Complications of Prosthetic Heart Valves

Transcription

1 COLLECTIVE REVIEW Thrombotic and Bleeding Complications of Prosthetic Heart Valves L. Henry Edmunds, Jr., M.D. ABSTRACT A review of articles published since 1979 indicates that thrombotic and bleeding complications account for about 5% of valve-related complications in patients with bioprosthetic aortic and mitral valves and for approximately 75% of the complications in patients with mechanical valves. Although compromised by lack of standard definitions and by variability in reporting and followup, the data suggest that the linearized rate of both thrombotic and bleeding complications in patients with aortic bioprostheses is approximately half that for aortic mechanical prostheses (2% versus 4%), but is approximately equal for both bioprostheses and mechanical valves in the mitral position (approximately 4%), and for mechanical and bioprosthetic aortic and mitral valves in combination. However, linearized rates for fatal thrombotic and bleeding events are two to four times higher in patients with mechanical prostheses. The adequacy of warfarin anticoagulation is the most important factor affecting thrombotic and bleeding complications in patients with mechanical valves and overshadows the dubious importance of other phenomena such as atrial fibrillation and left atrial thrombus. Short-term warfarin anticoagulation or the use of long-term platelet inhibitors, or both, do not appear to reduce the incidence of thrombotic complications in patients with aortic bioprostheses but increase bleeding. For mitral bioprostheses, the postoperative use of warfarin for three months or aspirin indefinitely is as effective in preventing thromboembolism as long-term warfarin. Acute prosthetic valve endocarditis is associated with a 13 to 4% incidence of thrombotic complications. Likewise, the recurrence rate of cerebral emboli is high (2-3%) in patients with prosthetic valves who are not anticoagulated. Bioprostheses are strongly preferred for women who wish to bear children; fetal wastage occurs in 25 to 3% of pregnant women with mechanical heart valves who receive either warfarin or heparin, or a combination of the two. Heparin, however, greatly increases the risk of maternal bleeding. In children, the efficacy of platelet inhibitors without warfarin anticoagulation is unproven; nearly all serious strokes occur when warfarin is omitted; and permanent disability from warfarin-related bleeding is rare. From the Department of Surgery, Division of Cardiothoracic Surgery, University of Pennsylvania, Philadelphia, PA. Address reprint requests to Dr. Edmunds, Hospital of the University of Pennsylvania, 4 Silverstein, 34 Spruce St, Philadelphia, PA All prosthetic cardiac valves initiate coagulation and affect the dynamic equilibrium between activated procoagulants and endogenous anticoagulants. Warfarin is the only available oral exogenovs anticoagulant. The complicated pharmacokinetics of this drug primarily determine the incidence of thrombotic and bleeding events in patients with prosthetic valves. Because of the lack of demonstrable platelet inhibition at clinical doses of dipyridamole and sulfinpyrazone, the efficacy of these drugs with or without warfarin is questionable. Conversely, aspirin is a potent platelet inhibitor and may be effective with few side effects if given once every three days. Emboli, thrombi, and bleeding-consequences of the inability to control the interaction between blood and synthetic materials [l]-remain the most frequent complications of prosthetic heart valves and the major deterrent to earlier operation. Thrombotic and bleeding complications represent 57 to 92% (median, about 75%) of all valve-related complications in patients with mechanical aortic prostheses [2-91 and 31 to 71% (median, about 5%) in patients with aortic bioprostheses [4, 6, 8, For mechanical prostheses and bioprostheses in the mitral position, the corresponding percentages are 55 to 79% (median, approximately 67%) [3, 9, 15-18], and 19 to 79% (median, approximately 55%) (1, 12-14, 181. The purposes of this review are threefold: (1) to determine the incidence of thrombotic and bleeding complications associated with popular current prostheses, some of which were introduced only a few years ago; (2) to review results of variations in anticoagulant and antiplatelet drug management; and (3) to reexamine the pathogenesis of the problem to identify potential new approaches. The review will focus on thrombotic and bleeding complications and will not consider other important valve-related problems such as durability, prosthetic valve endocarditis, hemolysis, paravalvular leak, pannus formation, and reoperation. Definitions, Data Stratification, and Reporting The adjective thrombotic is derived from the noun thrombosis and in this review refers to both valvular thrombosis and thromboembolism or embolism. Bleeding refers to anticoagulant-related hemorrhage. Standard definitions of what constitute thromboembolic events in patients with prosthetic heart valves do not exist, but are badly needed. Some events such as intraoperative stroke, transient ischemic attacks, sudden death, and myocardial infarction may be due to prosthe- 43 Ann Thorac Surg , Oct 1987

2 431 Collective Review: Edmunds: Prosthetic Valve Thromboembolism sis-generated thromboemboli or to other causes. Thus standard definitions necessarily are arbitrary, but are needed to compare data from different institutions. Thromboembolism associated with prosthetic heart valves is systematically underreported [19], primarily because the sensitivity of the central nervous system to injury is vastly greater than that of other organs and tissues. Most emboli outside the brain are undetected [19]. Thoroughness of follow-up also influences the incidence of detected thrombotic complications (21. Reports that state definitions of thrombotic and bleeding events and that present raw and processed data stratified into specified subsets are most useful for both informational and comparative purposes [2]. By increasingly accepted definition, thromboembolic complications include any transitory, temporary, permanent, or fatal postoperative central nervous system deficit; excluded from the definition are patients who fail to regain consciousness or who awake with a stroke after bypass. Unless visual deficits occur, funduscopic observation of emboli is not counted. Transient ischemic attacks are counted unless another cause is proven. Although this interpretation may be arbitrary, the overestimating effect is offset by not counting acute myocardial infarctions except in young (less than 4 years old) patients with minimal or no atherosclerosis and in patients in whom a coronary embolus is demonstrated at angiography or autopsy (rare events). Peripheral and visceral emboli proven by angiography, operation, or autopsy are included. Sudden unexplained death, which may be precipitated by an unrecognized embolus, is not considered valve-related although this event is responsible for 5 to 33% (median, approximately 15%) of all late deaths [6,8, 15, 16, 21-29]. This decision is supported by a similar incidence of sudden death in patients with free aortic homografts in whom thromboembolism does not occur (Barratt-Boyes BG, personal communication, 1987). Clearly valvular thrombosis in the absence of infection