Association of Timing of Aortic Valve Replacement Surgery After Stroke with Risk of Recurrent Stroke and Mortality

Research

JAMA Cardiology | Original Investigation Association of Timing of Aortic Valve Replacement Surgery After Stroke With Risk of Recurrent Stroke and Mortality

Charlotte Andreasen, MD; Mads Emil Jørgensen, MD; Gunnar H. Gislason, MD, PhD; Andreas Martinsson, MD; Robert D. Sanders, MD; Jawdat Abdulla, MD, PhD; Per Føge Jensen, MD, PhD; Christian Torp-Pedersen, MD, DSc; Lars Køber, MD, DSc; Charlotte Andersson, MD, PhD

Invited Commentary page 514

IMPORTANCE Timing of surgical aortic valve replacement (SAVR) in patients with aortic valve Supplemental content stenosis and previous stroke for the risk of recurrent stroke is insufficiently investigated.

OBJECTIVE To evaluate the association of time elapsed between previous stroke and SAVR with the risk of recurrent perioperative stroke, major adverse cardiovascular events (MACE), and mortality among patients with aortic valve stenosis.

DESIGN, SETTING, AND PARTICIPANTS This cohort study using data from Danish administrative registries included all patients with aortic valve stenosis older than 18 years who underwent SAVR between 1996 and 2014 (n = 14 030). Patients who received simultaneous mitral, tricuspid, or pulmonary valve surgery and patients with endocarditis 1 year prior to surgery were excluded. Data were analyzed from March 2017 to January 2018.

EXPOSURES Time elapsed between prior stroke and SAVR (<3 months, 3-<12 months, Ն12 months, and no prior stroke).

MAIN OUTCOMES AND MEASURES Thirty-day risks of MACE, ischemic stroke, and all-cause mortality reported as absolute events and multivariable adjusted odds ratios with 95% confidence intervals. Restricted cubic spline regression models were additionally applied on the subgroup with prior stroke.

RESULTS Of the 14 030 included patients, 616 patients (190 [30.8%] women; mean [SD] age, 72.0 [9.1] years) with prior stroke underwent surgery, and 13 414 (4837 [36.1%] women; mean [SD] age, 69.8 [10.8] years) without prior stroke underwent surgery. The absolute risk of ischemic stroke was significantly increased in patients with stroke less than 3 months prior to surgery compared with patients with no prior stroke (18.4% [37 of 201] vs 1.2% [160 of 13 219]; odds ratio, 14.69; 95% CI, 9.69-22.27). Likewise, compared with patients without stroke, patients with stroke less than 3 months prior surgery were at significantly increased risk of MACE (23.3% [53 of 227] vs 5.7% [768 of 13 414]; odds ratio, 4.57; 95% CI, 3.24-6.44) but not all-cause mortality (6.8% [50 of 730] vs 3.6% [374 of 10 370]; odds ratio, 1.45; 95% CI, 0.83-2.54). Spline analyses supported a declining risk over time, reaching nadir after 2 to 4 months.

CONCLUSIONS AND RELEVANCE Previous stroke is a major risk factor of recurrent ischemic stroke and MACE in patients undergoing SAVR, especially if time elapsed between previous stroke and surgery is less than 3 months.

Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Charlotte Andreasen, MD, Department of Cardiology, Copenhagen University Hospital Herlev and Gentofte, Kildegaardsvej 28, 2900 Hellerup, JAMA Cardiol. 2018;3(6):506-513. doi:10.1001/jamacardio.2018.0899 Denmark (andreasencharlotte7 Published online April 25, 2018. @gmail.com).

