840
Decennial Analysis of Interventional Left Atrial Appendage Closure BORIS SCHMIDT, M.D., F.H.R.S., STEFANO BORDIGNON, M.D., ALEXANDER FUERNKRANZ, M.D., LAURA PERROTTA, M.D., DETLEF SCHERER, M.D., and K.R. JULIAN CHUN, M.D. From the Cardioangiologisches Centrum Bethanien, Frankfurt/M., Germany
Long-Term Follow-Up of LAA Occlusion. Introduction: Data on long-term follow-up (LTFU) after interventional closure of the left atrial appendage (LAAC) in patients with nonvalvular atrial fibrillation (AF) are scarce. We sought to determine the outcome of patients after LAAC with the first generation device. Methods and Results: The Cardioangiologisches Centrum Bethanien (CCB) LAAC registry database was analyzed. Between October 2001 and July 2007, 45 AF patients (23 male, mean age 71 ± 6 years; mean CHA2 DS2 -VaSc 4.3 ± 1.7 [range 1–7]; mean HASBLED score 3.3 ± 1.2 [1–5]) received LAAC. Postimplant dual-platelet inhibition with clopidogrel 75 mg/day and aspirine (ASA) 300 mg/day was prescribed for 6 months, followed by ASA 300 mg indefinitely. The primary endpoint was defined as any thrombembolic complication and/or any bleeding complication. The median FU was 7.4 years (1–12.4 years) resulting in 292 patient years. Fourteen patients died due to heart failure (n = 4), noncardiac reasons (n = 7), or due to unknown etiology (n = 3). No patient died from a bleeding or a stroke. Five ischemic strokes occurred at a median of 794 days (range 304–3,706 days) after LAAC. The observed annual stroke rate was 1.7% (RR 0.43; 95% CI 0.24–0.74; P = 0.0028). In 6 patients bleeding occurred (2 acute procedural, 4 during follow-up). The observed annual bleeding rate was 2.1% (RR 0.56; 95% CI 0.48–0.66; P < 0.0001). Conclusion: During LTFU after LAAC in patients with nonvalvular AF, lower event rates than expected are observed for both thrombembolic and bleeding complications. (J Cardiovasc Electrophysiol, Vol. 26, pp. 840-844, August 2015) fibrillation, hemorrhage, occlusion, stroke Introduction
Methods
Interventional left atrial appendage closure (LAAC) is noninferior to warfarin treatment for prevention of thrombembolic complications and cardiovascular death in patients with nonvalvular atrial fibrillation (AF).1 A relatively high number of safety events including stroke and transient ischemic attacks occurred at the time of implant being a burden for the patients assigned to LAAC with regard to reducing the primary study endpoint (stroke/TIA, peripheral embolism, and cardiovascular death). During follow-up, the major driver for the beneficial effects attributable to LAAC was the significant reduction of hemorrhagic stroke.2 It may be speculated that this effect grew with prolonged follow-up time. Therefore, we sought to determine the outcome of patients who had undergone LAAC with the first generation LAAC device (PLAATO; Appriva Medical).3
We performed an analysis of the Cardioangiologisches Centrum Bethanien LAAC registry database. Between August 2001 and July 2007 a PLAATO LAAC device was implanted in patients with nonvalvular AF and contraindications for oral anticoagulation (OAC).
LP was supported by a research grant of the European Heart Rhythm Association.
Follow-Up
No conflicts of interest to disclose. Address for correspondence: Boris Schmidt, M.D., Cardioangiologisches Centrum Bethanien, Wilhelm Epstein-Str. 4, 60431 Frankfurt/M.; Germany. Fax: 49-69 945028119; E-mail: [email protected] Manuscript received 20 March 2015; Revised manuscript received 20 April 2015; Accepted for publication 29 April 2015. doi: 10.1111/jce.12704
Device and Procedure The PLAATO device consists of a self-expanding nitinol frame covered with an expanded polytetrafluoroethylene membrane. It is delivered to the LAA by a 14F transseptal sheath via the femoral vein. After transseptal access the implant procedure and final LAA occlusion are guided/adjudicated angiographically and echocardiographically by transesophageal echo (TEE). In order to avoid peri-procedural clot formation and embolic events the activated clotting time was adjusted to >250s throughout the procedure.
