Atrial fibrillation (AF) is one of the most challenging arrhythmias – perhaps even one of the most challenging diseases – because of its high prevalence (close to 2% of the population ) and associated risks of thromboembolism and stroke. Stroke is a devastating complication with a reported annual incidence of 4.4%. At least 25% of the 130,000 strokes that occur each year in France are complications of AF. For patients with AF-related cardioembolic stroke, up to 70% will result in death or significant disability.
Prevention of thromboembolic complications in AF is an old story leading to clear guidelines and robust therapies. The CHADS 2 score and more recently the CHA 2 DS 2 VASc score were developed to assess stroke risk in individuals with non-valvular AF, and their use is recommended to identify patients at moderate to high-risk of stroke but also to identify those considered truly low-risk .
Anticoagulation therapy with vitamin K antagonists (VKAs) such as warfarin has remained the standard of care for stroke prevention in AF. Despite clear evidence of efficacy, the limitations of VKAs, including potential bleeding complications and narrow therapeutic window, have resulted in poor compliance to treatment, low rates of time-in-therapeutic range, and important underutilization in patients with AF, even in those at high-risk. Antiplatelet therapy with aspirin has low efficacy compared with VKAs, and dual antiplatelet therapy with aspirin and clopidogrel, despite demonstrating an additional effect, has not matched the efficacy of VKAs.
The first revolution in anticoagulation for stroke prevention
A number of large randomized studies have proved the efficacy of several new oral anticoagulants for prevention of thromboembolic events in AF. The direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban and apixaban are non-inferior and even superior to warfarin for prevention of thromboembolic events in non-valvular AF. We have waited a long time for the advent of these new drugs; but despite their indisputable contribution to stroke prevention in AF not all of the problems of anticoagulation have been solved, leaving both clinicians and patients still facing difficult choices:
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a large proportion of patients at risk of stroke or systemic embolism remains untreated ;
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compliance to treatment remains problematic, with almost one-quarter of patients stopping medication within 2 years;
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anticoagulation is a life-long treatment, with necessary periods of interruption (e.g. for a surgical intervention), after which risk of thromboembolism is increased ;
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contraindications to warfarin are frequent, affecting around 17% of the AF population;
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treatment-associated bleeding still exists;
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the combination of antiplatelet and oral anticoagulant therapy dramatically increases risk of bleeding.
An alternative to anticoagulation: occlusion of the left atrial appendage
In non-valvular AF blood stasis in the left atrium is the major mechanism of thrombus formation, with clot migration in the cerebral circulation inducing stroke. The left atrial appendage (LAA) is the most important cardiac source of thromboemboli in non-valvular AF , and its exclusion should therefore prevent most cases of thrombus formation, without the need for life-long anticoagulation. Based on this hypothesis, surgeons widely perform LAA appendage exclusion as a concomitant procedure during open-heart surgery and several systems for percutaneous occlusion of the LLA have been developed. The randomized Watchman Left Atrial Appendage System for Embolic Protection in Patients With AF (PROTECT-AF ) trial demonstrated the validity of the concept and the therapeutic non-inferiority of LAA closure as an alternative to long-term warfarin treatment in preventing stroke in non-valvular AF patients with a CHADS 2 score ≥ 1. The primary composite efficacy endpoint was stroke, systemic embolism and cardiovascular death. Patients randomized to the LAA closure strategy had a lower event rate than those randomized to warfarin (3.0 vs. 4.9 per 100 patient-years, respectively), with a relative rate ratio of 0.62 (95% confidence interval 0.35–1.25), which translated to non-inferiority of the LAA closure strategy to warfarin treatment.
Even if the findings are extremely debatable, a systematic review of eight prospective non-comparative observational studies with the different systems of percutaneous LLA occlusion has estimated the annual stroke risk based on historical controls and CHADS 2 score. This comparison indicated an overall stroke reduction from 1.9–8.6% to 0–3.8% in respective studies .
Device and procedure description
In 2006 the manufacturer of Percutaneous Left Atrial Appendage Transcatheter Occlusion (PLAATO) – the first device to be developed for percutaneous LAA occlusion (PLAAO) – discontinued product development despite two prospective multicentre observational studies suggesting the feasibility of this technique with an acceptable risk . Two devices – Watchman™ (Boston Scientific, Natick, MA, USA) and Amplatzer Vascular Plug™ (Saint-Jude Medical, Saint-Paul, MN, USA) – are currently available in clinical practice and a third is in development.
The LAA occlusion implantation must be performed in centres with cardiac surgical facilities. The implanter must be experienced or have received specific training. The procedure is performed under transesophageal echocardiogram (TOE) control, requiring a general anaesthesia. A sheath is introduced into the right femoral vein. Access to the left atrium takes place via a transseptal puncture. After approximating the size and shape of the LAA under TOE or fluoroscopic guidance, the device is sized using a standardized chart and is then advanced into the LAA orifice. Imaging is used to confirm optimal positioning before the device is released and the delivery system withdrawn into the right atrium. To avoid thrombus formation and stroke during the procedure strong anticoagulation with low-molecular weight heparin is performed to reach an activated clotting time of 250–350 seconds.
In PROTECT-AF, warfarin was administrated for at least 45 days after device implantation to avoid excessive thrombus formation on the device, until device endothelialization supervened. In the ASA and Plavix (ASAP) study, involving 150 patients contraindicated to warfarin, post-procedural anticoagulation was replaced by an antiplatelet regimen with clopidogrel up to 6 months and aspirin indefinitely. An antiplatelet regiment is also used after Amplatzer device implantation. Follow-up TOE imaging was performed to assess for device stability, peridevice leaks and device-related thrombus.
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