Adding left atrial appendage closure to open heart surgery provides protection from ischemic brain injury six years after surgery independently of atrial fibrillation history: the LAACS randomized study

From August 2010 to September 2015, we conducted a prospective, randomized, open label study on patients scheduled for open heart surgery to receive either concomitant LAACS or standard care. The LAACS study is registered at clinicaltrials.​gov (NCT02378116). The study was initiated at the Department of Thoracic Surgery, University Hospital of Gentofte, Denmark. During 2010, the Department of Thoracic Surgery was transferred and merged with the equivalent department at Rigshospitalet, Copenhagen, where the study continued. Patients were randomized the day before surgery after signing informed consent. To ensure a balanced distribution of patients receiving OAC between the two study-arms, randomization was stratified according to ongoing use of anti-coagulation. This included patients undergoing surgical biological valve replacement until January 2012, as post-operative anti-coagulation was no longer recommended [17].

Patients were randomized 1:1 by a computer-generated randomization in blocks of 16 patients. Since we expected substantial cross-over, procedures were monitored at the end of each operation for cross-over. If one of the study groups reached a discrepancy of 4 between randomization allocation and the actual operation, the randomization block was suspended and substituted by a 3:1 randomization in the next block (n 16) to compensate for the difference.

The study protocol recommended double closure with both purse string and running suture, although this closure method was not mandatory. Patients were invited to pre-surgery magnetic resonance imaging (MRI) scan (MRI-0) whenever possible. Immediately after discharge, all patients were invited for a post-operative baseline brain MRI scan (MRI-1) scheduled between 2 and 4 weeks after discharge and a follow-up MRI (MRI-2) performed at least 6 months after surgery.

Consecutive patients undergoing planned first-time open-heart surgery (CABG, valve surgery or a combination of both) during the study period were asked to participate in the trial, provided that their residence was within 40 km radius from the hospital. Major exclusion criteria included endocarditis and implanted pacemaker (see Additional file 1: Table S1 for full inclusion and exclusion criteria). All patients in the LAACS arm were invited to undergo post-operative transesophageal echocardiography (TEE) by a senior cardiologist to visualize the LAA and the quality of the closure. Patients could decline TEE and remain in the study for follow-up.

The brain MRI included imaging of cerebrum, cerebellum and brainstem. All MRIs were reviewed by a fellow in radiology with years of experience, and the possibility of consulting unclear cases with a neuro radiologist. Radiologists were blinded to randomization. MRI-criteria for silent cerebral infarcts (SCI) were equivalent to those in the Framingham offspring study, i.e., cavitating lesions ≥3 mm with CSF-like signal intensities on T1, T2 and FLAIR [17]. Both acute and old SCIs were included. Differentiation from dilated Virchow-Robins spaces (dVRS) was attempted using the location criterion (i.e., excluding lesions along perforating or medullary arteries or in the lower third of the basal ganglia) and shape criterion (i.e. oval lesions criteria along the penetrating arteries with intensity close to CSF were considered dVRS) [18].

The pre-specified endpoint protocol was post-operative cerebral ischemic events defined as a composite of first ischemic stroke or transient ischemic attack (ICD-10: DG450–9), increased amount of SCI between MRI-1 and MRI-2 and post-operative findings of SCI by brain imaging (computed tomography [CT] or MRI) performed in clinical settings unrelated to study enrollment.

Secondary outcomes were strict symptomatic ischemic strokes. That is, ischemic stroke or transient ischemic attack, excluding cerebral ischemic events classified solely on imaging findings and all-cause mortality. We followed all patients for at least 1 year after surgery. The clinical outcomes Ischemic stroke and transient ischemic attack were ascertained by following the patient’s electronic records yearly. Patients vital status were obtained using data from the Central Office of Civil Registration, which comprises all citizens in Denmark. Additionally, telephone interviews were performed after minimum 1 year to ascertain whether the patients had experienced signs of clinically unrecognized cerebral ischemia. If so, it would be registered as a transient ischemic attack.