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rogression of aortic valve stenosis is medically unpre- ventable. Likewise, the mortality rate among severely Key Points symptomatic patients is markedly increased unless P Question Is there a time-dependent association of previous aortic valve replacement is performed. Ischemic stroke is a stroke and surgical aortic valve replacement with the risk of feared complication of surgical aortic valve replacement adverse outcomes among patients with aortic valve stenosis? (SAVR),1-3 and prior stroke is a well-established risk factor of Findings This cohort study using Danish administrative registry periprocedural stroke.4-6 For noncardiac surgery, the risk of re- data included 14 030 surgical aortic valve replacements. Patients 7 current stroke was shown in 2014 to be time dependent and with prior stroke had 14.7-, 4.0-, and 2.3-fold higher risk of appears to be particularly pronounced if time between stroke recurrent stroke compared with patients without prior stroke if and surgery is less than 9 months. Cerebral autoregulation is surgery was performed within 3 months, 3 to less than 12 months, impaired immediately after a stroke, making penumbral tis- and 12 months or more, respectively, after the incident stroke. sue vulnerable to alterations in blood pressure. Thus, peri- Meaning Surgical aortic valve replacement within the first 3 operative manipulation of blood pressure and interruption of months after a stroke may be associated with a particularly antithrombotic medication may pose a particular risk in pa- pronounced risk of recurrent ischemic stroke. tients with a recent stroke.8,9 As the prevalence of aortic valve stenosis increases with age10-12 and predictions forecast a sub- stantial increase in the proportion of elderly individuals (older ber 2014. Aortic valve stenosis was defined as a discharge di- than 65 years) in the Western world by 2080,13,14 the socio- agnosis any time prior surgery. Coding details for all diagno- economic burden of aortic valve stenosis and SAVR are ex- ses and procedures are available in eTable 1 in the Supplement. pected to grow notably. Recurrent stroke is associated with Surgical aortic valve replacement was identified using KFM more severe functional disability, greater financial burden, and codes (Nordic Medico-Statistical Committee Classification of increased mortality compared with an incident stroke.15,16 Con- Surgical Procedures). Patients who received simultaneous mi- sequently, it is of particular relevance to investigate the asso- tral, tricuspid, or pulmonary valve surgery were excluded. ciation of time elapsed between previous stroke and SAVR with Patients with an endocarditis diagnosis within 1 year prior to the risk of adverse outcomes in patients with aortic valve surgery were also excluded because endocarditis is associ- stenosis. ated with increased risk of stroke 5 to 6 months after initia- tion of antibiotic therapy.19 However, we chose a more con- servative cutoff value of 1 year prior to surgery to ensure Methods exclusion of any strokes caused by endocarditis. Ischemic stroke was identified using both ICD-8 and ICD-10 Every individual living in Denmark receives a personal iden- diagnostic codes. Ischemic stroke (ICD code I63) has been vali- tification number either at birth or immigration, permitting dated to have a positive predictive value between 88% and cross-linkage of several health care–related registries at an in- 97%. Most strokes classified as unspecified strokes (ICD code dividual level. Data were collected from 5 nationwide Danish I64) have been shown to be of ischemic origin (positive pre- registries. Register-based studies in which individuals can- dictive value between 72% and 80%).20,21 The stroke diagno- not be identified do not require ethical approval in Denmark, sis was considered outdated if more than 5 years had passed and informed consent was not needed because deidentified, between stroke and surgery.7 Validation of the ICD-10 diag- administrative databases were used. nostic coding system in the Danish National Patient Registry The Central Population Registry contains information on sex, has been performed for several cardiovascular conditions, in- date of birth, and vital status. The Danish National Patient Reg- cluding aortic valve stenosis, myocardial infarction, conges- istry contains information on all in-hospital admissions since tive heart failure, peripheral artery disease, and cerebrovas- 1977; diagnoses are coded according to the International Classi- cular disease, with positive predictive values between 82% and fication of Disease, Eight Revision (ICD-8) until 1993 and the In- 100%.17,22,23 ternational Statistical Classification of Diseases and Related Health Comorbidities were identified using both ICD-8 and ICD-10 Problems, Tenth Revision (ICD-10) from 1994 onwards.17 The Dan- codes for acute myocardial infarction, ischemic heart dis- ish National Prescription Registry contains information on all disease, chronic heart failure, atrial fibrillation, peripheral ar- pensed medical prescriptions since 1995, and prescribed drugs tery disease (composite of atherosclerosis in the peripheral have been registered by the Anatomical Therapeutic Chemical arteries or aorta, arterial embolism or thrombosis, or other Classification System. Cause of death was obtained from the Dan- peripheral vascular disease), carotid stenosis, chronic obstruc- ish Causes of Death Registry (since 1970), which contains infor- tive pulmonary disease, cancer, renal disease, rheumatic dis- mation on primary and contributing causes of death. The Dan- ease, and liver disease. Diabetes was defined as at least 1 ish Heart Registry contains information on European System for claimed prescription of glucose-lowering drugs.7 Use of car- Cardiac Operative Risk Evaluation (EuroSCORE), which is a com- diovascular medication within 120 days prior surgery was ob- monly used risk stratification score for prediction of 30-day tained using Anatomical Therapeutic Chemical codes (eTable mortality,18 body mass index, smoking status, and surgery pri- 1intheSupplement). ority for cardiac surgeries since 2003. We divided our study population into 4 groups: individu- We included patients with aortic valve stenosis older than als with no prior stroke, those with stroke less than 3 months 18 years who underwent SAVR from January 1996 to Decem- prior to surgery, those with stroke within 3 to less than 12

