Antithrombotic Therapy in Valvular Heart Disease

Antithrombotic Therapy in Valvular Heart Disease Herbert J Levine, M.D., Chairman; Stephen G. Pauker; M.D.; Edwin W Salzman, M.D. Few complications of valvular heart disease can be more devastating than systemic embolism. With little regard for the severity of the underlying valve lesion, a cerebral or mesenteric embolus in a moments time may cripple or kill a previously healthy patient. It is well recognized that antithrombotic therapy can reduce, although not eliminate, the likelihood of this catastrophe. Ifthis therapy were risk-free, all patients with valvular heart disease would be appropriate candidates for treatment. Unfortunately, antithrombotic therapy, particularly warfarin derivatives and heparin, includes an important risk of bleeding, which varies with the drug used, the intensity ofthe anticoagulant effect, and the clinical circumstances in individual patients. For example, risks of anticoagulant therapy are greater in older patients, endocarditis, pregnancy, and many other clinical situations. This review will examine the risks of thromboembolism in various forms of valvular heart disease and attempt to establish strategies for the use of antithrombotic drugs in each disease. For the most part, these analyses and guidelines will concern the long-term use of antithrombotic therapy in ambulatory patients with valvular disease. Basic to these considerations is the assessment of the risk of bleeding. For example, it is appreciated that the complications of anticoagulant therapy will be greater in some patients with a high risk of thromboembolism (ie, prosthetic valve endocarditis) than in those at low risk for this event. It is also important to emphasize that the permanent consequence of a thromboembolic event is generally more serious than the outcome of a hemmorhagic complication of anticoagulant therapy; and the rate of embolic phenomenon is not necessarily offset by an equal event rate of bleeding. Rahimtoola' reported that the risk of major bleeding in patients with prosthetic heart valves who received warfarin was 1-2%/patient year, and in a careful analysis of 10 reports of anticoagulant therapy in patients with prosthetic valves covering 215.5 patient centuries of follow-up, Edmunds" found the weighted mean of serious bleeding complications to be 2.19%/ year, with fatalities due to bleeding in O.17%/year. While the risks of anticoagulation will vary considerably in different patient groups, these data provide a framework for use in patients with prosthetic heart valves, although the risk of bleeding might be some- what lower in patients with less advanced native valve disease, since their incidence of embolic and associated hemorrhagic complications is lower. Another consideration that may influence greatly our assessment of the risk-benefit ratio of anticoagulant therapy relates to the recent study of less intense regimens of warfarin therapy It has been reported that PTs performedwith the commonly used commercial North American thromboplastin, maintairied in the range of 1.3-1.5 times normal control, retained effectiveness against recurrent venous thromboembolism with a greatly reduced frequency of bleeding complications." Of greater relevance to this issue of patients with valvular heart disease is the recent report by Turpie et al,' which suggests that a less intensive regimen of warfarin therapy is uno less effective, and is safer than standard anticoagulant therapy in patients with tissue heart valve replacement." RHEUMATIC MITRAL VALVE DISEASE The incidence of systemic embolism is greater in rheumatic mitral valve disease than in any other common form of heart disease. While the natural history of this disease has been altered during the past 30 years by surgery and the frequent use oflong-tetm anticoagulant therapy Wood 5 cited a prevalence of systemic emboli of9-14% in several large, early series of mitral stenosis, and in 1961 Ellis and Harken" reported that 27% of 1,500 patients undergoing mitral valvuloplasty had a history of clinically detectable systemic emboli. Among 754 patients followed for 5,833 patient years, Szekely? observed an incidence of emboliof1.5%/patientyear, while the figure was found to vary from 1.5 to 4.7%/year preoperatively in 6 reports of mitral valve disease. 8 As a generalization, it is perhaps reasonable to assume that a patient with rheumatic mitral valve disease has at least 1 chance in 5 of having a clinically detectable systemic embolus during the course of the disease. 9 The incidence of systemic emboli increases dramatically with the development of atrial fibrillation (AF). Szekely? reported that the risk of embolism was 7 times greater in patients with mitral valve disease and AF than in those with normal sinus rhythm, and among mitral patients with AF, Hinton et al lo found a 41% prevalence of systemic emboli at autopsy Three quarters of the patients with mitral stenosis and cerebral emboli reported by Harris and Levine" and 98S 2nd ACCPConference on Antithrombotic Therapy

