Aortic Valve Calcium Score Is Associated With Acute Stroke in Transcatheter Aortic Valve Replacement Patients

Background Transcatheter aortic valve replacement (TAVR) is the treatment of choice for patients with severe aortic stenosis who are at a moderate or higher surgical risk. Stroke is a recognised and serious complication of TAVR, and it is important to identify patients at higher stroke risk. This study aims to discover if aortic valve calcium score calculated from pre-TAVR computed tomography is associated with acute stroke in TAVR patients. Methods We conducted a retrospective, observational cohort study of 433 consecutive patients undergoing TAVR between January 2017 and December 2019 at the Hammersmith Hospital. Results This cohort had a median age of 83 years (interquartile range, 78-87), and 52.7% were male. Fifty-two patients (12.0%) had a history of previous stroke or transient ischemic attack. Median aortic valve calcium score was 2145 (interquartile range, 1427-3247) Agatston units. Twenty-two patients had a stroke up to the time of discharge (5.1%). In a logistic regression model, aortic valve calcium score was significantly associated with acute stroke (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.01-1.53; P = .02). Acute stroke was also significantly associated with peripheral arterial disease (OR, 4.32; 95% CI, 1.65-10.65; P = .0018) and a longer procedure time (OR, 1.01; 95% CI, 1.00-1.02; P = .0006). Conclusions Aortic valve calcium score from pre-TAVR computed tomography is an independent risk factor for acute stroke in the TAVR population. This is an additional clinical value of the pre-TAVR aortic valve calcium score and should be considered when discussing periprocedural stroke risk.


Introduction
Transcatheter aortic valve replacement (TAVR) has emerged as the treatment of choice for patients in need of aortic valve replacement, who have moderate or higher surgical risk. 1 Recent trials have demonstrated that TAVR is noninferior to surgical aortic valve replacement (SAVR), even in candidates with a low surgical risk. 2 In view of this, the worldwide utilisation of TAVR is likely to further increase.
4][5] Predictors of increased stroke risk after TAVR include baseline clinical factors such as the presence of peripheral arterial disease (PAD) and a history of transient ischemic attack, as well as procedural events such as balloon valvuloplasty post dilatation and valve dislodgement or embolization. 6odern TAVR programmes use preprocedural computed tomography (CT) scanning to establish vascular access routes, annular anatomy, and Abbreviations: AF, atrial fibrillation; AU, Agatston units; CEPD, cerebral embolic protection device; CT, computed tomography; IQR, interquartile range; LVOT, left ventricular outflow tract; PAD, peripheral arterial disease; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement.valve size. 7CT has demonstrated utility in predicting post-TAVR outcomes, with left ventricular outflow tract (LVOT) calcification on CT being associated with increased risk of stroke and right coronary cusp calcification being associated with increased pacemaker risk. 8CT prior to TAVR also quantifies aortic valve calcium, with a score generated from sequential 3-mm axial noncontrast slices.This score can lend support to a diagnosis of severe aortic stenosis when echo parameters are equivocal. 1,9ortic valve calcium score has already been demonstrated to correlate well with the severity of aortic valve stenosis. 9Echocardiographic and CT studies have shown that a more calcified aortic valve is a predictor of more rapid progression to clinically significant aortic valve stenosis. 10,11n a small TAVR cohort of 64 patients, aortic valve calcium score was an independent predictor of mortality at 1 year. 12Large prospective observational studies have assessed the prognostic value of aortic valve calcium in non-TAVR populations.][15] Whether the aortic valve calcium score calculated from the preprocedural TAVR CT scan can predict a higher risk of periprocedural stroke is unknown.

