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Antithrombotic Therapy in Valvular Heart Disease Herbert J. Levine, MD, FCCP, Chair; and Mark H. Eckman, MD Stephen G. Pauker, MD; studies of less-intense regimens of warfarin ported in recent been reported that prothrombin times (PTs) therapy. It has performed with the commonly used commercial North American thromboplastin, maintained in the range of 1.3 to 1.5 times normal control (international normalized ratio [INR], 2.0 to 3.0), retained effectiveness against recurrent thromboembolism with a greatly reduced frequency of bleeding complications.5 Of greater relevance to patients with valvular heart disease is the report by Turpie et al,6 which suggests that a less-intensive regimen of warfarin and is safer than standard an¬ therapy is "no less effective, in ticoagulant therapy patients with tissue heart valve replacement." Similar findings have been reported in pa¬ tients with mechanical heart valves. Among 258 patients randomized to regimens of moderate-intensity warfarin therapy (PT ratio, 1.5; INR, 2.65) vs high-intensity therapy (PT ratio, 2.5; INR, 9.0), thromboembolism occurred with similar frequency in the two groups, while the risk of bleeding was significantly lower in the moderate-intensity venous complications of valvular heart disease be Few devastating than systemic embolism. With little regard for the of the valve cerebral can severity underlying lesion, a more or mesenteric embolus can, in a moment's time, cripple or kill a previously asymptomatic patient. It is well recognized that antithrombotic therapy can reduce, although not eliminate, the likelihood of this catastrophe. If this therapy were risk free, all patients with valvular heart disease should be treated. Unfortunately, antithrombotic therapy, particularly with warfarin derivatives or heparin, carries a substantial risk of bleeding; that risk varies with the drug used, the intensity of the anticoagulant effect, and the clinical circumstances in individual patients. For example, risks of anticoagulant are greater in patients with endocarditis, pregnancy, therapy and bleeding diatheses. This review will examine the risks of thromboembolism in various forms of valvular heart disease and attempt to establish strategies for using 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. Basic to these considerations is assessment of the risk of bleeding. For example, it is appreciated that the rewards of anticoagulant therapy will be greater in patients with a high risk of thromboembolism than in those at low risk for this event, but the benefits of anticoagulation may be offset by the hemorrhagic complications of antithrombotic therapy. It is also important to emphasize that the permanent conse¬ quences of a thromboembolic event are generally more se¬ rious than the ultimate outcome of a hemorrhagic compli¬ cation of anticoagulant therapy, and thus the rate of embolic is not necessarily counterbalanced by an equal phenomenon event rate of bleeding. Rahimtoola1 reported that the risk of major bleeding in patients with prosthetic heart valves who received warfarin was 1 to 2 %/yr, and in a careful analysis of ten reports of anticoagulant therapy in patients with prosthetic valves cov¬ ering 215.5 patient centuries of follow-up, Edmunds2 found the weighted mean rate of serious bleeding complications to be 2.19%/yr, with fatalities due to bleeding in 0.17%/yr. In¬ terestingly,inthe same ratewithof serious bleeding (2.11%/yr) was atrial fibrillation during 284 reported patients patient-years of warfarin therapy.3 In a recent review of 46 studies of patients with mechanical heart valve prostheses who had undergone anticoagulation with warfarin deriva¬ tives (53,647 patient-years of follow-up), the incidence of major bleeding was 1.4%/yr 4 Another consideration that will influence greatly our as¬ sessment of the risk-benefit ratio of anticoagulant therapy relates to the intensity of anticoagulation, particularly as reReprint requests: Dr. Levine, 750 Washington St, Box 315, Boston, MA 02111 360S group.7 The utility and safety of a lower intensity of warfarin ef¬ fect has also been shown in patients with mechanical heart valves treated with concomitant antiplatelet therapy. Altman et al8 found that among patients given aspirin (330 mg/d) and dipyridamole (75 mg twice daily), those randomized to warfarin therapy (INR, 2.0 to 3.0) had less modest-intensity than those bleeding given higher-intensity warfarin (INR, 3.0 to 4.5), while the incidence of thromboembolism was similar in the two groups. Further evidence to support the use of lower-intensity warfarin anticoagulation comes from five large, multicenter, randomized studies of patients with nonvalvular atrial fibril¬ lation.9"13 In these studies, all of which showed a substantial benefit of warfarin, the utility of the anticoagulant therapy was independent of the target range