by Woods had AF, and among 839 patients with mitral valve disease reported by Coulshed and associates, 12 emboli occurred in 8% of mitral stenosis patients with normal sinus rhythm, 31.5% of those with AF, 7.7% ofthose with dominant mitral regurgitation and normal sinus rhythm, and 22% of those with mitral regurgitation and AF. WoodS confirmed that emboli occur 1'h times as frequently in mitral stenosis as in rheumatic mitral regurgitation. The risk of systemic emboli in rheumatic mitral disease is greater in older patients l3-16 and those with lower cardiac indices" but appears to correlate poorly with left atrial size,s,12,17 mitral calcification," mitral valve area," or clinical classification. 5,12,13,17 Indeed, several investigators have pointed out that mitral patients with emboli frequently are found to have minor valve disease, and WoodS reported that in 12.4% of cases, systemic embolization was the initial manifestation of rheumatic mitral disease. Recurrent emboli occur in 30-65% of cases,5,9,18,19 60-65% within the first year 18,19 and the majority occur within 6 months. Mitral valvuloplasty does not appear to decrease the risk of thromboembolism.v" except perhaps in those with AF and an "operable valve."12 Thus, a successful mitral valvuloplasty does not eliminate the need for anticoagulation, and most patients will continue to require this therapy postoperatively There is good reason to believe that the frequency of systemic emboli due to rheumatic valve disease is decreasing, while the number due to ischemic heart disease is on the rise. This reduction in the number of systemic emboli due to rheumatic heart disease is due both to a decrease in the absolute number of rheumatic heartdisease patients and to the widespread use of long-term anticoagulant therapy in these patients. Although never evaluated by randomized trial, there is little doubt that long-term anticoagulant therapy is effective in reducing the incidence of systemic emboli in patients with rheumatic mitral valve disease. In a level IV study the incidence of recurrent embolism in mitral valve patients who received warfarin derivative anticoagulation was found to be 3.4%/.patient year, while in the nonanticoagulation group it was 9.6%/ patient years," Adams et al 17 followed 84 patients with mitral stenosis and cerebral emboli for up to 20 years, halfof whom received no anticoagulant therapy (1949 59), and half who received warfarin (1959-69) (level IV study). Using life table analyses, a significant reduction in emboli was reported in the treated group, with 13 deaths from emboli in the untreated group and only 4 deaths in the treated group. Fleming and Bailey'? in a level IV study found a 25% incidence of emboli among 500 patients with mitral valve disease, while in 217 patients treated with warfarin only five embolic episodes occurred over a 9'h-year period, yielding an incidence of 0.8%/patient year. Although the evidence supporting the use of anticoagulant therapy is based on case series without concurrent controls, we think it is convincing. Therefore, as a general rule, all patients with rheumatic mitral valve disease and AF (paroxysmal or chronic) should be treated with long-term warfarin therapy Exceptions that require detailed analysis include the pregnant woman or the patient at high risk for serious bleeding, whether due to established concomitant disease, exposure to contact sports, or trauma or inability to control the PT. Otherunique circumstances might also lead the clinician to withhold warfarin therapy For example, since the longer a patient at risk goes without an embolus, the less likely he is to have one, a 65-yeaN>ld woman with mitral valve disease and a IS-year history of AF might be at low risk for a first embolus. Despite the powerful thromboembolic potential of AF, the rheumaticmitralvalve disease patientin sinus rhythm still has a substantial risk of systemic embolism and is, therefore, a candidate for long-term warfarin therapy Since, other than age, there are no reliable clinical markers of such cases, the decision to treat is problematic. Because the risk of AF is high in rheumatic mitral disease patients with a very large atrium, it has been suggested that such patients in normal sinus rhythm with a left atrial diameter greater than 55 mm should receive anticoagulant therapy21 Several studies have suggested that systemic embolism in patients with valvular heart disease occurs more frequently in those with shortened platelet survival times. 