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Ann Thorac Surg 1997;64:30-34
© 1997 The Society of Thoracic Surgeons

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Original Articles: Cardiovascular

Anticoagulation in Children With Mechanical Valve Prostheses

Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston, South Carolina

	Abstract

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 
Background. Clotting complications in patients with mechanical valve prostheses can be prevented with either warfarin sodium (Coumadin; DuPont, Wilmington, DE) or antiplatelet agents. In children, it is not known whether one treatment regimen is more effective or safe than the other.

Methods. We prospectively followed up 64 children and young adults (aged 18 years or younger at implantation) with a mechanical valve on the left side of the heart, from October 1986 through October 1996. Forty-eight patients were treated with Coumadin and 16 with aspirin and dipyridamole. The two groups were similar in age, sex, valve location and size, mean length of follow-up, and operative indication. There has been a total follow-up of 272 patient-years on Coumadin and 116 patient-years on aspirin and dipyridamole.

Results. There was no difference between the two groups in survival or freedom from thromboembolism. Bleeding occurred more often in the patients taking Coumadin, but this difference was not statistically significant. Analysis of the literature showed thromboembolism and bleeding rates to be similar in the patients receiving Coumadin and those receiving antiplatelet agents.

Conclusions. Coumadin and the combination of aspirin plus dipyridamole provided similar protection against complications in this group of children and young adults with left-sided St. Jude (St. Paul, MN) mechanical valves. The choice between the two regimens may depend on other factors, such as patient preference and convenience.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 
See also page 35.

Clotting complications in patients with mechanical heart valve prostheses can be prevented with either warfarin sodium (Coumadin; DuPont, Wilmington, DE) or antiplatelet drugs. In adults, there is evidence that Coumadin is more effective [1]. In children, there is no consensus that one treatment regimen is better than the other. Some groups favor antiplatelet drugs [2–6], and others favor Coumadin [7–13]. Further, the use of Coumadin in pediatric patients poses particular problems. Children may be more susceptible to trauma, and therefore to anticoagulant-related hemorrhage. The teratogenic effects of Coumadin are of concern to female patients who are, or will be, of child-bearing age. Finally, teenagers may be prone to poor compliance in taking medications, especially ones that significantly limit their activity.

To determine whether Coumadin or antiplatelet drugs are preferable in children with mechanical valve prostheses, we prospectively followed up all children and young adults (aged 18 years or younger at the time of implantation) who received anticoagulation for a left-sided mechanical heart valve from October 1986 through October 1996. This article compares the rates of late death, thromboembolism, and bleeding events in the patients given Coumadin with those in the patients given antiplatelet drugs. It also provides a pooled analysis of the currently available literature on this topic.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 
This study includes the 64 patients, aged 18 years or younger, who survived the implantation of a mechanical prosthetic valve in the aortic or mitral position. Three patients who underwent replacement of a tricuspid valve functioning as the systemic atrioventricular valve (2 after atrial repair for transposition of the great arteries and 1 with congenitally corrected transposition) were included. No patient was excluded from the study for any reason other than age at the time of operation. All valves were St. Jude Medical (St. Paul, MN) and were implanted at the Medical University of South Carolina.

Dates of valve replacement were from August 1979 to January 1996. Thirty-two of the 64 patients were operated on before October 1986. These patients usually were treated with no anticlotting prophylaxis until October 1986, when they were given either Coumadin or aspirin and dipyridamole [14]. The 32 patients operated on after October 1986 were started on anticlotting prophylaxis at the time of operation. Thus, all patients were treated with either Coumadin or aspirin and dipyridamole since October 1986. The choice between the two regimens was made by the patient's surgeon or referring physician. The dosage of Coumadin was adjusted to keep the prothrombin time about 1.5 times control. The dosage of aspirin was 5 to 6 mg • kg^-1 • d, and the dosage of dipyridamole was 6 mg • kg^-1 • d in three divided doses [2, 7].

All patients were followed up prospectively and actively beginning in October 1986. Follow-up was carried out yearly by a survey form completed by the patient or the patient's parents, or by direct contact with the patient, the patient's parents, or the referring physician. Such follow-up is done routinely for all patients, both pediatric and adult, who undergo valve operations at this institution. One patient was lost to follow-up. Therefore, follow-up was 98% complete (closing interval, January 1996 to October 1996) at a mean of 6.1 ± 3.5 years (range, 1 month to 10 years). Patient age at operation ranged from 6 months to 18 years (mean, 11.3 ± 4.9 years). Patient age at the start of follow-up ranged from 10 months to 25 years (mean, 13.5 ± 6.2 years). Patient age at the end of follow-up ranged from 3 to 35 years (mean, 19.3 ± 8 years).

