Original Contribution

Periprocedural Changes in Cognitive Function After Transcatheter and Surgical Aortic Valve Replacement: Results From a Pilot Study Assessing Cognition in Elderly Veterans

Santiago Garcia, MD1;  Laura S. Hemmy, PhD2,3;  Rosemary Kelly, MD3;  Howard A. Fink, MD, MPH2,3

Santiago Garcia, MD1;  Laura S. Hemmy, PhD2,3;  Rosemary Kelly, MD3;  Howard A. Fink, MD, MPH2,3

Abstract: Background. There is paucity of data comparing periprocedural changes in cognitive function between surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). Methods. We enrolled patients with severe aortic stenosis scheduled to undergo TAVR or SAVR at the discretion of the heart team. Participants completed a cognitive battery before and 3 months after TAVR or SAVR, including the Montreal Cognitive Assessment (MoCA), phonemic (letter) verbal fluency, semantic (category) verbal fluency, and the Trail Making test (TMT) A and B. Periprocedural differences in cognition were compared within (pre/post procedure) and between groups using the paired-samples or independent-sample t-test, respectively. The Wilcoxon test was used for non-normally distributed data. Results. Of the 63 patients (95% men) included, a total of 43 underwent TAVR and 20 underwent SAVR. Patients undergoing TAVR were older than SAVR patients (78 ± 8 years vs 70 ± 7 years, respectively; P<.001), but had similar STS surgical risk scores (4.9% vs 4.7%, respectively; P=.79). At baseline, there were no differences in cognition. At 3 months post TAVR or SAVR, there were no significant differences for MoCA blind score (16 ± 3 vs 16 ± 3, respectively; P=.61), correct responses in semantic fluency (15 ± 5 vs 15 ± 6, respectively; P=.93), correct responses in phonemic fluency (30 ± 12 vs 28 ± 15, respectively; P=.87), TMT A completion time (54 sec [IQR, 42-65 sec] vs 31 sec [IQR, 28-69 sec], respectively; P=.07), or TMT B completion time (161 sec [IQR, 118-300 sec] vs 173 sec [IQR, 110-300 sec], respectively; P=.87). Conclusions. In this pilot observational study, we observed no significant differences in cognition at baseline or 3 months between SAVR and TAVR groups. 

J INVASIVE CARDIOL 2019 November 15 (Epub Ahead of Print).

Key words: cognitive function, phonemic fluency, SAVR, semantic fluency, TAVR


Increasingly, invasive cardiovascular procedures are being performed on elderly patients with multiple comorbidities.1-4 Whether these procedures cause or accelerate cognitive impairment, which is highly prevalent in older adults, is relevant for patient decision making and procedural planning. 

Aortic stenosis (AS) is a disease of the elderly characterized by thickening and calcification of the valve leaflets, leading to restrictive opening of the aortic valve, pressure overload, and adaptive left ventricular hypertrophy. Once patients with severe AS develop symptoms, their prognosis is poor; thus, current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend aortic valve replacement (AVR).5 Surgical aortic valve replacement (SAVR) has been the standard operation to replace a diseased aortic valve. Transcatheter aortic valve replacement (TAVR) has emerged as an alternative to SAVR in patients with prohibitive or high surgical risk.3,4 Since its initial approval, procedural indications for TAVR have expanded to intermediate-risk and low-risk patients.6-8 

We recently conducted a review of controlled studies that evaluated cognitive outcomes after cardiac procedures.2 Although many observational and randomized studies after AVR reported stroke rates and/or findings on brain imaging studies,1-4 there is a paucity of data comparing periprocedural cognitive changes between SAVR and TAVR.9-12 The goal of this pilot investigation was to compare periprocedural changes in cognition after SAVR and TAVR using a real-world cohort of patients treated with contemporary techniques. 

Methods

Setting and study patients. The Minneapolis VA Healthcare System (MVAHCS) is a tertiary, 250-bed hospital within the VA Midwest Heath Care Network (Veterans Integrated Service Network VISN 23). The network serves more than 440,000 enrolled veterans residing in the states of Iowa, Minnesota, Nebraska, North Dakota, South Dakota, and portions of Illinois, Kansas, Missouri and Wyoming. The MVAHCS is the only approved VA TAVR program in a nine-state area and has an academic affiliation with the University of Minnesota.  

