was always associated with PFO and large shunt.

CONCLUSIONS

PFO and related ischemic strokes are frequent in intermediate-risk PE. TEE is much more efficient than TTE for PFO diagnosis. Considering the high risk of intracranial bleeding with thrombolysis in PE, which may be partly due to hemorrhagic transformation of subclinical strokes, screening PFO with TEE should be considered in intermediate-risk PE when thrombolytic treatment is discussed.

Section snippets

Study End Points

We aimed to evaluate PFO and ischemic stroke prevalence. We sought also to determine whether TEE or TTE is the best PFO diagnostic method in this context.

Patients

We performed a prospective monocentric observational study between October 2011 and June 2012 at the cardiac ICU of Pasteur University Hospital (Nice, France). Consecutive patients hospitalized for acute intermediate-risk PE were included. All PEs were confirmed with multidetector CT angiography. Intermediate risk was defined according to

Results

Over a 9-month period, 49 consecutive patients presenting with intermediate-risk PE were assessed. Six patients refused to participate in the study, one presented a contraindication to TEE (bleeding esophageal varices), and one presented a contraindication to MRI (pacemaker). Forty-one patients were finally included in the study.

Discussion

Patients with intermediate-risk PE present a high incidence of paradoxical embolism. Excluding other stroke causes, brain embolism in the context of PE cannot happen in the absence of a shunt, essentially a PFO. As such, looking for PFO is important in this context.

To our knowledge, this study is the first to show such a high incidence (17.7%) of paradoxical embolism in submassive PE. Clergeau et al³ demonstrated a lower PFO prevalence in mainly low-risk PE, with a paradoxical embolism

Conclusions

Intermediate-risk PE is associated with high PFO and related stroke prevalence. Diagnosis of PFO with TEE is clearly more efficient than with TTE. Approximately two-thirds of PFOs diagnosed with TEE are not detected with TTE. On TEE, one in three patients presenting with a PFO and up to one in two with a large shunt had a stroke. If these results are confirmed in larger cohorts and given the high ICH risk of thrombolysis in intermediate-risk PE, screening for PFO should be integrated into the

Acknowledgments

Author contributions: D. D., M. C., and E. F. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. D. D., M. C., D. B., and E. F. contributed to the study conception; D. D., M. C., O. C., R. L., P. C., and E. F. contributed to the data acquisition, analysis, and interpretation; D. D., M. C., P. M., C. C., and E. F. contributed to drafting the manuscript; and D. D., M. C., P. M., O. C., R. L., D. B., P. C.,

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Cited by (42)