of INR, which varied from 1.4 to 2.813 to 2.8 to 4.2,9 suggesting a better risk-ben¬ efit ratio with the lower-dose range. It should be empha¬ sized, however, that the utility of lower-intensity anticoagu¬ lation in patients with nonvalvular atrial fibrillation should not necessarily be extrapolated to patients with mitral valve disease. Rheumatic Mitral Valve Disease The incidence of systemic embolism is greater in rheu¬ matic 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 40 years by surgery and the frequent use of long-term anticoagulant therapy, Wood14 cited a prevalence of systemic emboli of 9 to 14% in several and in 1961, Ellis and large early series of mitral27%stenosis, of 1,500 patients undergoing Harken15 reported that mitral valvuloplasty had a history of clinically detectable systemic emboli. Among 754 patients followed up for 5,833 patient-years, Szekely16 observed an incidence of emboli of 1.5%/yr, while the figure was found to vary from 1.5 to 4.7%/yr preoperatively in six reports of rheumatic mitral valve disease.17 As a generalization, it is perhaps reasonable to assume that a patient with rheumatic mitral valve disease has at least one chance in five of having a clinically detect¬ able systemic embolus during the course of the disease.18 The incidence of systemic emboli increases dramatically Fourth ACCP Consensus Conference on Antithrombotic Therapy Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 of atrial fibrillation (AF). Szekely16 development that the risk of embolism was seven times greater reported in patients with rheumatic mitral valve disease and AF than in those with normal sinus rhythm, and among mitral patients with AF, Hinton et al19 found a 41% prevalence of systemic emboli at autopsy. Three quarters of the patients with mitral stenosis and cerebral emboli described by Har¬ ris and Levine20 and by Wood14 had AF. Among 839 patients with mitral valve disease described by Coulshed and associ¬ ates,21 emboli occurred in 8% of mitral stenosis patients with normal sinus rhythm, 31.5% of those with AF, 7.7% of those with dominant mitral regurgitation and normal sinus rhythm, and 22% of those with mitral regurgitation and AF. Wood14 confirmed that emboli occur VA times as frequently in pa¬ tients with mitral stenosis as in patients with rheumatic mi¬ tral regurgitation. The risk of systemic emboli in patients with rheumatic mitral disease is greater in older patients22"25 and those with lower cardiac indices22 but appears to correlate poorly with mitral calcification,21 mitral valve area,22 or clinical classifi¬ cation.14'21'22,26 Indeed, several investigators have pointed out that mitral patients with emboli frequently are found to have minor valve disease, and Wood14 reported that in 12.4% of cases, systemic embolization was the initial manifestation of rheumatic mitral disease. The relationship between thromboembolism and left atrial size remains unclear. In earlier studies of rheumatic mitral valve disease, a poor cor¬ relation was observed,14,21,26 but more recent reports, pri¬ marily in patients with nonvalvular atrial fibrillation, suggest that left atrial size is an independent risk factor for throm¬ with the boembolism.27"29 Among patients with valvular disease who suffer a firstof recurrent emboli occur in 30 to 65% cases,14183031 of which 60 to 65% are within the first year30,31 and the majority occur within 6 months. Mitral embolus, not appear to decrease the risk of throm¬ valvuloplasty doesThus a successful mitral valvuloplasty does boembolism.17,21 not eliminate the need for anticoagulation, and patients will continue to require this therapy postoperatively. There is good reason to believe that the frequency of sys¬ temic 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 ab¬ solute number of rheumatic heart disease 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 inci¬ dence of recurrent embolism in mitral valve patients who received warfarin was 3.4%/yr, while in the nonanticoagulation group it was 9.6%/yr. Adams et al32 followed up 84 patients with mitral stenosis and cerebral emboli for up to 20 years, half ofwhom received no anticoagulant therapy (1949 to 1959), and half of whom received warfarin (1959 to 1969) (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,26 in a level IV study, found a 25% incidence of emboli among 500 un¬ patients with mitral valve disease, while in 217 patients treated with warfarin, only five embolic episodes occurred with an incidence of thromboembolism of 0.8%/ patient-yr. In a retrospective study of 254 patients with AF (level IV study), an embolic rate of 5.46%/yr was reported for patients who did not receive anticoagulation vs 0.7%/yr for those receiving long-term warfarin therapy.3 the strongest evidence to date supporting the Perhaps of utility anticoagulation for the prevention of thromboem¬ treated bolism in mitral valve disease comes