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Ann Thorac Surg 2004;78:77-83
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Late incidence and determinants of stroke after aortic and mitral valve replacement

^a Division of Cardiac Surgery, Ottawa, Ontario, Canada
^b Department of Epidemiology and Community Medicine, University of Ottawa, Ottawa, Ontario, Canada

Accepted for publication December 22, 2003.

^* Address reprint requests to Dr Ruel, University of Ottawa Heart Institute, 40 Ruskin St, Suite 3403, Ottawa, Ontario, Canada K1Y 4W7
e-mail: mruel{at}ottawaheart.ca

	Abstract

Top Abstract Introduction Material and methods Results Comment Conclusions Acknowledgments References

 
BACKGROUND: Stroke is a devastating complication in patients with prosthetic valves, but characterization of its late occurrence from a large cohort is lacking.

METHODS: Three thousand one hundred eighty-nine adult patients who underwent a total of 3,576 operations for left-heart valve replacement were managed with contemporary anticoagulation guidelines and prospectively followed in a dedicated clinic. Total follow-up was 20,096 patient years. Bootstrapped survival analysis was used to determine the impact of patient and valve related factors on the incidence of stroke.

RESULTS: Most strokes were embolic. Linearized embolic stroke rates were 1.3% ± 0.2% per year for aortic bioprostheses, 1.4% ± 0.2% per year for aortic mechanical valves, 1.3% ± 0.3% per year for mitral bioprostheses, and 2.3% ± 0.4% per year for mitral mechanical valves (p = 0.002, vs other implant types). Age more than 75 years, female gender, and smoking were independent risk factors after aortic and mitral valve replacement. Atrial fibrillation, coronary disease, and tilting-disc mechanical prostheses were independent predictors of embolic stroke after aortic valve replacement. Preoperative left ventricular (LV) dysfunction was an independent risk factor in patients with mitral prostheses. Primary operative indication, diabetes, redo status, or the presence of two prosthetic valves were not associated with an increased hazard. The addition of acetyl salicylic or dipyridamole to warfarin anticoagulation did not significantly lower embolic stroke risk in patients with mechanical prostheses.

CONCLUSIONS: Approximately 20% of patients with valve prostheses have an embolic stroke by 15 years after valve replacement. Some risk factors such as the avoidance of smoking, mitral mechanical prostheses, aortic tilting-disc valves, and proceeding to mitral surgery before LV dysfunction occurs are potentially modifiable.

	Introduction

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Stroke is a devastating complication that may occur early or late after operation in patients with prosthetic heart valves and result from embolism, intracranial hemorrhage, or both [1]. Although intracranial hemorrhage is a relatively rare event except in elderly anticoagulated patients [2–4], an embolic stroke may occur in virtually any patient and with any type of valve prosthesis. Risk factors for stroke in the general population include advanced age, atrial fibrillation, coronary artery disease, congestive heart failure, mitral annular calcification, hypertension, diabetes, and smoking [5–7]. In patients with prosthetic heart valves, these and other patient-related characteristics could interplay with the design of the prosthesis, the site of implantation, and the adequateness of anticoagulation. Although unadjusted rates of stroke have been reported for several models of valve prostheses [8–13], studies that have focused on the independent effects of patient and prosthesis related variables on late stroke risk in patients with prosthetic valves are lacking. This study examines the incidence and risk factors associated with late postoperative stroke in a cohort of patients who were prospectively followed after aortic valve replacement (AVR) and(or) mitral valve replacement (MVR).

	Material and methods

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Patients, procedures, and follow-up
This study used prospectively collected data from 3,189 adult patients who underwent 3,576 left-heart valve replacement operations between 1970 and 2002 at the University of Ottawa Heart Institute, survived the operation, were mobile, and lived close enough to return for follow-up. Of the implants performed, 2,317 were AVR, 1,039 were MVR, and 220 were concomitant AVR and MVR. Coronary artery bypass grafting was performed at the time of valve replacement in 1,079 (30.2%) patients, who received a mean of 1.8 ± 0.9 graft. The prevalence and mean values of the operative population and follow-up cohort are displayed in Table 1. Patients who underwent valve repair procedures are not included in the present analyses.