is a valve-related thrombotic event and should be included in all tabulations of the incidence of thrombotic complications. Often it is included as a cause of reoperation and grouped with paravalvular leak or tissue overgrowth. Acute endocarditis greatly increases the incidence of both native and prosthetic valve thrombotic complications [3-331, but few reports stratify thrombotic complications with respect to infection. The incidence of thrombotic complications is similar for infected prosthetic and native valves (3, 34, 351, and the linearized rate of endocarditis does not vary between prostheses [4, 351. One can argue that thrombosis is a complication of the infection and should not be included in tabulations of the linearized rate of thrombotic events and anticoagulant-related bleeding. The alternative argument has equal merit; hence an arbitrary decision is needed to facilitate uniform reporting of thrombotic and bleeding complications in patients with active endocarditis. I vote to include all thrombotic complications, including those in infected patients, in actuarial and linearized rate calculations. In contrast to older articles, many recent reports document serious and fatal bleeding episodes, and wisely ignore minor bleeding events, which are underreported [19]. These investigators generally define serious bleeding as those episodes that require hospitalization or transfusion or that cause a transitory, temporary, permanent, or fatal stroke. As cardiac surgeons attempt to more precisely define benefits and risks of prosthetic cardiac valves, the need to stratify thrombotic and bleeding complications into standard subsets becomes more desirable [2]. For instance, fatal thrombotic complications (stroke, valvular thrombosis, and death after reoperation for valvular thrombosis) and fatal bleeding episodes should be distinguished from nonfatal events. Nonfatal events should be further stratified into those causing residual neurological deficits and those that do not. For the most part, a patient's well-being is not affected by a transitory or temporary central nervous system deficit or even by a peripheral embolectomy. Although these experiences are frightening, disability is not permanent. Similarly, successful reoperation for valvular thrombosis does not cause permanent disability. Tables 1, 2, and 3 stratify thrombotic and bleeding complications into fatal and nonfatal events, but data are insufficient to subdivide nonfatal events into those with temporary or permanent disability. Most recent reports calculate both the linearized rate of thrombotic and bleeding complications and the actuarial "thromboembolic complication-free" curves. To calculate the incidence or linearized rate of a complication, both the number of events (not patients) and the number of patient-years of follow-up must be known for each valve model for each location [16]. Calculation of linearized rates implies that the events occur at constant rates, which is probably true for anticoagulant-related bleeding. However, thrombotic complications are more common during the first few months after operation [16]; therefore, the simple linearized rate calculation is biased against new valves with comparatively short follow-up. This drawback can be exposed by calculation of annualized linearized rates [16], but these rates may be highly variable and misleading unless the denominator (patient-years) for each postoperative year is large (e.g., 3 to 5 patient-years). Actuarial curves indicate numbers of patients (not events) who sustain valve-related complications with respect to time [36]. These calculations reveal constant or nonconstant initial events and are not changed by subsequent events in the same patient. It is not practical to stratify actuarial curves into numerous subsets, but with respect to thrombotic and bleeding complications, five curves may more precisely define benefits of prosthetic valves, particularly in large well-studied series. These curves are usually presented as "complication-free" curves. Some investigators calculate patients free from all thrombotic complications and those free from all

3 432 The Annals of Thoracic Surgery Vol 44 No 4 October 1987 Table 1. Thrombotic and Bleeding Complications of Prosthetic Aortic Valves Incidence of Fatal Events Incidence of Nonfatal (No.il pt-yr) Events (No./lW pt-yr) Incidence of All Incidence of All % Free at 5 Yearsb Follow-up Throm- Hemor- Throm- Hemor- Fatal Events Events Thrombo- Hemor- Valve Type Reference (pt-yr) Embolus bosis rhage Embolus bosis rhage (No.il pt-yr) (No.il pt-yr) embolism rhage Starr-Edwards 126 Starr-Edwards 126 StamEdwards 126 Starr-Edwards 126 Bjork-Shiley std Bjork-Shiley std Bjork-Shiley std Bjork-Shiley std Bjork-Shiley cc St. Jude St. Jude St. Jude St. Jude Medtronic-Hall Omniscience Hancock Hancock Miller et al, 1984 [2] Macmanus et al, 198 [37] Farah et al, 1984 [7] Collected (6, 381 Karp et al, 1981 [25] Sethia et al, 1986 (171 Cohn et al, 1984 [4] Perier et al, 1985 [6] Sethia et al, 1986 (171 Arom et al, 1985 (391 Baudet et al, 1985 [21] Kinsley et al, 1986 (221 Collected [3, 8, 9, Collected [ Collected [ Oyer et al, 1984 [12] Gallo et al, 1981 [49] 2, ,857 1,531 1, , , ,175 1, , Hancodc Collected [4, 1, 5-52, 13al 4,261 Carpentier-Edwards David et al, 1985 [53] Carpentier-Edwards Soots et al, 1984 [14] Carpentier-Edwards Collected [6, 13, 54, 13al ,745 Ionescu-Shiley Brais et al, 1985 [55] 586 Ionescu-Shiley Collected [56, 571 1, d An attempt has been made to include each institution s experience only once. Collected figures are corrected for varying lengths of follow-up. All incidence ercentages have been rounded off to the nearest tenth. 4 his is percentage of patients free from an event. Recorded incidence is likely lower than actual incidence, since not all thrombotic and bleeding complications are included in citation(s). dfigure is based on fewer patient-years than the total listed. Std = standard or spherical-disc valve; cc = convexoconcave; = not available; No. = number of events p O.Sd *.3.2. Id c Zd d 2.e 1.4d.6 1.P d d %d I 1 Table 2. Thrombotic and Bleeding Complications of Prosthetic Mitral Valves Incidence of Fatal Events Incidence of Nonfatal (No.il pt-yr) Events (No./lW pt-yr) Incidence Incidence % Free at 5 Yearsb of All of All Follow-up Throm- Hemor- Throm- Hemor- Fatal Events Events Thrombo- Hemor- Valve Type Reference (pt-yr) Embolus bosis rhage Embolus bosis rhage (No.il pt-yr) (No./1 pt-yr) embolism rhage Starr-Edwards 612 Miller et al, 1983 [16] 3, Stam-Edwards 612 Sala et al, 1982 [15] 1, Starr-Edwards 612 Cobanoglu et al, 1985 [58] Bjork-Shiley std Marshall et al, 1983 [26] 1, Bjork-Shiley std Sethia et al, 1986 [17] 1, Bjork-Shdey std Karp et al, Bjork-Shiley std Perier et al, 1984 ( F 76 Bjork-Shiley cc Cortina et al, 1986 [59] Bjork-Shiley cc Sethia et al, 1986 [17] St. Jude Arom et al, 1985 [39] St. Jude Kinsleyet al, 1986 ( Y 89 St. Jude Collected [4, 9, 21, , Medtronic-Hall Collected [22, 45, d Omniscience Collected (46-48, d d 9.7d Hancock Oyer et al, 1984 [121 3, Hancock Gallucci et al, 1984 [6] 2, Hancock Collected [lo, 5, 4, , 67, 13aI Carpentier-Edwards Jamieson, 1985 ( Carpentier-Edwards Soots et al, 19M [14] 1, Carpentier-Edwards Collected (18, 26, 54, 13al 1, d Ionescu-Shiley Collected [ ,534 Od.8.6d 1.4 a-dsee Table 1 for explanation of footnotes and key.