For the first 6 months patients were treated with dual platelet inhibition (DPI) using 300 mg aspirin (ASA) and 75 mg clopidogrel once daily. Thereafter, indefinite ASA therapy was recommended. Sealing of the LAA was evaluated by means of TEE 4– 6 weeks after the index procedure. In 8/45 patients (18%) computed tomography was used in addition. After the initial TEE evaluation follow-up visits were scheduled on a 6–12 months basis according to the
Schmidt et al. Long-Term Follow-Up of LAA Occlusion
TABLE 1
TABLE 2
Baseline Characteristics
Summary of Patients with a Primary Endpoint Event
AF = atrial fibrillation; TIA = transient ischemic attack; INR = international normalized ratio.
physician’s discretion. Two independent physicians adjudicated all adverse events.
Patient with 1° Endpoint #
Time of Event
CHA2 DS2 VASc
HASBLED
Therapy at Time of Event
3 13 15 18 19
319 days 794 days 3,706 days 1,725 days 304 days
7 4 5 5 6
3 4 2 2 3
ASA ASA ASA ASA ASA
ASA = aspirin.
Stroke free survival (%)
71 ± 6 23 (51%) 40 (89%) 7 (16%) 35 (78%) 39 (87%) 17 (38%) 16 (36%) 16 (36%) 22 (49%) 7 (16%) 13 (29%) 22 (49%) 17 (38%) 22 (49%) 4 (1–7) 3 (1–5)
Age Male Permanent AF Congestive heart failure Hypertension Age >65 Age >75 Diabetes Stroke/TIA Coronary artery disease Peripheral artery disease Renal failure/liver disease History of bleeding Labile INR Drugs predisposing to bleeding CHA2 DS2 VASC score HASBLED score
841
100 80 60 40 20 0
Study Endpoints
0
Statistical Analysis Mean ± standard deviation was used to describe continuous variables with normal distribution. Median and range were used when appropriate. Contingency tables were used to calculate the relative risk of the study endpoints. Results Patient Characteristics Between August 2001 and July 2007 45 patients (23 male, mean age 71 ± 6 years) underwent LAAC using PLAATO (Table 1). All patients had nonvalvular AF (5 paroxysmal) and had an indication for OAC due to an increased risk for thrombembolic complications. The mean CHA2 DS2 -VaSc was 4.3 ± 1.7 (median 4; range 1–7), which translates into an annual stroke/TIA rate of 4%.5,6 Sixteen patients (36%) had had a prior thrombembolic event. Coronary artery disease or peripheral artery disease was prevalent in 28 patients (62%). Among the study population 22 patients (49%) had a history of bleeding complications and were therefore deemed contraindicated for OAC. The mean HASBLED score was 3.3 ± 1.2 (median 3; range 1–5) resulting in an annual bleeding rate of 3.74%.7 Follow-Up and Study Endpoints In 2 patients, the procedure was complicated by hemopericardium requiring pericardiocentesis. After drainage, the clinical course was uneventful. Four patients were lost to follow-up after the first postprocedural visit. The remaining 41 patients were followed up for a median of 7.4 years (1–12.4 years). This equals a follow-up
720
1440
2160
2880
3600
4320
5040
Days of follow up Figure 1. Annual stroke rate with different therapies. Expected without therapy (black), observed after LAAC (white) and expected on aspirin (ASA).8 LAAC = left atrial appendage closure; tx = therapy; w/o = without.
ANNUAL STROKERATE (%/YR)
The primary efficacy endpoint of this analysis was the occurrence of any stoke/TIA or peripheral embolism. The primary safety endpoint was the incidence of any bleeding fulfilling the BARC 2–5 criteria.4 The mode of death was graded into cardiovascular and noncardiac death.
