Continuing Cardiology Education

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1 Continuing Cardiology Education REVIEW ARTICLE Left atrial appendage occlusion for stroke prevention in patients with atrial fibrillation: indications diversity and future perspectives A. Tzikas 1 & T. Lewalter 2 1 AHEPA University Hospital, Thessaloniki, Greece 2 Peter Osypka Heart Center, Clinic Munich-Thalkirchen, Munich, Germany Keywords Atrial fibrillation, stroke, left atrial appendage Correspondence A. Tzikas, AHEPA University Hospital, Asklipiou 10, Thessaloniki, Greece Tel: ; Fax: ; aptzikas@yahoo.com Continuing Cardiology Education, 2016; 2(1), doi: /cce2.18 Abstract Left atrial appendage occlusion (LAAO) is a promising alternative to oral anticoagulation in patients with non-valvular atrial fibrillation. Recently, four-year results of PROTECT-AF demonstrated superiority of LAAO in all-cause mortality and stroke reduction compared to optimal medical treatment with warfarin. In this new era, it is important to identify the patients who would benefit more from LAAO and offer them priority for treatment. Answer questions and earn CME: /Activity.aspx Background and Present Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia [1]. Patients with AF have a fivefold increased risk for stroke, which is the most common cause of long-term disability and the third most common cause of death in this patient population [2]. Oral anticoagulation (OAC) with vitamin K antagonists (VKAs) like warfarin or coumadin has been the standard treatment for stroke prevention in patients with AF. Recently new OACs (NOACs), with several advantages, have been introduced to clinical practice. As compared to VKAs, NOACs have been shown to reduce the risk of stroke but also to reduce the rate of major bleeding [3]. However, the occurrence of major bleeding with NOAC is still remarkable, ranging between 1.6% and 3.11% per year. Moreover, despite their more predictable anticoagulant effect and easiness of use, permanent treatment discontinuation with NOACs in recent randomized trials were high ranging between 21% and 33%, similar to the rate of discontinuation seen with VKAs. Observational transesophageal echocardiography (TEE) studies have shown that in patients with non-valvular AF, the vast majority (>90%) of thrombus is located in the left atrial appendage (LAA) [4]. Left atrial appendage occlusion (LAAO) is a promising alternative to OAC in patients with non-valvular AF [5 8]. According to the latest ESC Guidelines for the management of AF and for myocardial revascularization, percutaneous LAAO may be considered in patients with AF and contraindications to long-term OAC therapy (Class IIb, Level of evidence B) [9, 10]. Currently, the two most commonly used devices for LAAO are the Watchman device (Boston Scientific, Plymouth, MN), and the Amplatzer Cardiac Plug (ACP)/ Amulet device (St. Jude Medical, Minneapolis, MN) [5 8]. The Watchman device has been evaluated in PRO- TECT AF and PREVAIL, two important randomized clinical trials for LAAO therapy. Recently, the 4-year results of PROTECT-AF demonstrated superiority of the Watchman device in the all-cause mortality and stroke reduction compared to the optimal medical treatment with warfarin [8, 11]. It should be noted that in these studies LAAO with the Watchman device was performed in patients with AF who were eligible to OAC. This lead to the following statement of device approval in the United States by the Food and Drug Administration (FDA) [12]: the Watchman device is indicated to reduce the risk of thromboembolism from the LAA in patients with nonvalvular AF who: 1 Are at increased risk for stroke and systemic embolism based on CHADS 2 or CHA 2 DS 2 - VASc scores and are recommended for anticoagulation therapy Continuing Cardiology Education, doi: /cce2.18 (32 of 36)