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Table 1. Baseline Characteristics for the Study Population

Prior Stroke, No. (%) None <3 mo 3-<12 mo ≥12 mo Characteristic (n = 13 414) (n = 227) (n = 106) (n = 283) Age, mean (SD), y 69.8 (10.8) 71.7 (9.1) 71.8 (9.0) 72.3 (9.3) Male 8577 (63.9) 157 (69.2) 74 (69.8) 195 (68.9) Valve replacement Mechanic 4181 (31.2) 50 (22.0) 25 (23.6) 53 (18.7) Biologic 9233 (68.8) 177 (78.0) 81 (76.4) 230 (81.3) Concomitant CABG 4738 (35.3) 97 (42.7) 48 (45.3) 116 (41.0) Comorbidity Diabetes 1697 (12.7) 33 (14.5) 15 (14.2) 59 (20.8) Chronic heart failure 2558 (19.1) 55 (24.2) 21 (19.8) 68 (24.0) Atrial fibrillation 2900 (21.6) 73 (32.2) 31 (29.2) 88 (31.1) Ischemic heart disease 6498 (48.4) 146 (64.3) 56 (52.8) 174 (61.5) COPD 1049 (7.8) 33 (14.5) 5 (4.7) 33 (11.7) Acute myocardial infarction 1860 (13.9) 42 (18.5) 11 (10.4) 54 (19.1) Peripheral artery diseasea 480 (3.6) 29 (12.8) 8 (7.5) 20 (7.1) Atherosclerosis of aortab 77 (0.6) NAc NAc 4 (1.4) Carotid stenosis 195 (1.5) 26 (11.5) 9 (8.5) 27 (9.5) Renal disease 650 (4.8) 25 (11.0) 7 (6.6) 16 (5.7) Medication Statin 5951 (44.4) 144 (63.4) 57 (53.8) 186 (65.7) Abbreviations: ASA, acetylsalicylic Dipyridamol 331 (2.5) 58 (25.6) 41 (38.7) 118 (41.7) acid; CABG, coronary artery bypass ASA 6194 (46.2) 129 (56.8) 60 (56.6) 173 (61.1) grafting; COPD, chronic obstructive Clopidogrel 651 (4.8) 39 (17.2) 27 (25.5) 42 (14.8) pulmonary disease; NA, not available. a Vitamin K antagonist 1599 (11.9) 39 (17.2) 21 (19.8) 57 (20.1) Defined as a diagnosis of atherosclerosis (including Loop diuretics 4075 (30.4) 81 (35.7) 25 (23.6) 96 (33.9) atherosclerosis of aorta), arterial Renin-angiotensin system inhibitors 4598 (34.3) 96 (42.3) 43 (40.6) 120 (42.4) embolism or thrombosis, or other Aldosterone antagonist 791 (5.9) 12 (5.3) 4 (3.8) 22 (7.8) peripheral artery disease. All main analyses are adjusted for the Thiazide diuretics 2340 (17.4) 40 (17.6) 26 (24.5) 44 (15.5) composite variable. Calcium channel blockers 3454 (25.7) 70 (30.8) 34 (32.1) 94 (33.2) b Atherosclerosis of aorta is included β-Blockers 5073 (37.8) 89 (39.2) 35 (33.0) 107 (37.8) in the definition of peripheral artery disease. Digoxin 1242 (9.3) 23 (10.1) 13 (12.3) 29 (10.2) c Data are not provided for categories Insulin 557 (4.2) 13 (5.7) NAc 23 (8.1) with 3 or fewer patients.

