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1
Mechanisms And Prevention Of TAVI-Related Cerebrovascular Events
Alexander Ghanem1, Amir S. Naderi2, Christian Frerker3, Georg Nickenig4, and Karl-Heinz Kuck5
1
A. Asklepios Klinik St. Georg, Department of Cardiology, Lohmühlenstraße 5, D-20099 Hamburg, B. Department
of Cardiology, University Hospital Bonn, Bonn, Germany; 2Asklepios Klinik St. Georg, Department of
Cardiology, Lohmühlenstraße 5, D-20099 Hamburg; 3Asklepios Klinik St. Georg, Department of Cardiology,
Lohmühlenstraße 5, D-20099 Hamburg; 4Department of Cardiology, University Hospital Bonn, Bonn, Germany;
5
Asklepios Klinik St. Georg, Department of Cardiology, Lohmühlenstraße 5, D-20099 Hamburg
Abstract: Introduction of transcatheter aortic valve implantation (TAVI) has resulted in a paradigm shift in the
treatment of patients with high risk or inoperable severe aortic stenosis. This article aims to comprehensively review the mechanisms of neurological injury per se, the read-outs of cerebrovascular events, and strategies currently
used to predict and prevent stroke in transcatheter aortic valve implantation.
Alexander Ghanem
Keywords: Transcatheter aortic valve implantation, TAVI, stroke, prevention, mechanisms, cerebral injury.
INTRODUCTION
Aortic valve stenosis is the most common valve disease in the
elderly with a prevalence of 3% among individuals 75 years of age
and up to 10% in octogenarians [1-4]. Patients with symptomatic
aortic stenosis have a poor prognosis with a rate of death estimated
to be more than 50% at two years if remained untreated [5-7]. Over
the last decade the introduction of transcatheter aortic valve implantation (TAVI) has resulted in a paradigm shift in the treatment of
patients with severe aortic stenosis in patients with very high or
prohibitive surgical risk [8, 9]. Despite the clear benefits of the
TAVI procedure, patients are exposed to the risk of disabling
stroke, complete heart block, paravalvular leakage, vascular complications, major bleeding, and valve migration [10]. Further, the
occurrence of cerebrovascular events (CVEs) is one of the most
worrisome complications in this frail and multimorbid patient population. More than 50% of CVEs occur during the acute phase after
TAVI and therefore prediction as well as prevention of CVEs remains to be one of the major methodological challenges [11-13].
This article aims to comprehensively review the mechanisms of
neurological injury per se, the read-outs of cerebrovascular events,
and strategies currently used to predict and prevent stroke in transcatheter aortic valve implantation.
STROKE: DEFINITION, INCIDENCE AND PREVALENCE
Over the last 10 years multiple studies have reported upon the
incidence of stroke after TAVI. Yet, in light of variable definitions
of clinically apparent events and disregard of subclinical events the
true incidence of CVEs after TAVI may not be reflected in some of
these studies. In order to standardize clinical endpoints after TAVI,
the Valve Academic Research Consortium (VARC) issued consistent definitions of CVEs, including the duration and neurological
outcome of patients [14]. In order to enhance the accuracy in the
description of a procedure-related stroke, VARC recommends using
the terms “disabling” and “non-disabling” stroke in substitution for
the old terms “major” and “minor” stroke.