2 A. Tzikas & T. Lewalter LAAO Indications Diversity and Future Perspectives 2 Are deemed by their physicians to be suitable for warfarin, and 3 Have an appropriate rationale to seek a non-pharmacologic alternative to warfarin, taking into account the safety and effectiveness of the device compared to warfarin. Regardless of the careful wording, this statement practically excludes patients with contraindication to OAC therapy. On the other hand, on November 10, 2015, the Centers for Medicare & Medicaid Services (CMS) in the United States proposed that the evidence is sufficient to determine percutaneous left atrial appendage closure (LAAC) therapy, using an implanted device is not reasonable and necessary to diagnose or treat an illness or injury or to improve the functioning of a malformed body member and therefore, is not covered under 1862(a) [1] (A) of the Social Security Act. However, Percutaneous LAAC therapy is covered for patients with non-valvular AF only, when all of the following conditions are met: 1 The device is FDA approved for patients with nonvalvular AF. 2 The patient has a b c a high CHADS2 or CHA2DS2-VASc score a high HAS-BLED score a contraindication to warfarin 3 The procedure is performed in an experienced center. 4 The procedure is performed by an experienced interventional cardiologist or electrophysiologist. 5 The patient is enrolled in & the treating physician team is participating in a prospective national registry that consecutively enrolls patients undergoing LAAC. 6 Outcomes compared with a comparator group. 7 Formal Heart Team approach. Therefore, if this statement does not change in the near future, it is obvious that despite FDA approval the Watchman device will not be reimbursed in the US. Reimbursement policy in the US is very important because many countries rely on and follow those recommendations. A possible explanation for this negative decision by CMS is related to cost. It is estimated that AF only in the US affects more than 3 million patients and the numbers are expected to rise between 6 and 12 million by 2050 [1]. Therefore, the relatively free indication put by the FDA could lead in a large number of LAAOs and an extreme cost for the health systems. A potential solution is to identify the patients who would benefit more from LAAO and offer them priority for treatment. However, the answer to this question is difficult as LAAO-related indications are characterized by enormous diversity and candidates for LAAO may have very different profiles. A list of potential indications for LAAO is shown in Figure 1. Indications Diversity There is indeed a great diversity in the indications for LAAO therapy. In real world registries like the ACP Registry [7] and the EWOLUTION Registry, [13] previous bleeding was the most common indication, followed by high bleeding risk (usually based on the HASBLED Score). However, a significant percentage of patients were treated for avoiding triple therapy after coronary stenting [7], whereas others underwent LAAO due to a stroke on OAC. These groups of patients typically have a very different background and may or may not be eligible for OAC therapy. Things get even more complicated due to the lack of a formal definition of absolute or relative contraindications to OAC therapy. Also, Figure 1. Indications for left atrial appendage occlusion (LAAO) therapy. Indications for LAAO therapy in the 1047 patient amplatzer cardiac plug (ACP) Registry. Results from 22 centers were collected from Dec 2008 to November Subgroup analysis of 198 with a history of intracranial bleeding was presented in TCT 2015 [13]. Continuing Cardiology Education, doi: /cce2.18 (33 of 36)

3 LAAO Indications Diversity and Future Perspectives A. Tzikas & T. Lewalter depending on the implanted device and procedural parameters, patients are taking OACs, single or dual antiplatelet therapy for short period after LAAO. For example, based on the PROTECT AF study patients should receive warfarin plus aspirin 100 mg for 45 days postprocedure, and then warfarin is stopped after verifying there is no leak >5 mm on TEE (aspirin is continued for life). The antithrombotic strategy after LAAO with an Amplatzer device does not include OAC at all: dual antiplatelet therapy is prescribed for 1 3 months and aspirin 100 mg monotherapy is needed for 6 months. However, this strategy is empirical as there is no robust data to support it other than retrospective observations from registries. According to these diverse indications for LAAO, several patients may be good candidates for the procedure. However, not all patients are alike and the benefit from LAAO may be quite different, depending on their background and comorbidities. For example, in an abstract that was recently presented in TCT 2015 (San Francisco, CA), patients with a history of intracranial bleeding had more benefit than others mainly due to an extremely low risk for major bleeding at follow-up (Figure 2) [14]. A reasonable explanation for this is that dual antiplatelet therapy in the first 1 3 months after LAAO may predispose the patients for gastrointestinal bleeding but does not increase the frequency of intracranial bleeding (at least it may be safer than OAC). Of course these results are just generating a hypothesis and should be confirmed by further studies. A common argument against LAAO therapy arises from the NOAC studies, ARISTOTLE study on apixaban in particular [15]. In this study, long-term therapy with apixaban had similar bleeding rates to long-term therapy with aspirin so there is a question on whether a patient that is treated with LAAO and is prescribed aspirin for life will actually benefit and have less bleeding risk. The key in this discussion is in fact the duration of antiplatelet therapy post-laao. In the absence of comorbidities Figure 2. Outcome of patients with a history of intracranial bleeding compared to others in the amplatzer cardiac plug (ACP) multicenter Registry. After left atrial appendage occlusion (LAAO) with the ACP, there was a 59% reduction in stroke/tia/per year and a 60% reduction of major bleeding/per year [7]. In patients with a history of intracranial bleeding, the reduction was 75% and 89%, respectively [14]. Continuing Cardiology Education, doi: /cce2.18 (34 of 36)

