Percutaneous Closure of Atrial Septal Defect in Adults: Very Long-Term Clinical Outcome and Effects on Aortic and Mitral Valve Function

Abstract: Aim. To investigate the very long-term clinical outcomes of atrial septal defect (ASD) percutaneous closure in adult patients and to evaluate the 12-month effects of the device on aortic and mitral valve function. Methods. Over a 12-year period, a total of 110 consecutive patients underwent percutaneous ASD closure. A yearly clinical follow-up was conducted and any adverse event was recorded. In a 55-patient echocardiographic subgroup, the baseline and 12-month aortic and mitral regurgitation rate was recorded. Results. Mean age was 50.9 ± 17 years and 75% of patients were female. Mean ASD echocardiographic dimension was 17.6 ± 6.2 mm (range, 5-36 mm). Procedural success rate was 97%. After a mean follow-up of 61.8 ± 34.9 months (range, 6–167 months), all-cause death occurred in 2 patients (1.8%) and the composite primary outcome of major adverse cardiovascular event (MACE) occurred in 5 patients (4.5%): 2 non-device related cardiac deaths occurred and 3 surgeries were required. The Kaplan-Meier analysis showed an event-free survival at 140 months of 90%. In the 12-month echocardiographic substudy, no case of significant (moderate or severe) new-onset aortic regurgitation was detected, while 1 case (1.8%) of worsening mild-to-moderate aortic regurgitation was described (P=.90). No case of significant new-onset or worsening mitral regurgitation was noted. No patient needed aortic or mitral surgical repair at very long-term follow-up. Conclusions. Transcatheter ASD closure is a safe procedure with satisfactory very long-term clinical outcomes. The ASD device does not significantly affect aortic and mitral valve function.

J INVASIVE CARDIOL 2015;27(1):65-69
Key words: atrial septal defect, device, aortic regurgitation, mitral regurgitation

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Atrial septal defect (ASD) is the most common congenital heart disease in adults.^1,2 Chronic volume and pressure overload of the right ventricle and the pulmonary circulation are the main indications to treatment, in order to prevent heart failure and irreversible pulmonary hypertension.^3,4 Cryptogenic stroke represents another important indication for closure.⁴

Percutaneous closure with specific devices has become an effective and reasonable treatment compared to surgery in experienced medical centers.⁵ Some studies describe device dislocation and thrombosis as a major clinical adverse event,^4,5 but the very long-term efficacy and safety data are lacking. Moreover, recent and inconclusive studies speculate some possible negative effects of ASD devices on mitral and/or aortic valve function⁶ secondary to traction on the aortic rim.⁷

The aim of this single-center study is to investigate the very long-term clinical outcome of adult patients undergoing percutaneous ASD closure and the effects of closure device on mitral and aortic valve function at 12 months.

Methods

Study population. This registry study involved 110 consecutive patients referred to our institution for percutaneous closure of an ASD over a 12-year period between July 1998 and April 2012 (outcome cohort). A subgroup of 55 patients with detailed baseline and 12-month echocardiographic characteristics was also described and analyzed (echocardiographic cohort).

Indications for closure were significant left-to-right shunt, defined as Qp/Qs >1.5 (assessed either by catheterization or echocardiography), with right heart chamber volume overload and/or pulmonary hypertension (95 patients; 86%) or cryptogenic cerebral embolism (15 patients; 14%).

All patients gave written informed consent in accordance with the ethical guidelines followed at our institution.

Follow-up and endpoints. All patients underwent a clinical follow-up every 12 months after the procedure and any adverse event was recorded. Major adverse cardiovascular event (MACE) was defined as follows: death from any cause, non-fatal myocardial infarction, need for heart surgery, percutaneous reintervention, device thrombosis, endocarditis, device erosion, and cardiac tamponade.