The scientific evidence, which has established the foundation
for the wide acceptance and use of TAVI is derived primarily fromthe pivotal cohorts A and B of the Placement of Aortic Transcathe*Address correspondence to this author at the Asklepios Klinik St. Georg,
Department of Cardiology, Lohmühlenstraße 5, D-20099 Hamburg; Tel:
+49 (0) 40 1818 85-2033; Fax: +49 (0) 40 1818 75-5122;
E-mail: [email protected]
1381-6128/16 $58.00+.00
ter Valve Trial (PARTNER; NCT00530894). In this milestone controlled randomized trial data on stroke risk was reported in patients
with severe aortic stenosis undergoing conservative, interventional
or surgical treatment [8, 9]. Although TAVI resulted in a significant
decrease of mortality in patients with prohibitive surgical risk
(PARTNER Cohort B trial), a significantly increased stroke rate
was reported early after the TAVI procedure (30 day risk of CVEs:
6.7% vs. 1.7%, p=0.02), which persisted over 3 years (first year:
11.2% vs. 5.5%, p=0.06; second year: 13.8% vs. 5.5%, p=0.01;
third year 15.7% vs. 5.5%, p=0.004). However, despite the higher
risk for strokes in the TAVI group, the 3-year incidence of the
composite of death or stroke was significantly lower in the TAVI
group in comparison with the standard therapy group (57.4% versus
80.9%, P<0.001) [8, 15]. According to the recently published 5year outcome data of the PARTNER cohort B trial there is no continuous hazard of stroke associated with TAVI after the initial procedural risk [16]. In contrast, high-risk patients (PARTNER Cohort
A), who underwent TAVI demonstrated a slight but not significantly higher stroke rate compared to patients in the control group
who underwent conventional surgical aortic valve replacement (first
year: 6% vs. 3.2%, p=0.08; second year: 7.7% vs. 4.9%, p=0.17)
[9]. Ultimately, stroke rates were similar 3 years after TAVI and
surgical aortic valve replacement (SAVR).
The incidence of CVEs after TAVI is especially high in the
acute peri-procedural period, and decays over the first subsequent
month [17]. The overall-incidence of stroke was comprehensively
investigated by two meta-analyses, encompassing data of more than
10.000 patients each. Eggebrecht and colleagues analyzed 53 studies published between January 2004 and November 2011 undergoing transfemoral, transapical or transsubclavian TAVI for native
aortic valve stenosis [18]. The risk of stroke was 2.9±1.8% 30 days
after TAVI, with the lowest stroke rate being reported after
transapical TAVI. The analysis of 49 studies by Kathri and coworkers revealed a similar overall stroke risk after TAVI and found no
association of stroke risk with valve type and access route [19]. The
temporal distribution of CVEs in the peri-procedural phase ( 24
hours), 30 days, and 12 months after TAVI was reported as 1.5%
(±1.4%), 3.3% (±1.8%), and 5.2% (±3.4%) [18]. However, conclusions of both meta-analyses are confined by unequivocal stroke
definitions and retrospective analysis. Besides, much of the clinical
data in meta-analyses reflects patients recruited and data collected
from as early as 2004. As over the last decade the TAVI procedure
and devices used have improved some have criticized that the current practice does not reflect the high event rate of stroke in older
© 2016 Bentham Science Publishers
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Table 1.
Lilly and Abraham
Definition, Classification, and Diagnostic criteria of Stroke and TIA [14]
Diagnostic criteria
Acute episode of a focal or global neurological deficit with at least 1 of the following: change in the level of consciousness, hemiplegia, hemiparesis, numbness, or sensory loss affecting 1 side of the body, dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or symptoms consistent with
stroke.
Stroke: duration of a focal or global neurological deficit 24 hours; or <24 hours if available neuroimaging documents a new hemorrhage or infarct; OR the
neurological deficit results in death.
TIA: duration of a focal or global neurological deficit<24 hours, any variable neuroimaging does not demonstrate a new hemorrhage or infarct.
No other readily identifiable nonstroke cause for the clinical presentation (eg, brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in conjunction with the designated neurologist*
Confirmation of the diagnosis by at least 1 of the following:
- Neurologist or neurosurgical specialist
- Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds
alone
Stroke classification:
- Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of
the central nervous system tissue.
- Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by
intraparenchymal, intraventricular, or subarachnoid hemorrhage.
A stroke may be classified as undetermined if there is insufficient information to allow categorization as ischemic or hemorrhagic.
Stroke definitions **
- Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least 1 mRS category
from an individual’s prestroke baseline.