4 A. Tzikas & T. Lewalter LAAO Indications Diversity and Future Perspectives dictating lifelong aspirin therapy (i.e. coronary artery disease) there is no real reason to extend aspirin therapy for >6 months. Again, this strategy has not been confirmed in large randomized studies but just reflects the current clinical practice of the vast majority of experts in the field of LAAO. Another argument related to apixaban is that in ARISTOTLE study patients with previous bleeding, very elderly, and patients with severe renal impairment were excluded. In fact, severe renal insufficiency or dialysis might be a really valid indication for LAAO; warfarin therapy is related to very high bleeding risk and NOACs are contraindicated in GFR of <15 30 ml per min. Future Perspectives The ideal future scenario for local therapy in stroke prevention for patients with AF should include a device design that would allow stopping all antithrombotic treatment post-procedure. The main reason for shortterm antithrombotic therapy after LAAO is the avoidance of device thrombosis in the first 1 3 months (a period required for device endotheliazation), which is not negligible ranging from 3 4% in most series. So far, device thrombosis has not been correlated with adverse events but, due to low event rates, studies were underpowered to prove if it is actually a benign phenomenon [7, 8]. Another potential issue that is practically implicating all available devices for LAAO is the presence of residual leaks after the procedure. Currently, these leaks are considered benign. Indeed, the significant reduction in mortality in the 4-year results of PROTECT AF, a very hard clinical endpoint, was observed in the frequent presence of such leaks [8]. Nevertheless, it is reasonable to aim to complete LAAO so future device designs should allow better apposition and sealing. Evidence-based medicine requires large-scale randomized clinical trials and surely this statement applies for new device-based therapies. In LAAO in particular, devices should be tested against NOACs as data on this matter are scarce. However, maybe it would more realistic to further investigate the use of LAAO in special patient populations like patients with previous intracranial bleeding or patients with renal insufficiency in order to prove a net clinical benefit with enough confidence. Such studies would include fewer patients and therefore fewer resources would be needed. Most importantly, focusing in patients that would benefit more from LAAO would allow health authorities to accept LAAO as a valid alternative for AF-related stroke prevention, a therapy that is safe, efficient, and also cost-effective, meeting all criteria for best clinical practice. Conflict of Interest Dr. Tzikas and Dr. Lewalter report grants and personal fees from St. Jude Medical, during the conduct of the study. References 1. Colilla, S, A Crow, W Petkun, et al Estimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population. Am. J. Cardiol. 112: Wolf, PA, RD Abbott, and WB Kannel Atrial fibrillation as an independent risk factor for stroke: the framingham study. Stroke 22: Ruff, CT, RP Giugliano, E Braunwald, et al Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383: Mahajan, R, AG Brooks, T Sullivan, et al Importance of the underlying substrate in determining thrombus location in atrial fibrillation: implications for left atrial appendage closure. Heart 98: Holmes, DR, VY Reddy, ZG Turi, et al Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomised non-inferiority trial. Lancet 374: Reddy, VY, SK Doshi, H Sievert, et al Percutaneous left atrial appendage closure for stroke prophylaxis in patients with atrial fibrillation: 2.3-year follow-up of the PROTECT AF (watchman left atrial appendage system for embolic protection in patients with atrial fibrillation) trial. Circulation 127: Tzikas, A, S Shakir, S Gafoor, et al Left atrial appendage occlusion for stroke prevention in atrial fibrillation: multicentre experience with the AMPLATZER Cardiac Plug. EuroIntervention 10: doi: /EIJY15M01_06. [Epub ahead of print]. 8. Reddy, VY, H Sievert, J Halperin, et al Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial. JAMA 312: Camm, AJ, GY Lip, R De Caterina, et al focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. developed with the special contribution of the European Heart Rhythm Association. Eur. Heart J. 33: Windecker, S, P Kolh, F Alfonso, et al ESC/ ECATS Guidelines on myocardial revascularization. Eur. Heart J. 35: Continuing Cardiology Education, doi: /cce2.18 (35 of 36)

5 LAAO Indications Diversity and Future Perspectives A. Tzikas & T. Lewalter 11. Holmes, DR.,Jr, S Kar, MJ Price, et al Prospective randomized evaluation of the watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial. J. Am. Coll. Cardiol. 64: , U.S. Food and Drug Adminstration. WATCHMAN left atrial appendage closure device with delivery system P130013d.pdf (accessed 13 March 2015). 13. Boersma, LV, B Schmidt, TR Betts, et al Implant success and safety of left atrial appendage closure with the WATCHMAN device: peri-procedural outcomes from the EWOLUTION registry. Eur. Heart J pii: ehv730. [Epub ahead of print]. 14. Tzikas, A, A Freixa, S Gafoor, et al TCT-53 Left atrial appendage occlusion in patients with atrial fibrillation and intracranial bleeding: results from the amplatzer cardiac plug registry. J. Am. Coll. Cardiol. 66: B Granger, CB, JH Alexander, JJ McMurray; ARISTOTLE Committees and Investigators, et al Sep 15. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365: Continuing Cardiology Education, doi: /cce2.18 (36 of 36)