4 3 2 1
LAAC
Expected w/o tx
Expected on ASA
Figure 2. Kaplan–Meier survival curve of stroke free survival.
time of 292 patient years. During follow-up 14 patients died due to cardiac (n = 4 due to heart failure) and noncardiac reasons (n = 7); in 3 patients the mode of death remained unclear. No patient died from a bleeding complication or a stroke. The primary efficacy endpoint occurred in 5 patients (Table 2). All strokes were ischemic and occurred at a median of 794 days (range 304–3,706 days) after LAAC while patients were on ASA therapy. Compared to the adjusted annual stroke/TIA rate of 4%, LAAC patients displayed an annual stroke/TIA rate of 1.7% (RR 0.43; 95% CI 0.24–0.74; P = 0.0028; Fig. 1). For comparison the annual stroke rate on aspirine as observed in the AVERRROES trial (3.81% per year) is also depicted in Figure 1.8 LAAC provided an additional benefit for stroke prevention compared to ASA therapy alone (RR 0.45; 0.25–0.79; P = 0.004). The Kaplan– Meier analysis depicts the stroke-free survival after LAAC in Figure 2.
842
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 8, August 2015
TABLE 3 Summary of Patients with a Primary Safety Event During Follow-Up Patients with 1° Safety Event During Follow-Up #
Type of Bleeding
3 9 31 45
Gastrointestinal Epistaxis Gastrointestinal Urinary tract
Time of Event
CHA2 DS2 VASc
HASBLED
Therapy at Time of Event
42 days 3,404 days 2,490 days 2,619 days
7 5 5 4
3 4 4 4
DPI DPI DPI ASA
ANNUAL BLEEDING RATE (%/YR)
DPI = dual platelet inhibition.
4 3 2 1
LAAC
Expected w/o tx
Expected on ASA
Figure 3. Annual bleeding rate with different therapies. Expected without therapy (black), observed after LAAC (white) and expected on aspirin.8 Abbreviations as in Figure 2.
The primary safety endpoint occurred in 6 patients 1– 3,404 days after LAAC including 2 acute procedural complications (Table 3). All but one bleeding during follow-up occurred under dual platelet inhibition (one patient due to LAAC, and two for percutaneous coronary interventions). Two patients had a gastrointestinal bleeding (BARC 3a and 3b, respectively), one had recurrent lower urinary tract bleeding (BARC 3a) and one suffered from epistaxis requiring medical intervention (BARC 3a). Compared to the adjusted annual bleeding risk of 3.74% LAAC patients exhibited an annual bleeding rate of 2.1% (RR 0.56; 95% CI 0.48–0.66; P
Decennial Analysis of Interventional Left Atrial Appendage Closure BORIS SCHMIDT, M.D., F.H.R.S., STEFANO BORDIGNON, M.D., ALEXANDER FUERNKRANZ, M.D., LAURA PERROTTA, M.D., DETLEF SCHERER, M.D., and K.R. JULIAN CHUN, M.D. From the Cardioangiologisches Centrum Bethanien, Frankfurt/M., Germany
Long-Term Follow-Up of LAA Occlusion. Introduction: Data on long-term follow-up (LTFU) after interventional closure of the left atrial appendage (LAAC) in patients with nonvalvular atrial fibrillation (AF) are scarce. We sought to determine the outcome of patients after LAAC with the first generation device. Methods and Results: The Cardioangiologisches Centrum Bethanien (CCB) LAAC registry database was analyzed. Between October 2001 and July 2007, 45 AF patients (23 male, mean age 71 ± 6 years; mean CHA2 DS2 -VaSc 4.3 ± 1.7 [range 1–7]; mean HASBLED score 3.3 ± 1.2 [1–5]) received LAAC. Postimplant dual-platelet inhibition with clopidogrel 75 mg/day and aspirine (ASA) 300 mg/day was prescribed for 6 months, followed by ASA 300 mg indefinitely. The primary endpoint was defined as any thrombembolic complication and/or any bleeding complication. The median FU was 7.4 years (1–12.4 years) resulting in 292 patient years. Fourteen patients died due to heart failure (n = 4), noncardiac reasons (n = 7), or due to unknown etiology (n = 3). No patient died from a bleeding or a stroke. Five ischemic strokes occurred at a median of 794 days (range 304–3,706 days) after LAAC. The observed annual stroke rate was 1.7% (RR 0.43; 95% CI 0.24–0.74; P = 0.0028). In 6 patients bleeding occurred (2 acute procedural, 4 during follow-up). The observed annual bleeding rate was 2.1% (RR 0.56; 95% CI 0.48–0.66; P < 0.0001). Conclusion: During LTFU after LAAC in patients with nonvalvular AF, lower event rates than expected are observed for both thrombembolic and bleeding complications. (J Cardiovasc Electrophysiol, Vol. 26, pp. 840-844, August 2015) fibrillation, hemorrhage, occlusion, stroke Introduction
Methods
Interventional left atrial appendage closure (LAAC) is noninferior to warfarin treatment for prevention of thrombembolic complications and cardiovascular death in patients with nonvalvular atrial fibrillation (AF).1 A relatively high number of safety events including stroke and transient ischemic attacks occurred at the time of implant being a burden for the patients assigned to LAAC with regard to reducing the primary study endpoint (stroke/TIA, peripheral embolism, and cardiovascular death). During follow-up, the major driver for the beneficial effects attributable to LAAC was the significant reduction of hemorrhagic stroke.2 It may be speculated that this effect grew with prolonged follow-up time. Therefore, we sought to determine the outcome of patients who had undergone LAAC with the first generation LAAC device (PLAATO; Appriva Medical).3
We performed an analysis of the Cardioangiologisches Centrum Bethanien LAAC registry database. Between August 2001 and July 2007 a PLAATO LAAC device was implanted in patients with nonvalvular AF and contraindications for oral anticoagulation (OAC).