- Nondisabling stroke: an mRS score of<2 at 90 days or one that does not result in an increase in at
least 1 mRS category from an individual’s prestroke baseline.
mRS, Modified Rankin Scale. *Patients with nonfocal global encephalopathy will not be reported as a stroke without unequivocal evidence of cerebral infarction-based upon neuroimaging studies (CT scan or Brain MRI). **Modified Rankin Scale assessments should be made by qualified individuals according to a certification process [65-67].
studies. In light of this, it is worthwhile looking at more recent studies which add to our knowledge about peri- and postinterventional
stroke after TAVI, which include the French national transcatheter
aortic-valve implantation registry [10], The Transcatheter Valve
Treatment Sentinel Pilot Registry [20], the ADVANCE study [21],
as well as the U.S. CoreValve Trial [22]. The results of these trials
is very similar to previous studies, showing an incidence of stroke
at 30 days of 3, 4% in the FRANCE 2 study, 3.0% (1.2% major
stroke, 1.8% minor stroke) in the ADVANCE study, 4.9% (3.9%
major stroke, 1.0% minor stroke) in the U.S. CoreValve Trial, and
1.8% in the Transcatheter Valve Treatment Sentinel Pilot Registry
(which did not report the 30 day incidence of stroke but the procedural/ in-hospital stroke rate). According to the recently presented
data of the CoreValve US pivotal trial, patients had a all stroke risk
of 10.9 % and 16.6% two years after TAVI and SAVR with a
strong trend towards better outcomes in patients undergoing TAVI
(p=0.05). Besides, the superior survival seen at 1 year for TAVI
over SAVR was maintained at 2 years. Thus, the CoreValve US
Investigators conclude that TAVI should be considered the preferred treatment in patients with symptomatic severe AS at increased risk for surgery, and could be considered in patients at intermediate surgical risk [23]. Recent data of the NOTION-Trial
demonstrate non-inferiority of TAVI as compared to surgical valve
replacement even in patients at lower surgical risk [24].
Interestingly, CVEs demonstrate a time dependent distribution
pattern after the procedure. Approximately 50% of CVEs occur
within the first 24 hours after the TAVI procedure [17]. Thereafter,
patients remain most vulnerable for approximately 30 days (associ-
ated with the procedure) before transitioning to a late, constant
hazard phase (associated with the co-morbidies).
As nearly half of the CVEs occur late, and therefore are not
directly related to the procedure itself, different pathomechanisms
of cerebral injury after TAVI were objectified [11, 17, 25]. Therefore, all neuroprotective approaches need to be tailored according to
the underlying mechanism.
MECHANISMS OF CVEs
Currently, four different mechanisms of cerebral injury after
TAVI are postulated, which could explain the temporal distribution
of CVEs after TAVI.
CEREBRAL INJURY DUE TO DEBRIS EMBOLIZATION
Acute CVEs are almost exclusively ischemic in nature and are
considered procedure related [11, 25]. A vast majority of patients
undergoing TAVI have multiple cardiovascular risk factors including hypertension, hyperlipidemia, a history of smoking, and diabetes mellitus, which often lead to atherosclerotic disease in this aged
patient population. Thus, it is conceivable that each and every manipulation during the TAVI procedure within the aortic arch and the
stenosed, calcified aortic valve could potentially lead to embolic
dislodgement of thrombotic, atheromatous or calcific debris [26].
Patients with severe aortic stenosis and with longer duration of
catheterization are at increased risk of embolic ischemic stroke [27,
28]. Furthermore, repeated attempts to cross the often friable calcified valve as well as balloon post-dilation is associated with a
higher rate of CVEs, with most strokes in patients who had balloon
Algorithms and Criteria for Transcatheter Aortic Valve Replacement Patient Selection
Current Pharmaceutical Design, 2016, Vol. 22, No. 00
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Fig. (1). Major disabling stroke incidence - an overview of major TAVI trials and meta-analysis
Meta analysis 1 [18], GARY [68], meta analysis 2 [20] , FRANCE 2 [10], SOURCE [69], ADVANCE [21], German [70], PRAGMATIC-MCV (Medtronic
CoreValve) [71], U.S. Core Valve [22], PARTNER A [9], PRAGMATIC-ESV (Edwards SAPIEN/SAPIEN XT transcatheter heart valve) [71], Belgian [72],
PARTNER B [8]
Fig. (2). Risk of cerebrovascular events according to time after transcatheter aortic valve implantation.
Risk of CVEs related to the time after TAVI (solid line). The dotted line indicates the baseline risk of an age, sex, and risk factor matched population with
aortic stenosis. Neuroprotective approaches encompass patient selection and allocation to therapeutic strategy, procedural issues, duration of anti-thrombotic
therapy and the utilization of a dedicated embolic protection device.