Frequency and incidence of arterial events in patients with venous thromboembolism compared to the general population: A systematic review and meta-analysis of cohort studies
2021, Thrombosis Research
Citation Excerpt :
Heterogeneity was assessed using the χ2 test on Cochrane's Q statistic and quantified by calculating the I2 which values greater than 60% indicate the presence of substantial heterogeneity [13]. In order to assess possible publication bias, we used funnel plots and Egger's test, with a p-value <0.10 considered statistically significant [19]. Generally, a p-value <0.05 characterized statistically significant results in our analysis.
Recent literature hypothesized that patients with venous thromboembolism (VTE) are at increased risk of developing arterial ischemic events than general population without VTE. However, data summarizing the epidemiology of arterial events among VTE population compared to the general population are lacking.
We conducted a systematic review and meta-analysis from current literature. PubMed, EMBASE, and Cochrane databases were searched between Jan 1, 2000, and December 31, 2020. Eligible studies were observational cohort studies published in English on arterial ischemic events in patients with VTE. Pooled effect size estimates and their 95% confidence intervals were obtained through random-effect models meta-analysis.
Twenty-eight observational studies enrolling 352,014 patients were identified and included. The pooled frequency of all arterial events was 6.1% (95% CI: 3.7–9.1) in patients with VTE and was significantly higher than the pooled frequency of 5.0% (95% CI: 3.1–7.2) found in controls, with a pooled risk ratio (RR) of 1.20 (95% CI: 1.01–1.44; p = 0.0422). The pooled incidence of all arterial events in patients with VTE was 11.3‰ per patient-year (95% CI: 4.6–18.0), and was significantly higher than the 9.2‰ per patient-year (95% CI: 2.0–16.4) obtained in controls (Incidence rate ratio, IRR: 1.32; 95% CI: 1.08–1.61; p = 0.0103). The pooled frequency and pooled incidence of arterial events were also higher in patients with unprovoked VTE than in patients with provoked VTE (RR: 2.12; 95% CI: 1.38–3.24; p = 0.0042; and IRR: 2.26, 95% CI: 1.45–3.49; p = 0.0032).
The frequency and incidence of arterial events in patients with VTE are considerably higher than in the general population, without VTE. Further studies are urgently needed to understand these differences and reduce the burden related to these diseases.
None.
Outcomes in patients with acute pulmonary embolism and patent foramen ovale: Findings from the RIETE registry
2021, Thrombosis Research
An increased risk of ischemic stroke in patients with acute pulmonary embolism (PE) and patent foramen ovale (PFO) was reported but few data exist regarding prognostic outcomes of those patients.
Using data in the RIETE registry, we compared the characteristics, therapeutic approaches and outcomes of patients with PE according to the presence or absence of PFO.
From August 2016 to January 2020, 4148 patients with acute PE were enrolled. Of these, 2775 (67%) had no transthoracic echocardiogram (TTE), 993 (24%) underwent TTE but had no reported results on PFO. Among the remaining 380 patients, 287 (74%) did not have PFO and 93 (26%) had PFO. Patients with PFO were more likely to have chronic heart failure, prior myocardial infarction or ischemic stroke than those without PFO. Patients with PFO had a higher rate of subsequent ischemic stroke than those without PFO (hazard ratio (HR): 9.28; 95% CI: 1.83–69.1), than those with TTE but no data on PFO (HR: 10.1; 95% CI: 2.56–42.4) or without TTE (HR: 9.78; 95% CI: 3.02–28.4). On multivariable analysis, patients with PFO were at increased risk for subsequent ischemic stroke than those without PFO (HR: 8.96; 95% CI: 1.68–47.7).
PFO was searched in a minority of patients with an acute PE in real life setting. Subject to possible selection and measurement biases, our results confirmed a higher risk of ischemic stroke in PE patients with PFO compared to those without PFO. This association warrants further investigation before determining the best therapeutic option in patients with acute PE and concomitant PFO.
Paradoxical Cerebral Embolism as Initial Manifestation of Chronic Thromboembolic Pulmonary Hypertension: A Case Report
2019, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
To our knowledge, this is the first case of CTEPH to be diagnosed with the onset of paradoxical cerebral embolism. Venous thrombosis may cause embolism in both the lungs and brain if a PFO exists.5-7 Unlike those with acute PE, however, approximately half of patients with CTEPH have no history of DVT, and D-dimer levels are increased in only about one-quarter of cases.8
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by chronic thrombi in the pulmonary arteries, causing pulmonary hypertension and right heart failure. Early and accurate diagnosis are essential for successful treatment but are often difficult because clinical signs and symptoms can be nonspecific and risk factors, such as history of venous thromboembolism, may not always be present. Here, we report a case involving a 76-year-old woman who demonstrated paradoxical cerebral embolism as the initial manifestation of CTEPH. She developed right hemiplegia without dyspnea or edema. Brain magnetic resonance imaging revealed multiple fresh infarctions, while transesophageal echocardiography revealed a patent foramen ovale. Based on these findings, she was diagnosed as having paradoxical cerebral embolism. During the search for the embolic source, right heart catheterization showed significant pulmonary hypertension and pulmonary angiography revealed chronic thrombi in the peripheral pulmonary arteries, consistent with a diagnosis of CTEPH. To our knowledge, this is the first case of CTEPH to be diagnosed with the onset of paradoxical cerebral embolism. Because CTEPH is the only potentially curable form of pulmonary hypertension, clinicians should consider paradoxical cerebral embolism as a possible initial manifestation of CTEPH.