22-26 Steele and Rainwater" reported that shortened platelet survival was a sensitive index of past thromboembolism in rheumatic valve disease, but the specificity of this finding was low; since 78% of patients without thromboembolism also had shortened platelet survival. Although su16npyrazone appeared to decrease the incidence of thromboembolism in these patients with mitral stenosis, two thirds were also taking warfarin, and efficacy of sulfinpyrazone as monotherapy for the prevention of thromboembolism remains unproved." It has also been shown that shortened platelet survival in patients with prosthetic heart valves can be normalized by sulfinpyrazone treatmentu and by dipyridamole.p and similar observations have been made in patients with mitral stenosis treated with sulfinpyrazone'i-" and in patients with arterial grafts treated with dipyridamole." Furthermore, in a level I study the addition of dipyridamole to warfarin therapy in a randomized study of patients with prosthetic heart valves proved effective in reducing the incidence of systemic emboli." Similar findings were reported in a level III s t u d and ~ 3the 1 combination of dipyridamole (450 mg/day) and aspirin (3.0 g/day) was also observed CHEST I 95 I 2 I FEBRUAR'( 1989 I Supplement 918

to reduce the incidence of thromboembolism in patients with prosthetic heart valves (level IV study).25 Dale and associates" performed a randomized study of aspirin (1.0 g/day) plus warfarin vs warfarin alone in 148 patients with prosthetic heart valves and noted a significant reduction of emboli in the aspirin-treated group. Intracranial bleeding complications occurred with equal frequency in both groups, while GI complications including bleeding were encountered more often in the patients taking aspirin. At the completion of the study all patients were treated with aspirin alone and had unsatisfactory control of embolic events. Thus, there is evidence that dipyridamole and sulfinpyrazone will normalize shortened platelet survival and reduce the incidence of emboli in some patients with valvular heart disease and that dipyridamole and/or aspirin added to warfarin therapy will reduce the incidence of thromboembolism in patients with prosthetic valves. However, until these findings have been confirmed and the effectiveness of plateletactive drugs compared with that ofwarfarin in randomized trials, patients with rheumatic mitral valve disease considered to be at risk for thromboembolism should be given warfarin. Ifthis therapy should fail, a plateletactive agent should be added; or, if warfarin is contraindicated, antiplatelet therapy might be a reasonable, albeit uncertain, alternative. The decision to treat will remain difficult in many cases. For example, should antithrombotic therapy be given to the 35-yeaN>ld active male with trivial mitral stenosis and normal sinus rhythm or to the asymptomatic mitral valve patient with AF and history of recurrent GI bleeding? In some instances decision analysis will help to clarify whether to use antithrombotic therapy In others, where the merits of anticoagulant therapy are questionable, the finding of a shortened platelet survival may lead the clinician to recommend the use of platelet-active drugs. In all cases, the risks of treatment will be inhuenced by the choice and dose of the agent to be used. MITRAL VALVE PROLAPSE Mitral valve prolapse (MVP) is the most common form of valve disease in adults.p' While generally innocuous, it is sometimes annoying, and serious complications can occur. During the past 15 years, embolic phenomena have been reported in several patients with MVP in whom no other source for emboli could be found. In 1974 BarnetfWobserved 4 patients with MVP who suffered cerebral ischemic events. Two years later, a total of 12 patients were described with recurrent transient ischemic attacks (TIAs) and partial nonprogressive strokes who had no evidence of atherosclerotic disease, hypertension, or coagulation disorders." Similar observations have been made by other investigators,36-38 and as many as 9 such patients 100s have been reported from a single center.38 Perhaps the most convincing evidence linking MVP to stroke is provided by the case control study of Barnett and associates." Among 60 patients under the age of 45 who had TIAs or partial stroke, MVP was detected in 40%, while in 60 age-matched controls the incidence was 6.8% (p<.(01), and in 42 stroke patients over the age of 45, MVP was found in 5.7%, an incidence comparable to that in the general population. 