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Thromboembolism in Patients with Aortic Porcine Bioprostheses
Thromboembolism in Patients with Aortic Porcine Bioprostheses Tirone E. David, M.D., Walter I. C. Ho, and George T. Christakis, M.D. ABSTRACT Thromboembolism was prospectively studied in 215 patients who survived aortic valve replacement with porcine bioprostheses. All patients were anticoagulated with warfarin sodium during the first 3 postoperative months. Thereafter, 80 patients received aspirin (325 or 650 m g per day) and 135 received no antiplatelet or anticoagulant drugs. The two groups of patients were similar. Thromboembolic complications were carefully searched for during the follow-up interviews. Patients were removed from the study after a thromboembolic event unless there was no change in their management. The follow-up ranged from 6 to 80 months (mean, 36 months). The linearized thromboembolic rate in patients on a regimen of aspirin was 1.3% per patient-year and in patients not taking aspirin, 5.2% per patient-year ( p < 0.02). Replacement of the ascending aorta and patch enlargement of the aortic annulus with a Teflon graft were identified as significant risk factors for thromboembolism in patients with aortic porcine bioprostheses. These findings indicate that patients with aortic porcine bioprostheses should receive aspirin, especially if they also had replacement of the ascending aorta or patch enlargement of the aortic annulus with a Teflon graft.
The rationale for using porcine bioprostheses for aortic valve replacement is their lessened tendency to cause thromboembolism without anticoagulation. Indeed, most reports indicate a relatively low incidence of thromboembolic complications in patients with aortic porcine bioprostheses [l-41.Although permanent anticoagulation with Coumadin (crystalline warfarin sodium) compounds is usually not necessary [5-81, antiplatelet agents are recommended to further decrease thromboembolic complications (8, 91. We prospectively studied thromboembolism in patients with aortic porcine bioprostheses, and evaluated the effect of aspirin in these patients during a seven-year period.
Material and Methods From January, 1978, to December, 1983, 222 patients underwent aortic valve replacement with porcine bio-
prostheses at the Toronto Western Hospital. Four patients died in the hospital 2 of myocardial infarction, l of multiorgan failure, and 1of sepsis. All survivors were sent home on a regimen of warfarin sodium and were instructed to take this medication for 3 months. The prothrombin time was maintained at 1.5 to 2.0 times the control. By the end of the third postoperative month, 3 additional patients had died: 1 of spontaneous retroperitoneal bleeding, 1 of perforation of the colon and sepsis, and 1 of rupture of a descending thoracic aortic aneurysm. The surviving 215 patients are the subject of this study. Patients were referred for aortic valve replacement by fourteen cardiologists. Four cardiologists routinely started their patients on a regimen of aspirin (325 mg of plain aspirin per day or 650 mg of enteric-coated aspirin per day) after discontinuation of warfarin sodium at the end of the third postoperative month. This difference in long-term management allowed us to prospectively study the effect of aspirin in patients with aortic bioprostheses. Patients were seen by their refemng cardiologist at least once a year, and we also contacted them by telephone or mail every summer. Specific questions regarding thromboembolism were asked at every interview. Questions related to the central nervous system, such as blurred vision, numbness or paralysis of a limb or other part of the body, blackouts, and double vision, were repeatedly asked of all patients. Any neurological event was recorded as a transient ischemic attack (TIA) when the duration was only a few minutes or as a stroke when it lasted more than thirty minutes. Similarly detailed questions were asked regarding the heart and the peripheral circulation. Patients who sustained a thromboembolic event were removed from the study unless there were no changes in their management as far as anticoagulation therapy was concerned. There were 80 patients On a regimen of aspirin and 135 patients taking no antiplatelet or anticoagulant agent. Table 1shows the clinical and heart catheterization data, and Table 2 provides operative data on these two groups of patients.
Statistical Analysis From the Division of Cardiovascular Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ont, Canada.
Presented at the Twenty-first Annual Meeting of The Society of Thoracic Surgeons, Phoenix, AZ, Jan 21-23, 1985. Address reprint requests to Dr. David, 399 Bathurst St, Toronto, Ont, Canada M5T 2S8.
229
Univariate and multivariate analyses were used to identify which of the following variables were possibly related to thromboembolism and late death in all patients: aspirin, gender, valvular lesion, left ventricular function, coronary artery disease, atrial fibrillation, type and size of the porcine bioprostheses, patch enlargement of
230 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
Table I. Clinical and Heart Catheterization Data on the Two Groups of Patientsa Aspirin
Table 2. Operative Data on the Two Groups of Patientsa No Aspirin (N = 135)
Variable
Aspirin
No Aspirin
(N = 80)
(N = 135)
9 (11.2)
12 (8.9)
Variable
(N
Age (yr) Sex Male Female Valvular lesion
58.4 (25-79)
59.0 (18-81)
Atrial fibrillatiodflutter Type of bioprosthesis
60 (75)
(71.1) (28.9)
Carpentier-Edwards Hancock I1 (supraannular) Size of bioprosthesis (mm)
59 (73.7) 21 (26.2)
110 (81.5) 25 (18.5)
21 23 25 27 29 Patch enlargement of aortic annulus Teflon patchb
5 (6.2) 17 (21.2) 19 (23.7) 24 (30) 15 (18.7)
8 (5.9) 29 (21) 52 (38.5) 32 (23.7) 14 (10.4)
11 (13.7) 4 (5.0) 11 (13.7)
15 (11.1)
53 (66.2) 7 (8.7) 11 (13.7) 9 (11.2)
82 (60.7) 19 (14) 13 (9.6) 21 (15.6)
Stenosis Insufficiency Mixed
Left ventricular function Mild impairment Moderate impairment Severe impairment Coronary artery disease None One vessel Two vessels Three vessels
Ascending aortic aneurysm
=
80)
20
(25)
96 39
46 27 7
(57.5) (33.7) (8.7)
82 35 18
(60.7) (25.9) (13.3)
68 9 3
(85) (11.2) (3.7)
115 17 3
(85.2) (12.6) (2.2)
53
(66.2)
8 12
(10) (15)
7 11
(8.7) (13.7)
82 16 15 22 11
(60.7) (11.8) (11.1) (16.3) (8.2)
aExcept for age, numbers in parentheses are percentages.