All patients underwent two-dimensional color Doppler transthoracic echocardiogram (TTE) and transesophageal echocardiogram (TEE) examination in order to confirm the diagnosis of ASD before referral to the catheterization lab for closure. The echocardiographic follow-up was performed either by our institution or by the referral hospital. Patients who performed the echocardiographic follow-up at our institution with complete and standardized data were included in the echocardiographic cohort in order to evaluate the presence and severity of aortic and mitral regurgitation.

The primary endpoints were mortality from any cause and MACE rate in the outcome cohort. The secondary endpoint was the baseline to 12-month variation in aortic and mitral regurgitation rate in the echocardiographic cohort.
Patient management. Patients were referred to cardiac catheterization laboratory after an overnight in our department. Intravenous femoral sheath was placed and weight-adjusted unfractionated heparin was routinely administered, in order to maintain the activated clotting time (ACT) above 250 seconds during the entire procedure. All procedures were performed using the standard techniques recommended by the device manufacturers, under fluoroscopic guidance and/or TEE guidance, according to the operator’s choice. TTE was never used as a guiding tool during the procedure. The sizing-balloon technique was always used in order to select the optimal device size, in one standardized angiographic projection (20° left anterior oblique, 10° cranial). Procedural success was defined as the correct implant of the device in the absence of complications (death, air embolization, pericardial effusion, cardiac wall perforation, thrombosis, device embolization, persistent atrial fibrillation), and no or trivial residual shunt at the end of the procedure. Before discharge, TTE was performed in all patients to rule out device dislocation/embolization, thrombosis, and significant pericardial effusion. Patients were discharged on single- or dual-antiplatelet therapy for at least 6 months.

Echocardiography. According to the American Heart Association (AHA)9 guidelines, valve regurgitation was graded as mild, moderate, or severe. The parameters used to grade aortic regurgitation were jet length, jet width, and its ratio to the ventricular outflow tract and pressure half-time. The parameters used to grade mitral regurgitation were a composite of the jet area and left atrial area ratio, continuous Doppler flow pattern, anterograde flow velocity, and vena contracta width. The examinations were performed by the same sonographer team using a standardized protocol.

Definitions. Mitral valve prolapse and aortic annulus/aortic root dilatation were defined according to American Society of Echocardiography guidelines.¹⁰ Diabetes was defined as any treatment with anti-diabetes drugs (including insulin), documentation at fasting glycemia test of a value ≥126 mg/dL (6.9 mmol/L), or documentation of HbA1c of ≥5.5%. Hypertension was defined as diastolic blood pressure >90 mm Hg and/or a systolic blood pressure >140 mm Hg at ambulatory evaluation, or any treatment with an antihypertensive drug. Dyslipidemia was defined as documentation of total cholesterol >200 mg/dL (5.15 mmol/L) or low-density lipoprotein (LDL) cholesterol >120 mg/dL (3.10 mmol/L), or any treatment with cholesterol-lowering drugs. Rheumatic valve disease was diagnosed in patients with previous rheumatic fever and echocardiographic findings of altered mitral valve apparatus.10 Coronary artery disease was identified by previous coronary artery percutaneous intervention or aortocoronary bypass grafting. Bacterial endocarditis was diagnosed according to the Duke criteria.¹¹ The clinical diagnosis of heart failure was derived from detailed previous history reviews, hospital admissions, and clinical examinations. Stroke was defined as a rapid loss of brain function due to disturbance in the blood supply to the brain.¹²

Statistical analysis. Variables with normal distribution were analyzed using parametric tests, while variables with a non-normal distribution were analyzed using non-parametric tests. Continuous variables were expressed as mean ± standard deviation; P-values <.05 were considered statistically significant. Categorical variables were expressed in counts and percentages, and were analyzed with a chi-square test. A Kaplan-Meier curve analysis was performed to study the event-free survival after the procedure, according to the clinical follow-up. All statistical analyses were performed with SPSS 11.0 (SPSS, Inc).