4 433 Collective Review: Edmunds: Prosthetic Valve Thromboembolism Table 3. Thrombotic and Bleeding Complications of Combined Aortic and Mitral Valve Prosthesesa Incidence of Fatal Events (No /lo pt-yr) ~. Incidence of Nontatal Events (No /lo pt vr) IncidenLe of All InodcnLe ok All YC Free at 5 Yearsb Follow up Throm- Hemor- Throm- Hemor- htal Events Evrnis Thrombo- Hemor Valve Type Reference (pt-yr) Embolus bosis rhage kmbolus bosis rhage (No/lo pt yr) (No /I pt yr) entbolism rhage Bjork-Shiley std Karp et al, 1981 [25] Bjork-Shiley std Setha et al, Bjork-Shiley cc Sethia et al, 1986 (171 St. Jude Kinsley et al, 1986 (221 St. Jude Armenti et al, 1987 [23] St. Jude Collected (9, 21, 39-41] Hancock Oyer et al, 1979 (681 Hancock Zussa et al, 1985 [lo] Hancock Collected [49, 5, 521 Carpentier-Edwards Janusz et al, 1982 [54] lonescu-shiley Silverton et al, 1984 ( , d ' ' a-dsee Table 1 for explanation of footnotes and key bleeding complications. A curve that combines both, that is, patients free from all thrombotic (both embolic and valvular thrombosis) and bleeding complications, indicates the magnitude of the combined problem. In addition, since fatal complications and complications that produce permanent residual neurological deficits are more serious than reversible injuries, calculation of patients free from all fatal thrombotic and bleeding complications and free from all fatal and irreversible thrombotic and bleeding complications is desirable. The latter curve best portrays the most serious consequences of valve-related thrombosis and bleeding, and deemphasizes the importance of reversible and treatable complica tions. Current Cardiac Valvular Prostheses The data used in Tables 1, 2, and 3 were gleaned from articles included in the Index of the United States Library of Medicine Interactive Retrieval Service (Medlars 11) since 1979 under the heading "Cardiac Valvular Prostheses.'' I cannot claim that every usable article is included, although that was the intention. I do claim that the data are presented without bias and reflect available information. The heterogeneity of definitions, investigators, anticoagulation policies, patient groups, and follow-up precludes valid statistical analysis. Conclusions must be considered tentative only. More data than those available to me and considerations other than thrombotic and bleeding complications must be included before one valve can be claimed to have superiority over another. The tabulated data show wide variability between identical valves in identical locations [2-4, 6-1, 12-18, 21-23, 25, 26, 37-68, 13al. There are many reasons for this, including differences in anticoagulation practice, thoroughness of follow-up, definitions of thrombotic events, and patient populations. With the exception of Carpentier-Edwards mitral prostheses, variation in the incidence of thrombotic complications between reports is present for both mechanical and bioprosthetic valves in all locations. There is also variation between smaller series, which are pooled to provide the collected citations. The tables also reveal important gaps in the data base. In some instances, actual experience with the prosthesis is limited; in other instances, modern experience with established prostheses has not been published. The paucity of data with simultaneous replacement of aortic and mitral valve prostheses is particularly evident in Table 3. Data from the majority of articles reviewed for Tables 1 through 3 could not be included because essential information was lacking, because valve models or locations were pooled, or because another citation reported the same experience [5, 11, 24, 27-29, 68-13a). To facilitate comparisons between different prostheses in different locations, data from Tables 1 through 3 were pooled to construct Figures 1 through 3. For aortic prostheses with 3, or more patient-years of follow-up, Figure 1 shows a higher incidence of both thrombotic and bleeding complications for mechanical aortic prostheses than for bioprostheses. The omission of warfarin sodium anticoagulation in most patients with bioprosthetic valves explains the lower incidence of bleeding; however, Figure 1 also suggests that the incidence of thrombotic complications is lower despite the lack of warfarin. As illustrated in Figure 2, the incidence of thrombotic and bleeding complications for Bj6rk-Shiley standard and St. Jude valves is similar to that for Hancock prostheses and only slightly higher than that for the other bioprostheses. The higher incidence for Starr-Edwards prostheses is in part due to the inclusion [16] of experience from the 196s and early 197s when the incidence of thrombotic complications was higher [37]. The linearized rate of valvular thrombosis appears to be higher for tilting-disc prostheses and is particularly high for mitral Omniscience prostheses (see Table 2). Thrombotic occlusion has occurred with all currently available heart valve prostheses [43, 48, 68, 69, 14-17al. When Figures 1 and 2 are compared, valve location (aortic or mitral) does not appear to affect linearized

5 434 The Annals of Thoracic Surgery Vol 44 No 4 October \ 5 + Fig 1. Mean linearized rates of thrombotic and bleeding complications of prosthetic aortic valves. Means were calculated for each type of prosthesis from data in Table 1 and were weighted according to years of patient follow-up. The solid bars represent all thrombotic complications; the open bars depict major bleeding events. The plus sign above a bar indicates that some reports did not include all bleeding complications. (S-E 126 = model 126 Starr-Edwards; B-S Std = Bjork- Shiley spherical-disc valve; 8-S C-C = Bjiirk-Shiley convexoconcave disc valve (recently recalled); St. Jude = St. Jude Medical bileaflet prosthesis; Medtronic = Medtronic-Hall tilting-disc valve; Omniscience = Omniscience tilting-disc prosthesis; Hancock = Hancock porcine heterograft; C-E = Carpentier-Edwards porcine heterograft; I-S = lonescu-shiley pericardial xenograft prosthesis.) l o 1 \ \ \ \ \ \ \ \ \.-.