Ten-Year Follow-up in Aortic Valve Replacement Using the Bjork-Shiley Prosthesis

Ten-Year Follow-up in Aortic Valve Replacement Using the Bjork-Shiley Prosthesis David Cheung, M.D., Robert J. Flemma, M.D., Donald C. Mullen, M.D., Denvard Lepley, Jr., M.D., Alfred J. Anderson, M.S., and Earl Weirauch, B.S. ABSTRACT An in-depth statistical analysis of early and late results of aortic valve replacement using the Bjork-Shiley tilting-disc prosthesis is presented. Our experience with this prosthesis indicates that replacement carries a low surgical risk, a low incidence of complications (embolization, infection, or hemorrhage due to long-term use of anticoagulants), and good long-term survival. Coexisting coronary artery disease increases surgical mortality significantly, and simultaneous, complete revascularization is essential. Patients un-.dergoing isolated aortic valve replacement did significantly better than those requiring other simultaneous procedures or those who had had previous operations. Earlier operation is imperative since progress of aortic valve disease is unpredictable by duration of symptoms, and patients in New York Heart Association Functional Class I1 have a low surgical risk and a greatly increased survival. It would appear from this study that additional criteria, such as increasing ventricular dilatation and hypertrophy determined by echocardiographic studies and gated nuclear studies showing deterioration of ejection fraction on exercise, should be used to help determine time of surgical intervention rather than symptomatology alone. Aortic valve replacement is now well established in the treatment of aortic valve disease [l, 21. However, there is still disagreement over the use of this approach for the asymptomatic or minimally symptomatic patient [31, and there is difficulty in assessing the risks to and longterm survival of patients undergoing valve replacement. Since the introduction of a valve From the Department of Thoracic and Cardiovascular Surgery, The Medical College of Wisconsin and St. Luke s Hospital, Milwaukee, WI. Presented at the Seventeenth Annual Meeting of The Society of Thoracic Surgeons, Jan 26-28,1981, Los Angeles, CA. Address reprint requests to Dr. Lepley, 9800 W Bluemound Rd, Milwaukee, WI 53226. prosthesis two decades ago, several different types of prosthesis have been developed, with frequent design modifications and numerous refinements in technique for valve replacement. Such developments have made the analysis of results of valve replacement more difficult, as numerous published papers have included data on prostheses of different types and models and changing surgical management. Since 1970, in Milwaukee, we have operated on approximately 1,500 patients for valve replacement in all positions using only the Bjork-Shiley tilting-disc prosthesis. Essentially the same method of surgical management and postoperative care were employed in all patients. No patient in the entire 10 years was refused operation based on severity of heart disease. This report, which summarizes the 10-year experience of aortic valve replacement, eliminates the yariables just mentioned and identifies more clearly surgical risk factors, incidence of complications, and long-term survival. Attention has been focused on the relationship between valve replacement combined with other procedures, and optimal time for operation. Material and Methods Between January 1, 1970, and December 31, 1979,579 patients underwent valve replacement in the aortic position. All patients who underwent associated procedures, who had had previous cardiac operation, or who fell into both categories were included. The mean follow-up was 48.8 months. Patients were divided into five groups according to the procedure performed (Table 1). In Group 1 were 280 patients who had isolated aortic valve replacement. Group 2 consisted of 92 patients who had aortic valve replacement and bypass operation. The 90 patients in Group 3 had both aortic and mitral valve replacement. In Group 4 were 109 patients who underwent aortic valve replacement as 138 0003-4975/81/080138-08$01.25 @ 1981 by The Society of Thoracic Surgeons

