We read the report by Waksman and Pendyala about the discussions between the US Food and Drug Administration and the sponsor regarding approval of the WATCHMAN device for interventional left atrial appendage closure (LAAC). We would like to stimulate the discussion by the following contribution: LAAC is primarily intended as an alternative for stroke prevention in patients with atrial fibrillation (AF) in whom oral anticoagulation is not possible because of contraindications about a high bleeding risk. However, according to the protocol of the WATCHMAN investigating trials, anticoagulant and antiplatelet therapies are mandatory after implantation of the device: A combination of warfarin plus aspirin 81 mg is recommended through 45 days after implantation, followed by aspirin 325 mg plus clopidogrel 75 mg through 6 months after implantation, followed by indefinite use of aspirin 325 mg. Previous studies in patients with AF showed, however, that the combination of aspirin with clopidogrel was associated with a major bleeding rate of 2% per year. The major bleeding rate while receiving aspirin 325 mg/d was 1.1% per year. Thus, the patients will be exposed to a considerable bleeding risk despite implantation of the device.

The combined therapy with warfarin and aspirin for 45 days after device implantation may even prevent complete LAA sealing and, thus, promoting leaks between the LAA wall and the device. Incomplete LAA exclusion creates a pouch with stagnant blood flow, which enhances thrombus formation. The high blood flow velocity jet at the small LAA orifice may promote embolization of thrombotic material from inside.

The LAA myocardium has a higher distensibility than the left atrial myocardium. Progressive dilation of the LAA is observed in AF, and thereby, leakage of an initially completely closed LAA may occur. Because it is unknown how many “late leaks” develop after LAAC, transesophageal examinations >12 months after implantation should be implemented in the protocol.

Only the total number of cardiovascular or unexplained deaths is reported. Thus, it remains unclear how many patients in the LAA closure group died. It would be of great interest to know how many patients underwent autopsy and what were the pathoanatomic findings of the left atrium and the LAA?

When occluding the LAA, it has to be considered that the LAA is an endocrine organ. The LAA is an important structure for release of atrial natriuretic peptide (ANP) and brain natriuretic peptide. In normal human hearts, ANP concentration is 40-fold higher in the LAA than in the rest of the atrial free wall and in the ventricular endocardium. Because natriuretic peptides play an important role in fluid regulation, volume homeostasis, and thirst perception, LAA elimination may impede physiological regulations of heart failure and thirst perception. Furthermore, dysregulation of ANP and BNP has been associated with obesity, glucose intolerance, type 2 diabetes mellitus, and essential hypertension. Moreover, natriuretic peptides have been implicated in the protection against atherosclerosis, thrombosis, and myocardial ischemia. Thus, the development of all these disorders and measurement of natriuretic peptides has to be evaluated and implemented as end points in studies investigating LAAC.