Results

Mean age of the population at the time of the index procedure was 50.9 ± 17 years and 75% of the patients were female. Hypertension was present in 37 patients (33.6%), diabetes in 6 patients (7.2%), coronary artery disease in 4 patients (3.6%), heart failure in 5 patients (4.5%), endocarditis in 1 patient (0.9%), mitral valve prolapse in 13 patients (11.8%), and aortic annulus dilatation in 1 patient (0.9%). Increased pulmonary flow represented the indication for closure in 86% of patients, while a cryptogenic stroke was the indication in 14% of cases. No differences in baseline clinical characteristics between the outcome and the echocardiographic cohorts were detected (Table 1).  

Mean atrial septal defect dimension was 17.6 ± 6.2 mm and mean Qp/Qs at the time of closure was 1.98 ± 0.83. Twelve percent of the patients were treated with implantation of a small device (10-15 mm), 62% were treated with a medium device (16-25 mm), and 29% were treated with a large device (26-40 mm). An Amplatzer septal occluder (AGA Medical Corporation/St Jude Medical) was used in 97% of cases. The procedure was guided by fluoroscopy only in 84% of cases, while an echocardiographic imaging was used in 18% of patients (Table 2). Procedural success was obtained in 97.3% of patients; 2 procedures were complicated by device embolization (1 percutaneously and 1 surgically retrieved), and 1 procedure was complicated by a paroxysmal atrial fibrillation. Both cases complicated by device embolization were not TEE guided. No MACE was detected during hospital stay.

After a mean follow-up of 61.8 ± 34.9 months (range, 6-167 months), the primary outcome of death from any cause occurred in 2 patients (1.8%; 1 case due to acute cardiac failure and 1 case due to metastatic cancer). Composite primary outcome of MACE occurred in 5 patients (4.5%; 2 cases of non-device related death and 3 cases of surgery [2 for incomplete atrial septal defect closure and 1 for late embolization of the device]). No device thrombosis, endocarditis, or erosion of cardiac structures was detected. Figure 1 shows the probability of MACE-free survival in the outcome cohort. The 12-month echocardiographic closure rate was 93.7%. A trivial residual shunt was detected in 6 patients (5.4%), and a significant residual shunt was detected in 1 patient (0.9%). Any atrial fibrillation occurred in 15 patients (13.6%) during follow-up. Mean age of patients experiencing atrial fibrillation was significantly higher (67 ± 16.6 years vs 51 ± 17.6; P=.01).

Table 3 shows the baseline and 12-month prevalence of aortic regurgitation in the echocardiographic cohort. A new mild aortic regurgitation was detected in 4 patients (7.2%; P=.50). One baseline mild aortic regurgitation worsened to moderate in 1 patient (1.8%; P=.90). No case of new moderate aortic regurgitation and no case of new or worsening severe aortic regurgitation was noted.

Table 4 shows the baseline and 12-month prevalence of mitral regurgitation in the echocardiographic cohort. A new mild mitral regurgitation was described in 2 patients (3.6%; P=.80). No case of new or worsening moderate or severe mitral regurgitation was noticed. No patient has required surgical repair or replacement of the valves.

Discussion

The main findings of our study are the following: (1) percutaneous closure of ostium secundum ASD in adults is a safe procedure with a satisfactory very long-term clinical outcome; and (2) the use of a closure device does not significantly affect the function of aortic and mitral valves at 12 months.

Percutaneous closure is considered the treatment of choice of ostium secundum ASD in adults when technically feasible¹ and in suitable interatrial septum anatomies,^13,14 but only sparse data on very long-term efficacy and safety are available. Moreover, controversial data on possible interactions of closure device on aortic and mitral valve function have been reported.⁶

Some registries show the outcomes of ASD percutaneous treatment in adults,^14,16 with a mean clinical follow-up ranging from 26-60 months. To our knowledge, our study presents the longest available clinical follow-up.
No perioperative fatal events were detected in our cohort, with a procedural success rate of 97%. Other studies on percutaneous treatment of ostium secundum ASD reported similar success rate (97%-99%).^15,16 The mortality rate from any cause at the very long-term follow-up was 1.8% (2 non-device related deaths). MACE-free survival at 140 months was 90%.