Anticoagulation
During the initial postoperative period in hospital, patients received heparin (2,500 U intravenously [IV] q6 hours or 5,000 U subcutaneously q12 hours) until the INR or prothrombin time was within therapeutic range. Oral anticoagulation was managed by the surgeon during the initial three-month postoperative period and subsequently by the primary care physician or cardiologist. Patients with mechanical prostheses or with chronic atrial fibrillation were anticoagulated with warfarin according to guidelines in effect at the time. These consisted, for mechanical valves, of a target prothrombin time or INR of 2.5 to 3.5x normal in patients with Harken, Lillhei-Kaster, or Bjork-Shiley aortic valves, 3.0 to 4.0x normal in patients with Harken, Lillhei-Kaster, or Bjork-Shiley mitral valves, 2.0 to 3.0x normal in patients with St. Jude (St. Jude Medical, Inc, St. Paul, MN), Medtronic Hall (Medtronic, Minneapolis, MN) , Carbomedics (Carbomedics, Austin, TX), or On-X (Medical Carbon Research Institute, Austin, TX) aortic valves, and 2.5 to 3.5x normal in patients with St. Jude, Medtronic Hall, Carbomedics, or On-X mitral valves [14]. These target ranges were increased by 0.5x normal if atrial fibrillation or another indication for anticoagulation, such as previous embolism or known thrombotic disorder, was also present. Patients with two mechanical valves or with a prosthetic tricuspid valve were kept in the 3.0 to 4.0x normal target range. The addition of aspirin (80 mg daily) or dipyridamole (50 to 100 mg three times daily) to the anticoagulation regimen was left to the discretion of the surgeon, cardiologist, or primary care physician.

Warfarin anticoagulation was used for a period of 3 months after operation at the discretion of the surgeon in 26.2% of patients who underwent bioprosthetic AVR and 55.9% of patients after bioprosthetic MVR. Warfarin was subsequently discontinued if sinus rhythm was observed and no other indication for anticoagulation was present. Nonanticoagulated bioprosthetic valve patients were kept on 325 mg of aspirin daily unless contraindicated, and the addition of dipyridamole was left to the discretion of the patient's physician. Bioprosthetic valve patients who remained in atrial fibrillation were kept anticoagulated at a prothrombin time or INR target range of 2.0 to 2.5x normal.

The INR of patients with mechanical valves was between 1.8 and 3.8 at 80% of patient follow-up visits, and between 1.6 and 4.2 at 90% of visits. For patients with aortic mechanical valves, 80% of INRs were between 1.8 and 3.7 and 90% were between 1.6 and 4.1. Eighty percent of patients with mitral mechanical valves had their INR between 1.8 and 3.6 and 90% between 1.5 and 4.6. For patients with both aortic and mitral mechanical valves, 80% of INRs were between 2.1 and 3.8 and 90% were between 1.8 and 4.3 at the time of follow-up visits.

Definition of stroke
The occurrence of stroke was defined, in accordance with the Guidelines for Reporting Morbidity and Mortality after Cardiac Valvular Operations, as the presence of a neurologic deficit lasting more than 3 weeks [1]. Patients diagnosed with a stroke after 1986 had computerized tomography (CT) of the head. Strokes were characterized either as embolic or as an intracranial bleeding event based on the primary mechanism and CT appearance of the lesion. The diagnosis was confirmed by a neurologist or internist in all cases.

Statistical analyses
All analyses were performed in Intercooled Stata 8 (College Station, TX). Continuous data are presented as mean ± standard deviation, except for survival and events rates which are reported as mean ± standard error. Patients were censored at the time of their last follow-up visit or death if they had not experienced or died from a stroke. Deaths from an unknown cause were not classified as a stroke and were also treated as a censored event. Nonparametric estimates of overall, nonrisk-adjusted freedom from stroke over time were determined by the method of Kaplan and Meier for each site of implantation and type of valve prosthesis. Potential univariate predictors were individually tested for equality of freedom from stroke with a log-rank test, and were selected for entry into the multivariate models if their univariate tvalue (not reported) was less than 0.05 and if no collinearity (ie, Spearman's rank correlation coefficient 0.30 and p value < 0.005) was shared with a more clinically meaningful predictor that also had a univariate p value of less than 0.05.