Data collection
We conducted a retrospective observational cohort study with consecutive patients undergoing a TAVR procedure at the Hammersmith Hospital between January 2017 and December 2019.Patients who could not have an accurate aortic valve calcium score calculated because of previous SAVR or TAVR were excluded.Patients who had a TAVR valve implanted in the mitral position were also excluded.
Patient baseline demographic, clinical, and procedural data were collected from the hospital clinical records.Acute stroke was defined as a neurological deficit of vascular origin, lasting more than 24 hours with concomitant radiological evidence of new intracerebral hemorrhage or infarct, occurring between the start of their TAVR procedure up until the point of hospital discharge.We additionally included patients with symptoms lasting <24 hours where there was imaging evidence of new hemorrhage or infarction or the stroke resulted in death in <24 hours according to the Valve Academic Research Consortium 2 definition. 16troke data were collected from the clinical record.PAD was defined according to the Society of Thoracic Surgeons/American College of Cardiology definition. 17rtic valve calcium scores were collected prospectively from the preprocedural TAVR CT.CT scans were undertaken at a voltage of 120 kV and included noncontrast sequences.Aortic valve calcium score calculation was performed using an inbuilt software program on the Vue PACS system (Philips Inc).Where the prospective calcium score was not available, the aortic valve calcium score was calculated retrospectively.The reporting radiologist was blinded to clinical details including stroke status.The aortic valve calcium was calculated manually from sequential 3-mm axial slices, taking care to exclude extra valvular calcium, such as mitral annular, coronary calcification, and LVOT calcium, according to a methodology previously described. 9The presence or absence of LVOT calcium was separately recorded in a binary fashion.An example of an axial 3-mm aortic valve calcium slice from which the score was calculated is shown in Figure 1.

TAVR procedure
The TAVR procedure was performed in a standard fashion via the transfemoral, transaxillary, transapical, or transcaval routes.Activated clotting time was kept above 250 seconds in all cases with intra-arterial heparin.No cerebral embolic protection devices (CEPDs) were used in this cohort.

Statistics
Data were analyzed using an open-source statistical environment (R studio version 4.0.2).Normally distributed data are presented as mean and standard deviation.Non-normally distributed data are presented as median and interquartile range (IQR).
The relationship among aortic valve calcium score, sex, age, preexisting comorbidities, procedure data, TAVR valve manufacturer, and stroke was assessed using univariate logistic regression models.In the event of multiple significant predictors, these would each be included in a multiple logistic regression model.We took this approach to minimize the number of covariates included in the model given we expected a relatively small number of events.For models with multilevel categorical predictors (device manufacturer), significance was reported using a Wald test across the levels.

Results
All 497 patients who underwent a TAVR procedure at the Hammersmith Hospital between January 2017 and December 2019 were assessed for inclusion in the study.We excluded 32 patients who had CTs in other centers with no appropriate calcium score sequences for analysis.Twenty-three patients who had valve-in-valve procedures and 9 patients who had TAVR valve implantation in the mitral valve position were excluded.This left a final cohort of 433 patients.

Baseline and procedural characteristics
The baseline characteristics of the cohort are shown in Table 1.The median age was 83 years (IQR, 78-87), and there were 228 (52.7%) male patients.One hundred and eight (24.9%) of the cohort were diabetic, 52 (12.0%) had a previous stroke or transient ischemic attack, and 127 (29.3%) had a history of atrial fibrillation (AF) or flutter.Fifty-six (12.9%) patients had a history of PAD, and 33 (7.6%) patients had a history of myocardial infarction.

Stroke data
There were 22 patients who had a stroke prior to discharge from hospital (5.1%).Twenty-one (95.5%) strokes were infarctions; 1 (4.5%) was caused by an aortic dissection.There were no hemorrhagic strokes.Ten (45.5%) of the strokes were multiterritory and embolic in nature.Four (18.2%) were diagnosed in the cardiac catheter laboratory.The median time from end of the TAVR case until stroke diagnosis was 469 minutes (IQR, 127-1768).
Patients who had a stroke had a similar age to patients in the nostroke group (median age of the stroke group was 83.5 years [IQR, 73.3-88.0],and the median age in the non-stroke stroke was 83.0 [IQR, 78-87]).There was a higher proportion of men in the stroke group than in the no-stroke group (14/22, 63.6% in the stroke group; 214/411, 52.1% in the no-stroke group).Among patients who had a stroke, 11 of 22 had an Edwards valve (50.0%), and 11 of 22 cases had a Medtronic valve (50.0%).The procedure time was significantly longer in stroke patients (median procedure time 168 minutes [IQR, 128-211]) than that in nonstroke patients (120 minutes [IQR, 94-154]).

Aortic valve calcium score
The median aortic valve calcium score in the whole cohort was 2145 Agatston units (AU) (IQR, 1427-3247).The median aortic valve calcium score was significantly higher in patients who had stroke (2727 AU [IQR, 1526-3547]) than that in patients who did not have a stroke (2140 AU [IQR, 1426-3189]).The distribution of aortic valve calcium scores in the whole cohort can be seen in Figure 2.

