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Ann Thorac Surg 2001;71:1172-1180
© 2001 The Society of Thoracic Surgeons
a Department of Cardiothoracic Surgery, St Antonius Ziekenhuis, Nieuwegein, The Netherlands
b Department of "Stichting Hartenzorg," St Antonius Ziekenhuis, Nieuwegein, The Netherlands
c Julius Center for General Practice and Patient Oriented Research, University Medical Center, Utrecht, The Netherlands
d Department of Cardiology, Rijnstate Ziekenhuis, Arnhem, The Netherlands
Accepted for publication November 13, 2000.
Address reprint requests to Dr Casselman, Department of Cardio-Thoracic Surgery, St Antonius Ziekenhuis, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands
e-mail: casself{at}hotmail.com
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Abstract |
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Methods. From December 1963 to January 1974, 249 patients survived a mechanical AVR at our institution. Mean age was 41.8 ± 12.4 years and 81% (n = 202) were male. Ball valves were implanted in 24% (n = 61) and disc valves in 76% (n = 188). Patients were anticoagulated with vitamin K antagonists and dipyridamole. A total of 4,855 patient–years was available for analysis. Mean follow-up was 19.5 ± 9.4 years and was 100% complete. Analyses were performed with Kaplan-Meier and multivariable Cox regression methods.
Results. One hundred and two patients had one TE or BLE postoperative event and 58 patients had two postoperative events. Six patients had more than five postoperative events. Freedom from a first postoperative event was 74.8% ± 2.9%, 55.3% ± 3.5%, and 46.8% ± 4.0% at 10, 20, and 30 years, respectively. Freedom from a second postoperative event was 45.4% ± 5.4%, 29% ± 6.0%, and 23.2% ± 7.1% at 10, 20, and 30 years, respectively. Multivariate predictors for TE or BLE complications were ball valve (Odds Ratio (OR) = 2.9), postoperative endocarditis (OR = 2.2), and any surgery (OR = 2.2). The incidence of events was highest the first 5 postoperative years.
Conclusions. The risk of adverse events is highest the first 5 postoperative years. Once an event has occurred, the risk for a second event is increased. The incidence and frequency of events is substantial and should be considered in the choice of a valve substitute.
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Introduction |
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This study focuses on the very long-term follow-up after mechanical aortic valve replacement with specific emphasis on the occurrence and frequency of thromboembolic (TE) and bleeding (BLE) complications and its determinants.
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Material and methods |
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Several types of mechanical valves were used during the study. Type and number of specific valve implantations are given in Table 2. Postoperatively, patients were anticoagulated with vitamin K antagonists in association with an antiplatelet agent (mostly dipyridamole). The level of anticoagulation was followed with the thrombotest and the target (during those years) was between 10% and 6%, which corresponds with an International Normalized Ratio (INR) between 2.8 and 4.2 [5]. Patients were regularly followed by the Dutch thrombosis service, a national organization with multiple regional offices, specifically created to follow up on anticoagulated patients to coordinate an adequate anticoagulation level.
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A repeat follow-up study was carried out by another author (FPC) between May and December 1999. A new individual patient file was created according to the official guidelines [6]. All definitions of events were made according to these guidelines with the exception of hemolysis, which was defined as any raise in lactate dehydrogenase not attributable to other causes (because of the definition used in 1975). Follow-up information was obtained from the Dutch thrombosis service and any doctor(s) possibly contacted by the patient. All patient files were personally seen by an author (F.P.C.) and scrutinized for events and causes of death. The anticoagulation treatment at the time of an event, and the INR if known, were recorded.
All surviving patients received and completed a questionnaire regarding their present status, past events, and the frequency of minor bleeding events, which were roughly graded as occurring weekly or more frequently, monthly, yearly, or only seldom. In addition, they were asked whether it bothered them to take anticoagulation medication.
A total of 4,855 patient–years was available for analysis. Mean follow-up was 19.5 ± 9.4 years, and it was 100% complete. The New York Heart Association functional class in 91 surviving patients at follow-up was I in 39% of patients (n = 35), II in 46% of patients (n = 42), and III in 15% of patients (n = 14).