CVE: Cerebrovascular event; NOAF: New onset atrial fibrillation; TAVI: Transcatheter
aortic valve implantation.
Adapted from Ghanem, et al. Expert Rev Cardiovasc Ther 11(10), 1311-1320 (2013).
post-dilation occurring immediately after or within the first 24
hours after the TAVI procedure [29].
Evidence for debris embolization during positioning and implantation of the valve prosthesis was brought by a study performed
4 Current Pharmaceutical Design, 2016, Vol. 22, No. 00
by van Mieghem, et al. [30]. In their study macroscopic material
liberated during the TAVI procedure was captured in a filter-based
embolic protection device and subsequently analyzed. The debris
consisted of fibrin, or amorphous calcium and connective tissue,
which were most likely derived from either the native aortic valve
leaflets or aortic wall.
Lilly and Abraham
left atrial enlargement and placement of the artificial valve by
transapical approach are associated with an increased risk of NOAF
[36, 37]. The impact of NOAF on delayed CVEs after TAVI was
shown by Amat-Santos and colleagues. In their study, NOAF was
associated with a higher rate of stroke and systemic embolism following the TAVI procedure, especially the late (>24 h) events. On
the contrary, the prevalence of NOAF was only 25% in patients
who experienced an acute CVE during TAVI. In conclusion, NOAF
increases the risk of early and subacute CVEs by 4.4 fold [25].
CEREBRAL INJURY DUE TO COMORBIDITIES
By analyzing data of a multi-center registry encompassing 1061
patients, Nombela-Franco, et al. demonstrated that both a history of
peripheral as well as cerebrovascular disease (carotid stenosis, prior
endarterectomy, prior CVE) each independently doubled the risk of
late CVEs after TAVI. Besides, it was shown that chronic atrial
fibrillation independently increases the risk of late CVEs (more
than 30 days after TAVI) almost three fold [11]. Likewise, Fairbairn, et al. demonstrated that the severity of aortic arch atheroma
was an independent risk factor for the development of new CVEs
after TAVI [38]. Hence, with respect to comorbidities, chronic
atrial fibrillation and presence of atherosclerotic disease burden are
key independent risk factors for TAVI related CVEs.
Image 1: Debris liberated during TAVI which has been captured by an
embolic protection system.
Image 2: Ischemic stroke after TAVI
The impact of the access route (transfemoral or transapical) and
the valve type (balloon- or self-expandable) on the occurrence of
CVEs has not been clearly elucidated yet [18, 19]. Yet, we and
others were not surprised that passing the semi-rigid, large-bore
delivery catheter containing the folded bioprosthesis using a catheter-based approach led to silent and apparent symptomatic cerebral
embolism in 73-84% and 3-10%, respectively [31-33]. Interestingly, CVE-risk was not related to the route of implantation (antegrade-transapical versus retrograde-transvascular).
CEREBRAL INJURY DUE TO THROMBOTIC EMBOLIZATION
New-onset atrial fibrillation (NOAF) frequently develops after
cardiovascular interventions and is associated with peri-procedural
CVEs [34, 35]. The incidence of NOAF after TAVI has been reported as high as 31.9% in patients with no prior history of atrial
fibrillation (AF), while NOAF was defined as any episode of atrial
fibrillation lasting more than 30 seconds. NOAF occurred in about
half of all events within 24 hours and in >80% of cases within 3
days after TAVI [36]. The pathogenesis of NOAF after TAVI procedure is not well understood. What is known is that pre-procedural
CEREBRAL INJURY DUE TO INSUFFICIENT CEREBRAL
PERFUSION PRESSURE
Several clinical settings may lead to hemodynamic instability
and impair cerebral perfusion pressure beyond cerebral autoregulatory capacity, namely general anesthesia, paravalvular leakage,
aortic regurgitation, vascular complications, as well as major bleeding. Besides, rapid ventricular pacing, which is used to decrease
cardiac output during balloon valvuloplasty and valve deployment
in an attempt to reduce the risk of valve malpositioning, causes
systemic hypotension. In a recent study, a time-dependent effect of
rapid ventricular pacing on microflow was demonstrated, leading to
50 and 25 % of baseline microflow at 8 and 18 seconds of rapid
ventricular pacing, respectively. Besides, in a substantial proportion
of patients, rapid ventricular pacing is associated with microcirculatory arrest and a delayed recovery of microflow [39].
