In the current issue of JAHA, Dalén et al1 report the results of a single‐center prospective
observational study of 47 patients with implantation of the Perceval sutureless bioprosthesis
(LivaNova, Milan, Italy). Cardiac computed tomography (CT) performed at a median of
491 days (range 36–1247 days) found hypo‐attenuated leaflet thickening (HALT) in 18
(38%) and reduced leaflet motion (RLM) in 13 (28%) patients. HALT affected a single
leaflet in 10 (56%), 2 leaflets in 6 (33%), and all leaflets in 2 patients (11%).
The mean HALT leaflet thickening was 3 mm. For RLM, 1 leaflet was affected in 11 and
2 leaflets in 2 patients. Surprisingly, 5 of 18 patients with HALT (28%) and 3 of
13 patients with RLM (23%) were receiving anticoagulants at the time of CT. In fact,
there was no significant difference in warfarin use between HALT and no HALT groups
(22% versus 14%, P=0.45), but there was a trend towards reduced novel oral anticoagulant
use in patients with HALT (6% versus 28%, P=0.06). Clinically, there were 3 strokes
and 1 transient ischemic attack but no association with presence of HALT and RLM.
Makkar et al2 first alerted the cardiovascular community to the existence of a significant
and previously unrecognized risk of prosthetic leaflet motion reduction following
transcatheter aortic valve replacement (TAVR) and bioprosthetic surgical aortic valve
replacement (SAVR) in the absence of formal anticoagulation. It was hypothesized that
this reduced leaflet motion was caused by subclinical leaflet thrombosis, which may
trigger premature structural valve deterioration and constitute a nidus for cerebral
thromboembolic events. The measures of valve thrombosis are HALT and RLM. The clinical
consequences of such phenomena, and the role of anticoagulation for prevention and
treatment are uncertain. This report by Dalén et al1 adds important data to the overall
literature of HALT and RLM and is the first report of protocol‐driven CT focusing
on sutureless SAVR.
Subclinical valve thrombosis is a newly recognized clinical entity that has been described
in a variety of surgical and transcatheter bioprostheses.3, 4, 5, 6, 7, 8, 9, 10 These
patients may present with early significant increases in transvalvular gradients and
even overt thrombosis. Del Trigo et al8 reviewed 1521 patients who underwent TAVI
to find that 4.5% experienced clinical premature valve hemodynamic deterioration and
an independent risk factor was no anticoagulation, suggesting that the mechanism was
thrombosis related. Egbe et al9 examined explanted bioprostheses at the Mayo Clinic
(mean 24 months) and found that overt thrombosis (11% in the aortic position) was
associated with HALT and RLM. The importance of this issue of subclinical valve thrombosis
is underscored by the fact that the seminal study prompted the Food and Drug Administration
to state that, “if reduced leaflet motion is detected by imaging, treatment options
should be discussed with the team of physicians responsible for the patient's care.”11
Full anticoagulation with warfarin is currently the only treatment shown to reverse
leaflet motion reduction in observational studies, although high‐quality data in this
regard are lacking.
Sutureless valves are bioprosthetic valves that are implanted in an open surgical
procedure but require few or no sutures, thus allowing for significantly shortened
cardiopulmonary bypass and cross‐clamp times.12, 13 Sutureless valves are particularly
useful for redo aortic procedures with calcified annuli that do not allow for conventional
annular suturing, multiple valve procedures to reduce surgical times, and to facilitate
minimally invasive procedures. There has previously been a single case report of early
valve thrombosis with a size S sutureless SAVR.14 Given that HALT and RLM have been
reported with conventional SAVR and TAVR, it is not surprising that they also occur
with sutureless SAVR.
What is surprising from this study is that the incidence of HALT and RLM was higher
than that in the published literature for SAVR and even for TAVR.2, 10 In a recent
report from the Assessment of TRanscathetEr and Surgical Aortic BiOprosthetic VaLVe
Thrombosis and Its TrEatment With Anticoagulation (RESOLVE) and the Subclinical Aortic
Valve Bioprosthesis Thrombosis Assessed with Four‐Dimensional Computed Tomography
(SAVORY) registries, 12% of 890 patients undergoing SAVR and TAVR had subclinical
leaflet thrombosis: 4% for SAVR and 13% for TAVR.10 As Dalén et al have correctly
explained, sutureless SAVR and some TAVR devices share the presence of a stent, the
need for leaflet crimping or collapsing, and the need for balloon dilation (Medtronic
Corevalve is self‐expandable), all of which may contribute to thrombogenic potential.