Data analysis
Data are expressed as the mean ± the standard deviation. Survival and event-free estimates were determined by life-table analysis [7] and expressed as proportion ± the standard error. Analysis was performed with the SPSS package version 8.0 (SPSS Inc, Chicago, IL).
Risk factors for outcome were evaluated using Cox proportional hazard models. The first event was used as outcome. Associations are presented as hazard ratios (ie, relative risk) with corresponding 95% confidence intervals (CIs). First analyses were performed using only the risk factor of interest in the Cox univariate model. Those risk factors with associations that showed a statistical significance of less than or equal to 0.10 were included in a multivariate Cox regression model. A priori, we evaluated the following risk factors of information that were collected at base line: age, sex, year of operation (before 1970 or after 1970), hypertension (systolic pressure 
160 or diastolic pressure 95 or treatment), atrial fibrillation, history of diabetes mellitus, aortic stenosis (peak gradient 75), aortic regurgitation (definition > grade 1), preoperative endocarditis, type of valve (Starr-Edwards versus Björk-Shiley), and type of operation (elective or emergency). Postoperative factors that were evaluated were paravalvular leaks, postoperative endocarditis, new onsets of atrial fibrillation, cardiac events and any operation (other than aortic valve reoperation). In addition, we evaluated whether base line characteristics were predictive of a recurrent anticoagulation-related complication.
Estimates of the linearized incidence rate with corresponding standard errors were obtained by dividing the number of first events by the corresponding patient–years of follow-up. The standard error was calculated as the square root of the incidence divided by the patient–years of follow-up, assuming a Poisson distribution. A two-sided p-value less than 0.05 was considered statistically significant.
Survival curves for the second and third event were estimated using the same method as for the first event. The population at risk for a second event was restricted to those who suffered a first event, irrespective of whether the first event was fatal or nonfatal. The same applies for the analyses of the third event: the population comprised the subjects who suffered a first and second event.
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Results |
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Freedom from TE or BLE mortality was 97.7% ± 1.3%, 93.2% ± 1.8%, and 90.5% ± 3.2% at postoperative years 10, 20, and 30, respectively (Fig 2). The linearized incidence rate was 0.3% ± 0.1% per year. Out of 14 total events, 8 were BLE events, whereas the remainder were TE phenomena (including 4 patients with valve thrombosis; see Table 4). Age was the only independent predictor for TE or BLE mortality with a hazard ratio increase of 1.1 per year (95% CI 1.0 to 1.2). Diabetes and emergency operations did not reach statistical significance in the multivariate model.
Thromboembolic and bleeding complications
Overall TE (minor and major) and BLE (major) complications are termed "events" and refer to any of these complications in this paragraph.
One hundred and two patients experienced an event, in the absence of endocarditis, during follow-up. The majority of patients experienced one or two events, (n = 102) or (n = 58), respectively. Thirty patients experienced three events and 13 patients experienced four events. Six patients had more than five events and 1 patient had more than 10 events.
Freedom from a first event was 74.8% ± 2.4%, 56.3% ± 3.5%, and 46.8% ± 4.1% at postoperative years 10, 20, and 30, respectively (Fig 3). Multivariate predictors for a first event were ball valve (hazard ratio 2.9 [95% CI 1.2 to 7.2]), postoperative endocarditis (hazard ratio 2.2 [95% CI 1.2 to 4.0]), and any surgery other than aortic valve reoperation (hazard ratio 2.2 [95% CI 1.3 to 3.7]). Atrial fibrillation and operation before 1970 did not reach statistical significance in the multivariate model. The linearized incidence rate of a first event was 3.0% ± 0.3% per patient–year.
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The risk of an event was highest within the first 5 years after aortic valve replacement. After 5 years the risk decreased (Table 5).