from extrapolation of the results of four, recent, large, randomized studies in pa¬ tients with nonvalvular atrial fibrillation.9"1113 Each of these level I studies demonstrated that warfarin was effective in reducing stroke in patients with nonvalvular AF. An addi¬ tional Canadian multicenter trial12 was terminated prema¬ a trend consistent with the turely when its results developedtrials. In one of these trials,10 data reported in the four earlier rate of thromboem¬ to the decrease was also found aspirin bolism in patients younger than 75 years of age. In view of these data, as a general rule, all patients with rheumatic mitral valve disease and AF (paroxysmal or chronic) should be treated with long-term warfarin therapy. include the Exceptions that require detailed tradeoff analysis for serious risk at or the woman patient high pregnant concomitant to established due whether disease, bleeding, exposure to contact sports or trauma, or inability to control the PT. Despite the powerful thromboembolic potential of AF, the rheumatic mitral valve disease patient in sinus rhythm still has a substantial risk of systemic embolism and is, therefore, a candidate for long-term warfarin therapy. Other than age, there are no reliable clinical markers in such cases, so 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 therapy.33 With the advent of percutaneous balloon mitral valvulo¬ clinicians are faced with a small chance that the plasty, catheter will dislodge the left atrial clot during the proce¬ dure. Accordingly, some centers have made it a practice to treat all such patients with warfarin, regardless of the pres¬ ence or absence of AF, for a minimum of 3 weeks before the balloon valvuloplasty. An alternate strategy might be to per¬ form transesophageal echocardiography (TEE) just prior to balloon mitral valvuloplasty and if the examination reveals no left atrial clot, anticoagulation prior to the valvuloplasty can be avoided.34,35 However, experience with patients under¬ going cardioversion of atrial fibrillation suggests that the absence of atrial clot by TEE at the time of the procedure does not preclude the need for prompt anticoagulation af¬ ter cardioversion to prevent thromboembofism. Therefore, one can make a good case for providing anticoagulation therapy for most patients after balloon mitral valvuloplasty for at least 4 weeks. Several studies have suggested that systemic embolism in patients with valvular heart disease occurs more frequently in those with shortened platelet survival times.36"40 Steele and Rainwater41 reported that shortened platelet survival was a sensitive index of past thromboembofism in patients CHEST /108 / 4 / OCTOBER, 1995 / Supplement Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 361S with rheumatic valve disease, but the specificity of this finding was low, since 78% of patients without thromboem¬ bolism also had shortened platelet survival. Although sulfin¬ pyrazone appeared to decrease the incidence ofthromboem¬ bolism in these patients with mitral stenosis, two thirds were also taking warfarin, and efficacy of sulfinpyrazone as monotherapy for the prevention of thromboembolism re¬ mains unproved.42 It has also been shown that shortened platelet survival in patients with prosthetic heart valves can be normalized by sulfinpyrazone36 and by dipyridamole.3' Similar observa¬ tions have been made in patients with mitral stenosis treated with sulfinpyrazone40,41 and in patients with arterial grafts treated with dipyridamole.43 Furthermore, in a level I ran¬ domized study of patients with prosthetic heart valves, the addition of dipyridamole to warfarin therapy proved effec¬ tive in reducing the incidence of systemic emboli.44 Similar findings were reported in a level III study,45 and the com¬ bination of dipyridamole (450 mg/d) and aspirin (3.0 g/d) was also observed to reduce the incidence of thromboembolism in patients with prosthetic heart valves (level IV study).39 Dale and associates46 performed a randomized study of as¬ pirin (1.0 g/d) 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 occurred with equal frequency in both groups, while GI encountered more complications, including bleeding, were often in the patients taking aspirin. At the completion of the were treated with aspirin alone and had study, all patients recently, unsatisfactory control of embolic events. More Turpie et al4' have reported that the addition of aspirin (100 to 4.5) reduced mortality and mg/d) to warfarin (INR, 3.0 major thromboembolism in patients with mechanical heart valves and in high-risk patients with bioprosthetic heart valves with no significant increase in major bleeding. The safety and effectiveness of combined warfarin and antiplate¬ let therapy have since been confirmed in a nonrandomized prospective study of patients with St. Jude Medical Valve prostheses.48 there is evidence that dipyridamole and sulfinpyra¬ 