Forty-eight patients initially were anticoagulated with Coumadin and 16 with aspirin and dipyridamole. During the study, 3 patients crossed over from Coumadin to aspirin and dipyridamole (1 because of a bleeding event, 1 because of difficulty in regulating the prothrombin time, and 1 by physician choice); 4 patients crossed over from aspirin and dipyridamole to Coumadin (2 because of embolic events and 2 by physician choice). For the purposes of analysis, patients were censored at the time of crossover; only events that occurred before crossover were included in all analyses. Standard definitions of valve-related morbidity and mortality were used [15].

Patient variables were analyzed as predictors of mortality, thromboembolism, and bleeding. For categorical predictors, event-free estimates were derived for each level of the variable by actuarial techniques, and subgroups were compared by Mantel-Cox [16]. Continuous predictors were broken down into quartiles and evaluated in a similar fashion. The following variables were analyzed as predictors: sex, race, valve location, valve size, operative indication, date of operation, age at operation, age at initiation of study, and anticlotting regimen. By univariate analysis, male sex (p = 0.03), mitral location (p = 0.09), and congenital disease as the operative indication (p = 0.05) were predictors of mortality. These variables were entered into a multivariate Cox proportional hazards model. Only male sex (relative risk, 7.4; 95% confidence interval, 0.9 to 59.1; p = 0.02) remained as a predictor of mortality. By univariate analysis, no variable was a significant predictor of either thromboembolism or bleeding. Year of operation was analyzed further as both a two-level (operation before versus after October 1986) and a continuous variable. By neither analysis was it a significant predictor of thromboembolism or bleeding. Therefore, patients operated on before and after October 1986 were considered together in all analyses.

Event rates in patients with aortic valve replacement were nearly identical to those in patients with mitral valve replacement (thromboembolism, 2.5% versus 2.7% per patient-year, respectively, p = 0.9; bleeding, 0.6% versus 1.2% per patient-year, respectively p = 0.6). This is in agreement with previously published information on St. Jude valves in adults [1]. Therefore, patients with aortic and mitral valve replacements were considered together in all analyses.

Data are presented as means plus or minus standard deviations. Comparisons between the two anticoagulation groups (Tables 1, 2) are by unpaired Student's t test for continuous variables and by ² for categorical variables. Time-related events (survival, thromboembolism, and bleeding) are presented as actuarial curves with the standard error of the estimate [16]. Comparison between groups is by Mantel-Cox. Time zero is the start date of a given anticoagulation regimen. Linearized event rates are presented as percent per patient-year, are shown with 70% confidence limits, and are compared by the likelihood ratio test. Calculation of power is by noncentral ² distribution. Statistical significance is defined as a p value less than 0.05.

	Results

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

	Mortality

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 
There was no difference in survival between the patients who received Coumadin and those who received aspirin and dipyridamole (Fig 1). There were nine deaths during the study, seven in patients who took Coumadin and two in patients who took aspirin and dipyridamole. Three of the deaths in the Coumadin group were considered to be valve-related [15]: one was due to a bleeding event resulting in massive hemothorax and two were due to sudden death. The other four deaths in patients who took Coumadin resulted from ventricular dysfunction. Neither of the deaths in the patients who took aspirin and dipyridamole was valve-related. One occurred at a non–valve-related reoperation; the other resulted from ventricular dysfunction.

View larger version (15K): [in this window] [in a new window]   Fig 1. . Actuarial survival. (A + D = aspirin and dipyridamole; C = Coumadin.)

	Thromboembolism

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

View larger version (15K): [in this window] [in a new window]   Fig 2. . Freedom from thromboembolism. (A + D = aspirin and dipyridamole; C = Coumadin.)

	Bleeding

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

View larger version (14K): [in this window] [in a new window]   Fig 3. . Freedom from bleeding. (A + D = aspirin and dipyridamole; C = Coumadin.)

	Linearized Rates of Thromboembolism and Bleeding Events

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

	Literature Analysis

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

	Comment

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

This study has several strengths and weaknesses. One strength is the method used to acquire data. All patients were followed up prospectively and actively for periods extending to 10 years. The data, therefore, avoid the incompleteness that can result from retrospective review and passive data acquisition. The total number of patient-years of follow-up is at least as great as that in most other studies in the literature (see Table 4). Another strength is the homogeneity of the valve replacement devices. All the valves used in these patients were of a single type (St. Jude Medical). Therefore, the study avoids variations that can result from the inclusion of data on different valve types. On the other hand, our results apply only to this valve type, and may not necessarily be applicable to other valves.