We based our power calculations on the incidence of AF among patients undergoing open heart surgery and the expected variation in a combined end-point of clinical stroke, transitory ischemic attack (TIA), and occurrence of silence infarctions, which included findings of newly silent lacunar infarctions with imaging in clinical settings and changes on number of lacunar infarctions from baseline MRI (at discharge) to MR2. Incident stroke occurs in 1–5% of heart surgery patients [19‐21], often within the first months following surgery [22]. At the initiation of the study, there were almost no studies with long-term MRI follow-up after open heart surgery [23]. Around 50% of patients undergoing surgery of carotid arteries have lacunar infarctions on MRI [24], and the presence of AF roughly doubles the risk of strokes [25]. We assumed an equivalent prevalence of 50–70% of infarctions counting both subclinical and clinical peri-operative strokes/TIA. This is equivalent to findings on CABG surgery [26] and valve surgery [23], respectively, where MRI changes occur in 40–70% of patients. Therefore, we assumed that closure of the LAA would reduce findings on MRI scans and clinical strokes/TIA from a total of 60 to 35% with a 5% margin. With a significance level of 5%, we calculated that we could demonstrate this benefit with a 5% margin and 90% power by including 90 patients. After the initiation of the study, it became apparent that MRI scans were not feasible for many patients. Hence, we recalculated the number of patients needed based on newer data on occurrence of stroke after heart surgery [27‐30], considering a three- to five-fold increased risk of stroke in patients with non-contracting, patent LAA who had undergone MAZE-procedure during surgery [31] combined with an occurrence of images of infarction after CABG over 20% [32], the latter including MRI changes [23, 26]. Without other available evidence on truly long-term follow-up studies after heart surgery associated to AF, we calculated that we could investigate the protective effect of LAACS based on any signs of cerebral infarction (stroke, TIA or imaging evidence of silent cerebral ischemia) through randomization of 400 patients, if LAACS could reduce events from 65 to 45% with a significance level of 5 and 91% power. With 88% power, a second calculation showed a necessity of including 100 patients in each group. Therefore, we maintained our plan to randomize 200 patients.

All analyses were performed using SAS statistical software package version 9.4 (SAS Institute Inc., Cary, NC). Continuous variables are presented as mean±standard deviation and categorical variables as number and percentages. After inspection for normality, differences between the LAACS and control group were evaluated by Student’s t-test (continuous variables) and by Chi-square and Fisher’s exact test (categorical variables) where appropriate. Cause specific Cox time to event analysis was used to estimate the rate ratios for incident stroke and all-cause mortality according to randomization. A cumulative probability plot of incident stroke according to randomization was generated by Fine and Gray competing risk regression using death as a competing event [33]. All outcome analyses were performed as intention to treat and per protocol. Patients were considered to have complied with the treatment protocol when LAAC was performed according to randomization. A sensitivity analysis was performed to evaluate model dependence on imaging findings by comparing overall results with a model that only included events due to symptomatic ischemic stroke or transient ischemic attack. A two-tailed p-value < 0.05 was regarded as statistically significant.

The project was approved by Regional Ethics Committee of Capital Region Denmark (protocol number H-3-2010-017) and follows the Helsinki declaration.

Follow up was up to 6 years, mean 3.7 ± 1.6 years (totaling 684 patient years of follow-up). End of study was 1 year after reaching our pre-specified sample size of 200 patients. Five patients were lost to follow-up for the primary endpoint and 24 (13%) died. At end of study telephone-interviews, no patient was suspected to have suffered a clinically unrecognized ischemic cerebral event. In the intention-to-treat analysis, there were 5 (5%) primary events in the LAACS-group and 14 (16%) in the control group (hazard ratio 0.3; 95% CI: 0.1–0.8, p = 0.02, Table 2, Fig. 1 and Additional file 4: Table S3 Contingency table of individual events). Tests of interaction revealed no dependency of the preventative effect of LAACS on baseline AF status, CHA₂DS₂-VASc score or use of OAC (p = 0.55, p = 0.56 and p = 0.49 for interaction, respectively). Secondary outcome analysis revealed no detectable difference in all-cause mortality (p = 0.79) between the LAACS group (n = 12, 12%) vs. the controls (n = 12, 14%, Table 2). Similarly, in a sensitivity analysis that excluded the eight patients that underwent primary events only based on radiological findings, there was a trend but no longer a significant reduction in ischemic strokes among patients randomized to LAACS (p = 0.08, Table 2 and Fig. 2).

In the per protocol sensitivity analysis (Table 3), there were 4 (6%) primary events in the LAACS group vs. 14 (18%) in the control arm (hazard ratio 0.3; 95% CI: 0.1–1.0, p = 0.05). Of note, in the control group, 9 (64%) of the 14 primary events occurred beyond the first year of follow-up (Fig. 1). Secondary outcome analyses again revealed no detectable difference in overall survival or strict symptomatic ischemic strokes between the two study-arms (Table 3).

The datasets used during the current study are available from the corresponding author on reasonable request.

The study was halted before reaching the planned randomization of 200 patients due to competing studies recruiting patients for heart surgery. Nevertheless, according to our findings, it would be sufficient to include 35 patients in each group with 90% power to find a difference on the combination of stroke, TIA and SCI 2 years after surgery with a significance level of 5%. Furthermore, due to the frailty of the patients included, the discomfort of cerebral MRI and the physically- and mentally challenging period postoperatively, it was only possible to perform full sets of MRI scans in 75 patients. However, the patients who were not able to participate in all MRI scans agreed to stay active in the study for future clinical follow up. The fact that all patients did not undergo the planned MRI scans may have introduced a selection-bias, as frail patients may be more prone to decline the brain MRI scans. However, results from sensitivity analyses restricted to symptomatic ischemic strokes support the results that included imaging findings. Another limitation is the fact that only 10 patients accepted postoperative TEE. An unnoticed incomplete LAA closure, may thus have provoked events.