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 war¬ farin therapy will reduce the incidence of thromboembofism in patients with prosthetic valves. However, until these findings are confirmed and the effectiveness of platelet-ac¬ tive drugs compared with that of warfarin in randomized trials, patients with rheumatic mitral valve disease consid¬ ered to be at risk for thromboembolism should be given warfarin unless the risk of bleeding is unusually high. If this should fail, a platelet-active agent should be added; therapy or, if warfarin is contraindicated, antiplatelet therapy might be a reasonable, albeit uncertain, alternative. The recom¬ mendation concerning the use of dipyridamole is to be re¬ as tentative as there is increasing evidence that the gardedoffers little beyond the effect of aspirin administered drug Thus, zone concomitantly.49 The relative utility of warfarin vs aspirin as antithrombotic fibrillation monotherapy patients with nonvalvular atrial fifteen been addressed.50 Seven hundred pa¬ recently tients aged 75 years or younger and 385 patients older than in has 362S 75 years were separately randomized to warfarin to 4.5) or aspirin (325 mg/d) therapy; mean (INR, 2.0 follow-up was 3.1 and 2.0 years in the two age groups, respectively. The pri¬ mary event rate (ischemic stroke and systemic embolism) was 1.3%/yr with warfarin and 1.9% with aspirin (p=0.24) in the younger group, and 3.6% with warfarin vs 4.8% with as¬ pirin (p=0.39) in the older group. While it was concluded that warfarin may be more effective than aspirin for prevention of ischemic stroke, the absolute reduction in stroke rate by warfarin was small and not statistically signif¬ icant. Furthermore, in the older age group, the rate of all stroke with residual deficit (ischemic and hemorrhagic) was 4.6%/yr with warfarin and 4.3% with aspirin, and again this difference was not statistically significant. While these findings suggest that risk stratification of in¬ dividual patients with nonvalvular atrial fibrillation is rec¬ ommended when choosing warfarin or aspirin therapy to prevent stroke and systemic emboli, extrapolation of these results to patients with rheumatic mitral valve disease or to those with significant nonrheumatic mitral disease is prob¬ lematic. Furthermore, an analysis of pooled data from five randomized, controlled studies of antithrombotic therapy in nonvalvular AF, the European Atrial Fibrillation Trial, and the SPAF II study concludes that, "Patients with risk factors are optimally protected from stroke with warfarin if they are individuals good candidates for anticoagulation. Unreliable or those with other contraindications to anticoagulation should be considered for aspirin therapy."51 Since to our knowledge randomized studies of the relative warfarin vs aspirin have not been carried out in utility ofwith mitral valve disease, guidelines for antithrom¬ patients botic therapy in this circumstance have been borrowed from studies of patients with nonvalvular AF. Since rheumatic mitral valve disease has long been associated with a high in¬ cidence of thromboembolism, extrapolation of the lessons learned from patients with nonvalvular AF to patients with mitral valve disease seems appropriate. The decision to treat will remain difficult in many cases. For example, should antithrombotic therapy be given to the 35-year-old, physically active male with trivial mitral steno¬ sis 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.52 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 these set¬ tings, the patient's preference may also be important. In all cases, the risks of treatment will be influenced 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.53 While generally innocuous, it is sometimes annoying, and serious complications can occur. During the past 20 years, embolic phenomena have been several patients with MVP in whom no other reportedforin emboli could be found. In 1974, Barnett54 source observed four patients with MVP who suffered cerebral is¬ chemic events. Two years later, a total of 12 patients were described with recurrent transient ischemic attacks (TIAs) Fourth ACCP Consensus Conference on Antithrombotic Therapy Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 and partial nonprogressive strokes who had no evidence of atherosclerotic disease, hypertension, or coagulation disor¬ ders.55 Similar observations have been made by other and as many as nine such patients have investigators,56"58 been described from a single center.58 Perhaps the most convincing evidence linking MVP to stroke is provided by the case-control study of Barnett and associates.59 Among 60 patients younger than 45 years who had TIAs or partial stroke, MVP was detected in 40%, while in 60 age-matched controls, the incidence was 6.8% and in 42 stroke patients older than 45 years, (p<0.001), MVP was found in 5.7%, an incidence comparable to