This study is registered at www.clinicaltrials.gov (identifier NCT02971020). 

Between May 2016 and November 2017, participants were recruited from individuals already scheduled to undergo SAVR or TAVR in the Minneapolis VA Health Care System. The clinical criteria for AVR during the study recruitment period was symptomatic (eg, angina, syncope, dyspnea) severe AS (aortic valve area <1.0 cm2, peak aortic velocity ≥4 m/sec, or mean gradient ≥40 mm Hg). The decision to undergo SAVR or TAVR was left to the discretion of the heart team, a multidisciplinary team comprising interventional cardiologists, cardiothoracic surgeons, anesthesia, and non-invasive cardiologists. Factors taken into consideration included Society for Thoracic Surgeons (STS) score, frailty assessment, need for concomitant bypass surgery (ie, coronary artery bypass grafting, double valve), etiology of AS (bicuspid), and suitability for transfemoral access and aortic cross-clamp. 

Cognitive testing. Study participants completed a 30-minute cognitive battery the day before their scheduled AVR procedure and again approximately 3 months later. Participants were offered two options — in-person cognitive testing comprised of the Montreal Cognitive Assessment (MoCA), the Trail Making test (TMT) A and B, and verbal fluency (phonemic/letter and semantic/category), or telephone cognitive testing comprised of the MoCA “Blind,” Digit Span (Forward and Backward), and verbal fluency (phonemic and semantic). Telephone cognitive testing was offered to increase participation in the study and decrease the number of patients with incomplete follow-up data.

Verbal fluency assessment provides clinical information about executive and linguistic function. Semantic fluency evaluates the ability to generate words that fit into a semantic category (animals), whereas phonemic fluency evaluates the capacity to generate words that begin with a particular letter.13 The MoCA-Blind briefly assesses multiple cognitive domains: attention and concentration, memory, language, conceptual thinking, calculations, and orientation. It contains the same items as the original MoCA except those requiring visual abilities.14,15 The total possible score is 22 points; a score of 18 or above is considered normal.14 Both parts of the TMT consist of 25 numbered circles distributed over a sheet of paper. In Part A, attention is evaluated by asking the patient to draw lines connecting the numbers in ascending order. In Part B, executive functions are evaluated by again asking the patient to draw lines connecting circles in an ascending pattern, but with the added task of alternating between numbers and letters (ie, 1-A-2-B-3-C, etc).16,17 The Digit Span task evaluated attention and executive functions in patients completing cognitive testing by telephone.18 In the Digit Span Forward, patients are presented series of digits of increasing length and asked to repeat each series back immediately after. In the Backward condition, patients are asked to repeat the digit series back in reverse order. Cognitive testing was performed by a trained research nurse.

Statistical analysis. Continuous variables are presented as mean ± standard deviation or as median with interquartile range (IQR). Categorical variables are reported as frequencies and percentages. Discrete variables were compared with the Chi-square test or Fisher’s exact test as appropriate. We compared cognitive outcomes between groups at baseline and at 3 months using an independent-sample t-test or Mann-Whitney U-test depending on the distribution of the data. To compare within-group cognitive outcomes, we used the paired-samples t-test or Wilcoxon test depending on the distribution of the data. For skewed data, we report median (IQR); for normally distributed data, we report mean with 95% confidence interval (CI). A 2-sided P-value <.05 was considered to be statistically significant. This is a pilot study with no formal sample-size calculation. Medcalc, version 17.2 statistical software was used.

Results

From May 2016 to November 2017, a total of 63 patients were included in this pilot study; of these, 43 underwent TAVR and 20 underwent SAVR. The mean age of the population was 76 ± 9 years and 95% were men. The mean STS score was 4.9 ± 3%, consistent with an intermediate-risk population. Relative to patients undergoing SAVR, patients undergoing TAVR were older (78 ± 8 years vs 70 ± 7 years; P<.001) and had a higher prevalence of prior myocardial infarction (34% vs 10%; P=.05), prior coronary artery bypass graft surgery (20% vs 0%; P=.03), and chronic obstructive pulmonary disease (40% vs 21%; P=.05), but similar STS scores (4.9% vs 4.7%; P=.79). Other baseline characteristics are presented in Table 1. 