months prior to surgery, and those with stroke 12 months or the study period was included. Using patients with no prior more prior to surgery. Subanalyses were performed for pa- stroke as a reference, we estimated ORs with 95% CIs by mul- tients with and without atrial fibrillation (preoperative atrial tivariable logistic regression models adjusted for the follow- fibrillation), with and without carotid stenosis at baseline, with ing variables: age, sex, concomitant coronary artery bypass available EuroSCORE only, and undergoing transcatheter grafting (CABG) surgery, renal disease, chronic obstructive lung aortic valve implantation (TAVI), identified using KFM codes. disease, diabetes, previous myocardial infarction, peripheral artery disease, atrial fibrillation, chronic heart failure, calen- Outcomes dar year, and preoperative antithrombotic therapy (eg, aspi- We investigated the 30-day risks of major adverse cardiovas- rin, clopidogrel, dipyridamole, and vitamin K antagonists). Be- cular events (MACE; composite of nonfatal myocardial infarc- cause of insufficient power, sensitivity analyses were adjusted tion, nonfatal ischemic stroke, or death from cardiovascular for fewer variables, as specified in the Results section. The pro- causes [ICD codes I00-I99]), ischemic stroke (ICD codes I63 and portions of variance in outcomes explained by the logistic re- I64), and all-cause mortality. Secondary outcomes included gression models were computed using Tjur R-squared24 and nonfatal myocardial infarction and death from cardiovascu- are presented in eTable 2 in the Supplement. lar causes. Tests for interactions were chosen a priori based on clinical relevance and included atrial fibrillation, concomitant CABG Statistical Analysis surgery, preoperative antithrombotic therapy, age, and sex. Baseline characteristics, crude event rates, and adjusted odds Time between stroke and surgery was evaluated by restricted ratios (ORs) were reported for each of the 4 a priori selected cubic spline regression models to determine continuous stroke groups. Only the first surgery for each individual over changes in risk over time among the subgroup with prior

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Figure 1. Crude Events and Adjusted Odds Ratios (ORs) for 30-Day Major Adverse Cardiovascular Events (MACE), Ischemic Stroke, and All-Cause Mortality Stratified in 4 Groups

No. of No. of OR Outcome Events Patients (%) (95% CI) 30-d MACE No prior stroke 768 13 414 (5.7) 1 [Reference] Prior stroke at any time 97 616 (15.7) 2.75 (2.12-3.58) Stroke <3 mo prior 53 227 (23.3) 4.57 (3.24-6.44) Stroke 3-<12 mo prior 15 106 (14.2) 2.51 (1.40-4.50) Stroke ≥12 mo prior 29 283 (10.2) 1.58 (1.03-2.41) 30-d Ischemic stroke No prior stroke 164 13 414 (1.2) 1 [Reference] Prior stroke at any time 57 616 (9.3) 6.96 (4.77-10.16) Stroke <3 mo prior 40 227 (17.6) 14.69 (9.69-22.27) Stroke 3-<12 mo prior 6 106 (5.7) 3.96 (1.63-9.59) Major adverse cardiac events include Stroke ≥12 mo prior 11 283 (3.9) 2.29 (1.16-4.51) acute myocardial infarction, ischemic 30-d All-cause mortality stroke, or cardiovascular death. Odds No prior stroke 522 13 414 (3.9) 1 [Reference] ratios adjusted for age, sex, Prior stroke at any time 37 616 (6.0) 1.39 (0.95-2.02) concomitant coronary artery bypass grafting surgery, ischemic heart Stroke <3 mo prior 15 227 (6.6) 1.45 (0.83-2.54) disease, chronic heart failure, prior Stroke 3-<12 mo prior 8 106 (7.5) 1.94 (0.91-4.16) acute myocardial infarction, atrial Stroke ≥12 mo prior 14 283 (4.9) 1.16 (0.65-2.07) fibrillation, peripheral artery disease, renal disease, chronic obstructive 0.1 1.0 10 30 pulmonary disease, diabetes, OR (95% CI) antithrombotic therapy, and calendar year.