that in the general population.59 However, in a recent preliminary report of 244 patients younger than 45 years with stroke or TIAs who were referred for transthoracic echocardiography (TTE) in search of a source of embolus, only 1.2% had MVP.60 The authors suggest that these results reflect the recently validated two-dimensional echocardiographic cri¬ teria for MVP. A pathologic basis for thromboembolism in MVP has been suggested by several investigators. Pomerance61 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 Edwards62 observed endothelial denudation of the mitral valve in patients with myxomatous degeneration with deposits of fi¬ brin on the denuded surface of the valve, and mural throm¬ bus has been reported at the junction of a prolapsed mitral leaflet and the atrial wall by Kostuk et al. While clinico¬ pathologic correlations have been lacking in most studies, fibrin thrombi on a prolapsed valve with myxomatous degeneration were demonstratedandin a patient who suffered to brain, heart, multiplethatemboli, kidneys.64 It also seems the of transmural likely myocardial in¬ phenomenon farction in MVP patients with angiographic normal coronary arteries may best be explained on the basis of coronary em¬ bolism65 Thus, although it appears that a small number of patients with MVP are at risk for systemic thromboembolism, consideration of denominators should temper our therapeu¬ tic approach to this problem. Assuming that 6% ofthe female and 4% of the male population have MVP, the incidence of thromboembolism in these more than 12 million Americans must be extraordinarily low. Indeed, it has been estimated that the risk of stroke in young adults with MVP is only As suggested by Cheitlin,67 informing the 1/6,000/yr.66 with MVP of this risk is not indicated, "nor is it patients reasonable to recommend prophylactic platelet-active drugs" to all patients with MVP. However, it seems reasonable that the MVP patient with convincing evidence of TIAs with no other source of emboli should receive antithrombotic ther¬ apy. Because repeated ischemic episodes are not uncom¬ mon,56'59'62,64 long-term aspirin therapy appears indicated.68 To our knowledge, 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 cerebral ischemic events despite aspirin therapy. The dilemma of cost-effective antithrombotic therapy in patients with MVP would best be solved by a reliable means of identifying the small cohort of patients at high risk for thromboembolism. In a retrospective study of 26 patients with MVP, Steele et al69 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 fraction at risk. Because myxomatous degeneration and denudation of the mitral endothelium are likely to be critical in the thrombogenic process, patients with "secondary" MVP,70 due solely to a reduction in left ventricular dimensions, would not be expected to be at risk. It would also be important to learn whether the "click-only" or silent MVP patient can be excluded from the risk of thromboembolism. However, past observations indicate otherwise as most MVP patients with cerebral ischemia are found to have a normal physical examination.'1 study valve on echocardiography constituted a subgroup of pa¬ tients at high risk for mitral regurgitation, infectious en¬ docarditis, sudden death, and cerebral embolic events. Most ofthese observations were confirmed in a retrospective study by Marks et al73 except that the risk of stroke was not cor¬ related with valve thickening. Thus, at this time, there appears to be no clinical or echocardiographic marker that clearly identifies the MVP patient at risk for cerebral In a prospective of 237 patients with MVP, Nishimura et al concluded that those with a redundant mitral ischemic events. Mitral Annular Calcification The clinical syndrome of mitral annular calcification (MAC), first clearly described in 1962,74 includes a strong female preponderance and may be associated with mitral stenosis and regurgitation, calcific aortic stenosis, conduction disturbances, arrhythmias, embolic phenomena, and en¬ docarditis. It must be emphasized that radiographic evi¬ dence of calcium in the mitral annulus does not in itself constitute the syndrome of MAC. While the true incidence of systemic emboli in this condition is not known, embolic events appear conspicuous with or without associated AF.74"79 Four ofthe 14 original patients described by Korn et al'4 had cerebral emboli, and 5 of 80 patients described by Fulkerson et al76 had systemic emboli, only 2 of whom had AF. In autopsy specimens, thrombi have been found on heavily calcified annular tissue,80 and echogenic densities have been described in the left ventricular outflow tract in this condi¬ tion among patients with cerebral ischemic events.7' Perhaps the best estimate of the thromboembolic potential of MAC comes from the Framingham Heart Study.'9 Among 1,159 of stroke at the index echocardio¬ subjects with