Logistic regression
In a logistic regression model (Table 2), the aortic valve calcium score was independently associated with stroke (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.01-1.53;P ¼ .02).Higher aortic valve calcium scores were associated with higher stroke risk.The logistic regression showing probability of stroke by aortic valve calcium score is shown in Figure 3.The presence or absence of LVOT calcification did not independently predict stroke (P ¼ .68),and the addition of LVOT calcification to the aortic valve calcium model did not incrementally predict stroke There was no difference in stroke across the 3 manufacturers in the study (P ¼ .79).Age (P ¼ .33),sex (P ¼ .29),AF or flutter (P ¼ .82),and diabetes (P ¼ .74)were not significant predictors of stroke.The characteristics of stroke and no-stroke patients are given in Table 3.

Sex-stratified data
Male (52.7%) and female patients were of similar age, had similar rates of diabetes, previous stoke, and AF or flutter (Table 4).Male patients had higher rates of previous myocardial infarction (11.4% in male patients, 6.3% in female patients) and PAD (18.9% of male patients, 7.3% of female patients).The median aortic valve calcium score in male patients was significantly higher (2608 AU [IQR, 1733-3703 AU] vs 1826 [IQR, 1109-2681 AU]) than that in female patients (P .0001).Sex was not significantly associated with stroke (P ¼ .29).

Discussion
In this retrospective, observational cohort study, we have demonstrated (1) a higher aortic valve calcium score, (2) PAD, and (3) longer procedural time are associated with stroke after TAVR.

Aortic valve calcium score
TAVR has led to a paradigm shift in the treatment of patients with aortic stenosis, providing a treatment option for patients when none was previously available and also providing a lower risk alternative to surgery in certain cohorts of patients. 5,18The rapid recovery times and low complication rates mean that it is now challenging conventional surgery in even lower risk patients. 2ortic valve calcium score is associated with more rapid aortic stenosis progression and is also used to help decisions with regard to intervention in patients with equivocal echocardiographic findings. 19Its role as a marker of periprocedural stroke, however, is less clear.Calcification in the LVOT has previously been associated with acute stroke in TAVR patients, but not the overall aortic valve calcium score. 20f all the complications that can occur during cardiac procedures, stroke is the most feared by patients. 21The long-term impact of a stroke is unpredictable and may significantly reduce the patient's quality of life.Results for the logistic regression models.Values are given for each predictor, with stroke as the outcome.CT, computed tomography.Data presented are n (%) or median (interquartile range).CT, computed tomography; TIA, transient ischemic attack.
At present, there is no clear means of determining an individual patient's stroke risk during TAVR.This study suggests that aortic valve calcium score is an independent risk factor for stroke; with higher aortic valve calcium scores predicting a higher risk (Central Illustration).Systematically identifying predictors of stroke will allow more refined discussions with patients with regard to their individual risk of stroke compared to population-based risks that are used to obtain consent from patients in clinical practice.

Aortic valve calcium score and stroke in lower risk populations
Randomized trial data have demonstrated that TAVR may be superior to SAVR in lower risk patients. 2This may lead to an increase in demand for TAVR in this patient cohort.These patients are at low risk due to younger age and lower comorbidity, often expecting to return to a more active lifestyle and live for many years after valve insertion.The relative impact of stroke on their quality of life is therefore arguably greater than that in older and more comorbid higher risk populations, who will have a lower predicted lifespan.
An understanding of the relative risk of stroke following TAVR vs SAVR is therefore paramount when discussing the relative merits of these competing therapies.These relative risks on a population basis may be very different from a patient's individual risk.Recent nonrandomized data have demonstrated a higher rate of stroke with SAVR than with TAVR in patients with previous stroke (8.0% vs 3.7%), with no difference seen in patients without previous stroke (2.1% vs 1.7%). 22A young patient with a high aortic valve calcium score may be at much higher risk of stroke after TAVR than a frail higher risk patient with a low aortic valve calcium score.A stroke in the younger patient may result in many years of dependent living, which could be avoided if predicted and the procedure with the lowest risk of stroke selected.Using predictors of stroke such as aortic valve calcium score will therefore allow us to have a more nuanced understanding of the risk of complication for each patient and help arrive at the most appropriate intervention for the individual patient in clinic.In light of the association of aortic valve calcium score with stroke in a TAVR population, a similar association should be investigated in patients undergoing SAVR to contribute to this discussion.