139 Cheung et al: Ten-Year Follow-up in Aortic Valve Replacement Table 1. Patient Profile of 579 Patients Based on Operation Performed Operative Group Procedure Done No. of Patients Mean Age (yr) Mortality (%)" Isolated AVR 280 AVR i- bypass 92 AVR + MVR 90 AVR f other 109 AVR i- AVR 8 55.3 60.9 54.1 51.7 48.6 6.4 15.4 12.4 21.1 0 "Comparison of operative mortality between Group 1 and Groups 2, 3, 4, and 5 is significant (p < 0.001). AVR = aortic valve replacement; MVR = 'mitral valve replacement. well as other associated cardiac and great vessel procedures, such as resection of the aorta. Group 5 consisted of 8 patients who had had at least one previous operative procedure for aortic valve disease. The patients ranged from 38 to 76 years old (mean, 55 years). Those who had bypass operation were significantly older ( p < 0.01) than the other four groups (mean, 61 years) (see Table 1). Patients were also divided into subgroups based on the preoperative New York Heart Association (NYHA) Functional Class and the nature of the lesion of the aortic valve: aortic insufficiency (AI), aortic stenosis (AS), or mixed A1 + AS (Table 2). Surgical management of our patients has been described in detail previously [4]. A bubble oxygenator and a roller pump with moderate hypothermia (30 C) and hemodilution were used in all patients. Valves were inserted by means of interrupted mattress sutures with pledgets of Teflon felt as a buttress. Deep regional cardiac hypothermia, utilizing electrolyte solution at 4 C in the pericardium and intracavitary hypothermia of the left ventricle, was used for myocardial protection. Anticoagulation with intermittent, intravenous administration of heparin was carried out soon after removal of chest tubes (usually the day following operation), and Coumadin (sodium warfarin) was begun as soon as the patient could take liquids orally. The goal was a prothrombin time of 1% to 2 times normal. Heparin was administered for a full seven days, even though a therapeutic range of Coumadin might have been achieved earlier. Table 2. Patient Profile Based on Type of Lesion and New York Heart Association Functional Class No. of Mean Operative Variable Patients Age (vr) Mortalitv (Yo) PATHOPHYSIOLOGY AS 145 60.2 10.4 A1 170 50.0 10.1 AS + A1 264 55.9 12.9 PREOPERATIVE FUNCTIONAL CLASS I1 219 55.3 3.7a I11 275 55.3 12. sash IV 85 54.8 27.1asb Tomparison of operative mortality between Functional Class I1 and Classes 111 and IV is significant (p < 0.001). bcomparison of operative mortality between Functional Classes I11 and IV is significant (p < 0.002). AS = aortic stenosis; A1 = aortic insufficiency. Follow-up consisted of yearly office visits and a mail survey. Those who did not respond were reached by telephone or located through their cardiologist, family physician, or relatives. All data were computer analyzed. Only 4 patients were lost to follow-up or did not have sufficient data to be included, an overall follow-up of 99.3%. Results Sixty-six of the 579 patients did not survive the perioperative period (thirty days). Overall surgical mortality was 11.4% but ranged from 6.4% in Group 1 (isolated valve replacement) to 21.1% in Group 4 (replacement plus asso-

~~ ~ 140 The Annals of Thoracic Surgery Vol 32 No 2 August 1981 Table 3. Causes of Mortality Among 579 Patients in 10-Year Study Cause Congestive heart failure Myocardial infarct Stroke Bleeding Cardiac arrest Infection Arrhythmia Low cardiac output Other heart-related Not heart-related Total 30 Day Late Total 11 20 31 15 13 28 2 10 12 11 9 20 6 12 18 3 8 11 4 2 6 7 0 7 6 2 8 1 21 22 66 97 163 (11.4%) (16.8%) (28.2'Yo) c 50-5 45-40- a 35-30. 25. 20. 15. 10. 5- A AV Only n AV+ *.,,,,. + A VS I P<0.02 ciated procedures) (see Table 1). No difference was found in the nature of the lesion, whether AS, AI, or mixed. Comparing Group 1 against the other groups in terms of operative mortality, a statistical difference is seen ( p < 0.001). Operative mortality for those in NYHA Functional Class I1 was considerably lower than for those in Classes I11 and IV [3.7% vs 12.8% and 27.1%, respectively ( p < O.OOl)] (see Table 2). Late mortality occurred in 97 patients or 16.8%. Table 3 lists the cause of death of these patients. Preoperatively, 19 were in Functional Class 11, 47 in Class 111, and 31 in Class IV. S u rv iv a 1 Although 7-year survival can be determined in this 10-year study, numbers at risk were small after the patients were divided into groups. Therefore, we elected to look at 5-year survival only. The overall 5-year survival was 70%. However, in those patients with isolated valve replacement, Group 1, 5-year survival was 73%. This figure is significantly higher than the 69% for those who had associated procedures ( p < 0.02) (Fig 1). The overall actuarial survival curve according to the type of procedure done also showed a significant difference between Group 1 and the other groups (p < 0.05). No difference in 5-year survival was observed when the groups were compared according to the nature of the lesion (A1 or AS) (Fig 2). However, the overall 5-year survival varied with preoperative NYHA Functional 100 951 w 85 80 75 70 3 65 5 60 In 55.. 