the ascending aorta, and replacement of the ascending aorta. A Cox regression model was employed to determine the relative importance of these variables. The group of patients taking aspirin was compared with the group not taking aspirin by unpaired Student t tests. Actuarial survival and thromboembolism-free rates were calculated, and curves were constructed. All analyses were done using a computer program from SAS Institute (Cary, NC).
Results Patients were followed for 6 to 80 months. The mean follow-up was 36 months for all patients, 34 months for the group of patients on aspirin, and 37 months for the group not taking aspirin. Follow-up was complete for 206 patients. The remaining 9 patients were lost at different postoperative intervals, but it was possible to determine whether they were alive or not through the Registrar General of Ontario. The two groups (aspirin and no aspirin) were statistically similar as far as all variables shown in Tables 1 and 2 were concerned.
Thromboembolism Fifteen patients experienced a TIA, 7 sustained a stroke, and 3 sustained a myocardial infarction. The following variables significantly increased the risk of thromboembolism: no aspirin, replacement of the ascending aorta, and patch enlargement of the aortic annulus with a Teflon graft. A stepwise logistical analysis of these three variables revealed that no aspirin was the most
Autologous pericardium Replacement of ascending aorta' Aortocoronary bypass grafts None One Two
Three or more
9 (6.7) 11 (8.2)
'Numbers in parentheses are percentages. bUSCl Teflon fabric outflow tract patch. 'Meadox Medicals woven low-porosity graft.
significant ( p = 0.005), followed by replacement of the ascending aorta ( p = 0.012) and then by patch enlargement of the aortic annulus with a Teflon graft ( p = 0.025). The average age of patients who experienced a TIA (50.3 years) was significantly lower ( p < 0.02) than the average age of patients who had a stroke (66.3 years). In the group of patients taking aspirin, there were two TIAs and one stroke. The latter occurred during medical treatment of infective endocarditis in an elderly woman who had had combined replacement of the ascending aorta and aortic valve three and one-half years earlier. She was cured of the infection, and she also improved neurologically. The 2 patients who experienced the TIAs remained on aspirin and did not have any further thromboembolic events. In the group of patients not taking aspirin, there were thirteen TIAs, six strokes, and three myocardial infarctions. Of the 13 patients who experienced TIAs, only 4 consulted their physicians and had aspirin prescribed; all 4 did well during a mean follow-up of 20 months. The diagnosis of TIA was made retrospectively in the other 9 patients, and no treatment was prescribed. Five of these patients had further episodes of TIA and eventually were started on a regimen of aspirin. Of the 6 patients who sustained strokes, 1died, 2 recovered partially, and 3 recovered completely. The 5 survivors ultimately were put on a regimen of aspirin or aspirin plus dipyridamole and had no further thromboembolic events during a
David, Ho, and Christakis: Thromboembolism with Aortic Porcine Bioprostheses
231
t
8o
I 0 4
70
Aspirin Group No Aspirin Group
75.3f6.0 70
11' 0
1
2
86.6f5.84
3
Years
4
5
L
I
1
I
0
1
2
3
-1
4
5
Years
Fig I . Actuarial curves for patients without thromboembolism.
Fig 2 . Actuarial survival, including operative deaths.
mean follow-up of 17 months. Two of the 3 patients who had a myocardial infarction died. None of these 3 patients had angiographic evidence of coronary artery disease. The incidences of TIA and stroke in patients taking aspirin were significantly lower than in patients not so doing. Including TIA, stroke, and myocardial infarction, the linearized thromboembolic rate was 1.3% per patient-year for the group of patients on a regimen of aspirin and 5.2% per patient-year for the group not taking aspirin ( p < 0.02). Actuarial curves for patients without thromboembolism are shown in Figure 1.