- l l l I Fig 2. Mean linearized rates of thrombotic and bleeding complications of prosthetic mitral valves. Symbols and most abbreviations are the same as in Figure 1. (S-E 612 = model 612 Starr-Edwards.) Fig 3. Mean linearized rates of thrombotic and bleeding complications of simultaneously placed aortic and mitral prostheses. Symbols and abbreviations are the same as in Figure I. rates of thrombotic or bleeding complications of standard Bjork-Shiley and St. Jude prostheses and rates of thrombotic complications of Carpentier-Edwards and Ionescu-Shiley valves. However, the very large reported experiences with the Hancock bioprostheses do show lower linearized rates of both thrombotic and bleeding complications in the aortic position. Although the tabulated data suggest that the linearized rates for thrombotic and bleeding complications are less for the Ionescu-Shiley valve than for other tissue valves, other reports [7, 711, which could not be included in these tabulations, do not support this conclusion. Data for combined aortic and mitral prostheses (see Figure 3) are limited and preclude firm comparisons between different prostheses. Interestingly, several prostheses do not appear to increase the incidence of thrombotic complications above that observed for mitral valves alone. Eighty to 9% of all thromboembolic complications [16, 19, 81 and 2 to 3% of bleeding complications involve the central nervous system [5, 16, 19, 81. The percentage of thrombotic or bleeding complications that are fatal generally ranges between 15 and 25%, and is presented for both types of prostheses for each location in Table 4. For aortic prostheses, the percentage of fatal events does not appear to differ between mechanical prostheses and bioprostheses. However, for mitral and for double prostheses, the data suggest that fewer thrombotic and bleeding complications are fatal in patients with bioprosthetic valves. Table 4 also presents the weighted mean linearized rates of fatal thrombotic and bleeding complications. These data reflect the likelihood of a fatal event (as opposed to the chances that an event will be fatal) and strongly suggest that the incidence is reduced by a factor of 4 for aortic bioprostheses and by a factor of approximately 2 for mitral and double bioprostheses.

6 ~~ 435 Collective Review: Edmunds: Prosthetic Valve Thromboembolism Table 4. Incidence of Fatal Thrombotic and Bleeding Complications of Prosthetic Heart Valvesa Aortic Mitral Aortic and Mitral Incidence Mechanical Bioprosthetic Mechanical Bioprosthetic Mechanical Bioprosthetic Fatal (%) Thrombotic Bleeding b 14.7 Thrombotic and bleeding FataI (%/pt-yr) Thrombotic Bleeding Thrombotic and bleeding athe data are compiled from Tables 1 through 3. The ratio of fatal events to thrombotic, bleeding, or both complications was determined for each entry in the tables. The final figure is the weighted mean of the ratios (weighted according to number of patient-years of follow-up) multiplied by 1. Linearized rates were weighted according to patient-years of follow-up to determine the weighted means. bthis figure is based on 2,88 patient-years of follow-up and is unexplainably low. Data are too few to calculate either the linearized rates or percentages of nonfatal permanent strokes due to thrombotic and bleeding complications. A perusal of articles suggests that between one-third and one-half of all nonfatal central nervous system emboli or hemorrhages cause permanent disability [2, 16, 41,43, 8, 81, 98, 991. Factors That Affect the Incidence Mechanical Valves For mechanical valves, anticoagulation with warfarin is the most important factor affecting the incidence of both thrombotic and bleeding complications. Without warfarin, the incidence of thromboembolism increases 3-fold to 8-fold in patients with mechanical aortic valves [9, 21, 5, 63, 14, 18, 191; with mitral prostheses, the increase is likely higher [19]. Platelet inhibitors without warfarin are ineffective [ ; therefore, ail patients with mechanical prostheses should be maintained for life on long-term warfarin. Adequate anticoagulation in patients with mechanical heart valves is defined as a prothrombin time (rabbit thromboplastin) between 1.5 and 2. times control or 3. and 4.5 international normalized ratios (INR) [28, The INR, the preferred method of reporting prothrombin times, is the ratio of the patient s prothrombin time divided by the control time when the thromboplastin standard of the World Health Organization is used [113, Manufacturers of various thromboplastins provide conversion factors to correct observed ratios to INR ratios. Inadequate anticoagulation, defined as patients who have prothrombin times 25% or more below the therapeutic range, increases the incidence of thromboembolism 2 to 6 times [7,28, 8, 116, This observation has led to recommendations for more intense anticoagulation and a more narrow therapeutic range [118, Compliance, however, is a major problem, and the problem is compounded by the fact that some foods (e.g., celery and broccoli) and many commonly used drugs, including the platelet inhibitors aspirin and sulfinpyrazone, affect the warfarin dose [12]. Spot pro- thrombin times show that 33 to 5% of patients maintained on long-term warfarin have prothrombin times outside the therapeutic range [28,111,115,117,121,122] and that approximately one-third of all prothrombin times measured are outside this window [115]. Excessive warfarin that increases the prothrombin time beyond 2.5 times control increases bleeding complications 4 to 8 times [19, The longer the bleeding time, the more likely a bleeding complication will result [125, Most bleeding complications involve the gastrointestinal tract [124]. Bleeding complications are 1.5 times more frequent in patients more than 7 years old than in those less than 6 years old [124]. As expected, preexisting potential bleeding sources (e.g., peptic ulcer, gastritis, diverticula, and genitourinary lesion) also increase the risk of bleeding with anticoagulation. Platelet inhibitors in addition to warfarin have reduced the incidence of thromboembolism associated with mechanical valves in some series [115, 122, 127, 1281 but not in others [129]. When aspirin is used (5 mg to 1 gdday), bleeding complications increase significantly [115]. The use of dipyridamole (225 to 4 mg/day) [115, 1281 or sulfinpyrazone (8 mg/day) [115, 1221 has not increased the rate of bleeding complications, but the doses used have not always effectively increased platelet survival times [ Steele and colleagues [ 1331 observed a positive correlation between the incidence of thromboembolism and reduced platelet survival times. Despite these data, the advantage of warfarin plus platelet inhibitors versus warfarin alone remains unclear. Other independent risk factors for thrombotic complications in patients with mechanical heart valves are less important than warfarin anticoagulation. The preponderance of reports identify atrial fibrillation [4, 5, 9, 28, 46, 62, 63, 73, 92, 98, 99, 12, 13a, 115, 1341, previous embolus [9, 17, 8, 98, 99, 121, left atrial thrombus [62, 66, 99, 121, recent operation [8, 16, 95, 1141, and operation before the mid-197s [7, 37, 581 as independent risk

