CRT 2017: Putting LAA closure in the age of DOACs into perspective Stefan Bertog, Laura Vaskelyte, Markus Reinartz, Ilona Hofmann, Predrag Matic, Bojan Jovanovic, Kolja Sievert, Horst Sievert Cardiovascular Center Frankfurt

Disclosure Statement of Financial Interest I, Stefan Bertog, DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.

Case 1 CHADS2VASC 4 (4.8% annual stroke) HASBLED 8.9 76 yo male with atrial fibrillation Referred for LAA closure because high stroke and bleeding risk PMH: Parkinson HTN Stable coronary artery disease History of GI bleeding requiring transfusion (diverticulosis) History of intracranial hemorrhage from a fall while on warfarin CHADS2VASC 4 (4.8% annual stroke) HASBLED 8.9

Case 1 Perspective in the age of DOACs? No data to show that DOACs are safe Multiple non-randomized studies demonstrating safety and efficacy with LAAC Hence, in the absence of other alternatives, LAAC should be considered Boersma at al. EHJ 2016;37:2465-2474 Reddy et al. 2013;61:2551-2556 Renou et al. in press Journal of Stroke and Cerebrovascular Disease 2017

Case 2 CHADS2VASC 5 (6.7% annual stroke) HASBLED 1.9-4.1 76 yo female with atrial fibrillation Referred for LAA closure because of patient’s stated fear of bleeding on anticoagulation PMH: HTN Stable coronary artery disease (stents 4 yrs ago) CHADS2VASC 5 (6.7% annual stroke) HASBLED 1.9-4.1

Case example Patient informed by referring provider that major bleeding risk with LAA closure is much lower than with anticoagulation

Case example Major bleeding: What does current randomized trial data comparing warfarin to LAA closure show?

All major bleeding A. B. C. D. Favors Warfarin 1 Favors Watchman

P=0.97 Watchman All major bleeding Holmes et al. Am Coll Cardiol 2015;65:2614–23 Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

Watchman P=0.97 Watchman All major bleeding Holmes et al. Am Coll Cardiol 2015;65:2614–23 Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

Case example What should we tell the patient regarding the bleeding risk with warfarin versus LAA closure?

Case example Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

Case example Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption Tzikas et al. EuroIntervention 2015;10 Reddy et al. JACC VOL . 69, NO. 3, 2017 3% The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account). Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

Case example Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account). Price et al. J Am Coll Cardiol Intv 2015;8:1925–32

Case example Your risk of suffering from major bleeding is no lower with LAAC than with warfarin If you live longer than 5 years, eventually, your major bleeding risk may be lower with LAAC but this is an assumption If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption What about the risk of major bleeding with DOACs compared with warfarin? The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

DOAC All major bleeding Ruff et al. Lancet, 383:955 (2014)

DOAC All major bleeding Ruff et al. Lancet, 383:955 (2014)

DOAC All major bleeding Ruff et al. Lancet, 383:955 (2014)

Case example If you are at low bleeding risk but major bleeding is your main concern, data currently would favor certain DOACs over warfarin and LAAC What about stroke protection with LAAC versus warfarin?

All stroke or systemic embolism Watchman All stroke or systemic embolism Holmes et al. Am Coll Cardiol 2015;65:2614–23

Case example What can we tell the patient regarding the stroke risk with warfarin versus LAA closure? The all stroke/systemic embolism rate is the same with warfarin compared with LAA closure What about the stroke/systemic embolism rate with DOACs compared to warfarin?

Stroke or systemic embolism DOAC Stroke or systemic embolism Ruff et al. Lancet, 383:955 (2014)

Case example Disabling strokes? LAA closure versus warfarin Reddy et al. JAMA. 2014;312(19):1988-1998

DOAC and strokes Connolly et al. N Engl J Med 2009;361:1139-51

DOAC and strokes Giugliano et al. Stroke. 2014;45:2372-2378

Case example Will I live any longer if I undergo LAA closure versus anticoagulation with warfarin?