cine bioprostheses. Carpentier [111 observed thromboembolic complicationsonly during the first postoperative year. Most investigators [l-41, however, have described a steady, although low, thromboembolic rate after aortic valve replacement with porcine bioprostheses. After analyzing several variables that could possibly affect thromboembolism, we found that only aspirin, replacement of the ascending aorta, and patch enlargement of the aortic annulus with a Teflon graft were significant in our patients. Aspirin, one of the oldest antiplatelet agents used for antithrombotic therapy, has been recommended for patients with porcine bioprostheses both in the aortic and mitral positions [8, 9, 121. Nudez and colleagues [8] reported no thromboembolism in a group of 201 patients taking 1 gm of aspirin per day and followed for 6 to 66 months (mean, 23 months). Geha and associates [9] reported no thromboembolic complicationsin 117 patients treated with aspirin plus dipyridamole during a mean follow-up of 38 months. In our study, aspirin significantly decreased the risk of thromboembolism in both male and female patients. Our 2 patients from the aspirin group who experienced TIAs were taking 650 mg of enteric-coated aspirin per day. Although the dose of aspirin may not be critical for its antithrombotic effect (131, recent evidence indicates that its effect is more intense when smaller doses are administered [14]. In a later study of patients with mitral bioprostheses by Nunez and co-workers [12], the incidence of thromboembolism was higher in patients taking 1,000 mg of aspirin every day compared with patients taking 500 mg every second day. The incidence of thromboembolism in our patients taking no anticoagulant or antiplatelet agents (5.2%per patient-year) appears excessively high compared with the 1 or 2% per patient-year frequently reported by others [l-41. However, most thromboembolic events in our patients were TIAs that seldom lasted more than a few minutes. These patients had frequently forgotten they experienced such neurological deficits until they were asked during the follow-up interview. We also considered myocardial infarction in patients without coro-
Other Complications Infective endocarditis developed in 3 patients; 2 were successfully treated with antibiotics alone and 1required reoperation. Two other patients also required reoperation: 1 because of prosthetic dehiscence and the other because of perforation of the cusps due to excessively long sutures. Late Mortality There were 10 late deaths: 2 among patients on a regimen of aspirin (both noncardiac and unrelated to thromboembolism) and 8 among patients not taking aspirin (2 due to myocardial infarction, 1 to congestive heart failure, 1 to stroke, and 4 noncardiac and unrelated to thromboembolism). There was no statistical difference in the linearized late mortality rate in these two groups of patients (0.88%per patient-year versus 1.91% per patient-year, respectively). Analysis of all variables revealed that only impaired left ventricular function was associated with increased late mortality ( p < 0.01). Figure 2 shows the actuarial survival for all patients, including operative deaths.
Comment The main advantage of tissue over mechanical prostheses for aortic valve replacement is their lessened tendency to cause thromboembolism without anticoagulation [1-2,6, lo]. Some investigators [5,9] have described no thromboembolism at all in patients with aortic por-
232 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
nary artery disease as a thromboembolic complication. Excluding TIA and myocardial infarction, t h e thromboembolic rate i n these patients was 1.4% p e r patient-
year. Patients who experienced a TIA tended to have recurrent TIAs if left untreated. The average age of patients who experienced a TIA was significantly lower than the average age of patients who sustained a stroke. This finding suggests that o t h e r circulatory factors m a y play a role i n t h e development of stroke i n older patients. Atrial fibrillation i s known t o increase t h e risk of thromboembolism i n patients w i t h mitral bioprostheses [lo]. Cohn and associates [ l ] found that atrial fibrillation also increased t h e incidence of thromboembolism in patients w i t h an aortic porcine bioprosthesis. Atrial fibrillation had no effect on thromboembolism in our patients. The five-year actuarial survival, including early deaths, in our patients was 86.6% and is similar to that i n o t h e r reports [l, 3, 41. There w a s no significant difference between patients taking aspirin a n d those taking no antiplatelet agents. Nonetheless, there were 3 late d e a t h s directly related t o thromboembolism a m o n g patients taking no aspirin a n d no late d e a t h s due t o thromboembolism i n patients on aspirin. Although this difference d i d n o t reach statistical significance, it may indicate a trend t o w a r d a lower late mortality i n patients taking aspirin. After analyzing several variables that could possibly affect late mortality, we found that only impaired left ventricular function was statistically significant. Unlike t h e findings i n o t h e r reports [l, 131, coronary artery disease d i d n o t affect late mortality i n our patients. This may be due to o u r relatively short follow-up. In conclusion, thromboembolism appears t o be a comm o n and serious complication i n patients with aortic porcine bioprostheses. T h e risk of thromboembolism i n these patients is increased when they have concomitant replacement of the ascending aorta or patch enlargem e n t of t h e aortic annulus with a Teflon graft. Aspirin is an effective antithrombotic a g e n t i n patients of both sexes who have aortic porcine bioprostheses.
References 1. Cohn LH, Alfred EN, DiSesa VJ, et al: Early and late risk of aortic valve replacement. J Thorac Cardiovasc Surg 88695, 1984 2. Joyce LD, Nelson RM: Comparison of porcine valve xenografts with mechanical prostheses. J Thorac Cardiovasc Surg 88:102, 1984 3. Jamieson WRE, Pelletier LC, Janusz MT, et al: Five-year evaluation of the Carpentier-Edwards porcine bioprosthesis. J Thorac Cardiovasc Surg 88:324, 1984 4. Pelletier C, Chaitman BR, Baillot R, et al: Clinical and hemodynamic results with the Carpentier-Edwards porcine bioprosthesis. Ann Thorac Surg 34:612, 1982 5. Cevese PG, Gallucci V, Morea M, et al: Heart valve replacement with the Hancock bioprosthesis: an analysis of longterm results. Circulation 56:Suppl3111,1977 6. Williams JB, Karp RB, Kirklin JW,et al: Considerations in selection and management of patients undergoing valve
7.
8.
9.
10.
11. 12.
13.