1 m o 1 i 3 i 5 6 i YEARS AS A 145 129 101 84 65 53 39 27 16 Al x 170 151 120 101 87 71 57 36 11 AStAI 0 264228 186 159 138 119 86 59 31 Fig 2. Comparison of 5-year survival based on the type of lesion. The difference in survival was not significant (NS). (AS = aortic stenosis; A1 = aortic insufficiency.) Class (Fig 3A); it was lower for those in Class IV, 36.6%, than for those in Class 111, 72.6%, or 11,85.1% ( p < 0.01 andp < 0.001, respectively). Similar results were seen in Group 1 (Fig 3B) and Groups 2, 3, 4, and 5 (Fig 3C). We analyzed the life-table survival curves of those who had symptoms for less than a year,

141 Cheung et al: Ten-Year Follow-up in Aortic Valve Replacement 100 1 9! 75 70 p 65 2 60 5 55 401 3s- b 40- a 301 30- A VS X P<ooo1 x FC 3 A VS 0 p<o.001 ofc4 x vso p<ooi ImoI 2 3, 4 I 5 1 6 1 7 YEARS A FC2 219 209 157 119 95 78 55 38 23 x FC3 275 237 201 182 159 I33 104 69 28 0 FC4 85 62 49 43 36 32 23 15 7 A c 100 60 40 \-- 30 \ A FC2 AVt A vsx p<oo5 A x VS 0 P<o.Ol vs 0 p<ool ImoI 2 3 4 5 6 7 YEARS A FC2 101 94 68 47 38 28 I8 10 4 x FC3 150 123 108 99 86 69 51 35 16 0 FC4 48 30 23 20 18 15 14 8 3 L 1 to 4 years, and 4 years or more. No significant difference was found in long-term survival (Fig 4). Functional Class Figure 5 shows the overall change in NYHA Functional Class from the preoperative to postoperative status of patients alive in 1981. Relatively few remained in Class I11 or IV. 80 75 ro -\ i/ ::::,, 20 x FC 3 A V S 0 P<oo1 10 5 1 Avs, x p, <0001, I m o I 2 3 4 5 6 7 YEARS A FC2 118 115 89 72 57 50 37 28, 19 X FC3 125 114 93 83 73 64 53 34 12 0 FC4 37 32 26 23 18 17 9 7 4 B Fig 3. (A) Overall survival based on preoperative New York Heart Association Functional Class. There was a significant difference between Functional Classes 11 (FC 2) and Ill (FC 3) compared with Class IV (FC 4). 03) Survival by preoperative Functional Class among patients having aortic valve replacement only. (C) Survival by preoperative Functional Class among patients having aortic valve replacement combined with other procedures (AV +). Overall, of those currently alive, 74% (303) have improved at least one NYHA Functional Class, 219'0 (86) remain the same, and only 5% (21) are reported to be worse. Tlie data for 6 patients are insufficient to include them. Complications HEMORRHAGE. In the postoperative period, 14 patients required exploration for hemorrhage, with infraxiphoid exploration in bed or return to the operating room and reopening of the sternum. Late tamponade was encountered in 8 patients. THROMBOEMBOLISM. Twenty-eight patients sustained 36 embolisms (Table 4). Six patients were not taking anticoagulants at the time of the incident. One of them refused to take medication regularly and died of a massive cerebral embolus 22 months after operation. At postmortem examination, the valve prosthesis was covered partly by clot (fresh and organized) and

142 The Annals of Thoracic Surgery Vol 32 No 2 August 1981 100 95 4 10-9 65' '5 60-2 55- - 50- g 45-40- 35-30 - 25-20- 15-10- 5- A Symptoms <I yr p = NS x Symptoms I-4yrs Symptoms >4 yrs ' I,,,, I I I Table 4. Incidence of Thromboembolic Episodes in 10-Year Follow-up of 513 Patients Episode NOT FATAL Cerebrovascular accident Without residuals 9 With residuals 7 Clotted valve surgically repaired 1 Peripheral embolus 2 Renal embolus 1 Coronary embolus 1 Total 21a FATAL No. of Embolisms Better 303 Same 86 Ome 2/ huff dato 6 100 951 90 Cerebrovascular accident 11 Clotted valve 3 Myocardial infarction 1 Total 15. aoverall: 1.2 episodes per 100 patient-years. hematuria, and a week later a saddle embolus developed. The patient recovered fully after embolectomy. In another patient a peripheral arterial embolus developed after he stopped taking the anticoagulant because of a postoper- % of ative sternal infection. The sixth patient sus- Patients