Raj R Makkar (Department of Interventional Cardiology, Cedars-Sinai Heart Institute, Los Angeles, USA) and others report in The New England Journal of Medicine that reduced leaflet motion may occur with all types of bioprosthetic valves—both surgical and transcatheter aortic valve implantation (TAVI) devices—and that the condition may be linked to an increased risk of stroke. Therefore, they state that further evidence is needed to better understand this condition and its potential clinical consequences.
Last year, enrolment in the PORTICO (Portico re-sheathable transcatheter aortic valve system) US IDE trial was halted after reduced leaflet motion was observed in some of the patients who had received a Portico TAVI device (St Jude Medical). Enrolment was subsequently resumed after the phenomenon was also observed patients in the control arm (who received commercially available TAVI devices) and was not found to be associated with an excess of clinical events. However, the finding prompted the establishment of two registries—RESOLVE (the assessment of transcatheter and surgical aortic bioprosthetic valve thrombosis and its treatment with anticoagulation) and SAVORY (Subclinical aortic valve bioprosthesis thrombosis assessed with four-dimensional computed tomography)—to further evaluate reduced leaflet motion after implantation of a bioprosthetic valve (both surgical and TAVI devices). In their study, Makkar et al reviewed data from these registries and from the PORTICO trial to examine the prevalence of reduced leaflet motion with bioprosthetic valves (as assessed on 4D, volume-rendered computed tomography; CT). They also sought to determine: “The association between reduced leaflet motion and strokes and transient ischaemic attacks; and the influence of anticoagulation on reduced leaflet motion.”
Overall, they found that 22 patients (40%) of 55 who had usable contrast CT scan data had evidence of reduced leaflet motion in the PORTICO study—of whom, 16 (of 37 overall) had received a Portico valve and six (of 14 overall) had received a Sapien valve (Edwards Lifesciences). In the pooled analysis of data from the registries, 17 patients of 132 with usable scan data had evidence of reduced leaflet motion; of whom, 15 (of 105 overall) had received a TAVI valve and two (of 27 overall) had received a surgical device.
In both cohorts, the use of therapeutic anticoagulation appeared to lower the risk of reduced leaflet motion occurring. In the PORTICO trial, the prevalence of reduced leaflet motion was significantly lower among patients who received therapeutic anticoagulation with warfarin at the time of index CT after TAVI: 0 of 8 vs. 21 of 41 patients receiving no or subtherapeutic anticoagulation (p=0.007). It was also less prevalent among those who received therapeutic anticoagulation with warfarin compared with those who received dual antiplatelet therapy. That therapeutic anticoagulation was associated with a lower prevalence of reduced leaflet motion than was dual antiplatelet therapy was also seen in the registries’ data. Additionally, after reviewing all of the data for patients with reduced leaflet motion (both from the PORTICO trial and from the registries), Makkar et al found that: “Normal leaflet motion recovered in all 11 patients who started or continued to receive therapeutic anticoagulation but persisted in nine of 10 patients who did not received anticoagulation.”
They report that the finding regarding the potential ability of therapeutic anticoagulation to prevent or treat reduced leaflet motion, alongside hypoattenuating opacities being observed on the leaflets of devices with reduced leaflet motion suggest that subclinical thrombosis is causing the reduced leaflet motion. However, Makkar et al note that they are unable to confirm this pathologically and that they are unable to precisely estimate how frequently subclinical thrombosis (if that is the cause of reduced leaflet motion) occurs.
Regarding the clinical outcomes of reduced leaflet motion, the authors state that, according to the PORTICO trial data, “there was no significant difference between patients with reduced leaflet motion and those with normal leaflet function with respect to the mean aortic-valve gradient”. They add that “This observation was consistent at the time of hospital discharge in 50 patients, at 30 days in 50 patients, and at six months in 28 patients.” Furthermore, they did not find any differences in clinical outcomes between groups in this cohort of patients.
However when Makkar et al reviewed the registry data, they found that patients with reduced leaflet motion in the registry had a higher incidence of stroke or transient ischaemic attack: 3 vs. 1 for the normal leaflet motion group (p=0.007). But they do note that the “total number of events was extremely small”. Calling this finding in the registries’ data of a higher incidence of stroke/transient ischaemic attack “preliminary and inconclusive”, they state that the cause of stroke or transient ischaemic attack after TAVI is “multifactorial”. The authors add that these causes include “embolisation of thrombotic and non-thrombotic material from the aortic, left ventricular native-valve instrumentation and new or pre-existing atrial fibrillation, in addition to thromboembolism from bioprosthetic valves.” “Nonetheless, our findings raise the concern that patients undergoing TAVI or surgical aortic valve replacement with a bioprosthetic valve could be at greater risk for leaflet thrombosis and consequent embolic stroke than has previously recognised. Further and more systematic study of this phenomenon to clarify the mechanism and assesses the clinical consequences seems desirable,” Makkar et al comment.
Concluding, the authors say: “Reduced aortic-valve leaflet motion occurred in patients with bioprosthetic aortic valves and was easily detected non-invasively by 4D, volume rendered CT. Therapeutic anticoagulation with warfarin but not therapy with antiplatelet drugs prevented and effectively treated this phenomenon. Better characterisation of this observation is needed to determine its frequency and evaluate its clinical effect.”
In an accompany commentary, on behalf of the FDA, John L Laschinger (Mayo Clinical, Rochester, USA) and others agree with Makkar et al further data are needed. They also note that the “available clinical evidence” for bioprosthetic valves shows that these devices “remain safe and effective” and that the findings to date “have not changed the overall favourable benefit-risk profile for these valves when they are used for their approved indications.” The FDA recently issued a notification about reduced leaflet motion with bioprosthetic valves