The proportional hazard assumption was tested with generalized Cox-Snell residuals, –ln[-ln(survival)] probabilities, and by addressing, in the case of continuous variables, whether a significant interaction with time was present. Multivariate semiparametric Cox proportional hazards models were developed by incorporating significant univariate predictors and by forcing into the model patient and prosthesis related variables (such as age, gender, comorbidities, atrial fibrillation, and valve type) that were considered important regardless of their individual p value. In order to account for positive or negative confounding, no automated model selection procedure was used and all reported variables were simultaneously used in the final models. Models were evaluated with a score test and rejected if p was greater than or equal to 0.05. Each final model was subjected to a total of 100 bootstrap sampling replications [15, 16]; adjusted bootstrapped hazard ratios and bias corrected 95% confidence intervals are reported.

	Results

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Incidence of late postoperative stroke
Embolic strokes
A late postoperative embolic stroke occurred in 156 (6.7%) patients at a mean of 5.7 ± 4.5 years after AVR, 89 (8.6%) patients 6.6 ± 4.6 years after MVR, and 14 (6.4%) patients 6.2 ± 3.6 years after double valve replacement. Linearized embolic stroke rates were 1.3% ± 0.2% per year in patients with aortic bioprostheses, 1.4% ± 0.2% per year with aortic mechanical valves, 1.3% ± 0.3% per year with mitral bioprostheses, and 2.3% ± 0.4% per year with mitral mechanical valves (p = 0.002, vs other implant types) (Fig 1). Ninety-seven patients, or 37.5% of those who had an embolic stroke, died with stroke as a primary or contributing cause at a mean of 1.6 ± 2.7 years after the event.

View larger version (34K): [in this window] [in a new window]   Fig 1. Incidence of late postoperative embolic stroke after valve replacement, by implant site and prosthesis type. The incidence of stroke was significantly higher in patients with mitral mechanical valves than in those with other types of implants. (*p = 0.002). — = aortic bioprotheses; · · · = mitral bioprostheses; – – = aortic mechanical; - · - · = mitral mechanical. (Bio = bioprostheses; Mech = mechanical prostheses.)

Risk factors for embolic stroke
Gender
Female gender was an independent risk factor for embolic stroke in patients with an aortic or a mitral prosthesis (Tables 3 and 4). Women with prosthetic valves had approximately 1.7 times the embolic stroke risk of men, despite adjustment for other risk factors.

Atrial fibrillation
Chronic atrial fibrillation was an independent risk factor for embolic stroke in patients with aortic prostheses, with a relative risk of 2.2 (Table 3). In patients with mitral prostheses, atrial fibrillation lost statistical significance as the stronger effects of advanced left ventricular dysfunction (see below) on embolic stroke risk concomitantly entered in the model (Table 4).

Coronary artery disease
Coronary disease was a significant risk factor for embolic stroke in patients with an aortic prosthesis, where a 24% increase in relative risk per additional graft required at operation was found (Table 3). This relationship was not significant in patients with mitral prostheses.

Left ventricular function
Depressed left ventricular function at the time of surgical referral (defined as grade 3 or 4; Table 4) was independently associated with an increased risk of embolic stroke in patients with mitral prostheses. Patients with grade 3 or 4 left ventricular dysfunction preoperatively who received a mitral prosthesis had 3.1 times the relative risk of embolic stroke of patients with a mitral prosthesis and normal or mildly depressed left ventricular function (grade 1 or 2), despite adjustment for other risk factors. Separate analyses similarly revealed that a 61% linearized augmentation in embolic stroke risk was observed for each unit increase in preoperative left ventricular grade (Fig 2).

View larger version (22K): [in this window] [in a new window]   Fig 2. Risk-adjusted effect of increased preoperative left ventricular grade on late postoperative embolic stroke in patients who underwent mitral valve replacement. With each unit increase in preoperative LV grade, a linearized stroke risk augmentation of 61% was observed. (LV = left ventricular.)