14.
replacement with glutaraldehyde-fixed porcine bioprostheses. Ann Thorac Surg 30:247, 1980 Grehl TM, Naifeh JG, Broda J, et al: Heterograft cardiac valve prostheses: a five-year follow-up. Ann Thorac Surg 30:173, 1980 Nuiiez L, Gil Aguado M, Celemin D, et al: Aspirin or Coumadin as the drug of choice for valve replacement with porcine bioprosthesis. Ann Thorac Surg 33:354, 1982 Geha AS, Hammond GL, Laks H, et al: Factors affecting performance and thromboembolism after porcine xenograft cardiac valve replacement. J Thorac Cardiovasc Surg 83377, 1982 Edmunds LH Jr: Thromboembolic complications of current cardiac valvular prostheses (collective review). Ann Thorac Surg 34:96, 1982 Carpentier AF: Discussion of Cohn et a1 [l] Nunez L, Gil Aguado M, Larrea JL, et al: Prevention of thromboembolism using aspirin after mitral valve replacement with porcine bioprosthesis. Ann Thorac Surg 37:84, 1984 Eichner ER PlateIets, carotid and coronaries: critique on antithrombotic role of antiplatelet agents, exercise and certain diets. Am J Med 77:513, 1984 Pedersen AK, FitzGerald GA: Dose-related kinetics of aspirin. N Engl J Med 311:1206, 1984
Discussion DR. WILLIAM R. E. JAMIESON (Vancouver, BC, Canada): I thank Dr. David and his colleagues for bringing to the attention of the Society the problem of thromboembolism with aortic valve replacement and porcine bioprostheses. 1 appreciated the opportunity to review the manuscript well in advance. For comparison, I will briefly discuss the experience of my coworkers and me with thromboembolism and aortic valve replacement with porcine bioprostheses at the University of British Columbia. Between 1975 and 1984, 581 patients with the Carpentier-Edwards standard porcine aortic prosthesis were evaluated. The total accumulated follow-up was 2,500 patientyears, with a mean of 52 months. The freedom from thromboembolism was 92% at 7 years for the total patient group. The freedom from minor thromboembolic events was 97% at 7 years and freedom from major events was 94% at 7 years. Twenty-one patients in this total group experienced thromboembolic events. The total number of events was 28, an incidence of 1.1%per patient-year. There were 13 major and 15 minor events. There was no mortality related to thromboembolism in the series. Sixteen of these 21 patients had 23 thromboembolic events while in sinus rhythm. The other 5 had a total of 5 events while in atrial fibrillation. A portion of our patients were managed on anticoagulants and antiplatelet agents. Eighty percent of the total patient population who had neither of these two medications experienced 18 events for an incidence of 0.9% per patient-year. This finding is in dramatic contrast to the incidence in Dr. David’s series of 5.2% per patient-year. Ten percent of our patients were on antiplatelet agents. These patients experienced 5 thromboembolic events, an incidence of 1.6% per patient-year. Eight percent of the patients were on a regimen of long-term anticoagulants; they experienced 5 events for an incidence of 2.4% per patient-year. For those patients on antiplatelet agents, we essentially agree with Dr. David and his associates. Our incidence of thromboembolic events is 1.6% per patient-year, and theirs is 1.2% per patient-year. On the contrary, our incidence of thromboem-
233 David, Ho, and Christakis: Thromboembolism with Aortic Porcine Bioprostheses
bolic events for patients receiving neither antiplatelet agents nor anticoagulants is 0.9% per patient-year, whereas theirs is 5.2% per patient-year. Dr. David, would you please explain this difference?
c. CALLAGHAN (Edmonton, Alta, Canada): It rather seems odd that the presenter and both discussants of this paper are from Canada. This probably has nothing to do with the Food and Drug Administration regulations concerning bioprostheses, but it probably does have to do with those for mechanical prosthetic valves. I think in order to discuss thromboembolism, it is important that there be something to compare. My colleagues and I are in the throes of a review of all our prosthetic valves (approximately 1,600) at the University of Alberta Hospital. We are attempting to examine, from the thromboembolic aspect, all the valves we have used, which include bioprostheses and ball valves. What concerned me in comparing our results with those of Dr. David’s group is the same thing Dr. Jamieson mentioned: the high incidence of thromboembolic phenomena in the series of Dr. David and his co-workers in patients with bioprostheses treated after 3 months with warfarin sodium alone. The 5.2% incidence is much higher than that previously reported in the literature.
DR. JOHN
We have used two prostheses of the tilting-disc type, the Lillehei-Kaster and the Omni, in 139 patients. In this group, there was 1 TIA and 1 stroke and mortality was 2.5% over the 36-month study period. Dr. David, would you explain the high incidence in your baseline group from which you extrapolated the benefit of using aspirin anticoagulation? DR. DAVID: I thank Drs. Jamieson and Callaghan for their comments. Most of the minor thromboembolic events were noted by third- and fourth-year medical students during the followup interviews. The interviewers were entirely unbiased and were looking specifically for valve-related complications. Whenever a medical student recorded that a patient sustained a TIA, a physician reviewed the case record. The incidence of thromboembolism in our patients was higher than in other reports, but remember that many of our patients had patch enlargement of the aortic annulus or replacement of the ascending aorta. We discovered that these associated procedures increased the risk of thromboembolism. Besides, we included myocardial infarction as a thromboembolic complication. Even after all these factors were excluded, the difference between patients on aspirin and those not taking aspirin remained significant.