tained a cerebral embolism 14 months after operation but recovered partially. Emboli developed in-3 additional patients despite their being on a therapeutic dose of anticoagulant. One of them had a successful operation on the clotted valve 2 years after the initial operation. Thromboembolic complications resulted in 15 deaths. Among those whose complication was not fatal, 9 patients had no residual effects. ALL CLASS CLASS CLASS Excluding patients who were not on a regi- CLASSES II. IlI Ip men of anticoagulants, there were 28 emboli per PRE-OPERATIVE CLASS 23,095 patient-months or 1.2 emboli per 100 Fig 5. Preoperative to postoperative change in New York Heart Association Functional Class at late patient-years. This compares favorably with follow-utl. other reported series [5, 61. All episodes were carefully traced. ANTICOAGULATION. Hemorrhage due to anthere were numerous infarcts in the heart and ticoagulant therapy during the 10-year study kidneys from embolization. Three of the pa- resulted in 5 deaths from subdural subtients had the anticoagulants stopped on ac- arachnoid and cerebral hemorrhage. Location count of bleeding. In 2 of them, gastrointestinal of severe but not fatal hemorrhage was as folhemorrhage clotted the prosthesis and they lows: nose, 2; renal, 3; gastrointestinal, 6; redied of congestive heart failure. The third had spiratory, 1; musculoskeletal, 4; and eye, 2.

143 Cheung et al: Ten-Year Follow-up in Aortic Valve Replacement Apart from the 2 patients who had partial loss of vision from retinal hemorrhage, the remaining patients experienced no residual effects. The overall incidence of hemorrhage from anticoagulation is 1.2 per 100 patient-years. VALVE MALFUNCTION. Four out of 579 patients were known to have thrombotic obstruction of the prosthesis. Only 1 was operated on successfully. In the remaining 3 patients, the malfunction was not recognized and was found only at postmortem examination. Paraprosthetic leak occurred in 3 patients in the entire series. Only two of the leaks were sufficiently severe to require surgical correction. All followed bacterial endocarditis. One of the 2 patients requiring reoperation lived; the other died after a third replacement. INFECTION. Sixteen patients (2.8%) had bacterial endocarditis: 5, early and 11, late. Four of the 5 patients seen early had endocarditis of the aortic valve prior to replacement. Five underwent emergency valve replacement; 3 of these patients lived. The other 11 patients were treated medically; 6 of them died and 5 survived, although 1 had a mild paraprosthetic leak. Total mortality from infection was 1.4% (0.14% per year). The most common organism was Staphylococcus epidermidis, and most patients sought medical treatment late. Infection developed in 1 patient, a drug addict, when antibiotic cover was omitted after a dental operation and in another patient, an alcoholic, when antibiotic cover was not provided after cholecystectomy. The survivors were seen early and either underwent operation despite infection and hemodynamic failure or had reoperation after the infection was controlled or treated with a long-term course of antibiotics. Comments Valve Replacement and Bypass Operation Coronary atherosclerosis is a frequent finding in adults with aortic valve disease but its coexistence cannot be accurately predicted on the basis of presence of angina [7]. In our series, preoperative coronary arteriography was carried out in each of the 579 patients. Angina was present in 60% of patients who underwent aortic valve replacement only and had normal coronary vessels, while it was absent in 25% of patients who had simultaneous bypass operation. We agree with Jacob and colleagues [8] that preoperative coronary arteriography should be carried out routinely, especially in the adult patient with valvular heart disease. Aortic valve replacement combined with bypass operation in this study carried a significantly higher mortality than isolated valve replacement (p < 0.01). Such a discrepancy from the results of other series prompted us to analyze our data more closely. The decision to combine bypass operation with aortic valve replacement was made in the presence of a critical, obstructive lesion (> 70% stenosis) in a coronary artery. In our practice, during a combined procedure, lesions between 40 and 50% obstructed were often simultaneously revascularized. On