39 A pathologic basis for thromboembolism in MVP has been suggested by several investigators. Pomerance'? examined the hearts of 35 patients with a ballooning deformity of the mitral valve and found that 10 exhibited a "fibrinous endocarditis" of the mitral valve. Guthrie and Edwards" observed endothelial denudation of the mitral valve in patients with myxomatous degeneration with deposits of fibrin on the denuded surface of the valve, and mural thrombus hasbeen reported at the junction of a prolapsed mitral leaflet and the atrial wall by Kostuk et al. 42 While clinicopathologic correlations have been lacking in most studies, fibrin thrombi on a prolapsed valve with myxomatous degeneration was demonstrated in a patient who suffered multiple emboli, to brain, heart, and kidneys.v It also seems likely that the phenomenon of transmural MI in MVP patients with angiographic normal coronary arteries may best be explained on the basis of coronary embolism." Thus, although it appears that a small number of patients with MVP are at risk for systemic thromboembolism, consideration of denominators should temper our therapeutic approach to this problem. Assuming that6% of the female and 4% of the male population have M the ~ percentage of the more than 10 million Americans with MVP at risk for thromboembolism must be extraordinarily small. Indeed, it has been estimated that the risk of stroke in young adults with MVP is only l/6,ooo/year. 45 As suggested by Cheitlin," informing patients with MVP of this risk is not indicated, "nor is it reasonable to recommend prophylactic platelet-active drugs" to all patients with MV}! On the other hand, it seems reasonable that the MVP patientwith convincing evidence oftias with no other source of emboli should receive antithrombotic therapy. Since repeated ischemic episodes are not uncommon,36.39.42.43 long-term aspirin therapy appears indieated." No studies of antithrombotic therapy in this disease have been reported, so guidelines for therapy are at best empiric and drawn from experience with other thromboembolic conditions. Long-term warfarin therapy is appropriate for those patients with AF and for those who continue to have ischemic events despite aspirin therapy. The dilemma of cost-effective antithrombotic therapy in patients with MVP would best be solved by a 2nd ACCPConference onantithrombotic Therapy

reliable means of identifying the small cohort of patients at risk for thromboembolism. In a retrospective study of 26 patients with M V Steele ~ at al 48 reported that platelet survival time was significantly shortened in all 5 patients with a history of thromboembolism, but this abnormality was also observed in one third of the patients without thromboembolism. Future studies of the clinical and laboratory characteristics of MVP patients may succeed in reducing the denominator at risk. Since myxomatous degeneration and denudation of the mitral endothelium is likely to be critical in the thrombogenic process, patients with "secondary" MVp49 due solely to a reduction in LV dimensions would not be expected to be at risk. It would alsobeimportant to learn, for example, whether the "click-only" or silent MVP patient can be excluded from the risk of thromboembolism. Recent observations indicate otherwise and that most MVP patients with cerebral ischemia have normal results of a cardiac examination. so In any case, antithrombotic therapy for patients with MVP should be limited to those who have presumed embolic events or have AF. MITRAL ANNULAR CALCIFICATION The clinical syndrome of mitral annular calcification, first clearly described in 1962,51 includes a strong female preponderance and may be associated with mitral stenosis and regurgitation, calcific aortic stenosis, conduction disturbances, arrhythmias, embolic phenomena, and endocarditis. It must be emphasized that radiographic evidence of calcium in the mitral annulus does not in itself constitute the syndrome of mitral annular calcification. While the true incidence of systemic emboli in this condition is not known, embolic events appear conspicuous with or without associated AF.51-55 Four of the 14 original patients described by Korn et al 51 had cerebral emboli, and 5 of 80 patients reported by Fulkerson et al 53 had systemic emboli, only 2 of whom had atrial fibrillation. In autopsy specimens, thrombi have been found on heavily calcified annular tissue," and echogenic densities have been described in the LV outflow tract in this condition among patients with cerebral ischemic events. 54 In addition to the embolization of fibrin clot, calcific spikules may become dislodged from the ulcerated calcified annulus and present as systemic emboli. 