7 436 The Annals of Thoracic Surgery Vol 44 No 4 October 1987 factors. The experiences of others do not indicate an increase in thromboemboli in patients with atrial fibrillation [2, 7, 16, 22, 75, 8, 81, 9, 1161, previous embolus [63, 75, 141, left atrial thrombus [9, 16, 75, 81, or recent operation (first postoperative year) [17, 25, 73, 121. However, an embolic event in a patient with a mechanical valvular prosthesis increases the likelihood of another by a factor of 2 to 4 times (16, 37, 8, 981. Other factors such as low cardiac output [64], age greater than 6 years [92], previous heart operation [92], large left atrium [28, 98, 121, and additional operative procedures [62, 661 have not been convincingly established as independent risk factors. In truth, the sustained adequacy of warfarin anticoagulation supersedes all other factors. Biopros theses Patients with aortic bioprostheses commonly receive warfarin anticoagulation [6, 1, 12, 14, 26, 27, 5-53, 56, 1161 or platelet inhibitors [ll] for three months and then either no drugs [ll, 52, 561 or platelet inhibitors without warfarin [55,67l. Although the incidence of thromboembolism with aortic bioprostheses is greater in the first three months after operation in some series [8, 12, 52, 561 but not in others [54, 85, 1351, there are no data to indicate that warfarin anticoagulation during this period significantly reduces the incidence of thromboembolism [51,94, 13al. Likewise, data are not available to support the long-term use of platelet inhibitory drugs in patients with aortic bioprostheses [5, 51, 561. Without new contrary data, most patients with aortic bioprostheses are probably best managed without postoperative warfarin or platelet inhibitors [6, 51, 561. This policy avoids the bleeding complications associated with these drugs [8]. The question remains whether to prescribe warfarin for patients with atrial fibrillation [4, 1361, concomitant mitral disease [7, 13a], a history of embolus, or a recent embolus. For patients with aortic bioprostheses, these risk factors are not well established. Furthermore, the effectiveness of warfarin or platelet inhibitors in reducing the incidence of thromboembolism in the presence of these risk factors is not established at all. The incidence of thromboembolism is greater in patients with mitral bioprostheses, but the ability of longterm warfarin anticoagulation to reduce this incidence is also unclear [56, 63, 64, 13a, Atrial fibrillation [54, 55, 62, 64, 93, 13a, 137, 1381, the first three postoperative months [56, 64, 134, 136, 1371, left atrial thrombus [64], and previous emboli [63, 641 are associated with increased thromboembolism in most series but not in all [62, 67, An enlarged left atrium, a subjective determination in reports published to date, is uncommon in patients with mitral disease who do not also have atrial fibrillation, and may not be an independent risk factor. Long-term warfarin is usually prescribed in the presence of one or more of these risk factors [lo, 14,27,54,55,93, 13a] and is used for only two or three months when risk factors are absent [lo, 14, 27, 54-56, 931. This policy prescribes warfarin for 3 I121 to 8% [64] of all patients who receive mitral bioprostheses, and correspondingly increases the risk of anticoagulant-related bleeding [64]. In contrast, Hill and associates [63] and Nunez and coworkers [134, 1371 do not recommend warfarin at all, but do recommend low-dose aspirin (.6 gdday;.5 gd48 hr) for all patients regardless of risk factors. Hetzer [64], Ionescu [56], and their colleagues recommended warfarin for three months and then no antithrombotic drugs. These data, increased bleeding complications associated with warfarin, and the doubtful efficacy of warfarin in patients with single risk factors question the use of longterm warfarin in patients with mitral bioprostheses and atrial fibrillation. With the possible exception of patients with combinations of atrial fibrillation, atrial thrombus, and previous embolus, long-term warfarin can no longer be recommended for patients with mitral bioprostheses. However, some method to suppress coagulation (shortterm warfarin, low-dose aspirin, or subcutaneous administration of heparin) [ 1391 immediately after operation is needed in patients with mitral bioprostheses, since the incidence of thrombotic complications increases without any antithrombotic drugs during this period [64, Special Situations Tricuspid Prostheses Emboli from tricuspid prostheses enter the pulmonary circulation and are largely undetected. Thus the incidence of thromboembolic events for tricuspid prostheses is unknown. Massive pulmonary embolism does occur, but infrequently (14, Thrombosis of the tricuspid valve occurs with both mechanical [ and bioprosthetic valves [142, The incidence is highest with Bjork-Shiley valves [141, 142, 1461, is less common with Starr-Edwards [142] and St. Jude prostheses [142, 1471, and is least common with bioprostheses [ Warfarin anticoagulation is mandatory for patients with mechanical tricuspid prostheses [148,149] and is recommended for those with tricuspid bioprostheses [142]. The value of platelet inhibitors [143] is unproven. Acute thrombosis may be successfully treated with intravenous administration of streptokinase [141, 146, Currently, most triscupid valves can be repaired and few are replaced. However, when a triscuspid prosthesis is used, usually one or more left-sided valves are also replaced [14, 142, 151. The incidence of systemic thromboembolism appears to be higher in patients with three prosthetic valves than in those with two left-sided prostheses [14, 151. Prosthetic Valve Endocarditis The percentage of patients with active early or late prosthetic valve endocarditis who suffer thrombotic complications ranges from 13 to 4% [3, With fungous prosthetic valve endocarditis 7 to 9% 1155,1561 of patients will sustain emboli. The percentage of patients who have thrombotic complications does not appear to differ between mechanical and bioprosthetic valves [34,