Notice from the American Board of Thoracic Surgery The American Board of Thoracic Surgery began its recertification process in 1984. Diplomates interested in participating in recertification should maintain a documented list of the cardiothoracic operations they performed during the year prior to application for recertification. They should also keep a record of their attendance at thoracic surgical meetings and other continuing education medical activities for the two years prior to application for recertification. In place of a cognitive examination, candidates for recertification will be required to complete both the general thoracic and cardiac portions of the SESATS I1 Syllabus (Self-Education/Self-Assessmentin Thoracic Surgery). It is not necessary for candidates to purchase
SESATS I1 prior to applying for recertification. SESATS I1 booklets will be forwarded to candidates after their applications have been received. Diplomates whose ten-year certificates will expire in 1988 may begin the recertification process in 1986. This new certificate will be dated ten years from the time of expiration of the original certificate. Recertification is also open to any Diplomate with an unlimited certificate. The deadline for submission of applications for recertification is July 1, 1986. A recertification brochure outlining the rules and requirements for recertification in thoracic surgery is available on request from the American Board of Thoracic Surgery, 14640 E Seven Mile Rd, Detroit, MI 48205.
The rationale for using porcine bioprostheses for aortic valve replacement is their lessened tendency to cause thromboembolism without anticoagulation. Indeed, most reports indicate a relatively low incidence of thromboembolic complications in patients with aortic porcine bioprostheses [l-41.Although permanent anticoagulation with Coumadin (crystalline warfarin sodium) compounds is usually not necessary [5-81, antiplatelet agents are recommended to further decrease thromboembolic complications (8, 91. We prospectively studied thromboembolism in patients with aortic porcine bioprostheses, and evaluated the effect of aspirin in these patients during a seven-year period.
Material and Methods From January, 1978, to December, 1983, 222 patients underwent aortic valve replacement with porcine bio-
prostheses at the Toronto Western Hospital. Four patients died in the hospital 2 of myocardial infarction, l of multiorgan failure, and 1of sepsis. All survivors were sent home on a regimen of warfarin sodium and were instructed to take this medication for 3 months. The prothrombin time was maintained at 1.5 to 2.0 times the control. By the end of the third postoperative month, 3 additional patients had died: 1 of spontaneous retroperitoneal bleeding, 1 of perforation of the colon and sepsis, and 1 of rupture of a descending thoracic aortic aneurysm. The surviving 215 patients are the subject of this study. Patients were referred for aortic valve replacement by fourteen cardiologists. Four cardiologists routinely started their patients on a regimen of aspirin (325 mg of plain aspirin per day or 650 mg of enteric-coated aspirin per day) after discontinuation of warfarin sodium at the end of the third postoperative month. This difference in long-term management allowed us to prospectively study the effect of aspirin in patients with aortic bioprostheses. Patients were seen by their refemng cardiologist at least once a year, and we also contacted them by telephone or mail every summer. Specific questions regarding thromboembolism were asked at every interview. Questions related to the central nervous system, such as blurred vision, numbness or paralysis of a limb or other part of the body, blackouts, and double vision, were repeatedly asked of all patients. Any neurological event was recorded as a transient ischemic attack (TIA) when the duration was only a few minutes or as a stroke when it lasted more than thirty minutes. Similarly detailed questions were asked regarding the heart and the peripheral circulation. Patients who sustained a thromboembolic event were removed from the study unless there were no changes in their management as far as anticoagulation therapy was concerned. There were 80 patients On a regimen of aspirin and 135 patients taking no antiplatelet or anticoagulant agent. Table 1shows the clinical and heart catheterization data, and Table 2 provides operative data on these two groups of patients.
Statistical Analysis From the Division of Cardiovascular Surgery, Toronto Western Hospital, University of Toronto, Toronto, Ont, Canada.
Presented at the Twenty-first Annual Meeting of The Society of Thoracic Surgeons, Phoenix, AZ, Jan 21-23, 1985. Address reprint requests to Dr. David, 399 Bathurst St, Toronto, Ont, Canada M5T 2S8.
229
Univariate and multivariate analyses were used to identify which of the following variables were possibly related to thromboembolism and late death in all patients: aspirin, gender, valvular lesion, left ventricular function, coronary artery disease, atrial fibrillation, type and size of the porcine bioprostheses, patch enlargement of
230 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
Table I. Clinical and Heart Catheterization Data on the Two Groups of Patientsa Aspirin
Table 2. Operative Data on the Two Groups of Patientsa No Aspirin (N = 135)
Variable
Aspirin
No Aspirin
(N = 80)
(N = 135)
9 (11.2)
12 (8.9)
Variable
(N
Age (yr) Sex Male Female Valvular lesion
58.4 (25-79)
59.0 (18-81)
Atrial fibrillatiodflutter Type of bioprosthesis
60 (75)
(71.1) (28.9)
Carpentier-Edwards Hancock I1 (supraannular) Size of bioprosthesis (mm)
59 (73.7) 21 (26.2)
110 (81.5) 25 (18.5)
21 23 25 27 29 Patch enlargement of aortic annulus Teflon patchb
5 (6.2) 17 (21.2) 19 (23.7) 24 (30) 15 (18.7)
8 (5.9) 29 (21) 52 (38.5) 32 (23.7) 14 (10.4)
11 (13.7) 4 (5.0) 11 (13.7)
15 (11.1)
53 (66.2) 7 (8.7) 11 (13.7) 9 (11.2)
82 (60.7) 19 (14) 13 (9.6) 21 (15.6)
Stenosis Insufficiency Mixed
Left ventricular function Mild impairment Moderate impairment Severe impairment Coronary artery disease None One vessel Two vessels Three vessels
Ascending aortic aneurysm
=
80)
20
(25)
96 39
46 27 7
(57.5) (33.7) (8.7)
82 35 18
(60.7) (25.9) (13.3)
68 9 3
(85) (11.2) (3.7)
115 17 3
(85.2) (12.6) (2.2)
53
(66.2)
8 12
(10) (15)
7 11
(8.7) (13.7)
82 16 15 22 11
(60.7) (11.8) (11.1) (16.3) (8.2)
aExcept for age, numbers in parentheses are percentages.
the ascending aorta, and replacement of the ascending aorta. A Cox regression model was employed to determine the relative importance of these variables. The group of patients taking aspirin was compared with the group not taking aspirin by unpaired Student t tests. Actuarial survival and thromboembolism-free rates were calculated, and curves were constructed. All analyses were done using a computer program from SAS Institute (Cary, NC).