Also, all patients in this study were treated with low‐dose aspirin or warfarin/novel
oral anticoagulant alone. This is consistent with routine medical management post‐SAVR.15
However, whether the metallic stent of the sutureless SAVR is thrombogenic remains
to be determined. If so, there may be an advantage to the use of more potent antithrombotic
therapy with sutureless SAVR. On the other hand, unlike TAVR, in which the native
valve is left in situ, for sutureless SAVR, the diseased leaflets and any large annular
calcific deposits are removed, thus theoretically optimizing aortic root blood flow.
Furthermore, there is less risk of suboptimal device implantation as the sutureless
valve is placed under direct vision and an improperly implanted valve can easily be
recognized, removed, and reimplanted. Finally, as a possible explanation of the increased
incidence of HALT and RLM, the time point for CT in this study was considerably longer
than in previous studies of early valve thrombosis.3, 4, 5, 6, 7, 8, 9, 10 More information
about the incidence of RLM in sutureless and stentless aortic valves will be provided
from the upcoming BELIEVE (Behavior of Valve Leaflets) study (NCT03200574).
Contrary to published studies, HALT and RLM were seen in patients receiving oral anticoagulation,
and there was no significant difference in the use of warfarin or novel oral anticoagulant
in patients with subclinical thrombosis compared with those without.1 In the RESOLVE
and SAVORY registries, subclinical leaflet thrombosis was seen less frequently among
patients receiving anticoagulants and, in patients not already on anticoagulants,
leaflet thrombosis completely resolved with initiation of anticoagulation.2, 10 It
is possible that differences in warfarin management including the involvement of a
thrombosis clinic or the use of home international normalized ratio monitoring may
account, in part, for the variability in the observed incidence of subclinical thrombosis.
Also, in this study, there were few cerebral embolic events reported and no association
with stroke was identified, but HALT and RLM were associated with increased rates
of transient ischemic attacks. Early reports of subclinical thrombosis suggested a
possible association with cerebral embolism,1 but more recent studies have not found
this link.16, 17 Further studies with protocol‐driven cerebral imaging will be needed
to better understand the cerebral embolic risk. Other important questions to address
include whether subclinical valve leaflet thrombosis occurs in bioprostheses implanted
in the mitral, tricuspid, or pulmonic positions, and what the natural history of this
phenomenon is for all valve positions.
Given the uncertain but potentially adverse clinical consequences, there is an urgent
and unaddressed need to study early postoperative valve structure and function, and
evaluate the safety and efficacy of oral anticoagulation approaches for all prostheses.
There are discordant positions in current clinical practice guidelines regarding short‐term
oral anticoagulation post‐SAVR and no specific guidelines regarding the use of antiplatelet
agents and anticoagulation for sutureless SAVR.18, 19, 20 In the www.clinicaltrials.gov
database, several recently posted randomized controlled trials are comparing standard
of care versus anticoagulation following TAVR and SAVR with HALT and RLM as an outcome:
(1) 1 small single‐center, pilot trial at the Cleveland Clinic (Frequency of Reduced
Leaflet Motion After Surgical Aortic Valve Replacement and Transcatheter Aortic Valve
Replacement; NCT02696226); (2) a 300‐patient randomized controlled trial comparing
aspirin versus rivaroxaban postbioprosthetic SAVR (Comparison of a Rivaroxaban‐based
Strategy With an Antiplatelet‐based Strategy Following Successful TAVR for the Prevention
of Leaflet Thickening and Reduced Leaflet Motion as Evaluated by Four‐dimensional,
Volume‐rendered Computed Tomography [4DCT] [GALILEO‐4D]; NCT02833948); (3) a 200‐patient
randomized controlled trial comparing anticoagulation versus standard of care for
thrombosis post‐TAVR: RETORIC (Rule Out Transcatheter Aortic Valve Thrombosis With
Post Implantation Computed Tomography; NCT02826200); and (4) a 1000‐patient randomized
controlled trial comparing aspirin versus rivaroxaban postbioprosthetic SAVR (NCT02974920).
In the RESOLVE (NCT02318342), 1000 patients with early bioprosthetic valve thrombosis
will be treated with warfarin for 3 months and resolution will be assessed by CT.
These prospective studies along with the BELIEVE study will introduce high‐quality
evidence regarding the incidence of subclinical thrombosis and the optimal antithrombotic
therapy for the subacute period following TAVR and bioprosthetic SAVR. The results
of these studies may provide data supporting a possible change in current recommendations
and practice patterns, and may lead to a larger end‐point trial of major adverse cardiovascular
events. The work by Dalén et al is an important early step in this journey.
Disclosures
Mazer is supported by a Merit Award from the University of Toronto Department of Anesthesia.
The remaining authors have no disclosures to report.