8 437 Collective Review: Edmunds: Prosthetic Valve Thromboembolism 151, Because the risk of valve thrombosis or embolus is so high during active infection, anticoagulation is recommended for all patients regardless of the type or location of the prosthesis [156]. Most patients will require early operation [3, 1511; therefore, intravenous administration of heparin in doses sufficient to double the partial thromboplastin time is recommended preoperatively. To counteract increased platelet sensitivity induced by heparin [157], dipyridamole probably should be added until 6 to 8 hours before operation. Postoperatively, heparin and dipyridamole are recommended when wound bleeding subsides. Presumably infection is controlled, and these drugs can be tapered over a few days. Warfarin is required over the long term for all patients with mechanical valves and may be beneficial during the postoperative course of antibiotics in patients with bioprosthetic valves [ Warfarin may also be beneficial (unproven) during the course of antibiotics in those patients who do not undergo reoperation [ Cerebral Emboli The combination of stroke, a prosthetic heart valve, and anticoagulation raises the differential diagnosis of embolus, bleeding, or embolus with bleeding. Computerized axial tomography of the brain can usually determine whether bleeding has occurred in the area of infarction. Between 2 and 3% of patients with nonseptic emboli will have recurrent emboli if they are not on a regimen of anticoagulation [8, In the absence of infection, the risk of hemorrhagic extension of a cerebral embolus [161] is very low [158, 159, 1621; therefore anticoagulants should be continued or initiated unless contraindicated for other reasons [158-16, The incidence of hemorrhagic extension is higher in patients with septic emboli [34, 1631, but nevertheless, carefully controlled anticoagulation probably represents less risk than no anticoagulation [16]. Either tomographic evidence of hemorrhagic extension or deterioration in the clinical condition is reason to modify or stop anticoagulation. There are few data regarding emergency or urgent cardiopulmonary bypass after a recent cerebral embolus. If hemorrhagic extension has not occurred, bypass is probably safe in most instances. Pregnancy Bioprosthetic valves are strongly recommended for women who wish to bear children [ Neither warfarin nor heparin is required; thus the teratogenic effects and bleeding complications associated with these drugs are avoided. Although pregnancy may have an adverse effect on the durability of bioprosthetic valves [167] and may induce periods of hypercoagulability [169], the risks of thrombotic and bleeding complications to both mother and fetus are substantially less than with mechanical valves. Both low-dose aspirin (.5 gd48 hr) or dipyridamole may be given safely [164, 171 (both cross the placenta), but their efficacy in pregnant women with bioprostheses who have or do not have incremental risk factors is not established. Pregnant women with mechanical heart valves are exposed to increased risk of thrombotic complications if anticoagulation is interrupted [171, However, warfarin taken by the mother crosses the placenta and can cause warfarin embryopathy (nasal hypoplasia and stippled epiphyses) if the fetus is exposed between the sixth and ninth week of gestation. The incidence of typical warfarin embryopathy is 4 to 8% [166, 173, 1741, but an additional 22% have some features suggestive of the syndrome [174]. Warfarin taken during the second and third trimesters can cause a variety of central nervous system abnormalities (i.e., optic atrophy and mental. retardation) in approximately 3% of pregnancies [173]. Warfarin also increases the risk of spontaneous abortion, stillbirth, prematurity, and fetal hemorrhage, so that only 7 to 75% of pregnancies end with live, healthy babies [ Although warfarin increases fetal wastage, the drug causes few additional thrombotic and bleeding risks for the mother [172, Heparin also increases the incidence of fetal lass due to prematurity, spontaneous abortion, and stillbirth (173, 174, 1771, and greatly increases the incidence of bleeding complications in the mother [172,173]. Heparin in full or low doses is associated with an increased incidence of valve thrombosis, thromboembolism, and maternal death [166, 171, 173, 174, Although heparin does not cross the placenta, only two-thirds of pregnancies end with healthy babies [173, 1741 and nearly onesixth of mothers sustain important bleeding complications [172, To date, various combinations of heparin and warfarin (e.g., heparin in the first trimester then warfarin until the 38th week) have failed to protect expectant mothers with mechanical valves and their fetuses from complications associated with the two drugs [174, Platelet inhibitors without anticoagulation do not provide sufficient protection for the mother [166]. Although thrombosed valves have not been treated with streptokinase or tissue plasminogen activator, streptokinase has been used in pregnant women [17]. Faced with a determined young woman with a mechanical heart valve who desires a family, all choices are unattractive. Elective reoperation with insertion of a bioprosthetic valve is one option. Otherwise, one can only counsel the couple, choose one of the unattractive anticoagulation schemes, and hope for the best. Children Mechanical valves are recommended for the left-sided, systemic chambers in children because accelerated calcification and deterioration require reoperation in most patients within four years [ Calcification occurs more slowly in prosthetic tricuspid and pulmonary valves [178, 1791 and is least rapid in antibioticsterilized homografts [181, Tissue valves in children do not require warfarin anticoagulation and have a low rate of thrombotic complications [181, Ini-

9 438 The Annals of Thoracic Surgery Vol 44 No 4 October 1987 tially, this advantage and mandatory, growth-dictated reoperations made tissue valves attractive for young children [lsl], but rapid calcification has largely preempted this strategy [189]. In children, mechanical valves have been used without warfarin or platelet inhibitors [185, , with platelet inhibitors [191, 193, 1941 only, and with warfarin anticoagulation [ , Most studies report a mixture of valve models [183, 185, 186, 188, 189, 1931, often less than 1 patient-years of follow-up [188, 19, 191, 1931, and a variety of antithrombosis protocols [186, 191, 193, Thus it is not possible to reliably estimate linearized rates of thrombotic and bleeding complications for various valve models and positions. The fact that some series report on children with mechanical prostheses who receive no drugs [185, 191 suggests that natural defense systems, anticoagulants, and fibrinolysins in children are more effective than in adults [196]. Despite this circumstantial evidence, the preponderance of data [181, 183, 186, , 1981 supports the use of warfarin, and indeed, many of the severe and fatal thrombotic complications seem to occur when warfarin is omitted [183, 185, 192, Warfarin anticoagulation is difficult to manage in children, and serious bleeding complications occasionally occur [184, Most bleeding complications are not serious [183, 186, 193, The linearized rate of serious bleeding complications in children with prosthetic heart valves ranges between.24 and 8.7% per patient-year (median, approximately 1% per patientyear) [183, 186, 193, The