stroke.25 Five knots were placed at the p5, p25, p50, p75, and (768 of 13 414) in patients without prior stroke compared with p95 percentiles. The median value was used as reference. 23.3% (53 of 227) in patients with stroke less than 3 months All analyses were performed using SAS version 9.4 (SAS prior to surgery. In adjusted analyses, stroke less than 3 months Institute), and RStudio version 1.1.383 (RStudio Inc) was used prior to surgery remained associated with markedly infor illustrations. Two-sided P values less than .05 were con- creased risk of MACE (OR, 4.57; 95% CI, 3.24-6.44) and sidered statistically significant for all tests. ischemic stroke (OR, 14.69; 95% CI, 9.69-22.27) compared with patients with no prior stroke. All-cause mortality did not differ significantly between the groups after adjustment for Results various confounders (Figure 1). Risk estimates of the secondary outcomes, ie, periopera- We identified 14 030 patients who underwent SAVR for the first tive myocardial infarction and cardiovascular death, are avail- time during the study period (eFigure in the Supplement). Of able in eTable 3 in the Supplement.Eventrateswerelowfor these, 616 patients (190 [30.8%] women; mean [SD] age, 72.0 these outcomes, and adjusted analyses did not show any dif- [9.1] years) with prior stroke underwent surgery, and 13 414 pa- ferences in risk between the groups. tients (4837 [36.1%] women; mean [SD] age, 69.8 [10.8] years) The association of MACE, recurrent stroke, and all-cause without prior stroke underwent surgery. Baseline character- mortality with time since prior stroke and surgery among the istics for the study population stratified by stroke history and subgroup with prior stroke is illustrated in Figure 2 (splines). time from stroke to surgery are presented in Table 1. For all outcomes, the ORs declined with time and appeared Most patients in each stroke group were men (range, 63.9%- stable after approximately 2 to 4 months. 69.8%) and received bioprosthetic valves (range, 68.8%- 81.3%). Concomitant CABG surgery was performed in 35.3% Interaction Analyses to 45.3% of patients in the stroke groups. Patients with prior Stroke any time prior to surgery was associated with a higher stroke had a higher prevalence of preoperative atrial fibrilla- risk of 30-day MACE among patients with atrial fibrillation (OR, tion, ischemic heart disease, peripheral artery disease, and ca- 5.26; 95% CI, 3.49-7.92) compared with patients without atrial rotid stenosis and more commonly used antithrombotic medi- fibrillation (OR, 1.81; 95% CI, 1.27-2.59) (P < .001). Prior stroke cation, statins, and renin-angiotensin system inhibitors was also associated with a higher risk of 30-day MACE in pa- compared with patients with no prior stroke. Furthermore, dia- tients younger than 75 years (OR, 3.19; 95% CI, 2.24-4.54) com- betes and insulin treatment was more common in patients with pared with patients older than 75 years (OR, 2.22; 95% CI, 1.48- stroke 12 months or more prior to surgery compared with pa- 3.32) (P = .03). No statistically significant difference was found tients without stroke. in the association between prior stroke and our outcomes for Sample sizes, crude events, and adjusted ORs for 30-day the remaining variables (including similar risks observed for risks of MACE, ischemic stroke, and all-cause mortality are pre- patients with and without concomitant CABG) (eTable 4 in the sented in Figure 1. The absolute percentage of MACE was 5.7% Supplement).

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10 938 patients without known preoperative atrial fibrilla- Figure 2. Association of Major Adverse Cardiovascular Events (MACE), Recurrent Stroke, and All-Cause Mortality With Time Since Prior Stroke tion, 1025 patients (9.4%) developed postoperative atrial Among Patients With Prior Stroke fibrillation (defined as a diagnosis of atrial fibrillation within 30 days after surgery) and were equally distributed among A 30-d MACE the groups (eTable 5 in the Supplement). Crude events, 10 sample size, and adjusted ORs (adjusted for age, sex, and antithrombotic therapy) for patients with and without preoperative atrial fibrillation are presented in eTables 6 and 7, respectively, in the Supplement. We identified 257 patients with and 13 773 patients without preoperative carotid stenosis (eTables 8 and 9 in the Supplement). For patients without known preoperative ca- Odds Ratio rotid stenosis and stroke less than 3 months prior to surgery,

1 the absolute rate of recurrent ischemic stroke was 18.4% (37 of 201) compared with 1.2% (160 of 13 219) in patients with no stroke (eTable 9 in the Supplement).