LP was supported by a research grant of the European Heart Rhythm Association.
Follow-Up
No conflicts of interest to disclose. Address for correspondence: Boris Schmidt, M.D., Cardioangiologisches Centrum Bethanien, Wilhelm Epstein-Str. 4, 60431 Frankfurt/M.; Germany. Fax: 49-69 945028119; E-mail: [email protected] Manuscript received 20 March 2015; Revised manuscript received 20 April 2015; Accepted for publication 29 April 2015. doi: 10.1111/jce.12704
Device and Procedure The PLAATO device consists of a self-expanding nitinol frame covered with an expanded polytetrafluoroethylene membrane. It is delivered to the LAA by a 14F transseptal sheath via the femoral vein. After transseptal access the implant procedure and final LAA occlusion are guided/adjudicated angiographically and echocardiographically by transesophageal echo (TEE). In order to avoid peri-procedural clot formation and embolic events the activated clotting time was adjusted to >250s throughout the procedure.
For the first 6 months patients were treated with dual platelet inhibition (DPI) using 300 mg aspirin (ASA) and 75 mg clopidogrel once daily. Thereafter, indefinite ASA therapy was recommended. Sealing of the LAA was evaluated by means of TEE 4– 6 weeks after the index procedure. In 8/45 patients (18%) computed tomography was used in addition. After the initial TEE evaluation follow-up visits were scheduled on a 6–12 months basis according to the
Schmidt et al. Long-Term Follow-Up of LAA Occlusion
TABLE 1
TABLE 2
Baseline Characteristics
Summary of Patients with a Primary Endpoint Event
AF = atrial fibrillation; TIA = transient ischemic attack; INR = international normalized ratio.
physician’s discretion. Two independent physicians adjudicated all adverse events.
Patient with 1° Endpoint #
Time of Event
CHA2 DS2 VASc
HASBLED
Therapy at Time of Event
3 13 15 18 19
319 days 794 days 3,706 days 1,725 days 304 days
7 4 5 5 6
3 4 2 2 3
ASA ASA ASA ASA ASA
ASA = aspirin.