linearized rate of thrombotic complications in warfarin-anticoagulated children with mechanical heart valves ranges between and 3.2% per patient-year (median, approximately 2% per patient-year) "1, 183, 193, Aspirin (6 mg per kilogram of body weight per day) with [191, 1931 or without [191] dipyrimadole (2 to 3 mgl kg/day) has been used without warfarin. Bleeding complications are rare [191, 193, 1941, and in two series [191, 1941, no thrombotic complications occurred. However, because the data base involves less than 5 patients, the efficacy of aspirin without warfarin in the control of thrombotic complications in children with mechanical heart valves is not established. Pathogenesis and Pharmacology Pa thogenesis Valve design and materials influence the incidence of thrombotic complications. Free aortic homografts in the aortic position mimic the natural valve and are the only valvular prostheses devoid of thrombosis and thromboembolism [2]. Rough surfaces, large surface area, stagnant flow, narrow flow paths, and turbulence enhance thrombosis [21]. Until healing occurs, the projecting sewing ring is a potential site of thrombus attachment. No synthetic material, including preserved tissue, is nonthrombogenic, but some materials appear to activate the coagulation system more slowly than others [22]. Successful mechanical heart valves are made from these thromboresistant materials [23]. The reduced thrombogenicity of bioprosthetic valves probably is related more to central flow, flexible leaflets, and cyclic sinusoidal washout than to thromboresistance of the preserved tissue [24]. In view of the multiple material, fabrication, and design constraints, new prosthetic valves are unlikely to solve the problem of prosthetic valve thrombogenicity. All prosthetic valves except possibly free aortic homografts [133] activate platelets [122, 131, Platelets adhere to both bioprosthetic [24] and mechanical valve surfaces. Both types of valve decrease platelet survival [122, 131, 133, 291. Mechanical valves (bioprostheses not studied) decrease platelet adhesiveness [21]. Most reports, but not all [211], indicate that both mechanical and bioprosthetic valves increase plasma beta-thromboglobulin and thromboxane B2 [25-281, and some investigators have observed a correlation between thromboembolism and both plasma concentration of beta-thromboglobulin [25, 2111 and shortened platelet survival [l, 212, Although neither type of prosthesis increases fibrinopeptide A concentration [28], other data, including studies of blood in extracorporeal circulatory systems, suggest that prosthetic valves probably activate other coagulation components such as Factor XII, complement, and leukocytes in addition to platelets [l, 212, Therefore all prosthetic heart valves are thrombogenic, yet most patients survive many years without a thrombotic event. This happy fact reflects the dynamic equilibrium between the constant thrombotic stimulus of the prosthesis and the defense systems, which continuously maintain the fluidity of blood. High flow velocity across small synthetic surfaces that are washed clean with each cardiac cycle minimizes the number of coagulation elements activated by synthetic surface contact [21]. The vast endothelial cell surface, estimated at 1, to 6,3 m2 [214, 2151, and natural inhibitors counteract the activated procoagulant proteins. Protein C [216], heparin sulfate, antithrombin 111, alpha 2- macroglobulin, a-l-antitrypsin, protein S, thrombomodulin, prostacyclin, and plasmin (2171 inhibit steps in the coagulation cascade, remove procoagulant products from the bloodstream, and maintain the fluidity of blood. Without these inhibitors and the constant cleansing action of endothelial cells, all prosthetic valves would fail. As the biochemistry and interrelationships of endothelial cell metabolism and the coagulation cascade unfold, new opportunities to favorably influence this dynamic equilibrium in patients with prosthetic heart valves will arise. Pharmacology Coumarin compounds currently are the only available orally administered long-term anticoagulants. Warfarin, a water-soluble derivative of coumaric acid, is available parenterally and orally, and is most commonly used in the United States. Warfarin is completely absorbed from

10 439 Collective Review: Edmunds: Prosthetic Valve Thromboembolism the gut [ and has a long plasma half-life (mean, 42 hours) [219], which varies greatly between patients [218]. Most of the drug is bound to plasma albumin [ , and only the 3% unbound portion inhibits the oxidation-reduction cycle of vitamin K in liver mitochondria [217, By competitively blocking vitamin K epoxide reductase [ , less vitamin K is available to participate as a cofactor in the addition of gamma-carboxyglutamic acid residues (gla residues) to the vitamin K-dependent coagulation factors-11, VII, IX, X, protein C, and protein S [216, Gla residues are essential for binding calcium, and in their absence, activated clotting factors cannot bind phospholipids and participate in clotting. Therefore, within the coagulation cascade, warfarin establishes a new dose-dependent equilibrium [218] that is very sensitive to changes in both warfarin and vitamin K concentration. Although coumarin derivatives are the only available oral anticoagulant, they are far from ideal. Warfarin inhibits four procoagulant factors with plasma half-lives ranging between 5 and 1 hours [218]. Consequently, establishment of effective anticoagulation is slow. Warfarin also inhibits two natural anticoagulants and may induce a transitory hypercoagulable state because the concentration of protein C falls before the concentrations of factors 11, IX, and X decrease appreciably [216, Most importantly, the inhibitory effect of warfarin is strongly influenced by the ingestion and absorption of vitamin K, albumin binding, and liver enzyme metabolism [219]. A wide variety of foods and drugs affect warfarin and vitamin K concentrations in vivo, thereby causing marked variations in the dose required to maintain therapeutic suppression of the coagulation system both between patients [218] and, more importantly, within patients. The problem of constant, even suppression of coagulation is compounded by the fact that the therapeutic range is very narrow [113, 114, 221 and can be monitored only by a laboratory test that requires a venipuncture and usually is performed only once or twice a month [22]. Given these disadvantages, it is not surprising that 33 to 5% of all measured prothrombin times in patients with prosthetic heart valves are outside the therapeutic range [lll, Although intelligent patients and diligent physicians can tightly control warfarin