0 2 4 6 9 12 18 24 36 48 60 In the Danish Heart Registry, information on EuroSCORE Time From Stroke to Surgery, mo was available for 11 100 patients who underwent nonacute SAVR. Mean EuroSCORE did not differ markedly among the 4 B 30-d Stroke groups (eTable 10 in the Supplement), and most patients were 10 at intermediate risk of 30-day mortality. The absolute rate of ischemic stroke for patients with stroke less than 3 months prior to surgery was 14.8% (48 of 325) compared with 1.2% (121 of 10 370) for patients with no prior stroke. Full results (crude events and total sample size as well as adjusted ORs for sex, age, and EuroSCORE) stratified by the 4 stroke groups for 30- day risks of MACE, ischemic stroke, and all-cause mortality are Odds Ratio shown in Table 2. Additional adjustment for body mass index

1 and smoking status yielded similar results (eTable 11 in the Supplement). A total of 1508 patients with aortic valve stenosis under-

0 2 4 6 9 12 18 24 36 48 60 went TAVI surgery. Prior stroke was identified in 132 patients. Time From Stroke to Surgery, mo Crude events and sample size as well as adjusted ORs for sex and age of 30-day MACE, ischemic stroke, and all-cause mor- C 30-d All-cause mortality tality are available in eTable 12 in the Supplement. In line 10 with the main results, among patients undergoing TAVI, the absolute rates of 30-day ischemic stroke and MACE were 26.5% (9 of 34) and 34.2% (12 of 34), respectively, in patients with stroke less than 3 months prior to surgery compared with 1.1% (15 of 1376) and 4.5% (62 of 1376) in patients with no prior stroke. Odds Ratio

1 Discussion

This nationwide study examined the 30-day risk of adverse out-

0 2 4 6 9 12 18 24 36 48 60 comes associated with SAVR in patients with and without prior Time From Stroke to Surgery, mo stroke, with particular focus on the importance of time elapsed between stroke and surgery. Patients with recent stroke (within Restricted cubic splines regression of the association of time elapsed between 3 months) had markedly heightened risk of recurrent stroke prior stroke with risk of MACE, ischemic stroke, and all-cause mortality among during surgery, and the risk declined with time. We found no patients with prior stroke. All splines were adjusted for age, sex, and concomitant coronary artery bypass grafting surgery. The median time between stroke and association of time from stroke to surgery with the risk of all- surgery (9.2 months) was used as a reference. From left to right, the knots indicate cause mortality. The splines of the subgroup with prior stroke the fifth, 25th, 50th, 75th, and 95th percentile. Gray lines indicate 95% CIs. supports that the risk of recurrent stroke declines with time and reaches a nadir after approximately 4 months. Thus, data Sensitivity Analyses suggest that postponement of SAVR for at least 3 to 4 months We identified 3092 patients (22.0%) with and 10 938 (78.0%) after a stroke, if possible, may reduce the risk of recurrent stroke without preoperative atrial fibrillation at baseline. Of the during surgery. However, because of the observational na-

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Table 2. Sensitivity Analysis–Adjusted Odds Ratios for 30-Day Major Adverse Cardiovascular Events (MACE), Ischemic Stroke, and All-Cause Mortality for 11 100 Patients With Accessible EuroSCORE Data

Stroke Subgroup Crude Events, No. (%) Sample Size, No. Odds Ratio (95% CI)a 30-d MACE No prior stroke 557 (5.4) 10 370 1 [Reference] Prior stroke at anytime 114 (15.6) 730 2.60 (2.08-3.25) Stroke <3 mo prior 68 (20.9) 325 3.78 (2.83-5.04) Stroke 3-<12 mo prior 14 (11.9) 117 2.02 (1.14-3.57) Stroke ≥12 mo prior 32 (11.1) 288 1.69 (1.15-2.49) 30-d Ischemic stroke No prior stroke 121 (1.2) 10 370 1 [Reference] Prior stroke at anytime 65 (8.9) 730 7.37 (5.36-10.14) Stroke <3 mo prior 48 (14.8) 325 13.39 (9.30-19.27) Stroke 3-<12 mo prior 5 (4.3) 117 3.50 (1.40-8.75) Stroke ≥12 mo prior 12 (4.2) 288 3.18 (1.73-5.85) 30-d All-cause mortality No prior stroke 374 (3.6) 10 370 1 [Reference]

Prior stroke at anytime 50 (6.8) 730 1.50 (1.94-2.05) Abbreviation: EuroSCORE, European Stroke <3 mo prior 25 (7.7) 325 1.71 (1.11-2.64) System for Cardiac Operative Risk Evaluation. Stroke 3-<12 mo prior 8 (6.8) 117 1.61 (0.77-3.35) a Adjusted for sex, age, and Stroke ≥12 mo prior 17 (5.9) 288 1.23 (0.74-2.05) EuroSCORE.