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Thromboembolic phenomena
A total of 140 TE phenomena (excluding valve thrombosis) took place in 77 patients who did not have endocarditis at the time of the TE event. Twenty-eight patients experienced a second TE event, 17 patients experienced a third TE event, and 4 patients experienced a fourth TE event. Transient ischemic attack occurred in the majority of patients: 82 events in 47 patients. No reversible ischemic neurologic deficits were noted. Stroke occurred 35 times in 28 patients. All of them resulted in some degree of permanent deficit. A minority of the TE events were peripheral emboli (seven events in 6 patients). Sixteen events were classified as "other," including nine probable embolic events (according to history) and seven nonspecified. Lethal outcome was noted in 2.6% (two TE events). The INR at the time of the first event was known in 23 patients (30% of the events). Mean INR at the time of the event was 1.9 ± 1.2 and 85% of these values were below the target base line of 2.8. Sixty-seven percent of the values were even below 2.0. Of all 140 TE events, 12.8% of the patients (n = 18) were not using anticoagulant drugs at the time of the event. Of 77 patients with a first TE event, 27 patients were taking vitamin K antagonists solely and 42 patients took antiplatelet drugs in addition to vitamin K antagonists. Five patients took only antiplatelet drugs.
Freedom from a first TE event was 79.9% ± 2.6%, 68.5% ± 3.3%, and 57.3% ± 4.3% at postoperative years 10, 20, and 30, respectively (Fig 4). Multivariate independent risk factors for first thromboembolic event, excluding valve thrombosis, were age [hazard ratio increase of 1.0 per year (95% CI 1.0 to 1.0)], operation year before 1970 [hazard ratio of 2.2 (95% CI 1.3 to 3.7)], and not using anticoagulant drugs at the time of the event [hazards ratio 4.1 (95% CI 2.1 to 8.0)]. A trial fibrillation was significantly related to first thromboembolic event in the univariate model, but not in the multivariate model.
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The incidence of TE events was higher within the first 5 postoperative years. After that it remained relatively constant (Table 5).
Freedom from a major TE event (35 strokes in 28 patients) was 95% ± 1%, 87% ± 3%, and 85% ± 3% at postoperative years 10, 20, and 25, respectively (Fig 5).
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Freedom from a first major BLE event was 91.1% ± 1.9%, 78.6% ± 2.4%, and 74.1% ± 3.4% at postoperative years 10, 20, and 30, respectively (Fig 6). Multivariate independent risk factors for a first major BLE event were increasing age (hazard ratio increase of 1.0 per year [95% CI 1.0 to 1.1]) and any surgery (hazard ratio 3.8 [95% CI 2.0 to 7.7]). Atrial fibrillation was significantly related to first major BLE event in the univariate model, but not in the multivariate model.
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The incidence of major BLE events was relatively constant over time (Table 5).
Minor bleeding events
The frequency of minor bleeding events was estimated by the 91 survivors and graded as very seldom (n = 59), yearly (n = 17), monthly (n = 5), and weekly or more (n = 10).
Attitude towards anticoagulation
Among 91 survivors, 13 patients would prefer not to take anticoagulation medication, whereas 75 patients did not care. The remainder had no opinion.
Other valve-related events
Valve dysfunction
There were no structural valve deteriorations. Leaflet obstruction due to pannus overgrowth necessitating reoperation occurred in 2 patients.
Paravalvular leak
Paravalvular leak occurred once in 28 patients, twice in 3 patients, and three times in 1 patient. The linearized incidence rate was 0.7% ± 0.1% per patient–year. Paravalvular leak was the major cause of aortic valve reoperation (Table 6).
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Endocarditis
Postoperative endocarditis occurred in 20 hospital survivors. The linearized incidence rate of endocarditis in hospital survivors was 0.4% ± 0.1% per patient–year. The incidence of postoperative endocarditis was relatively constant over time (Table 5).
Aortic valve reoperation
A total of 60 aortic valve reoperations occurred in 46 patients. Twelve patients underwent a third aortic valve reoperation and 2 patients a fourth reoperation. Causes of aortic valve reoperation are listed in Table 6. Paravalvular leak was the leading cause occurring in 60.6% of cases (n = 37). Freedom of aortic valve reoperation was 88.7% ± 2.1%, 82.4% ± 2.7%, and 67.5% ± 6.2% at postoperative years 10, 20, and 30, respectively. The linearized incidence rate was 1% ± 0.1% per patient–year. The incidence of aortic valve reoperation was highest within the first 5 postoperative years and beyond 25 years of follow-up (Table 5). None of the patients died at aortic valve reoperation.