Cognitive evaluation. Prior to AVR, cognitive testing occurred in person (n = 52; 82%) and by phone (n = 11; 17.5%). Post AVR, cognitive testing occurred in person (n = 34; 54%) and by phone (n = 13; 20%), while 16 patients (25%) declined follow-up cognitive testing. 

Of the 43 patients undergoing TAVR, a total of 34 (79%) had their baseline cognitive testing performed in person while 9 (21%) had it by phone. At 3 months, a total of 24 patients (55%) had cognitive testing in person, while 8 patients (18%) had it by phone and 11 patients (25%) were lost to follow-up.

Of the 20 patients undergoing SAVR, a total of 18 patients (90%) had their baseline cognitive testing performed in person and 2 (10%) had it by phone. At 3 months, a total of 10 patients (50%) had cognitive testing in person, 5 patients (25%) had it by phone, and 5 patients (25%) were lost to follow-up. 

Baseline cognitive assessment. Results of baseline cognitive testing for TAVR and SAVR patients are presented in Table 2 and Figure 1. The MoCA-Blind score was 16 ± 2 for the TAVR group and 16 ± 3 for the SAVR group (P=.28). No difference was observed between the TAVR group and the SAVR group in the number of correct responses in the semantic fluency assessment (16 ± 4 vs 17 ± 7, respectively; P=.37) or in the phonemic fluency assessment (31 ± 13 vs 27 ± 13, respectively; P=.27). Similarly, no differences were observed in the time to complete the TMT A (52 sec [IQR, 36-67 sec] vs 41 sec [IQR, 32-56 sec], respectively; P=.08) or TMT B (198 sec [IQR, 107-300 sec] vs 120 sec [IQR, 85-200 sec], respectively; P=.13). 

Cognitive assessment after AVR. Results of 3-month cognitive testing for TAVR and SAVR patients are presented in Table 2 and Figure 2. At 3 months post AVR, there were no significant differences between the TAVR and SAVR groups for MoCA-Blind score (16 ± 3 vs 16 ± 3, respectively; P=.61), correct responses in semantic fluency (15 ± 5 vs 15 ± 6, respectively; P=.93), correct responses in phonemic fluency (30 ± 12 vs 28 ±15, respectively; P=.87), TMT A completion time (54 sec [IQR, 42-65 sec] vs 31 sec [IQR, 28-69 sec]; P=.07), or TMT B completion time (161 sec [IQR, 118-300 sec] vs 173 sec [IQR, 110-300 sec]; P=.87). 

There was no significant difference after TAVR or after SAVR between cognition at baseline and 3-month follow-up (Table 3). 

Discussion

In this pilot study, we assessed periprocedural changes in cognition after AVR in a real-world cohort of elderly veterans at intermediate surgical risk. We employed a battery of tests aimed at assessing several cognitive domains and found no significant differences in cognitive function at baseline or 3 months after TAVR or SAVR. Our results could be used to inform the consent process and may provide estimates of baseline cognitive function that can aid in the design of future comparative trials. 

Comparative studies of TAVR and SAVR are scant, and when present have severe methodological limitations.1,2,11 One such study compared the outcomes (Mini-Mental State Examination or TMT A) of 60 older adults 4 months after transapical TAVR or SAVR19 and found that neuropsychological test-defined incident cognitive impairment was lower after SAVR (6%) than TAVR (28%; P=.04). However, patients in the SAVR group were significantly younger (mean age, 68 years vs 82 years in the TAVR group) and were better operative candidates than the TAVR group.19 Ghanem et al evaluated cognitive trajectories up to 2 years post TAVR in 111 patients. Despite the high burden of comorbidities at baseline, they found that 91% of patients had preserved long-term cognitive function.9 Similarly, Lai et al conducted a meta-analysis of 6 studies including 349 patients and found that cognitive function remained unchanged up to 2 years after TAVR.12 Taken together, these observations suggest that baseline rather than procedural characteristics account for the differences in cognitive outcomes.