Our findings point out the safety of a percutaneous approach and are concordant with a population-based cohort study,16 which describes comparable hard endpoints for percutaneous and surgical closure. Surgical series reported a MACE-free survival at 5 years ranging from 92%-95%.^2,17

In our series, procedural complications were very rare, but we noted 2 cases of device embolization. Of note, both procedures were not TEE guided. On this basis, we could speculate that TEE guidance could be a safety tool for percutaneous ASD closure.  

Device-related complications are a matter of concern.^4,5 In our population, no events of device thrombosis, endocarditis, or erosion were detected at the very long-term follow-up.

Atrial fibrillation is the most frequent arrhythmia noticed after ASD percutaneous closure.18 In our study, the incidence of atrial fibrillation was not negligible, rising to 13.6%. In a mixed series of surgical and percutaneous ASD closures, atrial fibrillation can reach up to 25%.18 In our series, the arterial hypertension (33% of patients) and the advanced age (37% of the patients were older than 60 years and the mean age of the patients experiencing atrial fibrillation was significantly higher) are certainly contributory causes.

Few studies have indicated the possible adverse influence of ASD and patent foramen ovale (PFO) closure device on mitral and aortic valve function.^6,8

TTE is the first-line method to follow patients treated percutaneously.³ TEE and magnetic resonance imaging are more accurate than TTE,⁸ but in clinical practice they are used only for investigational purposes or as a second-line method.

One TEE study, based on a mixed ASD and PFO population, found a 10% excess of new onset aortic regurgitation at 12 months.⁷ A similar TEE study presented non-conclusive data, with a non-significant 0.6% increase in severe aortic regurgitation rate.⁴ Finally, a magnetic resonance study demonstrated no significant interference with valvular function at 12 months after PFO closure.⁶ ASD and PFO are distinct anatomical and pathological conditions, treated with similar but not identical closure devices. To analyze a mixed series of ASD and PFO closures may bias the regurgitation rate endpoint. Our study focused on an ASD-only closure cohort. A 12-month follow-up was chosen in order to provide an adequate endothelialization period and to minimize the effect of risk factors for valve dysfunction (hypertension, coronary artery disease, age-related degeneration).¹⁹ Our results shows minor and not statistically significant differences in baseline to 12-month aortic and mitral regurgitation rates. Only 1 case (1.8%) of worsening moderate aortic regurgitation at 12 month was noted. No significant new-onset or worsening mitral regurgitation was detected. No patient required mitral or aortic surgical repair at the very long-term follow-up.

Study limitations. The present study was designed as a prospective single-center registry and therefore lacks any surgical or medical control group. Sample size was relatively small and event adjudication was not blinded.
Nevertheless, given the absence of large randomized trials or registry studies on percutaneous treatment of ostium secundum ASD in adults, and particularly of any papers reporting correlations between ASD closure devices and valve function, our study adds a useful piece of information to this discussion.

Conclusion

Transcatheter closure of ASD is safe and effective, with satisfactory long-term clinical follow-up. ASD closure devices seem not to significantly interfere with aortic and mitral valve function, even if larger population studies are needed to definitely address this topic.

References

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From 1Cardiovascular and Thoracic Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Turin, Italy; and 2Cardiovascular and Thoracic Department, University of Turin, Turin, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted February 3, 2014, provisional acceptance given February 26, 2014, final version accepted April 7, 2014.

Address for correspondence: Paolo Scacciatella, MD, Cardiovascular and Thoracic Department, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Corso Bramante 88, 10126 Turin, Italy. Email: paolo.scacciatella@tin.it