53 ss. 57 While the relative frequency of calcific emboli and thromboembolism is unknown, it is likely that the incidence of the former has been underestimated, since this diagnosis can be established only by pathologic examination of the embolus or by the rarely visualized calcified fragments in the retinal circulation. 53 58 Since there is little reason to believe that anticoagulant therapywould be effective in preventing calcific emboli, the rationale for using antithrombotic drugs in patients with mitral annular calcification rests primarily on the frequency of true thromboembolism. In the Framingham study, the incidence of AF was 12 times greater in patients with mitral annular calcification than in those without this lesion," and 29% of the patients with annular calcification reported by Fulkerson et al 53 had AF. In addition, left atrial enlargement is not uncommon, even in those with normal sinus rhythm. Thus, the many factors contributing to the risk of thromboembolism in mitral annular calcification include AF, the hemodynamic consequences of the mitral valve lesion itself (stenosis and regurgitation), and the phenomenon of fragmentation of calcificannular tissue. In light of these observations, a good argument can be made for prophylactic anticoagulant therapy in patients with AF or a history of an embolic event. However, since most of these patients are elderly (mean age, 73-75 51.53 ), the risks of anticoagulation with warfarin will be increased. Therefore, if the mitral lesion is mild or ifan embolic event is clearly identified as calcific rather than thrombotic, the risks from anticoagulation outweigh the benefit of warfarin therapy Certainly, theclinician should reconsider initiating anticoagulant therapy merely on the basis of radiographic evidence of mitral annular calcification. Antiplatelet drugs might represent an uncertain compromise for those with advanced lesions, although no studies indicate that this therapy is effective in preventing thromboembolism in mitral annular calcification. For patients with repeated embolic events despite warfarin therapy or in whom multiple calcific emboli are recognized, valve replacement with a bioprosthesis should be considered. AORTIC VALVE DISEASE Clinically detectable systemic emboli in isolated aortic valve disease are distinctly uncommon. However, Stein et al 60 emphasized the thromboembolic potential of severe calcific aortic valve disease and demonstrated microthrombi in 10 of 19 calcified and stenotic aortic valves studied histologically In only one, however, was a thrombus grossly visible on the excised valve, and clinical evidence of systemic embolism was not reported. Four cases of calcific emboli to the retinal artery in patients with calcific aortic stenosis were reported by Brockmeier et al,58 and 4 cases of cerebral emboli were observed in patients with bicuspid aortic valves in whom no other source of emboli could be found." In the latter group, all 4 patientswere treatedwith aspirin, and no recurrences were observed. Perhaps the most startling report of calcific emboli in patients with calcific aortic stenosis is that of Holley et al. 62 In this autopsy study of 165 patients, systemic emboli were found in 31 patients (19%); the heart and kidneys were the most common sites of emboli, but, again, clinically detectable events CHEST I 95 I 2 I FEBRUAFrf, 1989 I Supplement 101S

were notably rare. It appears, therefore, that calcific microemboli from heavily calcified, stenotic aortic valves are not rare, but, because of their small size, they are not readily detected unless they can be visualized in the retinal artery. Indeed, the small but consistent frequency of systemic emboli reported in earlier studies of aortic valvular disease may best be explained by unrecognized mitral valvular or ischemic heart disease or to coexisting AF. It is of interest in this regard that of 194 patients with rheumatic valvular disease and systemic emboli reported by Daley et al,63 only 6 had isolated aortic valve disease, and in each AF was also present. More recently, the association of AF and aortic valve disease was examined by Myler and Sanders." In 122 consecutive patients with proved isolated severe aortic valve disease, only 1 had atrial fibrillation, and in that instance advanced coronary heart disease with infarction was present as well. Thus, in the absence of associated mitral valve disease, systemic embolism in patients with aortic valve disease is uncommon, and long-term anticoagulation is not indicated. However, a significant number of patients with severe calcific aortic valve disease do have microscopic calcific emboli, although not often associated with clinical events or evidence of infarction. Since the value of anticoagulant therapy in