Lazar et al showed that 27% of patients undergoing TAVR as part of a clinical trial had cognitive dysfunction at baseline, which is 4 times the expected proportion in the normative population.10 Using brain magnetic resonance imaging with T2 fluid-attenuated inversion recovery (FLAIR) sequence, the authors found an inverse relationship between brain lesion volume and baseline cognition. Therefore, assessing the preprocedure health status of the brain is critically important when interpreting periprocedural cognitive outcomes. The findings of this pilot study suggest that persistent cognitive impairment after SAVR or TAVR may be uncommon or reflect pre-existing cognitive impairment. 

In the United States, approximately 50,000 cardiac valve repair or replacement procedures are performed annually in adults ≥65 years old.20,21 The older U.S. population has a combined incidence of cognitive impairment/dementia of 77.5 cases/1000 person years in adults ≥72 years old.22 Therefore, understanding the potential detrimental effects of cardiac procedures in older adults with valvular heart disease is clinically relevant. 

Surgical AVR can have negative effects on cognitive function through multiple mechanisms, including anesthesia, cardiopulmonary bypass, hypothermia, and perioperative stroke.23 Although less invasive than SAVR, the TAVR option also has the potential to cause or accelerate cognitive decline. Rapid pacing, with its ensuing hypotension, and embolization of debris from the native aortic valve are common during valve deployment.24 

As the indications of TAVR expand to lower-risk patients with longer life expectancy, understanding the long-term cognitive effects of these procedures should be an important goal of future research. The role of neuroprotection — with devices designed to prevent embolization of debris to the brain — also remains an area of active research. At the moment, the effect of neuroprotection on cognitive outcomes is uncertain.25 

Study limitations. This study has several important limitations. First, the study was conducted at a single center, which limits the generalizability of the results. Second, patients were not randomly assigned to TAVR or SAVR, which could have biased our results. Third, the sample size is small in statistical terms. Fourth, the study subjects are predominantly male. Caution is advised when extrapolating to women. Finally, the study had a short follow-up time and limited postprocedural testing. A longer-term study with repetitive testing might have been able to define cognitive trajectories. 

Conclusion

We conducted a pilot study assessing multiple cognitive domains in patients with severe AS and intermediate surgical risk. We found no difference between cognition at baseline and 3 months in SAVR or TAVR groups. 

References

1. Oldham MA, Vachon J, Yuh D, Lee HB. Cognitive outcomes after heart valve surgery: a systematic review and meta-analysis. J Am Geriatr Soc. 2018;66:2327-2334. 

2. Fink HA, Hemmy LS, MacDonald R, et al. Intermediate- and long-term cognitive outcomes after cardiovascular procedures in older adults: a systematic review. Ann Intern Med. 2015;163:107-117.

3. Leon MB, Smith CR, Mack M, et al; the PARTNER Trial Investigators. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med. 2010;363:1597-1607. Epub 2010 Sep 22.

4. Smith CR, Leon MB, Mack MJ, et al; the PARTNER Trial Investigators. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med. 2011;364:2187-2198.

5. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2008;118:e523-e661.

6. Leon MB, Smith CR, Mack MJ, et al; PARTNER 2 Investigators. Transcatheter or surgical aortic-valve replacement in intermediate-risk patients. N Engl J Med. 2016;374:1609-1620. Epub 2016 Apr 2.

7. Thourani VH, Kodali S, Makkar RR, et al. Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis. Lancet. 2016;387:2218-2225. Epub 2016 Apr 3.

8. Mack MJ, Leon MB, Thourani VH, et al; PARTNER 3 Investigators. Transcatheter aortic-valve replacement with a balloon-expandable valve in low-risk patients. N Engl J Med. 2019;380:1695-1705. Epub 2019 Mar 16.

9. Ghanem A, Kocurek J, Sinning JM, et al. Cognitive trajectory after transcatheter aortic valve implantation. Circ Cardiovasc Interv. 2013;6:615-624.