Watchman All cause death Holmes et al. Am Coll Cardiol 2015;65:2614–23

DOAC All cause mortality Ruff et al. Lancet, 383:955 (2014)

Case 2 conclusion: Whereas LAAC is equivalent to warfarin in stroke prevention in patients who are not at high bleeding risk, some DOACs appear to be more effective than warfarin and should remain the first choice If, with newer generation LAA closure devices and more implant experience, the procedural risk can be improved, the risk/benefit ratio may favor LAA closure to warfarin even in patients at low bleeding risk

The safety of DOACS and warfarin is not likely to change However…. LAAC experience and technology will continue to improve

The analysis of 3822 consecutive cases in the US Reddy et al. JACC VOL . 69 , NO.3, 2017

Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption 3% The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

Case example Your risk of suffering from major bleeding is no lower with LAA closure than with warfarin If you live longer than 5 years eventually your major bleeding risk may be lower with LAA but this is an assumption If you find an operator who can do the procedure with a < 3% pericardial hemorrhage rate then your major bleeding risk at 5 years or earlier may be lower, but this is an assumption The pericardial effusion rate was 4% in PROTECT AF (1.6% required surgery and 2.4% pericardiocentesis). It was 1.9% in PREVAIL (1.5% required pericardiocentesis and 0.4% surgery). The total pericardial effusion rate requiring either pericardiocentesis or surgery was 3% (taking both PROTECT AF and PREVAIL into account).

Apixaban Major bleeding Ruff et al. Lancet, 383:955 (2014)

Stroke and systemic embolism Apixaban Stroke and systemic embolism Ruff et al. Lancet, 383:955 (2014)

Apixaban All cause mortality Granger et al. N Engl J Med 2011;365:981-92

Warfarin Apixaban Watchman All stroke/systemic embolism ICH All cause death All major bleeding

Case 1 Perspective in the presence of DOACs: No studies addressing the safety of DOACs in patients considered at high bleeding risk or prior intracranial hemorrhage What about left atrial appendage closure? No randomized trials assessing safety and efficacy of LAA closure in patients at high bleeding risk or risk of ICH

Case 1 ASAP study 150 patients considered to have contraindications to oral anticoagulation Mean CHADS2VASC 4.4 LAAC with the Watchman device ASA indefinitely and clopidogrel for 6 months Mean follow-up 16.5 months Observed ischemic stroke rate was 1.5% (the overall stroke rate was 2.3%). In red is the expected stroke rate based on CHADS2 score (this was 2.8). In terms of safety, there were 2 pericardial effusions requiring percutaneous drainage (1.3%) and 6 (4%) device-associated thrombi only one of which was associated with a stroke. There were two embolizations that were managed percutaneously. Median time of device thrombus 165 days Reddy et al. 2013;61:2551-2556

Case 1 1021 patients who underwent Watchman implantation 27% on AC, 59% dual antiplatelet, 7% on single, 6% without any therapy 62% were deemed anticoagulant therapy ineligible, successful deployment: 98.5%, pericardial effusion requiring drainage in 3 (0.3%), procedure related stroke (1, 0.1%), major bleeding requiring transfusion in 17 patients, 8 were procedure related (groin complications) and 4 GI hemorrhage. In these 17 patients three were anticoagulated, single AP in five, DAPT in 7 and 2 without AC. Periprocedural events captured Boersma at al. EHJ 2016;37:2465-2474

738 patients did not undergo anticoagulant therapy after implant Case 1 Overall event rate low 738 patients did not undergo anticoagulant therapy after implant 62% were deemed anticoagulant therapy ineligible, successful deployment: 98.5%, pericardial effusion requiring drainage in 3 (0.3%), procedure related stroke (1, 0.1%), major bleeding requiring transfusion in 17 patients, 8 were procedure related (groin complications) and 4 GI hemorrhage. In these 17 patients three were anticoagulated, single AP in five, DAPT in 7 and 2 without AC. Serious adverse event rates at 30 days demonstrates that it was at least as safe if not safer not being anticoagulated. There were 3 ischemic strokes that occurred within 30 days (two had a complete recovery), they occurred on day 15 21 and 23. Two were on double antiplatelet therapy, one on single antiplatelet therapy Boersma at al. EHJ 2016;37:2465-2474

Case 1 How about safety of LAAC in patients with previous ICH? No routine TEE follow-up but 82% had CT follow-up with one device-associated thrombus that resolved after 6 months of dual AP therapy 46 patients with prior ICH, ACP in 40, Watchman in 6. All patients received aspirin only postprocedure Renou et al. in press Journal of Stroke and Cerebrovascular Disease 2017

Case 1 DOACs: no data, cannot be recommended However, there is reasonable non-randomized data suggesting LAAC can be performed safely in these patients, hence this should be the first choice

Reddy et al. JACC VOL . 69 , NO.3, 2017

Warfarin DOACs Watchman Disabling stroke ICH All cause death All major bleeding