All of the above mentioned non-embolic mechanisms may
cause malperfusion and consecutive brain dysfunction. Depending
on the duration and severity of cerebral hypoperfusion, patients
may suffer from postoperative alternating states of consciousness,
transient or irreversible neurologic impairment after TAVI. Nuis, et
al. demonstrated that moderate aortic regurgitation was associated
with an approximately 3-fold increase of risk of non-embolic cerebral ischemia in computed tomography. In this study, lacunar
strokes and watershed infarction occurred in 26% and 2% of patients, respectively [25].
In conclusion, embolic as well as non-embolic mechanisms
may lead to cerebral injury following TAVI. Hence, the underlying
mechanisms are to be considered with respect to read-outs and prevention of TAVI-related CVEs (see Table 2).
MECHANISMS OF TAVI-RELATED CEREBROVASCULAR EVENTS
Clinical parameters of cerebrovascular events
Among TAVI related complications, cerebrovascular events
causing focal or global neurologic deficit are dreaded because of
their excessive morbidity and mortality [40]. Yet, postoperative
stroke may also cause subtle clinical symptoms (e.g. cognitive decline or impairment in activities of daily living), which are not diagnosed until a neuropsychological exam, e.g. the Mini-mental
State Exam (MMSE) or the Repeatable Battery for the Assessment
of Neuropsychological Status (RBANS), is used.
Algorithms and Criteria for Transcatheter Aortic Valve Replacement Patient Selection
Table 2.
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Embolic and non-embolic mechanisms leading to CVEs following TAVI.
Embolic origin
Acute onset
Non-embolic origin
- Debris embolization due to device
- Bleeding / vascular complications
manipulation in the aortic arch and valvular
- Pericardial tamponade
ring.
- Rapid ventricular pacing
- SIRS
-Thrombotic embolization due to thrombus
- Carotid stenosis
formation on the device.
- NOAF
Chronic onset
- Atrial fibrillation
- Low output / heart failure
- Paravalvular leakage
NOAF - New-onset of atrial fibrillation, SIRS - Systemic inflammatory response syndrome
The Valve Academic Research Consortium limits the diagnostic criteria of perioperative cerebrovascular events to clinically apparent acute neurologic signs or symptoms consistent with stroke.
For standardized assessment of a patient’s neurologic status, use of
the National Institutes of Health Stroke Scale (NIHSS) is recommended. While clinical findings like changes in the level of consciousness, unilateral neurologic deficits, or aphasia are easily diagnosed, other neurologic signs or symptoms like hemianopsia,
amaurosis fugax, or spinal cord dysfuntion can only be diagnosed if
a more detailed history is taken and a dedicated neurologic exam is
performed.
In order to assess cognitive performance or the degree of disability or dependence in the daily activities of patients who have
suffered from stroke, the MMSE and the modified Rankin Scale
(mRS) can be used. Several investigators examined cognitive function after TAVI utilizing the MMSE, and found stable cognitive
performance for up to 24 months after TAVI [31, 33, 41]. In our
experience, no sub-clinical parameter of brain injury was related to
lifestyle or to activities of daily living one year after TAVI [42].
In conclusion, NIHSS and mRS are the basic clinical characteristics defining procedure-related CVEs. Available data on sustained
cognitive performance, improved quality of life, and activities of
daily living after TAVI are encouraging and should be considered
in the individual decision-making of the heart team [43, 44]. It is
indeed very interesting, that clinical measures of neurological deficits are up to 4-fold higher in trials with clinical assessment by a
board-certified neurologist as compared to trials with neurological
assessments performed by a surgeon, cardiologist or intensivist
[22]. This important observation should be of interest for future
comparative trials in lower risk patient subsets.