The major weakness of this study is the small number of patients, particularly in the aspirin and dipyridamole group. This small sample size limits the power of the study and means that there may be real differences between the two groups that we were unable to detect. To address this limitation in part, we performed the literature analysis, which provided information on a total of 497 patients (see Table 4). This analysis confirmed the apparent equivalence of treatment with either Coumadin or antiplatelet agents in children with mechanical valves (see Table 5).

Another weakness of this study is its lack of randomization. Although the clinical characteristics of the two groups appear to be equivalent (see Tables 1, 2), it is impossible to exclude a hidden bias in the assignment of patients to the treatment groups. A further, potential weakness is the fact that 32 of the patients (50%) were operated on before the start of the study. Most of these 32 patients were maintained without anticoagulation until the study start date, October 1986, when they were begun on one of the two anticoagulation regimens. It is possible that these patients would have different event rates than the patients who received anticoagulation from the time of operation. However, separate analysis of the patients operated on before and after the study start date produced results that did not differ significantly.

The literature analysis pooled information available in the English literature since 1985 on thromboembolism and bleeding rates in children with left-sided mechanical valves. This analysis showed no detectable differences in event rates with the use of Coumadin or antiplatelet agents (see Table 5). Several reports were excluded from this analysis because they did not contain enough information to derive discrete event numbers or patient-years of follow-up on a given treatment regimen. Two of the excluded reports contained follow-up information on a large number of patients (396) [17, 18]. One found no difference in event rates between Coumadin and antiplatelet agents [17]. A second favored antiplatelet agents in patients with aortic valve replacements, and Coumadin in patients with mitral valve replacements [18]. Although the information in these reports cannot be combined with that from other studies to give pooled, linearized event rates, it does not appear to be at odds with our analysis (see Table 5).

Patient compliance in taking medication will affect the results of any study of anticoagulation for valve prostheses. We attempted to obtain information on compliance in our follow-up surveys. However, in practice, it proved difficult to obtain either reliable or complete information on the adequacy of anticoagulation. Thus, we were unable to factor compliance into our analyses.

A question remains: If Coumadin is a more effective anticoagulant in adults with mechanical valves [1], why is it not also more effective in children? One possibility is that the coagulation system is intrinsically different in children and adults. Information on this possibility is conflicting, but most indicates that this probably is not the case [19]. Another possibility is that hemodynamic differences between children and adults account for the difference [2, 20]. Compared with adults who receive anticoagulation for mechanical heart valves, children would be expected to have higher resting heart rates and lower incidences of atrial arrhythmias, atrial enlargement, and depressed ventricular function. These differences may make children less susceptible in general to thromboembolic events than adults. Another question is at what age should children with mechanical valves be considered adults, and be switched from antiplatelet agents to Coumadin? There is no exact answer to this question. Rather, the transition probably takes place over a period of years. In this study, 2 of the 4 patients who crossed over from aspirin and dipyridamole to Coumadin did so because their primary physician believed they were old enough (at the ages of 17 and 21 years) to be considered adults.

In conclusion, Coumadin and aspirin plus dipyridamole provided similar protection against complications in this group of children and young adults with left-sided St. Jude mechanical valves. Bleeding occurred somewhat more often in the patients who received Coumadin, but this difference was small. These findings are in agreement with the information currently available in the literature. Further useful information would be provided by a prospective, randomized study of children with mechanical valves treated with either Coumadin or antiplatelet agents. In the absence of such a study, we suggest that it is reasonable to consider the preferences of the patient, family, and physician, the lifestyle of the patient, and the convenience of medication dosing and prothrombin time monitoring in choosing anticlotting prophylaxis for children with mechanical valves.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 
Presented at the Forty-third Annual Meeting of the Southern Thoracic Surgical Association, Cancun, Mexico, Nov 7–9, 1996.

Address reprint requests to Dr Bradley, Division of Cardiothoracic Surgery, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425-1095.