preventing calcific microemboli has not been established and their clinical consequences are few, the risks of long-term anticoagulant therapy in isolated aortic valve disease outweigh the potential usefulness. INFECflVE ENDOCARDITIS With the advent of effective antimicrobial therapy, the incidence of systemic emboli in infective endocarditis has decreased. In the preantibiotic era, clinically detectable emboli occurred in 70-97% of patients with infective endocarditis.s" while, since that time, the prevalence has been reported to be 12-40%.66-71 Emboli occur more frequently in patients with acute endocarditis than in those with subacute disease," and the incidence of pulmonary emboli in right-sided endocarditis is particularly high.68.73 Cerebral emboli are considerably more common in mitral valve endocarditis than in infection of the aortic valve; interesti n gthis l ~ observation is not explained by the occurrence of AF.69 While embolic rate (in terms of events per patient-week) has not been reported in endocarditis, considering the relatively short course of the disease, an unusually high event per unit time may be inferred. The use of anticoagulant therapy in infective endocarditis was initially introduced in the sulfonamide era, not as a means of preventing thromboembolism but to improve the penetration of antibiotic into the infected vegetations." While complications of this 1028 therapy were not always enoountered.tv" most workers reported an alarming incidence of cerebral hemorrhage.f:" and it was suggested that the routine use of anticoagulant therapy in endocarditis be abandoned. 78 80 81 However, the issue remained controversial. While reference to the early adverse experience ofanticoagulant therapy in endocarditis frequently has been made, Lerner and Weinstein 68 concluded that anticoagulants were "probably not contraindicated" in infective endocarditis. With the advent of echocardiography, improved means ofidentifying the patientat risk for embolization have emerged, and a high correlation between echocardiographically demonstrable vegetations and embolism has been reported. 73 8 2-84 However, in a recent review of this subject, O'Brien and Geiser" report that 80% of patients with infective endocarditis have vegetations detected by echocardiography while only one third have systemic emboli. Thus, the specificity of this finding for predicting the patient at risk for systemic embolism is not high enough to provide a useful guide for management. Further, there is no convincing evidence that prophylactic anticoagulant therapy reduces the incidence of emboli in native valve endocarditis, and it is generally believed that the routine use of anticoagulant drugs is not justified in this circumstance. However, in the patient with a special indication, eg, the patient with mitral valve disease and a recent onset of AF, appropriate anticoagulant therapy should not be withheld. The patient with prosthetic valve endocarditis deserves special comment. With the exception of those patients with bioprostheses in normal sinus rhythm, patients with prosthetic valves are at constant risk of thromboembolism and there are important reasons not to interrupt anticoagulant therapy in this circumstance. The risks of thromboembolic events in prostheticvalve endocarditis are higher than that in native valve endocarditis; emboli have been reported in 50 88% of patients with prosthetic valve endocarditis.69-71.86.87 However, opinion is divided on the effectiveness of anticoagulation in reducing the number of embolic events associated with prosthetic valve endocarditis. Wilson et al 87 reported ens complications in only 3138 patients with prosthetic valve endocarditis who received adequate anticoagulant therapy, while events were observed in 10/14 patients who received either inadequate or no anticoagulation. On the other hand, Yeh et a1 88 found that adequate anticoagulation failed to control emboli during prosthetic valve endocarditis, and the risk of bleeding appears to be greater among patients with infected prostheses." Pruitt and associates" found that 23% of the hemorrhagic events occurred in the 3% of patients receiving anticoagulants and a 50% incidence of hemorrhage was observed by johnson'" in patients with prosthetic valve endocarditis 2nd ACCPConference onantithrombotic Therapy