Imaging modalities of cerebral injury
Different imaging modalities have been used to detect cerebrovascular events after TAVI, namely computed tomography
(CT), transcranial Doppler (TCD) and diffusion-weighted (DW)MRI. Although new ischemic events have been documented in as
many as 93% of patients after the TAVI procedure [45, 46], most of
these events are silent infarctions with no clinical apparent neurologic deficit [31-33] and have no effect on self-sufficiency in
lifestyle, health-related quality of life and mortality [38, 42]. Cerebral imaging has yielded mechanistical insights into an alternative
origin of cerebral injury after TAVI, displaying non-embolic, cortical watershed infarction as indirect sign of non-embolic, hemodynamic impairment in 10.5% of patients undergoing TAVI [25].
In contrast to the tomographic modalities, TCD identified critical intra-procedural steps with respect to cerebal embolism by recognition and quantification of high-intensity transient signals and
microembolic signals [47]. Microemboli have been detected during
all stages of the TAVI procedure but are most frequent during the
stages of valve positioning and valve implantation. In the largest
and most comprehensive study to date investigating TCD-detected
emboli, Kahlert, et al. demonstrated a high number of highintensity transient signals during the stage of valve implantation,
suggesting release of calcific debris and valve tissue from the native
aortic valve during release of the prosthesis [48]. Long-term followup studies are needed to elucidate the consequences of cerebral
embolism in regards to neurocognitive decline, mild cognitive impairment and vascular dementia [49, 50].
Serological parameters of cerebral injury
Over the last two decades, different serologic markers have
been assessed as surrogates for neurologic injury after traumatic
brain injury or cerebral ischemia. The concentrations of the serologic markers S-100 B and neuron-specific enolase (NSE) have
been shown to predict infarct volume and the long-term neurological outcome of patients after ischemic brain infarction [51]. In small
studies, a correlation between infarct volume and the degree of
post-procedural release of S-100B was demonstrated [52, 53]. In
contrast, studies could not demonstrate a correlation between the
post-procedural increase in serum concentration of NSE neither in
relation to cerebral injury in DW-MRI nor to neurological and cardiovascular outcome up to 1 year after TAVI [32, 42].
“c-RIFLE” Criteria and the prognostic value of cerebral injury
Analogous to the RIFLE criteria [54], which consist of three
graded levels of kidney dysfunction (Risk, Injury, and Failure),
based upon either the magnitude of increase in serum creatinine or
urine output, and two outcome measures (Loss and End-stage renal
disease) conceptual analogies can be found for myocardial injury
(see Table 3).:
Table 3. Cerebral RIFLE criteria (c-RIFLE) - in analogy to the
RIFLE criteria.
Risk: asymptomatic patients at increased risk of developing stroke after
TAVI, e.g. due to NOAF
Injury: postprocedural increase of biomarkers or evidence of new ischemic
stroke on MRI imaging in patients without focal or global neurologic deficit
Failure: postprocedural clinical evidence of temporary focal or global neurologic deficit lasting less than 24 hours (TIA)
Loss: postprocedural clinical evidence of persistent focal or global neurologic deficit lasting longer than 24 hours with evidence of cerebral injury
in specific tomographic imaging modalities (stroke)
6 Current Pharmaceutical Design, 2016, Vol. 22, No. 00
Patients suffering from early CVEs after TAVI demonstrated a
significantly higher mortality rate as compared to patients who did
not suffer from stroke [17]. Major, disabling stroke was associated
with higher 30-day (7.4-fold) and late (1.75-fold) mortality [11]. A
meta-analysis including more than 10.000 patients reported on a
3.5-fold increase of mortality after CVE [18]. Several measures of
subclinical cerebral injury have been reported to be associated with
TAVI, but only apparent CVEs seem to have an adverse impact on
prognosis [42]. Long-term studies are needed to assess if the subclinical emboli which many patients are exposed to during TAVI
procedure will ultimately cause mental impairment or effect. Interestingly, the lack of silent ischemic events does not lead to improvement of cognitive outcome [42].
Prevention of cerebrovascular events
Because of the increased risk of CVE associated with TAVI,
adjunctive pharmacotherapy to prevent thrombosis, periprocedural
measures to prevent non-embolic cerebral injury, and use of neuroprotectice devices may be discussed. Scientific evidence, especially
randomized trails on neuroprotection during TAVI is scarce. Most
of the few studies that have been conducted have focused on use of
antiplatelet therapy and anticoagulation during an after TAVI. In
the following we discuss several preventive strategies in regard to
the timing and underlying mechanisms CVE and propose interventional measures.