Aortic valve calcium may help refine the use of embolic protection devices
Identifying that a patient is at higher risk of stroke may also allow physicians to adapt the TAVR procedure to minimize risk.CEPDs have been used as an adjunct to TAVR in an attempt to reduce the incidence of acute stroke.A recent large registry study found a signal suggesting small reduction in stroke risk with CEPD in a propensity-matched analysis. 23owever, a meta-analysis of 16 trials of CEPDs including all comers found no overall reduction in clinically evident stroke or mortality at 30 days. 24The benefit of CEPDs in higher stroke risk patients may have been masked by the inclusion of patients at low risk of stroke.It is therefore plausible that aortic valve calcium score can be used to target the patients in which CEPDs may have the most benefit.A large prospective randomized trial of CEPDs in TAVR patients with a high aortic valve calcium score would address this question.

PAD and procedure times
In our study, acute stroke after TAVR was associated with patients with PAD and longer procedure times.6][27] Longer procedure time may reflect a complication during the procedure such as valve embolization, the need to balloon valvuloplasty before or after valve insertion, or a more difficult procedure in anatomically complex patients with no causal relationship. 6Given that 18.2% of the strokes in this cohort were diagnosed during the procedure, the longer procedure time may also be a consequence of stroke, rather than being predictive of it.

Study limitations
This single-center, retrospective cohort study has demonstrated an association between aortic valve calcium score and stroke.While we have attempted in this study to correct for confounders, such as age and comorbidity, this association may not be causal.The findings of this study would be strengthened by replication in a prospective trial including multiple centers, and this will be the focus of future work.Additionally, as a retrospective study, the criteria used for post-TAVR neuroimaging is not standardized which may have influenced the diagnosis of stroke in the cohort.
This study was designed to detect periprocedural and early stroke, and as such, we curtailed follow-up at the point of discharge.As such, the effect of aortic valve calcium score on later strokes cannot be commented upon.
The majority of aortic valve calcium scores in this cohort were reported in a single center, which could have impacted the reproducibility of these data. 28However, aortic valve calcium score is highly reproducible (the Philips system for Agatston scoring of the aortic valve has an Data presented as n (%) or median (interquartile range).AU, Agatston units; TIA, transient ischemic attack.
Central Illustration.In this cohort of 433 patients, the aortic valve calcium score from the preprocedural cardiac CT was significantly associated with acute stroke after TAVR (P ¼ .02).CT, computed tomography; TAVR, transcatheter aortic valve replacement.
intraobserver variability of 9 AE 42 AU). 29These findings would be strengthened by replication in other centers and multicenter cohorts.

Conclusion
Aortic valve calcium score from pre-TAVR CT is an independent risk factor for stroke in the TAVR population.This is an additional clinical value of the pre-TAVR aortic valve calcium score and should be considered when discussing periprocedural stroke risk.

Declaration of competing interest
Dr Foley and Dr Al-Lamee report a relationship with Menarini International Pharmaceutics that includes speaking and lecture fees.Dr Al-Lamee, Dr Sen, Dr Petraco, and Dr Foley report a relationship with Philips Healthcare that includes speaking and lecture fees.Dr Rana reports a relationship with Occlutech GmbH and Holistick Medical that includes consulting or advisory and speaking and lecture fees.All other authors report no conflicts to disclose.

Figure 1 .
Figure 1.An example 3-mm axial slice from a calcium score sequence of the pre-TAVR CT from a patient in the cohort.CT, computed tomography; TAVR, transcatheter aortic valve replacement.

Figure 3 .
Figure 3. Logistic regression analysis showing the association of CT aortic valve calcium score and probability of stroke.The gray area represents the 95% confidence interval.CT, computed tomography.

Table 1 .
Baseline characteristics.P ¼ .52).PAD was significantly associated with stroke in a regression model (OR, 4.32; 95% CI, 1.65-10.65;P ¼ .0018).When incorporating the independent predictors of aortic valve calcium and PAD into a combined model, they remained significantly associated with stroke Figure 2. The distribution of aortic valve calcium score in the transcatheter aortic valve replacement cohort.The dashed line represents the study median.((aorticvalve calcium P ¼ .032and PAD P ¼ .0023).A longer procedure time was also significantly associated with stroke (OR, 1.01; 95% CI, 1.00-1.02;P ¼ .00057).

Table 3 .
Stroke vs no-stroke patient characteristics.