Results Patients were followed for 6 to 80 months. The mean follow-up was 36 months for all patients, 34 months for the group of patients on aspirin, and 37 months for the group not taking aspirin. Follow-up was complete for 206 patients. The remaining 9 patients were lost at different postoperative intervals, but it was possible to determine whether they were alive or not through the Registrar General of Ontario. The two groups (aspirin and no aspirin) were statistically similar as far as all variables shown in Tables 1 and 2 were concerned.
Thromboembolism Fifteen patients experienced a TIA, 7 sustained a stroke, and 3 sustained a myocardial infarction. The following variables significantly increased the risk of thromboembolism: no aspirin, replacement of the ascending aorta, and patch enlargement of the aortic annulus with a Teflon graft. A stepwise logistical analysis of these three variables revealed that no aspirin was the most
Autologous pericardium Replacement of ascending aorta' Aortocoronary bypass grafts None One Two
Three or more
9 (6.7) 11 (8.2)
'Numbers in parentheses are percentages. bUSCl Teflon fabric outflow tract patch. 'Meadox Medicals woven low-porosity graft.
significant ( p = 0.005), followed by replacement of the ascending aorta ( p = 0.012) and then by patch enlargement of the aortic annulus with a Teflon graft ( p = 0.025). The average age of patients who experienced a TIA (50.3 years) was significantly lower ( p < 0.02) than the average age of patients who had a stroke (66.3 years). In the group of patients taking aspirin, there were two TIAs and one stroke. The latter occurred during medical treatment of infective endocarditis in an elderly woman who had had combined replacement of the ascending aorta and aortic valve three and one-half years earlier. She was cured of the infection, and she also improved neurologically. The 2 patients who experienced the TIAs remained on aspirin and did not have any further thromboembolic events. In the group of patients not taking aspirin, there were thirteen TIAs, six strokes, and three myocardial infarctions. Of the 13 patients who experienced TIAs, only 4 consulted their physicians and had aspirin prescribed; all 4 did well during a mean follow-up of 20 months. The diagnosis of TIA was made retrospectively in the other 9 patients, and no treatment was prescribed. Five of these patients had further episodes of TIA and eventually were started on a regimen of aspirin. Of the 6 patients who sustained strokes, 1died, 2 recovered partially, and 3 recovered completely. The 5 survivors ultimately were put on a regimen of aspirin or aspirin plus dipyridamole and had no further thromboembolic events during a
David, Ho, and Christakis: Thromboembolism with Aortic Porcine Bioprostheses
231
t
8o
I 0 4
70
Aspirin Group No Aspirin Group
75.3f6.0 70
11' 0
1
2
86.6f5.84
3
Years
4
5
L
I
1
I
0
1
2
3
-1
4
5
Years
Fig I . Actuarial curves for patients without thromboembolism.
Fig 2 . Actuarial survival, including operative deaths.
mean follow-up of 17 months. Two of the 3 patients who had a myocardial infarction died. None of these 3 patients had angiographic evidence of coronary artery disease. The incidences of TIA and stroke in patients taking aspirin were significantly lower than in patients not so doing. Including TIA, stroke, and myocardial infarction, the linearized thromboembolic rate was 1.3% per patient-year for the group of patients on a regimen of aspirin and 5.2% per patient-year for the group not taking aspirin ( p < 0.02). Actuarial curves for patients without thromboembolism are shown in Figure 1.
cine bioprostheses. Carpentier [111 observed thromboembolic complicationsonly during the first postoperative year. Most investigators [l-41, however, have described a steady, although low, thromboembolic rate after aortic valve replacement with porcine bioprostheses. After analyzing several variables that could possibly affect thromboembolism, we found that only aspirin, replacement of the ascending aorta, and patch enlargement of the aortic annulus with a Teflon graft were significant in our patients. Aspirin, one of the oldest antiplatelet agents used for antithrombotic therapy, has been recommended for patients with porcine bioprostheses both in the aortic and mitral positions [8, 9, 121. Nudez and colleagues [8] reported no thromboembolism in a group of 201 patients taking 1 gm of aspirin per day and followed for 6 to 66 months (mean, 23 months). Geha and associates [9] reported no thromboembolic complicationsin 117 patients treated with aspirin plus dipyridamole during a mean follow-up of 38 months. In our study, aspirin significantly decreased the risk of thromboembolism in both male and female patients. Our 2 patients from the aspirin group who experienced TIAs were taking 650 mg of enteric-coated aspirin per day. Although the dose of aspirin may not be critical for its antithrombotic effect (131, recent evidence indicates that its effect is more intense when smaller doses are administered [14]. In a later study of patients with mitral bioprostheses by Nunez and co-workers [12], the incidence of thromboembolism was higher in patients taking 1,000 mg of aspirin every day compared with patients taking 500 mg every second day. The incidence of thromboembolism in our patients taking no anticoagulant or antiplatelet agents (5.2%per patient-year) appears excessively high compared with the 1 or 2% per patient-year frequently reported by others [l-41. However, most thromboembolic events in our patients were TIAs that seldom lasted more than a few minutes. These patients had frequently forgotten they experienced such neurological deficits until they were asked during the follow-up interview. We also considered myocardial infarction in patients without coro-
Other Complications Infective endocarditis developed in 3 patients; 2 were successfully treated with antibiotics alone and 1required reoperation. Two other patients also required reoperation: 1 because of prosthetic dehiscence and the other because of perforation of the cusps due to excessively long sutures. Late Mortality There were 10 late deaths: 2 among patients on a regimen of aspirin (both noncardiac and unrelated to thromboembolism) and 8 among patients not taking aspirin (2 due to myocardial infarction, 1 to congestive heart failure, 1 to stroke, and 4 noncardiac and unrelated to thromboembolism). There was no statistical difference in the linearized late mortality rate in these two groups of patients (0.88%per patient-year versus 1.91% per patient-year, respectively). Analysis of all variables revealed that only impaired left ventricular function was associated with increased late mortality ( p < 0.01). Figure 2 shows the actuarial survival for all patients, including operative deaths.