Prevention of acute procedural embolic cerebral injury
In one of the few published clinical trails to date, Ussia, et al.
randomized 79 patients undergoing TAVI to receive a 300-mg loading dose of clopidogrel on the day of procedure plus postprocedural maintenance therapy consisting of 3 months of 75 mg of
clopidogrel daily plus aspirin 100 mg lifetime or aspirin 100 mg
alone. The study did not show a benefit of adding clopidogrel to
aspirin for 3 months after TAVI to be superior to aspirin alone at 30
days and after 6 months [55].
In analogy to the aforementioned trial, Durand et. al. compared
use of dual antiplatelet therapy (DAPT) in patients undergoing
TAVI to monoantiplatelet therapy alone [56]. The results demonstrated a reduced risk of life-threatening and major bleeding but no
reduction of risk in regards to stroke and myocardial infarction by
using monoantiplatelet therapy versus DAPT. The ongoing randomized multicenter “BRAVO 2/3 trial” will assess the safety and efficacy of using bivalirudin instead of unfractionated heparin in TAVI
with the hypothesis that bivalirudin reduces bleeding rates and improves clinical outcomes relative to heparin (NCT01651780).
Although prevention of acute CVEs can be tackled in the preprocedural setting, several preventive measures can be implemented
during the intervention. On the one hand improvements in the design of delivery catheters, such as smaller size or steerabiliy, can
reduce contact with vulnerable lesions [12]. On the other hand,
transcranial Doppler studies have demonstrated that cerebral embolism occurs throughout the multi-step TAVI procedure, but cumulate predominantly during valve positioning and deployment within
the calcified native valve [48]. Therefore, the ‘no contact’, ‘minimal contact’, or ‘direct’ TAVI approach, without preparatory balloon valvuloplasty to minimize the dislodgment of calcified atherosclerotic emboli, have been proposed to reduce the risk of periprocedural stroke [57]. In this regard precise sizing of the annulus
and the correct valve-selection is essential to avoid valve dislodgement, valve malposition, post-dilatation or deployment of a second
valve, each of which might increase the risk of CVEs. Therefore, a
meticulous planning and rapid performance of the procedure is of
paramount importance.
In addition, patients undergoing TAVI may also benefit from
the use of distal cerebral embolic protection devices. The rational
for their use relies on the reduction of cerebral embolic debris by
either deflecting or capturing embolized material from entering the
Lilly and Abraham
supraaortic-cerebral arteries. Distal cerebral embolic protection
devices consist of a filter membrane placed either in the aortic arch
to deflect debris toward the descending aorta (TriGuardTM Cerebral
Protection Device, Keystone Heart Ltd., EmbrellaTM, Edwards Inc.)
or placed in the anonymous and common carotid arteries (MontageTM, Claret Medical Inc., Lumen Biomedical) to either deflect
(TriGuardTM, EmbrellaTM) or capture (MontageTM) embolic debris
during the procedure. Proof of efficacy for cerebral protection devices was demonstrated in a few pilot studies in patients with severe
aortic stenosis undergoing TAVI in 2010 and 2012 [58-60]. In the
recently published PROTAVI-C trial (n=41), Rodés-Cabau, et al.
demonstrated that deployment of the Embrella Embolic Deflector
system did not prevent the occurrence of cerebral microemboli
during TAVI or new transient ischemic lesions as evaluated by
DW-MRI, but that it’s use was associated with a reduction in cerebral lesion volume [33].
In a recent randomized controlled trial Linke, et al. could demonstrate that in patients with severe aortic stenosis who are at increased surgical risk, the use of Claret MontageTM dual filter cerebral protection system during TAVI significantly reduced the number and volume of cerebral lesions as determined by DW-MRI subtraction at 2 and 7 days after TAVI (Linke, et al., „Oral presentation
at TCT 2014“).
Future larger outcomes studies are needed in order to validate
the observed beneficial effects of routine cerebral protection during
TAVI in improving acute neurological outcome and reducing stroke
rate.