anticoagulation at great cost and sacrifice [221], this approach is unlikely to succeed for most patients with prosthetic heart valves. What is needed is a new, more usable oral anticoagulant or a practical means to self-monitor the warfarin dose at home. Dipyridamole and sulfinpyrazone are weak antithrombotic drugs at dosages that can be tolerated by patients (4 mg and 8 mg/day, respectively). Neither drug prolongs bleeding time [132, Dipyridamole (4 mg/day) produces plasma concentrations of 5 p,m [222, 2231, which is well below the 1 p,m required to partially inhibit platelet function in vitro [224, Lower concentrations of dipyridamole inhibit phosphodiesterase and possibly potentiate prostacyclin in vivo [224, 2251, but demonstrated beneficial effects of these actions are elusive [132, 222, Sulfinpyrazone reversibly inhibits cyclooxygenase [226] and weakly inhibits platelets in vitro at high concentrations [226, In vivo sulfinpyrazone forms a more potent platelet inhibitory metabolite [224]; however, platelet inhibition at clinically tolerated concentrations is minimal [224, The strongest evidence that dipyridamole and sulfinpyrazone are beneficial for patients with prosthetic heart valves is that both drugs reverse shortened platelet survival times in some, but not all, patients [122, 13, 131,133,291. The weak and ambiguous efficacy of these drugs explains their inability to suppress thrombotic complications of prosthetic heart valves. Combinations of warfarin with dipyridamole or sulfinpyrazone have been recommended periodically [115, 122, 13, 131, Although sulfinpyrazone affects warfarin dose [219], neither platelet inhibitor appears to increase bleeding complications [115, 13, 131, 133, A few groups have observed a reduced incidence of thromboembolism in patients with mechanical valves with the combination of warfarin and dipyridamole or sulfinpyrazone [115, 122,2281; however, the beneficial effect of the platelet inhibitor has been difficult to understand [114]. Because of dose, the inhibitory effect on platelets is likely minimal, and moreover, platelets may already be partially inhibited because of trauma associated with the prosthesis [131, If, in fact, the combination of warfarin and either dipyridamole or sulfinpyrazone has a beneficial effect, it may be due to the fact that the platelet inhibitors partially compensate for inadequate warfarin anticoagulation [114]. Dissolved aspirin is rapidly absorbed and has a plasma half-life of 15 to 2 minutes [224]. Aspirin in doses as low as 8 mg/day inhibits platelet cyclooxygenase [ , inhibits platelet production of thromboxane A2 [231, 2321, increases platelet sensitivity to some aggregation agents [132, 222, 231, and prolongs template bleeding times [132, In contrast to dipyridamole and sulfinpyrazone, aspirin, even in low doses, effectively inhibits most platelet functions, although it does not inhibit soluble coagulation proteins. Compared with warfarin alone, the combination of aspirin and warfarin reduces thromboembolic complications [115, 128, 1321, but also increases the likelihood of serious bleeding. Aspirin inhibits both platelet and endothelial cell cyclooxygenase and stops platelet production of thromboxane A2 and endothelial cell production of prostacyclin. The inhibition is permanent for the life of the platelet (six to eight days), but endothelial cells can regenerate cyclooxygenase and resume full prostaglandin biosynthesis within 36 hours [215]. Daily low-dose aspirin (8 mg) inhibits both thtomboxane production and prostaglandin biosynthesis, and therefore probably does not achieve selective inhibition of platelets [224, However, low-dose aspirin (12 to 2 mg) given every three days is sufficient to completely suppress thrombox-

11 44 The Annals of Thoracic Surgery Vol 44 No 4 October 1987 ane A2 production [232] and theoretically may partially spare prostacyclin production. As yet this concept is unproven. Conclusion To the extent that this review reflects available data, it appears that bioprosthetic valves produce fewer thrombotic and bleeding complications than mechanical prostheses. Admittedly, the data base is porous, and lacks both consensus definitions of thrombotic complications and uniform reporting and follow-up. Warfarin anticoagulation remains the most important risk factor for both complications. The data question the need for warfarin or other antithrombotic drugs in patients with aortic bioprostheses, and suggest more restricted use of warfarin for patients with mitral bioprostheses. Questions are also raised about the use of various platelet inhibitors. Thrombotic and bleeding complications remain the most important valve-related complications of prosthetic heart valves. New approaches, particularly those that offer more precise control over the fragile equilibrium between procoagulants and anticoagulants, are needed before surgeons can offer patients with valvular heart disease more than palliation. Supported in part by HC 1955, National Heart, Lung, and Blood Institute. References 1. Edmunds LH Jr: The sangreal. J Thorac Cardiovasc Surg W1, Miller DC, Oyer PE, Mitchell RS, et al: Performahce characteristics of the Starr-Edwards model 126 aortic valve prosthesis beyond ten years. J Thorac Cardiovasc Surg 88193, Crawford FA Jr, Kratz JM, Sade RM, et al: Aortic and mitral valve replacement with a St. Jude Medical prosthesis. Ann Surg 199:753, Cohn LH, Allred EN, DiSesa VJ, et al: Early and late risk of aortic valve replacement. J Thorac Cardiovasc Surg , Cheung D, Flemma RJ, Mullen DC, et al: Ten-year followup in aortic valve replacement using the Bjork-Shiley prosthesis. 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13 442 The Annals of Thoracic Surgery Vol 44 No 4 October 1987 with the Ionescu-Shiley bovine pericardial bioprosthesis: analysis of 2,68 patients. J Vasc Surg 2:192, Becker RM, Sandor L, Tindel M, Frater RWM Mediumterm follow-up of the Ionescu-Shiley heterograft valve. Ann Thorac Surg 3212, Gonzalez-Lavin L, Chi S, Blair TC, et al: Five-year experience with the Ionescu-Shiley bovine pericardial valve in the aortic position. Ann Thorac Surg 36:27, Bjork VO, Henze A: Ten years experience with the Bjork- Shiley tilting disc valve. J Thorac Cardiovasc Surg 78331, Cohn LH, Koster JH, Mee RBB, Collins JJ Jr: Long-term follow-up of the Hancock bioprosthesis heart valve: a 6- year review. Circulation 6O(suppl I):187, Marshall WG Jr, Kouchoukos NT, Pollock SB, Bradley EL: Early results of valve replacement with the Bjork-Shiley convexoconcave prosthesis. Ann Thorac Surg 37:398, Hatcher CR Jr, Craver JM, Jones EL, et al: The porcine bioprosthesis. 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