treated with anticoagulants. Other workers, too, have reported a high incidence of intracranial hemorrhage in patients who received anticoagulation therapy with prosthetic valve endocarditis. 70,90 Thus, the use of anticoagulants in prosthetic valve endocarditis must steer a path between the Scylla of thromboembolism and the Charybdis of serious bleeding. There seems little doubt that the risk of the former is substantial without the protection of continued anticoagulation, yet the consequence of intracranial hemorrhage may be irreversible and not infrequently fatal. It should be appreciated that embolic events in prosthetic valve endocarditis may represent dislodged vegetations or, alternatively, true thromboembolism unrelated to the valve infection. While the incidence of the latter can be expected to be reduced by anticoagulation therapy, there is no evidence that embolic vegetations are controlled by this therapy. Nonetheless, most workers suggest that long-term anticoagulant therapy should be continued in prosthetic valve endocarditis,69,86,87,89 while others express some doubt about its value."-?' Since the most serious and potentially lethal complications of cerebral embolic events are due to intracranial bleeding, CT scanning may provide the means of identifying the patient at high risk for this complication." Based on experience in patients without endocarditis, the Cerebral Embolism Study Group recommends that in nonhypertensive patients with cardiogenic cerebral emboli, if there is no evidence of hemorrhage on CT scan 24-48 h after stroke, immediate anticoagulation should be undertaken, although a delay of 7 days might be prudent in those patients with large cerebral infarctions.v-" Since the risk of thromboembolism in nonanticoagulated patients with bioprostheses who are in normal sinus rhythm is low,94 anticoagulation therapy is not indicated. While Pruitt et al69 suggest a possible role for antiplatelet drugs in prosthetic valve endocarditis, the utility of this form of therapy has not been established. CONCLUSION The decision to initiate long-term anticoagulant therapy in a patient with valvular heart disease is frequently difficult because of the many variables that influence the risks of thromboembolism and of bleeding in a given individual. The patient's age, the specific valve lesion, the heart rhythm, the duration of the valve disease, patient attitude and lifestyle, associated diseases and medications, etc, all must be considered. Also, because each variable may change with time, a proper decision at one time in a patients life may be inappropriate at another time. In some instances, too, the literature on a given subject is sparse or contains conflicting data which further confound the issue. Since the data base for these guidelines is constantly being modified, particularly as a consequence of new, randomized clinical trials, the clinician would do well to review his decision at frequent intervals. S UMM ARY A N D R E COMMENDATIONS Mitral Valve Disease 1. It is strongly recommended that long-term warfarin th erapy sufficie nt to prolong the prothrombin time to 1.5-2.0 tim es control using North American thromboplastin (standa rdized INR = 3.0-4.5)* be used in pati ents with rheumatic mitral valve disease who have documented syste mic e mbolism. This regimen should be continu ed for a minimum of 1 year following the embolism, at which time the PT may be reduced to 1.3-1.5 tim es control to lessen th e risk of bleeding. This grade C re commendation is based on three level IV studies.7,17,20 2. It is recommended that if recurrent systemic embolism occurs despite adequate ~arfarin therapy, the addition of dipyridamol e (225-400 mg/day) may be con sidered. This grad e C recommendation is based on extrapolation from studies of mechanical prosthetic valves (see referen ces 4 and 6 in th e chapte r on pro sthetic heart valves). 3. It is strongly recommended that long-t erm warfarin th erapy sufficient to prolongthe prothrombin tim e to 1.3-1.5 tim es control using North American thromboplastin (IN R = 2.0-3. 0)t be used in all patients with rh eumatic mitral valve diseas e with associat ed chronic or paroxysmal AF. This grade C recommendation is based on numerou s studies that have demonstrate d a high risk of systemic embolism when mitral val ve di s eas e is complicated by atrial fibrillation7.10-14.16 and a level IV study suggesting ben efit of treatment with warfarin. 17 4. It is recommended that long-term warfarin th erapy sufficient to prolong th e PT to 1.3-1.5 times control u sing No r t h Am erican thromboplastin (IN R = 2.0-3.0) be used in pati ents with rheumatic mitral valve disease and normal sinus rh ythm if the left atrial diam et er is in exces s of 5.5 cm. This recommendation is based on th e belief that the likelihood of developing paroxysmal or chronic AF in such cases will be high. Aortic Valve Disease 1. It is strongly recommended that long-term anti thrombotic th erapy not be given to patients with aortic valve diseas e without associate d mitral valve disease or AF. This grade C recommendation is mad e because of th e low incidence of syste mic thromboembolism in th ese patients. *Exact conversion of INR of 3.0-4.5=PT ratio of 1.6-1.9 with rabbit brain thromboplastin. texact conversion ofinr of2.0-3,0= PT ratio of 1.3-1.6. CHEST / 95 / 2 / FEBRUARY, 1989 / Supplement 1035