Other events
Other reoperations
A total of 25 cardiac reoperations, other than aortic valve reoperations occurred in 20 patients. They included coronary artery bypass grafting (n = 9), mitral valve operation (n = 9), ascending aortic replacement (n = 2) and other reoperations (n = 5). A total of 27 pacemakers were implanted during follow-up.
A total of 199 other, noncardiac, surgical interventions took place in 100 patients. Freedom from any first surgical intervention (excluding aortic valve reoperation) was 71.2% ± 3.1%, 48.3% ± 3.7%, and 28.8% ± 4.5% at postoperative years 10, 20, and 30, respectively.
Other cardiac events (excluding cardiac mortality)
A total of 395 cardiac events in 168 patients were noted during follow-up. They included heart failure (87 events), myocardial infarction (24 events), angina (35 events), supraventricular arrhythmias (93 events), ventricular arrhythmias (41 events), electrical cardioversions (31 events), hypertension treatment (43 events) and other (41 events). Freedom from any first nonoperative cardiac-related event was 56.7% ± 3.3%, 33.1% ± 3.3%, and 12.8% ± 4.8% at postoperative years 10, 20, and 30, respectively.
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Comment |
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Fifty-eight patients (23.3%) had multiple events. Although this incidence is certainly substantial, this series demonstrates that only a few patients experienced more than four events over the entire study period. However, Figure 3 demonstrates that patients who had a first event are at an increased risk for subsequent events.
Although the literature usually reports TE phenomena and BLE complications separately, we also wanted to report the global rate because we want to inform patients about the global risks of any complication. In addition, patients experiencing a TE or bleeding event are by no means separate patient groups, because they overlap considerably as previously reported [13].
Interestingly, one of the risk factors for TE or BLE complications was the occurrence of any operation other than aortic valve reoperation, during follow-up (OR = 2.2). Anticoagulation is commonly interrupted and the patient is protected from adverse events with intravenous heparin [11, 14]. The risk of this interruption has been estimated [12] and reported [14] to be low but nevertheless, emerges as a risk factor in this series. It is conceivable that fluctuations in levels of anticoagulation make the patient more prone to complications as both the intensity and consistency of the anticoagulation are important factors in avoiding adverse events [9, 11].
Thromboembolic events
Out of a total of 140 TE events, two had lethal outcomes and 35 were strokes with residual impairment. This high incidence of 26.4% is undoubtedly related to the fact that 85% of the known INR at the time of the TE event were below the target base line. Inadequate or stopped anticoagulation is known to be strongly associated with increased risk of TE events [11–13], as also evidenced by the hazard ratio of 4.1. On the other hand, the current first event linearized incidence rate of 2% per patient–year is very comparable with previously reported rates of 2% to 2.8% per patient–year for the Björk-Shiley and Starr-Edwards valve [3, 4, 15]. Equally, the 10-year freedom from a first TE event is situated around 80%, which is, however, lower than the 86.7% reported by the Mayo Clinic in their long-term follow-up study of Starr-Edwards valves [16].
As for the global anticoagulation-related complications, patients who had a first TE event were at increased risk for multiple events (Fig 4). This was already demonstrated in a previous study, which in addition proved that the interval to a second TE event depends on the severity of the first event and not on its timing [17].
Bleeding events
Outcome for BLE events was generally worse than for TE events (eight lethal events versus two) as already stated by Cannegieter and colleagues [18]. Although the INR was known only in a minority of BLE events, most of these INRs were above the target maximum, in accordance with the literature [10–14, 18, 19].