Comment The main advantage of tissue over mechanical prostheses for aortic valve replacement is their lessened tendency to cause thromboembolism without anticoagulation [1-2,6, lo]. Some investigators [5,9] have described no thromboembolism at all in patients with aortic por-
232 The Annals of Thoracic Surgery Vol 40 No 3 September 1985
nary artery disease as a thromboembolic complication. Excluding TIA and myocardial infarction, t h e thromboembolic rate i n these patients was 1.4% p e r patient-
year. Patients who experienced a TIA tended to have recurrent TIAs if left untreated. The average age of patients who experienced a TIA was significantly lower than the average age of patients who sustained a stroke. This finding suggests that o t h e r circulatory factors m a y play a role i n t h e development of stroke i n older patients. Atrial fibrillation i s known t o increase t h e risk of thromboembolism i n patients w i t h mitral bioprostheses [lo]. Cohn and associates [ l ] found that atrial fibrillation also increased t h e incidence of thromboembolism in patients w i t h an aortic porcine bioprosthesis. Atrial fibrillation had no effect on thromboembolism in our patients. The five-year actuarial survival, including early deaths, in our patients was 86.6% and is similar to that i n o t h e r reports [l, 3, 41. There w a s no significant difference between patients taking aspirin a n d those taking no antiplatelet agents. Nonetheless, there were 3 late d e a t h s directly related t o thromboembolism a m o n g patients taking no aspirin a n d no late d e a t h s due t o thromboembolism i n patients on aspirin. Although this difference d i d n o t reach statistical significance, it may indicate a trend t o w a r d a lower late mortality i n patients taking aspirin. After analyzing several variables that could possibly affect late mortality, we found that only impaired left ventricular function was statistically significant. Unlike t h e findings i n o t h e r reports [l, 131, coronary artery disease d i d n o t affect late mortality i n our patients. This may be due to o u r relatively short follow-up. In conclusion, thromboembolism appears t o be a comm o n and serious complication i n patients with aortic porcine bioprostheses. T h e risk of thromboembolism i n these patients is increased when they have concomitant replacement of the ascending aorta or patch enlargem e n t of t h e aortic annulus with a Teflon graft. Aspirin is an effective antithrombotic a g e n t i n patients of both sexes who have aortic porcine bioprostheses.
References 1. Cohn LH, Alfred EN, DiSesa VJ, et al: Early and late risk of aortic valve replacement. J Thorac Cardiovasc Surg 88695, 1984 2. Joyce LD, Nelson RM: Comparison of porcine valve xenografts with mechanical prostheses. J Thorac Cardiovasc Surg 88:102, 1984 3. Jamieson WRE, Pelletier LC, Janusz MT, et al: Five-year evaluation of the Carpentier-Edwards porcine bioprosthesis. J Thorac Cardiovasc Surg 88:324, 1984 4. Pelletier C, Chaitman BR, Baillot R, et al: Clinical and hemodynamic results with the Carpentier-Edwards porcine bioprosthesis. Ann Thorac Surg 34:612, 1982 5. Cevese PG, Gallucci V, Morea M, et al: Heart valve replacement with the Hancock bioprosthesis: an analysis of longterm results. Circulation 56:Suppl3111,1977 6. Williams JB, Karp RB, Kirklin JW,et al: Considerations in selection and management of patients undergoing valve
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replacement with glutaraldehyde-fixed porcine bioprostheses. Ann Thorac Surg 30:247, 1980 Grehl TM, Naifeh JG, Broda J, et al: Heterograft cardiac valve prostheses: a five-year follow-up. Ann Thorac Surg 30:173, 1980 Nuiiez L, Gil Aguado M, Celemin D, et al: Aspirin or Coumadin as the drug of choice for valve replacement with porcine bioprosthesis. Ann Thorac Surg 33:354, 1982 Geha AS, Hammond GL, Laks H, et al: Factors affecting performance and thromboembolism after porcine xenograft cardiac valve replacement. J Thorac Cardiovasc Surg 83377, 1982 Edmunds LH Jr: Thromboembolic complications of current cardiac valvular prostheses (collective review). Ann Thorac Surg 34:96, 1982 Carpentier AF: Discussion of Cohn et a1 [l] Nunez L, Gil Aguado M, Larrea JL, et al: Prevention of thromboembolism using aspirin after mitral valve replacement with porcine bioprosthesis. Ann Thorac Surg 37:84, 1984 Eichner ER PlateIets, carotid and coronaries: critique on antithrombotic role of antiplatelet agents, exercise and certain diets. Am J Med 77:513, 1984 Pedersen AK, FitzGerald GA: Dose-related kinetics of aspirin. N Engl J Med 311:1206, 1984
Discussion DR. WILLIAM R. E. JAMIESON (Vancouver, BC, Canada): I thank Dr. David and his colleagues for bringing to the attention of the Society the problem of thromboembolism with aortic valve replacement and porcine bioprostheses. 