:U.N :. ~ ".,ana...aitieu wd. ~ A F s h e u 1 d. I. It isstro.r recommended : t h a t : 1, 8o1 In t i K ~ ~ l.tmatedwltb. lessiidtenselodl.;term'wufaria 'therap,-), : : : - : : ; : :. = ~ = : :l'iaiaed '...iebt. ~ D l ~ i C~ 01: AF. ' Tbts,gnMle. "'C\reeommemlatiOD [is based 011 the by ideideace Dr., j: ~ p t e l 1 l 1 C,",.,...mie. embolism.irt_ oammoa d i s D. t ;. ~ " ;. I: It'is recommended that;_'dbwith M W ~ ' _ o, ~. ~ " & u t ~ _ ~ ~. --11-::'.1:-4.,_--.:.,I,' " _..._..,..,......,.. '.,.: i:.-b in; treatedwltll: la.term 1"'$:' blteue _hid W : 7 \ N J U v. " J, u\ u. le n. ~ up to ;eomllaryanery',; ed r.' ~ Q I l :; thenpj1'he!dose ;,curredtlyrecbmmtmded i s : O.,disimse). ~ : :) 1.0 ;glhy. This, grad., C l1klmud.dlttlo ;: ~. O J! I :th lt1_ :,."1;1_11'''ad 1" le\ei:u.arm ;:'patieals'witd, :TlM 'Iee.pter,onC8rebnwalCUlar d ) ~ 1. It; i I ;.ftrqmmeaded.that,lilticoapjant';: ~ " ; dtelljpr.-t' :be pea :;to :patients with 1D1f;OmpltQited;; : $ ~,I t, g ~ _ e. d...":m.,"fl' e c l _ _ ' T a. I ~. ve,wltil M f... t ~, ~~...I..!'.,J ;1blopnJSIhetic 11ve. ~patiebts WIth IlQnmd S ~ U S ' : 1,:;iDteB": warfarin thera;pp.(pr. l. ~ l,times:. &.'OO1ltrOl:' ;:'rl\_. This pule:: 0,.'...reeommeDdatioa is: 'based'.:011.::, 0'".... '".. o.....] : u l k I g ' N O d h _ e r i c t m " t l l m m b,."'thllidcreased o p J a s t m meld.llce,de' ; I N B / = a h. e M m ~ Q. r Q tiathest! ) h a 8 ~ p a ~! = : ~ ~,, = C " " ~ : I $ " " '.., " ":11 t ~ _ '. :.. J' L '.,.... J ~ :. naliii'. J A l... 1 ts - t -a:l. ~... ':: '.S :.gv..., ~ I D D' lq IeI D. Wlw I ~. ~ _:\'cerebralemljolism)i;, 'MYP _ D,have : ~ doeumbdted,srstemic! emoo1ismle: ":.1. I t I s ;, r e e o m m e J l d e d l : t h a t l o D I I t e r : ~ W l..., ; ~ l _ '!<n -.cl.n'.o _ ;."".i O ). * u. a w L f ) ',_,._,,_1$; I I J i l ~ t i t o..-iroi'.biin _ ' r i _ ' ~,:",t\: b : o ~ p ~. - l; yt a.. l t ~ i j c ' utho'- a J e, s~ ;.._.,coil-; s ": J : N J t ; - ; a. H ~ ' f o r cil a, p. alr D~ if Doil ml.. u otm w rpa~ ei nr d i oc this ad t' i grade: O B S ~ C; moommendatiqd'is based: inti: 'the eldb9lmd:.themaler.the PT ~ s h obew d '.the hiih & e f P()f:_ stemie 1 ~. emwism'tn: tllese) t o, l."qqd.l".i.. :. ~ ~ $ M. O ). ~ t ' ~ t 1 t L " l 1 ; 8 8.tiS to ben0te4 a o. t v ~. that,. the') " I. ltu.. ~., t.pltiedts h aw it t h I';risk:ofiDtra.erauial,MmorrhllfJ:';in:tbe ~ ~ _ \ l m s:'1, t~ i a u e e cotnplttsted.,brehmnloqrparoays. AF i h o u l d ibse B~ b s b m,.:chapter ~ ~ ~ t ~ OD'. cerebral.embolism)., 1 : t r e a t M I, w l t h WIlfStmI: ;. i l tlt...,,'t8 I ~ l e r m pmlolll,, 3 'Tbe'mdicatiQ8S : ~ [or': a n t tberajj1wh,n::' i ~ t : ~ " : : ~ 1.. : i& t c, J ~. ~ '. ' ~. s ~ a ~ I. ' ~ I N ~ ~ r i _ : d u v m 1 > Q p J M q : < nu.:pade,c. D I ; R = : I. ~ N. ~.', Q } ~. c : : : ~ ~ :. ~ : ~, : v a' l _, u. a etb_thetap6.tl.c; e t. ~ '._iou,:1.:,should consider,coll1qjjbtdfactors,illdiodidr,.af,,':evif-- J. 'I.,:It:is ;,stmngl,jeeoidmended:that l o. ~ t _ a a t i -. : : e ~ - =, ~ ; o = ' : r ~ ' e..1ml1mb.. ;AF. 'ThiI pa4. C, ~ m. D a a t i o D i t :,based on,'- _mcidedc8,'of,: tbrmnboemlmlismia this,common. disorder-'. I., 1t i$:'recommended that b. with iniw :meadatiojl litbas8d 011 UU_.I1M,"I'IV'.at.s m patients with meumaticmitral'valq: disease complieatedb, A F ~ ' ' ' J. l. i ' ' ' : :"'1,.14"tltll4, Cillr:;pte_- '_; " ". : ~ _, _. p l., " ~ _ 3. Hull ~ R,, Hirsh. J, IJay C, Q Carter i. C, et, ale Different intensities of ~ b o l i l m IOP_,, ( I to S...-OIBe,.mbllilat>. be, treated with 10lll.rmwuf-.therapy:.10,_10. timt,:f1' ttl 1.5-I..O'::-. I:...<N...-ericl.n' 1mt._-';(JNll-$.(b4.e);.--1.,...11lergy:: then should 'be CODtiaued.iaaehitely 'withal :'Thhpad.,C i "_- taterse, :reglrhea, C D l B. I ;. & - 3. ' ~ ). mldldatto.,:im ' hued'..: the irewlts Of.several levelly:,*,,_ Q1: ;_th:, _atio. ve, '. d I:' s ~...2.t'.. - 3,.; ~ tis: :recoldlljlqldedthat.,.. t i ; ~ m _:.JttjMt- ~.:".I0_:;.R J ~, ; 1, titn. ', ~ 1 eoa ~ 5 I. _ I f ~ l Q I t h ) l = - ~ ~ ~ emllebsm,m patients wttll. n o n v a 1 w J 1 r ' : h e a r t! S l = Z - ~ ''''.ifjj E ~ r t l f * ~.,I ; ~. ~., ~ i = = : ; : C l n dence'mt,a, atrtlltimj.mhua,eudt!bce,and _ize, oti._vuw\ veg"til.u<ut&: lliiafle:'clisb:ibutioa _.seyojift; ~ ~ _ e l D ~ I ~ D ) : ~ - Reprint requests: Dr. Uoine, 750 Washington Street, Box 315, Boston 02111 REFERENCES 1 Rahimtoola SHe Valvularheart disease: a perspective. 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