	References

Top Footnotes Abstract Introduction Material and Methods Results Mortality Thromboembolism Bleeding Linearized Rates of... Literature Analysis Comment References

 

1. Edmunds LH. Thrombotic and bleeding complications of prosthetic heart valves. Ann Thorac Surg 1987;44:430–45.[Abstract]
2. Verrier ED, Tranbaugh RF, Soifer SJ, Yee ES, Turley K, Ebert PA. Aspirin anticoagulation in children with mechanical aortic valves. J Thorac Cardiovasc Surg 1986;92:1013–20.[Abstract]
3. Ilbawi MN, Lockhart CG, Idriss FS, et al. Experience with St. Jude Medical valve prosthesis in children. J Thorac Cardiovasc Surg 1987;93:73–9.[Abstract]
4. Cornish EM, Human DG, de Moor MMA, et al. Valve replacement in children. Thorac Cardiovasc Surg 1987;35:176–9.[Medline]
5. Harada Y, Imai Y, Kurosawa H, Ishihara K, Kawada M, Fukuchi S. Ten-year follow-up after valve replacement with the St. Jude Medical prosthesis in children. J Thorac Cardiovasc Surg 1990;100:175–80.[Abstract]
6. LeBlanc JG, Sett SS, Vince DJ. Antiplatelet therapy in children with left-sided mechanical prostheses. Eur J Cardiothorac Surg 1993;7:211–5.[Abstract]
7. Bradley LM, Midgley FM, Watson DC, Getson PR, Scott LP III. Anticoagulation therapy in children with mechanical prosthetic cardiac valves. Am J Cardiol 1985;56:533–5.[Medline]
8. Milano A, Vouhé PR, Baillot-Vernant F, et al. Late results after left-sided cardiac valve replacement in children. J Thorac Cardiovasc Surg 1986;92:218–25.[Abstract]
9. McGrath LB, Gonzalez-Lavin L, Eldredge WJ, Colombi M, Restrepo D. Thromboembolic and other events following valve replacement in a pediatric population treated with antiplatelet agents. Ann Thorac Surg 1987;43:285–7.[Abstract]
10. Schaffer MS, Clarke DR, Campbell DN, Madigan CK, Wiggins JW, Wolfe RR. The St. Jude Medical cardiac valve in infants and children: role of anticoagulant therapy. J Am Coll Cardiol 1987;9:235–9.[Abstract]
11. Stewart S, Ciancotta D, Alexson C, Manning J. The long-term risk of warfarin sodium therapy and the incidence of thromboembolism in children after prosthetic cardiac valve replacement. J Thorac Cardiovasc Surg 1987;93:551–4.[Abstract]
12. Duran CMG, Gometza B, Martin-Duran R, Saad E, Al-Halees Z. Performance of 96 Carbomedics valve replacements in 75 patients less than twenty-one years of age. Ann Thorac Surg 1994;58:639–45.[Abstract]
13. Ibrahim M, Cleland J, O'Kane H, Gladstone D, Mullholland C, Craig B. St. Jude Medical prosthesis in children. J Thorac Cardiovasc Surg 1994;108:52–6.[Abstract/Free Full Text]
14. Pass HI, Sade RM, Crawford FA, Hohn AR. Cardiac valve prostheses in children without anticoagulation. J Thorac Cardiovasc Surg 1984;87:832–5.[Abstract]
15. Edmunds LH, Clark RE, Cohn LH, Grunkemeier GL, Miller DC, Weisel RD. Guidelines for reporting morbidity and mortality after cardiac valvular operations. Ann Thorac Surg 1996;62:932–5.[Abstract/Free Full Text]
16. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958;53:457–81.
17. El Makhlouf A, Friedli B, Oberhansli I, Rouge JC, Faidutti B. Prosthetic heart valve replacement in children. J Thorac Cardiovasc Surg 1987;93:80–5.[Abstract]
18. Rao PS, Solymar L, Mardini MK, Fawzy ME, Guinn G. Anticoagulant therapy in children with prosthetic valves. Ann Thorac Surg 1989;47:589–92.[Abstract]
19. Lee GR, Bithell TC, Foerster J, Athens JW, Lukens JN, eds. Wintrobe's clinical hematology, 9th ed. Philadelphia: Lea & Febiger, 1993:597.
20. Ebert PA. Discussion of Gardner TJ, Roland JMA, Neill CA, Donahoo JS. Valve replacement in children. J Thorac Cardiovasc Surg 1982;83:178–85.[Abstract]

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Scott M. Bradley Robert M. Sade Fred A. Crawford, Jr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bradley, S. M. Articles by Stroud, M. R. Search for Related Content PubMed PubMed Citation Articles by Bradley, S. M. Articles by Stroud, M. R. Related Collections Related Article