ture of this study, the results are only hypothesis generating, performed a study on preoperative stroke and outcomes af- and more studies are encouraged before drawing such a ter CABG surgery. Similar to our study, they observed that pre- conclusion. operative stroke increased the risk of postoperative recurrent Consistent with previously reported rates, we found an stroke. However, in contrast to our study, they found no evi- overall perioperative stroke rate of 2.0% for SAVR with con- dence of any vulnerable period in the first 3 to 6 months after comitant CABG and 1.3% for SAVR without concomitant a stroke. Notably, the number of patients with recent stroke CABG.18,26-28 For both surgical and nonsurgical patients, the was low, with only 28 patients with stroke less than 3 months risk of recurrent stroke has been reported to be particularly pro- prior to surgery (<0.1%) and 64 patients with stroke less than nounced during the first months after an incident stroke.29-31 6 months prior to surgery (0.1%). Somewhat surprisingly, they Importantly, the event rate of recurrent stroke that our sample found a small increase in risk of postoperative stroke with would have experienced if they did not undergo surgery is un- longer duration between surgery and preoperative stroke; the known. However, our estimates were substantially higher than reason for discrepancy of our study results and those by Bottle those reported in prior cohort studies of nonsurgical patients et al39 is unknown. (approximately 3% at 30 days),32 and our regression models Although atrial fibrillation (preoperative or postopera- were adjusted for key clinical factors that predict the risk of tive) has been associated with worse postoperative out- recurrent stroke, supporting the assumption that surgery may comes, including increased risks of ischemic stroke, a few fac- heighten the risk of recurrent stroke.16 Similarly, in a noncar- tors suggest that it may not drive the observed increased risks diac surgery setting, we observed in 2014 that the relative risk of recurrent stroke in our cohort of patients with prior of recurrent stroke was strikingly higher in patients undergo- stroke.42-44 First, the association of recent stroke (less than 3 ing surgery shortly after a recent stroke compared with pa- months) with increased risk of ischemic stroke was apparent tients who did not undergo surgery shortly after a stroke.7,33 both in patients with and without atrial fibrillation. Second, Nevertheless, for the present study, we were unable to find a postoperative atrial fibrillation was not more commonly ob- suitable comparison group because the groups would have served in patients with recent stroke. Potential mechanisms been inherently different—the controls would not have an in- underlying our observations remain unknown and warrant dication for surgery. Therefore, ideally, a randomized clinical more studies. trial would be needed to show whether postponement of surgery reduces the risk of recurrent stroke and improves neuro- Strengths and Limitations logical outcomes. The main strength of our study was the unselected cohort of Numerous studies have indicated that previous stroke is 14 030 patients undergoing aortic valve replacement surgery. an independent predictor for postoperative stroke and However, the number of patients with prior stroke within 5 years mortality.6,34-40 In 2008, Gulbins et al41 presented a hazard ra- prior to surgery was rather small, potentially caused by pre- tio of 2.6 for postoperative stroke among patients with a his- exclusion because of, for example, a high EuroSCORE. The small tory of stroke receiving a stentless aortic valve; however, the sample size may have influenced the estimates to become more follow-up began 6 months after surgery. In 2013, Bottle et al39 uncertain, and it cannot be excluded that some of the interac-

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tion analyses had insufficient power to reveal a true difference Although we adjusted our analyses for several clinical vari- (ie, a statistical type 2 error). Moreover, the number of patients ables, we lacked information on symptoms and severity of aor- with prior stroke undergoing TAVI (n = 132) was also small, hin- tic valve stenosis, neurological status, general frailty, and cir- dering any conclusions to be drawn on this population. culating biomarkers, including creatinine values, troponins Stratification of the patients in the stroke groups re- concentrations, and natriuretic peptide levels. Moreover, we vealed that surgeries were more frequently performed less than lacked data on the perioperative handling of antiplatelet and an- 3 months or 12 months or more after a stroke. Although ad- ticoagulation therapy (continuation vs interruption), which may ministrative data may not enable us to provide full granular- have influenced the outcomes. Finally, adjustment for carotid ity of our data and, thus, we cannot exclude that the patients stenosis was not performed because of unknown validity of this undergoing surgery less than 3 months after a stroke might con- diagnosis in our registries. However, excluding patients with pre- stitute a specific group of critically ill patients where postoperative carotid stenosis did not alter the results. ponement may not be an option (and thus, the indication rather than the history of stroke may heighten the risk of recurrent stroke), the stroke groups were fairly similar with regards to Conclusions comorbidity burden. Moreover, mean EuroSCORE values were not markedly different among the stroke groups, and exclu- Previous stroke is a major risk factor for recurrent ischemic sion of all acute surgery did not alter the results. stroke and MACE in patients undergoing SAVR, especially if The Danish population is predominantly white, which may time elapsed since previous stroke and surgery is less than 3 limit generalizability of our findings to other races/ethnicities. months.