Stroke free survival (%)
71 ± 6 23 (51%) 40 (89%) 7 (16%) 35 (78%) 39 (87%) 17 (38%) 16 (36%) 16 (36%) 22 (49%) 7 (16%) 13 (29%) 22 (49%) 17 (38%) 22 (49%) 4 (1–7) 3 (1–5)
Age Male Permanent AF Congestive heart failure Hypertension Age >65 Age >75 Diabetes Stroke/TIA Coronary artery disease Peripheral artery disease Renal failure/liver disease History of bleeding Labile INR Drugs predisposing to bleeding CHA2 DS2 VASC score HASBLED score
841
100 80 60 40 20 0
Study Endpoints
0
Statistical Analysis Mean ± standard deviation was used to describe continuous variables with normal distribution. Median and range were used when appropriate. Contingency tables were used to calculate the relative risk of the study endpoints. Results Patient Characteristics Between August 2001 and July 2007 45 patients (23 male, mean age 71 ± 6 years) underwent LAAC using PLAATO (Table 1). All patients had nonvalvular AF (5 paroxysmal) and had an indication for OAC due to an increased risk for thrombembolic complications. The mean CHA2 DS2 -VaSc was 4.3 ± 1.7 (median 4; range 1–7), which translates into an annual stroke/TIA rate of 4%.5,6 Sixteen patients (36%) had had a prior thrombembolic event. Coronary artery disease or peripheral artery disease was prevalent in 28 patients (62%). Among the study population 22 patients (49%) had a history of bleeding complications and were therefore deemed contraindicated for OAC. The mean HASBLED score was 3.3 ± 1.2 (median 3; range 1–5) resulting in an annual bleeding rate of 3.74%.7 Follow-Up and Study Endpoints In 2 patients, the procedure was complicated by hemopericardium requiring pericardiocentesis. After drainage, the clinical course was uneventful. Four patients were lost to follow-up after the first postprocedural visit. The remaining 41 patients were followed up for a median of 7.4 years (1–12.4 years). This equals a follow-up
720
1440
2160
2880
3600
4320
5040
Days of follow up Figure 1. Annual stroke rate with different therapies. Expected without therapy (black), observed after LAAC (white) and expected on aspirin (ASA).8 LAAC = left atrial appendage closure; tx = therapy; w/o = without.
ANNUAL STROKERATE (%/YR)
The primary efficacy endpoint of this analysis was the occurrence of any stoke/TIA or peripheral embolism. The primary safety endpoint was the incidence of any bleeding fulfilling the BARC 2–5 criteria.4 The mode of death was graded into cardiovascular and noncardiac death.
4 3 2 1
LAAC
Expected w/o tx
Expected on ASA
Figure 2. Kaplan–Meier survival curve of stroke free survival.
time of 292 patient years. During follow-up 14 patients died due to cardiac (n = 4 due to heart failure) and noncardiac reasons (n = 7); in 3 patients the mode of death remained unclear. No patient died from a bleeding complication or a stroke. The primary efficacy endpoint occurred in 5 patients (Table 2). All strokes were ischemic and occurred at a median of 794 days (range 304–3,706 days) after LAAC while patients were on ASA therapy. Compared to the adjusted annual stroke/TIA rate of 4%, LAAC patients displayed an annual stroke/TIA rate of 1.7% (RR 0.43; 95% CI 0.24–0.74; P = 0.0028; Fig. 1). For comparison the annual stroke rate on aspirine as observed in the AVERRROES trial (3.81% per year) is also depicted in Figure 1.8 LAAC provided an additional benefit for stroke prevention compared to ASA therapy alone (RR 0.45; 0.25–0.79; P = 0.004). The Kaplan– Meier analysis depicts the stroke-free survival after LAAC in Figure 2.
842
Journal of Cardiovascular Electrophysiology
Vol. 26, No. 8, August 2015
TABLE 3 Summary of Patients with a Primary Safety Event During Follow-Up Patients with 1° Safety Event During Follow-Up #
Type of Bleeding
3 9 31 45
Gastrointestinal Epistaxis Gastrointestinal Urinary tract
Time of Event
CHA2 DS2 VASc
HASBLED
Therapy at Time of Event
42 days 3,404 days 2,490 days 2,619 days
7 5 5 4
3 4 4 4
DPI DPI DPI ASA
ANNUAL BLEEDING RATE (%/YR)
DPI = dual platelet inhibition.
4 3 2 1
LAAC
Expected w/o tx
Expected on ASA
Figure 3. Annual bleeding rate with different therapies. Expected without therapy (black), observed after LAAC (white) and expected on aspirin.8 Abbreviations as in Figure 2.
The primary safety endpoint occurred in 6 patients 1– 3,404 days after LAAC including 2 acute procedural complications (Table 3). All but one bleeding during follow-up occurred under dual platelet inhibition (one patient due to LAAC, and two for percutaneous coronary interventions). Two patients had a gastrointestinal bleeding (BARC 3a and 3b, respectively), one had recurrent lower urinary tract bleeding (BARC 3a) and one suffered from epistaxis requiring medical intervention (BARC 3a). Compared to the adjusted annual bleeding risk of 3.74% LAAC patients exhibited an annual bleeding rate of 2.1% (RR 0.56; 95% CI 0.48–0.66; P