Type of prosthesis
Patients with mechanical mitral valves had 1.24 the risk of embolic stroke of patients with bioprosthetic mitral valves after adjustment for other risk factors (Table 4). This relationship was not observed in the aortic position, where the embolic stroke risk was not significantly different between mechanical and bioprosthetic valve patients.

Within the subset of aortic mechanical prostheses, contemporary tilting-disc aortic prostheses (ie, Medtronic-Hall) were associated with a 1.7 times higher stroke risk than contemporary aortic bileaflet valves (ie, St. Jude and Carbomedics). This relationship was not observed with mitral mechanical valves.

Antiplatelet and anticoagulation therapy
There was no difference in embolic stroke rates between patients with bioprosthetic valves who had been anticoagulated for a period of 3 months after operation versus those who had not. The adjunct of aspirin or dipyridamole had no significant effect on the incidence of embolic stroke in patients with mechanical valves, regardless of implant site or valve model.

Patients with two left-heart valve prostheses
Patients who underwent replacement of both aortic and mitral valves had a lower incidence of coronary artery disease and more often had previously had a valve replacement procedure than other subgroups (Table 1). Two mechanical prostheses were implanted in 71.4% of these patients. The overall incidence of embolic stroke in patients with two valve prostheses was 0.6% ± 0.6%, 3.3% ± 1.7%, 12.8% ± 3.8%, and 29.8% ± 13.4% at 1, 5, 10, and 15 years, respectively, with a linearized incidence of embolic stroke of 2.0% ± 0.9% per year. Smoking and atrial fibrillation were the only two independent risk factors for embolic stroke in patients with two valve prostheses.

	Comment

Top Abstract Introduction Material and methods Results Comment Conclusions Acknowledgments References

 
This study determined the late incidence of stroke after aortic and mitral valve replacement and identified independent patient and prosthesis related risk factors for stroke from a cohort of patients whose cumulative follow-up exceeded 20,000 years. Most strokes were embolic in nature. Patient related factors for embolic stroke included age more than 75 years, female gender, past and present cigarette smoking, coronary disease, and atrial fibrillation in patients with aortic prostheses, and advanced left ventricular dysfunction in patients with mitral prostheses. Prosthesis related risk factors for embolic stroke included the use of contemporary tilting-disc over bileaflet prostheses in the aortic position, and of any type of mechanical valve in the mitral position. In contrast, patients with aortic mechanical valves as a whole did not experience an increased risk of embolic stroke compared to those with an aortic bioprosthesis, possibly as a result of the high flow velocity and low stasis potential in the aortic root compared to within the vicinity of the mitral annulus. Of note is that the incidence of intracranial bleeding events, of which warfarin use was found to be the sole independent predictor, was comparatively low at 0.2% and 0.3% per year for anticoagulated patients with aortic and mitral prostheses, respectively.

Cigarette smoking, a modifiable risk factor, was associated with a detrimental independent effect on the incidence of embolic stroke after valve replacement. The effect of current smoking was additive to that of previous smoking, suggesting that smoking cessation in patients with prosthetic valves may lower the risk of stroke despite a history of previous smoking, a known risk factor for vascular disease and stroke [7]. This may have been due to the additional effects of current smoking on diffuse impairment of endothelial function and procoagulability [17], which may be particularly relevant for patients with prosthetic heart valves.

Another potentially modifiable risk factor identified was the referral of patients for mitral valve replacement after left ventricular dysfunction had already occurred, which was associated with a significantly increased risk of late embolic stroke to an extent that outweighed the impact of chronic atrial fibrillation. It is possible that MVR in the presence of advanced left ventricular functional impairment may result in increased stasis around the mitral prosthesis, thereby adding to the list of outcomes that can benefit from early referral for mitral valve procedures, such as increased freedom from heart failure and survival [18, 19].