examining these moderate, obstructive lesions in our analysis, we found that they influenced the operative mortality. In Group 1, the presence of such a lesion increased the operative mortality from 2.5 to 6% if not bypassed, although the difference was not statistically significant. In Group 2, patients in NYHA Functional Class I1 also showed no significant difference in operative mortality between those with and without bypass of the moderately stenotic arteries; however, in patients in NYHA Functional Class IV, operative mortality dropped from 22 to 9% when 40 to 50% stenotic lesions were also bypassed (p < 0.3). It would appear that moderately stenotic lesions in the presence of critical lesions should also be corrected when patients with aortic valve disease are in NYHA Functional Class IV. Timing of Operation Following aortic valve replacement, the majority of patients improved, as shown in our series and others [5, 6, 9, 101, irrespective of the preoperative NYHA Functional Class. Yet, the significantly higher operative mortality and shorter survival time in patients in Functional Class IV or I11 compared with those in Functional Class I1 suggest that early operation is desirable. The left ventricle in aortic valve disease compensates in the early stage of the disease for pressure or volume overload or both by hypertrophy and dilatation. The degree of compensation and the length of time before decompen-

144 The Annals of Thoracic Surgery Vol 32 No 2 August 1981 Table 5. Probability of Surviving 5 Years following Aortic Valve Replacement Alone or Combined with Other Procedures according to Regression Analysis of the Three Most Important Risk Factors 40 AVR 0.87 0.61 AVR+ 0.82 0.51 50 AVR 0.83 0.52 AVR+ 0.77 0.41 60 AVR 0.78 0.42 AVR+ 0.71 0.31 40 0.91 0.79 0.56 50 0.88 0.74 0.47 60 0.85 0.67 0.37 N = 579 Age FC t = 3.77; p < 0.001 t = 7.83; p < 0.001 N = 579 Age AVR, AVR+ FC t = 3.81; p < 0.001 t = 1.96; p < 0.05 t = 7.39; p < 0.001 40 AVR+ 0.89 0.77 0.55 50 AVR+ 0.86 0.71 0.47 60 AVR+ 0.83 0.65 0.38 40 AVR 0.93 0.82 0.58 50 AVR 0.91 0.76 0.45 60 AVR 0.87 0.68 0.35 N = 299 Age FC t = 2.48; p < 0.02 t = 5.14; p < 0.001 N = 280 Age FC aoperative procedure is not under consideration in this section of table. t = 2.93; p < 0.01 t = 5.76; p < 0.001 NYHA = New York Heart Association; AVR = aortic valve replacement; AVR+ = aortic valve replacement plus other procedures; FC = Functional Class. sation resulting in irreversible myocardial damage are variable and unpredictable. In this study, there was no significant difference in long-term survival in patients with symptoms of different duration (see Fig 4). Thus, the duration of symptoms cannot be used to predict when a patient will move from Functional Class I1 to IV. At the present time, reliable and durable valve prostheses, low surgical risk (surgical mortality in patients with only valve disease was less than 2o/d), and minimal complications appear to justify the recommendation of earlier valve replacement in minimally symptomatic patients. Table 5 was constructed using Cox regression analysis [ll] of the three risk factors-age, Functional Class, and operative procedurefound to be significant in predicting 5-year survival in patients who have had aortic valve replacement. We again note that Functional Class is highly significant in determining long-term survival. References 1. Barnhorst DA, Oxman HA, Connolly DC, et al: Isolated replacement of the aortic valve with the Starr-Edwards prosthesis: a 9-year review. J Thorac Cardiovasc Surg 70:113, 1975 2. Lee SJK, Barr C, Callaghan JC, et al: Long-term survival after aortic valve replacement using the Smeloff-Cutter prosthesis. Circulation 52:1132, 1975 3. Rahimtoola ST: Early valve replacement for preservation of ventricular function. Am J Cardiol 40:472, 1977 4. Lepley D Jr, Reuben CF, Flemma RJ, et al: Experience with the Bjork-Shiley prosthetic valve. Circulation 47:Suppl 3:51, 1973 5. Bjork VO, Henze A: Results five to seven years after aortic valve replacement with the original Delrin disc model Bjork-Shiley prosthesis. Scand J Thorac Cardiovasc Surg 11:177, 1977