1 appreciated the opportunity to review the manuscript well in advance. For comparison, I will briefly discuss the experience of my coworkers and me with thromboembolism and aortic valve replacement with porcine bioprostheses at the University of British Columbia. Between 1975 and 1984, 581 patients with the Carpentier-Edwards standard porcine aortic prosthesis were evaluated. The total accumulated follow-up was 2,500 patientyears, with a mean of 52 months. The freedom from thromboembolism was 92% at 7 years for the total patient group. The freedom from minor thromboembolic events was 97% at 7 years and freedom from major events was 94% at 7 years. Twenty-one patients in this total group experienced thromboembolic events. The total number of events was 28, an incidence of 1.1%per patient-year. There were 13 major and 15 minor events. There was no mortality related to thromboembolism in the series. Sixteen of these 21 patients had 23 thromboembolic events while in sinus rhythm. The other 5 had a total of 5 events while in atrial fibrillation. A portion of our patients were managed on anticoagulants and antiplatelet agents. Eighty percent of the total patient population who had neither of these two medications experienced 18 events for an incidence of 0.9% per patient-year. This finding is in dramatic contrast to the incidence in Dr. David’s series of 5.2% per patient-year. Ten percent of our patients were on antiplatelet agents. These patients experienced 5 thromboembolic events, an incidence of 1.6% per patient-year. Eight percent of the patients were on a regimen of long-term anticoagulants; they experienced 5 events for an incidence of 2.4% per patient-year. For those patients on antiplatelet agents, we essentially agree with Dr. David and his associates. Our incidence of thromboembolic events is 1.6% per patient-year, and theirs is 1.2% per patient-year. On the contrary, our incidence of thromboem-
233 David, Ho, and Christakis: Thromboembolism with Aortic Porcine Bioprostheses
bolic events for patients receiving neither antiplatelet agents nor anticoagulants is 0.9% per patient-year, whereas theirs is 5.2% per patient-year. Dr. David, would you please explain this difference?
c. CALLAGHAN (Edmonton, Alta, Canada): It rather seems odd that the presenter and both discussants of this paper are from Canada. This probably has nothing to do with the Food and Drug Administration regulations concerning bioprostheses, but it probably does have to do with those for mechanical prosthetic valves. I think in order to discuss thromboembolism, it is important that there be something to compare. My colleagues and I are in the throes of a review of all our prosthetic valves (approximately 1,600) at the University of Alberta Hospital. We are attempting to examine, from the thromboembolic aspect, all the valves we have used, which include bioprostheses and ball valves. What concerned me in comparing our results with those of Dr. David’s group is the same thing Dr. Jamieson mentioned: the high incidence of thromboembolic phenomena in the series of Dr. David and his co-workers in patients with bioprostheses treated after 3 months with warfarin sodium alone. The 5.2% incidence is much higher than that previously reported in the literature.
DR. JOHN
We have used two prostheses of the tilting-disc type, the Lillehei-Kaster and the Omni, in 139 patients. In this group, there was 1 TIA and 1 stroke and mortality was 2.5% over the 36-month study period. Dr. David, would you explain the high incidence in your baseline group from which you extrapolated the benefit of using aspirin anticoagulation? DR. DAVID: I thank Drs. Jamieson and Callaghan for their comments. Most of the minor thromboembolic events were noted by third- and fourth-year medical students during the followup interviews. The interviewers were entirely unbiased and were looking specifically for valve-related complications. Whenever a medical student recorded that a patient sustained a TIA, a physician reviewed the case record. The incidence of thromboembolism in our patients was higher than in other reports, but remember that many of our patients had patch enlargement of the aortic annulus or replacement of the ascending aorta. We discovered that these associated procedures increased the risk of thromboembolism. Besides, we included myocardial infarction as a thromboembolic complication. Even after all these factors were excluded, the difference between patients on aspirin and those not taking aspirin remained significant.
Notice from the American Board of Thoracic Surgery The American Board of Thoracic Surgery began its recertification process in 1984. Diplomates interested in participating in recertification should maintain a documented list of the cardiothoracic operations they performed during the year prior to application for recertification. They should also keep a record of their attendance at thoracic surgical meetings and other continuing education medical activities for the two years prior to application for recertification. In place of a cognitive examination, candidates for recertification will be required to complete both the general thoracic and cardiac portions of the SESATS I1 Syllabus (Self-Education/Self-Assessmentin Thoracic Surgery). It is not necessary for candidates to purchase
SESATS I1 prior to applying for recertification. SESATS I1 booklets will be forwarded to candidates after their applications have been received. Diplomates whose ten-year certificates will expire in 1988 may begin the recertification process in 1986. This new certificate will be dated ten years from the time of expiration of the original certificate. Recertification is also open to any Diplomate with an unlimited certificate. The deadline for submission of applications for recertification is July 1, 1986. A recertification brochure outlining the rules and requirements for recertification in thoracic surgery is available on request from the American Board of Thoracic Surgery, 14640 E Seven Mile Rd, Detroit, MI 48205.