10. Lazar RM, Pavol MA, Bormann T, et al. Neurocognition and cerebral lesion burden in high-risk patients before undergoing transcatheter aortic valve replacement: insights from the SENTINEL trial. JACC Cardiovasc Interv. 2018;11:384-392.

11. Khan MM, Herrmann N, Gallagher D, et al. Cognitive outcomes after transcatheter aortic valve implantation: a meta-analysis. J Am Geriatr Soc. 2018;66:254-262.

12. Lai KS, Herrmann N, Saleem M, Lanctot KL. Cognitive outcomes following transcatheter aortic valve implantation: a systematic review. Cardiovasc Psychiatry Neurol. 2015;2015:209569.

13. Tombaugh TN, Kozak J, Rees L. Normative data stratified by age and education for two measures of verbal fluency: FAS and animal naming. Arch Clin Neuropsychol. 1999;14:167-177.

14. Wittich W, Phillips N, Nasreddine ZS, Chertkow H. Sensitivity and specificity of the Montreal Cognitive Assessment Modified for Individuals Who Are Visually Impaired. JVIB. 2010;104:360-368.

15. Nasreddine ZS, Phillips NA, Bedirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005;53:695-699.

16. Loonstra AS, Tarlow AR, Sellers AH. COWAT metanorms across age, education, and gender. Appl Neuropsychol. 2001;8:161-166.

17. Salthouse TA. What cognitive abilities are involved in trail-making performance? Intelligence. 2011;39:222-232.

18. Wechsler D. WAIS-R Manual. 1981. New York, NY: Harcourt Brace Jovanovich [for] Psychological Corp.

19. Knipp SC, Kahlert P, Jokisch D, et al. Cognitive function after transapical aortic valve implantation: a single-centre study with 3-month follow-up. Interact Cardiovasc Thorac Surg. 2013;16:116-122.

20. Roger VL, Go AS, Lloyd-Jones DM, et al. American Heart Association statistics C and stroke statistics S. Heart disease and stroke statistics — 2012 update: a report from the American Heart Association. Circulation. 2012;125:e2-e220.

21. Go AS, Mozaffarian D, Roger VL, et al, American Heart Association statistics C and stroke statistics S. Heart disease and stroke statistics — 2014 update: a report from the American Heart Association. Circulation. 2014;129:e28-e292.

22. Plassman BL, Langa KM, McCammon RJ, et al. Incidence of dementia and cognitive impairment, not dementia in the United States. Ann Neurol. 2011;70:418-426.

23. Selnes OA, Gottesman RF, Grega MA, Baumgartner WA, Zeger SL, McKhann GM. Cognitive and neurologic outcomes after coronary-artery bypass surgery. N Engl J Med. 2012;366:250-257.

24. Kahlert P, Al-Rashid F, Dottger P, et al. Cerebral embolization during transcatheter aortic valve implantation: a transcranial Doppler study. Circulation. 2012;126:1245-1255.

25. Kapadia SR, Kodali S, Makkar R, et al; SENTINEL Trial Investigators. Protection against cerebral embolism during transcatheter aortic valve replacement. J Am Coll Cardiol. 2017;69:367-377. Epub 2016 Nov 1.


From 1Minneapolis Heart Institute at Abbott Northwestern Hospital, Minneapolis, Minnesota; 2Geriatric Research Education and Clinical Center, Minneapolis VA Healthcare System, Minneapolis, Minnesota; and 3University of Minnesota Medical School, Minneapolis, Minnesota.

Clinicaltrials.gov identifier: NCT02971020

Funding: This study was supported by the Minnesota Veterans Research Foundation. 

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Garcia reports grant support from Boston Scientific; consultant income from Edwards Lifesciences, Medtronic, and Abbott Vascular. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted June 27, 2019, provisional acceptance given July 1, 2019, final version accepted July 5, 2019.

Address for correspondence: Santiago Garcia, MD, Minneapolis Heart Institute, 920 East 28th Street, Suite 300, Minneapolis, MN 55407. Email: garci205@umn.edu

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