ARTICLE INFORMATION Gislason, Torp-Pedersen, Køber. 5. Brown JM, O’Brien SM, Wu C, Sikora JAH, Griffith Accepted for Publication: February 14, 2018. Study supervision: Jørgensen, Gislason, Martinsson, BP, Gammie JS. Isolated aortic valve replacement in Sanders, Abdulla, Jensen, Torp-Pedersen, Køber, North America comprising 108,687 patients in 10 Published Online: April 25, 2018. Andersson. years: changes in risks, valve types, and outcomes doi:10.1001/jamacardio.2018.0899 Conflict of Interest Disclosures: All authors have in the Society of Thoracic Surgeons National Author Affiliations: Department of Cardiology, completed and submitted the ICMJE Form for Database. J Thorac Cardiovasc Surg. 2009;137(1): Copenhagen University Hospital Herlev and Disclosure of Potential Conflicts of Interest. Dr 82-90. Gentofte, Gentofte, Denmark (Andreasen, Gislason has received grants from AstraZeneca, 6. Bucerius J, Gummert JF, Borger MA, et al. Stroke Jørgensen, Gislason, Andersson); The Danish Heart Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, after cardiac surgery: a risk factor analysis of 16,184 Foundation, Copenhagen, Denmark (Gislason); The and Pfizer. Dr Torp-Pedersen has received grants consecutive adult patients. Ann Thorac Surg. 2003; National Institute of Public Health, University of from Bayer during the conduct of the study. Dr 75(2):472-478. Southern Denmark, Copenhagen, Denmark Køber has received personal fees from Novartis as a 7. Jørgensen ME, Torp-Pedersen C, Gislason GH, (Gislason); Department of Cardiology, Lund speaker. No other disclosures were reported. University Hospital, Lund, Sweden (Martinsson); et al. Time elapsed after ischemic stroke and risk of Department of Anesthesiology, University of Funding/Support: Dr Andreasen was supported by adverse cardiovascular events and mortality Wisconsin School of Medicine and Public Health, an unrestricted grant by the Danish Heart following elective noncardiac surgery. JAMA. 2014; Madison (Sanders); Division of Cardiology, Foundation and Gerda & Hans Hansens Fund. 312(3):269-277. Department of Medicine, Glostrup University Role of the Funder/Sponsor: The funders had no 8. Sanders RD, Degos V, Young WL. Cerebral Hospital, Copenhagen, Denmark (Abdulla); The role in the design and conduct of the study; perfusion under pressure: is the autoregulatory Multidisciplinary Pain Center, Department of collection, management, analysis, and ‘plateau’ a level playing field for all? Anaesthesia. Anaesthesia, Copenhagen University Hospital interpretation of the data; preparation, review, or 2011;66(11):968-972. Herlev and Gentofte, Gentofte, Denmark (Jensen); approval of the manuscript; and decision to submit 9. Aries MJH, Elting JW, De Keyser J, Kremer BPH, Department of Health, Science, and Technology, the manuscript for publication. Vroomen PCAJ. Cerebral autoregulation in stroke: Aalborg University, Aalborg, Denmark a review of transcranial Doppler studies. Stroke. (Torp-Pedersen); The Heart Centre, Rigshospitalet, REFERENCES 2010;41(11):2697-2704. Copenhagen University Hospital, Copenhagen, 1. Oliveira-Filho J, Massaro AR, Yamamoto F, 10. Otto CM, Prendergast B. Aortic-valve stenosis: Denmark (Torp-Pedersen); Department of Bustamante L, Scaff M. Stroke as the first Cardiology and Epidemiology, Aalborg University from patients at risk to severe valve obstruction. manifestation of calcific aortic stenosis. N Engl J Med. 2014;371(8):744-756. Hospital, Aalborg, Denmark (Køber). Cerebrovasc Dis. 2000;10(5):413-416. 11. Iung B, Vahanian A. 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