The linearized incidence rate of 1.1% for the first BLE event in this series is better than in the previously mentioned studies [3, 4, 9] where rates of 1.2% to 2.2% per patient per year were found. An exceptionally high incidence rate of 5% per patient per year was found in the study by Borkon and colleagues [15] without obvious reason. In the conference discussion of that article it was suggested that the favorable incidence in the Netherlands was probably thanks to the nationally organized thrombosis service. However, equally good or even better results have also been reported without the aid of such an organization [16].
As for the global adverse event rate and the TE events, patients with a first BLE event were at increased risk for subsequent events (Fig 6).
Practical inferences
One hundred and two patients (41% of all study patients) had 37 major TE events (out of 140 events), six valve thromboses and 72 major bleeding events. This means that out of a total of 218 TE and BLE events, with the exception of minor bleeding events, 115 or 53% were major events. In addition, 6.4% of all events were lethal. This high proportion occurred despite the fact that the target INR of 2.8 to 4.2 was not much different from the current recommendations: according to the literature, the overall target INR should be between 2.5 and 4.0 [18–21]. Therefore, although INR levels were regularly followed by a specialized organization that closely adhered to the official guidelines for anticoagulation, it is clear that the incidence of adverse events for the extremely long-term is still considerable and above all, in this series, not substantially inferior to other published series. Since a lot of patients experiencing an event had an inadequate anticoagulation level, it seems imperative to increase the INR control frequency, rather than change the target INR level, in order to reduce the frequency of events.
Age per year was a risk factor for both TE events and bleeding events in the current series. This is still controversial in the literature because it confirms the findings by Cannegieter and colleagues [15], but contradicts the findings of several other studies [1, 9, 10, 13, 22, 23]. The fact that younger age could be less prone to complications than older age may be an argument in favor of mechanical aortic valve replacement versus other types of valve replacement.
Of all other identified risk factors, only the type of valve and careful consistent anticoagulation regimen are correctable factors. As the incidence of adverse events was highest during the first 5 years, but remained present throughout the study period, careful monitoring seems the most important determinant of outcome.
Limitations of the study
This series is a retrospective analysis over a long period of time. This inevitably raises the concern of the completeness of our data collection, despite major efforts to reduce this error to a minimum. Although it is unlikely that we missed major events, the registration of minor events (especially minor bleeding events) was more difficult. The reported risk may therefore be underestimated and the proportion of major events consequently overestimated.
A limitation is the lack of registration of preoperative neurologic events. Some reports indicated a history of neurologic events as a risk factor for future events [11, 18], but the original 1975 follow-up of the patient cohort did not register this information, and therefore, we were unable to evaluate this variable. However, the demographics of the patient population suggest that probably only very few patients might have had a preoperative neurologic event: mean age was 41.8 years, only 13 patients (5.2%) had an aortic valve reoperation and only 7 patients (2.8%) had simultaneous coronary artery bypass grafting (indicative of systemic arteriosclerosis). Therefore, it is unlikely that the lack of this information affected our risk estimates.
Another remark concerns the valves implanted in this series. Ball valves were implanted in 24% of hospital survivors and tilting disc valves in the remainder. While these valves are known to have an increased risk of anticoagulation-related complications as compared to the more recently available bileaflet mechanical valves [3, 4, 9, 11, 12, 14, 18, 19, 24], ball valves and tilting disc valves are currently still being implanted. Moreover, some recent reports suggest a lower target INR in current bileaflet valves with consequently lower bleeding complications without increasing TE events [25, 26]. It is not doubtful, but yet unproven, that the extremely long-term incidence of anticoagulation-related complications with the currently available bileaflet prostheses will be less than the currently reported incidence. With this in mind, we believe that this series should serve as a reference for future extremely long-term follow-up studies.
Finally, in this retrospective study, we recorded all medication at the time of an event, but not in between events or in patients without events. Therefore, it was impossible to evaluate the use of antiplatelet drugs in the occurrence of TE or BLE events.
In conclusion, at 30 years of follow-up, 46.8% of the patients remained free of any TE or BLE event and about one fourth of the patients (23.3%) experienced multiple events. This incidence of adverse events should be considered whenever an aortic valve operation is being considered for a particular patient.
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