145 Cheung et al: Ten-Year Follow-up in Aortic Valve Replacement 6. Copeland JG, Griepp RB, Stinson EB, Shumway NE: Long-term follow-up after isolated aortic valve replacement. J Thorac Cardiovasc Surg 74:875, 1976 7. Bonchek LI, Anderson RP, Rosch J: Should coronary arteriography be performed routinely before valve replacement? Am J Cardiol 31:462, 1973 8. Jacobs ML, Fowler BN, Vezeridis MP, et al: Aortic valve replacement: a 9-year experience. Ann Thorac Surg 30:439, 1980 9. Barnhorst DA, Oxman HA, Connolly DC, et al: Long-term survival follow-up of isolated replacement of aortic and mitral valve with the Starr-Edwards prosthesis. Am J Cardiol 35:228, 1975 10. Roberts DL, DeWeese JA, Maloney EB, Yu PN: Long-term survival following aortic valve replacement. Am Heart J 91:311, 1976 11. Cox DR: Regression models and life tables. J R Statis SOC Series B 34:187, 1972 Discussion DR. VIKING 0. BJORK (Stockholm, Sweden): In their paper the authors gave reference only to my early Delrin-disc valve, which has functioned excellently as shown by 10-year follow-up aortography. They do not state whether they use the pyrolytic carbon, or the standard convexo-concave discs. Today, with 260,000 Bjork-Shiley valves implanted, 2,500 in the Karolinska in Stockholm, some follow-up is available. The authors had a 99.3% follow-up, which is excellent, but their 10-year follow-up averages 4 years. This reminds me of a comment by a Texas friend who said that in his state they can do a 5-year follow-up in just a little more than a year. Of the 125 patients I operated on 10 years ago or more, 65% are living today. That is actual survival and is, as you remember, 10% more than the value reported by Albert Starr. The oldest is 75 years old. I seldom comment on the mortality rate reported by others, but the authors did not analyze whether the mortality decreased in recent years, as it has in my material from 5.8 to 3.8%. Among their patients having double-valve replacement, aortic and mitral, the mortality was 12% compared with my 8%. My question is whether in the longer operation, their myocardial preservation technique using cold fluid in the pericardium and inside the heart with thick myocardium is as effective as cardioplegia with oxygenated blood given every twenty minutes. The incidence of paravalvular leak-3 of 579 patients-compares favorably with my 2.4%. I learned from their manuscript that mattress sutures with pledgets are much better than the single overand-over suture, which, of course, in a very narrow aortic root, permits a larger prosthesis. The functional investigation using the New York Heart Association Classes is not as objective as transseptal catheterization measuring how the stroke volume at rest increases during an exercise test-before operation and after operation-and how it compares with that of normal 60-year-old patients. I think that test is more objective. The convexo-concave disc now available has a better hemodynamic response with a shorter closing time and less regurgitation. There is a 4-year follow-up survival of 91% including operative mortality in the aortic position, a nonfatal thromboembolic complication rate of 1.4 per 100 patient-years, and no valve thrombosis. In 1980, we implanted 100 valves with an opening angle of 70 degrees. I am convinced that the valve should not open more than 70 degrees, unlike the St. Jude valve. The latter has a 0.5 mm lower gradient in the smaller aortic valves, but has a much higher pulsative regurgitation in both the aortic and mitral positions. I congratulate Dr. Cheung and his co-authors on a careful and valuable analysis of risk factors when other procedures are added to aortic valve replacement with the Bjork-Shiley valve. DR. CHEUNG: Thank you, Dr. Bjork, for your kind comments and for sharing your series. In regard to myocardial protection in patients having double-valve replacement, perhaps the cardioplegic method is safer, but in our series most of these patients were in Functional Classes I11 and IV. The high mortality is probably related to the fact that these patients have a poor left ventricle. Perhaps our mortality could be improved if we used the cold cardioplegic way of protecting the heart. Our low incidence of thromboembolism is probably related to the fact that we routinely anticoagulate our patients with heparin, usually twenty-four hours after operation, and start orally administered Coumadin at the same time. The heparin is continued for a full course of seven days even though the patients are given a therapeutic dose of Coumadin. We believe that the thrombus is formed in the early stages, and Coumadin alone could not prevent it.