Role of echocardiography and cardiac biomarkers in prediction of in-hospital mortality and long-term risk of brain infarction in pulmonary embolism patients
2018, Cor et Vasa
Citation Excerpt :
The rate of PFO was reported in a population of acute PE patients at between 19.5 and 56.1% depending on the method of contrast echocardiography used. Clinically presented IS was recorded in 17% of patients with PE during a 9-month FUP [28]. TEE is considered a reference method for visualizing the right-to-left shunt and detecting PFO.
The aim of prospective study was to evaluate the ability of echocardiography and cardiac biomarkers to predict in-hospital mortality and the risk of brain infarction during a 12-month follow-up period (FUP) with anticoagulation in pulmonary embolism (PE) patients.
Eighty-eight consecutive acute PE patients (39 men, mean age 63 years) were enrolled; 78 underwent baseline echocardiography and brain magnetic resonance imaging (MRI). After a 12-month FUP, 58 underwent brain MRI. In-hospital mortality and the rates of new ischemic brain lesions (IBL) on MRI with clinical ischemic stroke (IS) events were predicted based on echocardiography (patent foramen ovale presence with right-to-left shunt – PFO/RLS; right/left ventricle diameter ratio – RV/LD; tricuspid annulus plane systolic excursion – TAPSE; tricuspid annulus systolic velocity – S_T; pulmonary artery systolic pressure – PASP) and biomarkers results (amino-terminal fragment of brain natriuretic peptide – NT-proBNP and cardiac troponin T – cTnT).
Our series involved 88 patients, of whom 11 (12.5%) presented high-risk PE, 24 (27.3%) intermediate-high risk PE, 19 (21.6%) intermediate-low risk PE and 34 (38.6%) patients had low risk PE.
Nine patients (10.2%) died during hospitalization including high-risk PE [6/9 (66.6%)] and intermediate-high-risk PE [3/24 (12.5%)]. cTnT [odds ratio (OR) 4.3; 95% confidence interval 0.59–31.3, P = 0.014], NT-proBNP (OR 14.2 [1.5–133.4], P = 0.02), RV/LD ≥0.79 (OR 36.6 [4.2–316.4], P = 0.001), TAPSE (OR 0.55 [0.34–0.92, P = 0.022) and PASP ≥51.5 mmHg (OR 33.3 [3.8–292.6], P = 0.022) were predictors of in-hospital mortality.
Seventeen patients (19.3%) experienced IS (n = 8) or new IBL (n = 9). On multivariate analysis, PFO/RLS (OR 27.1 [3.0–245.3], P = 0.003) and S_T ≤14.5 cm/s (OR 34.1 [CI 3.4–344.0], P = 0.003) were independent predictors of IS and IBL risk.
High blood troponin T, NT-proBNP, RV dilatation/systolic dysfunction and pulmonary hypertension predicted in-hospital mortality. PFO/RLS presence and S_T were predictors of clinically apparent/silent brain infarction.
Patent Foramen Ovale and the Risk of Cerebral Infarcts in Acute Pulmonary Embolism—A Prospective Observational Study
2018, Journal of Stroke and Cerebrovascular Diseases
Citation Excerpt :
In about one third of patients, right-to-left shunting through a PFO can be detected by echocardiography. Due to an inverted pressure gradient between the right atrium and the left atrium, right-to-left shunting may lead to an increased risk of mortality, paradoxical embolism, and stroke.4-7,11,14 A PFO may be found in up to 30% of otherwise normal hearts.
Pulmonary embolism (PE) is associated with a risk of consecutive paradoxical embolism with brain infarction through a patent foramen ovale (PFO). The aims of this study were to assess the rate of new ischemic brain lesions (IBLs) using magnetic resonance imaging (MRI) during a 12-month follow-up period with anticoagulation and to evaluate the potential relationship with the presence of PFO on transesophageal echocardiography (TEE).
Seventy-eight patients with acute PE underwent baseline contrast TEE with brain MRI. After the 12-month follow-up, 58 underwent brain MRI. The rates of MRI documenting new IBLs were measured based on the presence of PFO.
PFO was detected in 31 patients (39.7%). At baseline MRI, IBL was present in 39 of 78 patients (50%). The presence of IBL was not significantly higher in patients with PFO than in patients without PFO (20 [64.5% patients with PFO] versus 19 [40.4% without PFO] of 39 patients with baseline IBL, P = .063).
At the follow-up MRI, in the group with new IBL (9 of 58 patients, 15.5%), the number of patients with PFO was significantly higher than that without PFO (7 [33.3%] versus 2 [5.4%], P = .008). PFO was identified as an independent predictor of new IBL (odds ratio 4.6 [1.6-47.4], P = .008).
The presence of PFO was associated with new IBL in patients with PE. These patients are at a higher risk of ischemic stroke despite effective anticoagulation therapy.
Diuretics versus volume expansion in acute submassive pulmonary embolism
2017, Archives of Cardiovascular Diseases
Citation Excerpt :