Prevention of acute procedural non-embolic cerebral injury
Intraoperative arterial hypotension and transient decay of unior bilateral cerebral perfusion pressure can lead to non-embolic
mechanisms of cerebral injury. In a study by Nuis, et al. watershed
infarction could be demonstrated in 10.5% of patients by means of
computer tomography. Different mechanism can lead to intraoperative arterial hypotension, e.g. anesthesiological regime, hypovolemia, the use of rapid ventricular pacing during valve positioning and deployment, valvuloplasty, post-dilatation, and periprosthetic regurgitation. Besides, vascular or bleeding complications, SIRS or sepsis, and other mechanisms leading to hypotension
can impair cerebral blood flow, especially in patients with underlying cerebrovascular disease. Future neuroprotective trials should
evaluate if near infrared spectroscopy (NIRS) can contribute to the
management of patients in terms of preoperative risk stratification
as well as intraoperative decision making [61, 62].
Prevention of subacute post-procedural embolic cerebral injury
Stroke is an independent predictor of morbidity and mortality
after surgical aortic valve replacement and TAVI. Prevention of
subacute post-procedural embolic cerebral injury is of paramount
interest, since more than half of the TAVI-related CVEs occur later
than 24 hours after implantation. Evidence regarding the optimal
treatment strategy is scarce and unequivocal. In small-scale trials no
change in clinical status was detected in patients treated with monoantiplatelet therapy (MAPT), as compared to dual-antiplatelet therapy (DAPT) [55, 63]. Based on current available data the intensity
of antiplatelet therapy does not seem to change the incidence of
subacute CVEs. Ongoing large multicenter randomized trials will
clarify whether MAPT after TAVI is safe enough with respect to
prevention of subacute CVEs (NCT02247128).
New onset atrial fibrillation occurs in approximately one-third
of patients after TAVI, and its onset significantly increases the risk
of subacute CVEs [36]. Based on the compelling data of the recent
ASSERT Trial [64] even very short time periods of atrial fibrillation (6 minutes) are indicative for future strokes. Hypothetically,
the combination of MAPT and limited-dosage of oral anticoagulants could be a compromise between excessive bleeding risk of
transient “triple therapy”. On-going trials are investigating the syn-
Algorithms and Criteria for Transcatheter Aortic Valve Replacement Patient Selection
ergistic effects of Aspirin, Clopidogrel or newer anti-thrombotic
agents, as well as direct thrombin-inhibitors and their combinations
with APT to decrease bleeding risk utilizing combination of APT
and OAC following the principle “as low as reasonably achievable”, weighting out embolic and bleeding risk (REDUAL-PCI:
NCT02164864, Pioneer AF-PCI: NCT01830543). Hence, we assume that future studies will concentrate on synergistic effects of
APT and OAC in adapted dosage after TAVI, to address the underlying complex pathophysiological mechanisms of subacute stroke.
Prevention of subacute post-procedural non-embolic cerebral
injury
The mechanism of late cerebral embolism beyond the high-risk
period (first week to 30 days after TAVI) appear to be mainly related to thrombotic origin and are associated with the underlying
comorbidities of the aged TAVI patient. Atrial fibrillation, carotid
stenosis, arterial hypertension, and peripheral vascular disease,
among other known predictors of late cardiovascular events, need
to be treated in order to prevent late CVEs. With respect to patients
at high risk of bleeding, use of new anticoagulants could be of help
to prevent this major challenge [11, 17].
ABBREVIATIONS
AF
= atrial fibrillation
AVR
= aortic valve replacement
CT
= computed tomography
CVEs
= cerebrovascular events
DAPT
= dual antiplatelet therapy
DW-MRI
= Diffusion weighted Magnetic Resonance Imaging
LBBB
= left bundle branch block
mRS
= modified Rankin Scale
MAPT
= mono-antiplatelet therapy
MMSE
= Mini-mental State Exam
NIHSS
= National Institutes of Health Stroke Scale
NOAF
= new-onset atrial fibrillation
NSE
= neuron-specific enolase
RBANS
= repeatable Battery for the Assessment of Neuropsychological Status
SAVR
= surgical aortic valve replacement
TCD
=
transcranial Doppler
TAVI
= transcatheter aortic valve implantation
VARC
= Valve Academic Research Consortium
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
ACKNOWLEDGEMENTS
Declared none.
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