An increased risk of stroke was noted in patients who underwent mechanical AVR if a Medtronic Hall valve, a tilting-disc prosthesis, was used rather than a St. Jude or Carbomedics bileaflet prosthesis. This was observed in the aortic position only and was independent of potential confounders such as gender, age, atrial fibrillation, level of anticoagulation, and surgical era. These results are somewhat in conflict with good results reported with the Medtronic Hall valve in the aortic position [8], but consistent with previous reports from our institution which indicated that the 5-year freedom from thromboembolism was 80.1% ± 2.7% with the Medtronic Hall, 85.8% ± 2.5% with the St. Jude, and 85.9% ± 3.5% with the Carbomedics mechanical valves (p = 0.04) [20, 21].

Important negative findings also arose from this study. Of note was that antiplatelet therapy, using either aspirin or dipyridamole in patients with mechanical prostheses, was not found to be beneficial. These results are in agreement with a systematic review, which found only marginal, if any, benefit from the addition of aspirin to warfarin therapy [22], and in contrast with a study that suggested a potentially beneficial role for dipyridamole [23]. No evaluation could, however, be made of the role of aspirin in patients with bioprosthetic valves, since virtually all patients with bioprosthetic valves were on life-long aspirin therapy.

Oral anticoagulation of patients with bioprosthetic valves for a period of three months after operation was not significantly associated with a reduction in embolic stroke risk. However, the low number of events during the time window extending from hospital discharge to 3 months postoperatively limited the statistical power to ascertain whether such an association truly existed or not; in this regard, meta-analytic techniques may be required to fully examine this issue. Confounding by indication, a form of selection bias encountered in observational studies and which cannot be fully accounted for by multivariate analyses, may also have prevented the observation of such a relationship [24]. Because the allocation of warfarin therapy for bioprosthetic valves was not randomized, the indication for anticoagulation may have been directly related to the risk of embolism perceived by the surgeon, with a resulting imbalance in the true underlying risk profile between warfarin and nonwarfarin bioprosthetic valve groups.

Another important negative finding was that prosthetic valve size did not correlate with embolic stroke risk in any subgroup, suggesting that previous data correlating the frequency of cerebral embolic signals and valve size in 92 patients who received a Carbomedics mechanical prosthesis probably do not translate into a clinically relevant difference in event rates [9].

Limitations
Censoring and follow-up
The Kaplan-Meier and Cox regression methods require an underlying assumption of independent censoring which may not always be met. In this regard, it is possible that patients lost to follow-up after a number of visits may have had subsequent outcomes, such as missed strokes, that were not accounted for in the analyses.

Selection bias and generalizability
As with other large observational cohorts, the results of these analyses may not be generalizable to all patients who have undergone prosthetic valve replacement at other cardiac centers. Demographic and valve selection factors unique to the study cohort could have resulted in computational leverage from statistically influential patients. Potential generalizability and statistical overfitting issues were, however, limited by the use of bootstrapped simulations and bias-corrected confidence intervals for the hazard ratios [15].

	Conclusions

Top Abstract Introduction Material and methods Results Comment Conclusions Acknowledgments References

 
The findings of this study allow patients and clinicians to better understand and quantify stroke risks after heart valve replacement, and may help identify those at particularly high risk for consideration of additional prophylactic measures such as the use of patient self-managed anticoagulation [25]. In addition, potentially modifiable factors were identified that may help decrease the incidence of embolic stroke in patients with prosthetic heart valves. Earlier referral for mitral valve surgery before left ventricular dysfunction occurs may result in a lesser long-term risk of embolic stroke if mitral valve replacement proves necessary at operation. Concomitant atrial fibrillation surgery in affected patients undergoing aortic valve replacement could have a role in decreasing the late incidence of embolic stroke, and deserves further study. Embolic stroke risk may also be minimized if patients in need of mechanical aortic valve replacement receive a bileaflet instead of a tilting-disc prosthesis. And finally, the results of this study mandate for complete smoking cessation in all patients with prosthetic heart valves, since current smoking was demonstrated to be an additive risk factor that was independent of previous smoking history and other risk factors for stroke.

	Acknowledgments

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The authors thank Mary Thomson for her assistance with the organization of the valve clinic and the management of the database.

	References

Top Abstract Introduction Material and methods Results Comment Conclusions Acknowledgments References

 

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