If the 2008 European Society of Cardiology guidelines [27] favoured modest fluid challenge in patients with low cardiac index and normal blood pressure, those of 2014 [3] did not rule out any recommendations on haemodynamic conditioning. In submassive PE, the two main physiopathological responses to the brutal RV afterload increase are catecholamine-driven tachycardia and RV dilatation [1,28–30]. Interestingly, we observed a very early significant improvement in HR in patients who received one single bolus of furosemide.
The benefit of volume expansion (VE) in submassive pulmonary embolism (PE) with right ventricular (RV) dysfunction is unclear.
To compare the effects of diuretic treatment versus VE in patients hospitalized for PE with RV dysfunction.
We prospectively included 46 consecutive patients with submassive PE treated on admission with a 40 mg bolus of furosemide (D group, n = 24) or 500 mL of saline infusion (VE group, n = 22). The primary endpoint was the timing of normalization of B-type natriuretic peptide and troponin Ic concentrations. The secondary endpoints were variations in RV function variables, recorded at baseline, at the 4th hour after treatment initiation (H4) and every day until discharge, and a clinical composite endpoint of thrombolysis or death at 7 and 30 days.
No differences were observed between patients at baseline. The primary endpoint occurred earlier in the D group than in the VE group (67.5 ± 34.8 vs 111.6 ± 63.3 hours; P = 0.006). Furosemide treatment on admission was well tolerated, and was not associated with serious adverse events. At H4, substantial improvements were observed in the D group versus the VE group in terms of heart rate reduction (–8.15 ± 21.0 vs –0.71 ± 6.30 beats/min; P < 0.01) and peak tricuspid annular systolic velocity (Doppler tissue imaging) (11.4 ± 2.10 vs 9.90 ± 2.80 cm/s; P = 0.02). There was no significant difference between groups in terms of severe outcomes at 7 and 30 days.
In the acute management of submassive PE patients, a single furosemide bolus on admission seems to produce significant and earlier improvements in RV function markers compared with VE, without adverse events.
Le bénéfice du remplissage dans l’embolie pulmonaire (EP) aiguë avec dysfonction ventriculaire droite (VD) est incertain. Nous avons comparé les effets d’un traitement diurétique versus un remplissage chez des patients hospitalisés pour EP avec dysfonction VD.
Nous avons prospectivement inclus 46 patients consécutifs hospitalisés pour une EP aiguë avec dysfonction VD traités à l’admission soit par un bolus de 40 mg de furosémide (groupe D, n = 24), soit un remplissage de 500 cm³ de chlorure de sodium (groupe R, n = 22). Le critère de jugement principal était le temps de normalisation du Brain natriuretic peptide (BNP) et de la troponine Ic. Les critères de jugement secondaires étaient l’analyse de paramètres cliniques, biologiques et échographiques enregistrés à l’admission, après 4 heures de traitement, puis quotidiennement jusqu’à la sortie d’hospitalisation et la survenue d’un critère clinique composite (décès ou thrombolyse) aux 7^e et 30^e jours.
Il n’y avait pas de différence significative entre les 2 groupes à l’admission. La normalisation du BNP et de la troponine Ic est survenue plus rapidement dans le groupe D que dans le groupe R (67,53 ± 4,8 vs 111,6 ± 63,3 heures, p = 0,006). L’administration de furosémide à l’admission était bien tolérée et ne s’est pas compliquée d’effets indésirables graves. À la 4^e heure, une réduction significative de la fréquence cardiaque et une amélioration significative du pic de vitesse systolique tricuspide (onde S, évaluée en doppler tissulaire pulsé) étaient observées dans le groupe D avec respectivement −8,15 ± 21,0 vs −0,71 ± 6,30 bpm dans le groupe R, p < 0,01 et 11,4 ± 2,10 vs 9,90 ± 2,80 cm/s dans le groupe R, p = 0,02. Il n’y avait pas de différence significative en termes de décès ou thrombolyse aux 7^e et 30^e jours entre les 2 groupes.
Dans la prise en charge de l’EP aiguë avec dysfonction VD, un bolus de furosémide à l’admission entraîne une amélioration rapide et significative de paramètres pronostics cliniques, biologiques et échographiques sans survenue d’effets indésirables graves.

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Part of this article has been presented in abstract form at the European Society of Cardiology Congress, August 31-September 4, 2013, Amsterdam, The Netherlands.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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CHEST

Original Research: Pulmonary Vascular DiseasePatent Foramen Ovale and Stroke in Intermediate-Risk Pulmonary Embolism

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Study End Points

Patients

Results

Discussion

Conclusions

Acknowledgments

J Am Soc Echocardiogr

Am Heart J

J Am Soc Echocardiogr

J Am Soc Echocardiogr

J Am Soc Echocardiogr

Mayo Clin Proc

Am J Cardiol

Am J Med

JACC Cardiovasc Imaging

ESC Committee for Practice Guidelines (CPG). Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)

Eur Heart J

Patent foramen ovale is an important predictor of adverse outcome in patients with major pulmonary embolism

Circulation

Silent cerebral infarcts in patients with pulmonary embolism and a patent foramen ovale: a prospective diffusion-weighted MRI study

Stroke

Original Research: Pulmonary Vascular Disease
Patent Foramen Ovale and Stroke in Intermediate-Risk Pulmonary Embolism