no history examination, the relative risk of stroke in those with graphic MAC was 2.10 times that without MAC (p=.006), indepen¬ dent of traditional risk factors for stroke. Even in those sub¬ jects without prevalent AF, the risk of stroke in subjects with MAC was twice that of those without MAC. In addition to embolization of fibrin clot, calcified spicules may become dislodged from the ulcerated calcified annulus and present as systemic emboli.76,78,81 While the relative frequency of calcific emboli and thromboembolism is unCHEST /108 / 4 / OCTOBER, 1995 / Supplement Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 363S known, it is likely that the incidence of the former problem has been underestimated, because this diagnosis can be es¬ tablished only by pathologic examination of the embolus or by the rarely visualized calcified fragments in the retinal circulation.76,82 Since there is little reason to believe that therapy would be effective in preventing cal¬ anticoagulant cific emboli, the rationale for using antithrombotic drugs in patients with mitral annular calcification rests primarily on the frequency of true thromboembolism. In the Framing¬ ham Study, the incidence of AF was 12 times greater in pa¬ tients with MAC than in those without this lesion,83 and 29% of the patients with annular calcification described by Fulkerson et al76 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 throm¬ boembofism in MAC include AF, the hemodynamic conse¬ quences of the mitral valve lesion itself (stenosis and regur¬ gitation), and fragmentation of calcific annular tissue. In light of these observations, a good argument can be made for prophylactic anticoagulant therapy in patients with AF or a because most of these history ofarean embolic event. However, to 73 75 patients elderly (mean age, years,72,76), the risks of anticoagulation with warfarin will be increased. Therefore, if the mitral lesion is mild or if an embolic event is clearly identified as calcific rather than thrombotic, the risks from outweigh the benefit of warfarin ther¬ anticoagulationthemayclinician should be discouraged from ini¬ apy. Certainly tiating anticoagulant therapy merely on the basis of radiographic evidence of MAC. Antiplatelet drugs might represent an uncertain compromise for those with advanced lesions, our knowledge, no studies indicate that this althoughis toeffective in preventing thromboembolism in pa¬ therapy tients with MAC. For patients with repeated embolic events despite warfarin therapy or in whom multiple calcific emboli are recognized, valve replacement should be considered. Aortic Valve Disease Clinically detectable systemic emboli in patients with isolated aortic valve disease are distinctly uncommon. How¬ ever, Stein et al84 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 on the excised valve, and clinical evidence of grossly visible was not reported. Four cases of calcific embolism systemic emboli to the retinal artery in patients with calcific aortic stenosis were reported by Brockmeier et al,82 and four cases of cerebral emboli were observed in patients with bicuspid aortic valves in whom no other source of emboli could be found.85 In the latter group, all four patients were treated with aspirin, and no recurrences were observed. Perhaps the most startling report of calcific emboli in a patient with cal¬ cific aortic stenosis is that of Holley et al. In this autopsy study of 165 patients, systemic emboli were found in 31 pa¬ tients (19%); the heart and kidneys were the most common sites of emboli, but again, clinically detectable events were notably rare. It appears, therefore, that calcific microemboli from are not rare, but, be¬ heavily calcified, stenotic aorticarevalves not readily detected unless cause of their small size, they they can be visualized in the retinal artery. Indeed, the small 364S but consistent frequency of systemic emboli reported in earlier studies of aortic valvular disease may best be ex¬ plained by unrecognized mitral valvular or ischemic heart disease or by coexisting AF. It is of interest in this regard that of 194 patients with rheumatic valvular disease and systemic emboli described by Daley et al,8' 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.88 In 122 consecutive patients with proved isolated severe aortic valve disease, only 1 had AF, 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 cal¬ cific aortic valve disease do have microscopic calcific emboli, although they are not often associated with clinical events or evidence of infarction. Because the value of anticoagulant es¬ therapy in preventing calcific microemboliarehas not been tablished and their clinical consequences few, the risks of long-term anticoagulant therapy in patients with isolated aortic valve disease apparently outweigh the potential use¬ fulness, unless there is a history consistent with prior thromboembolism. Patent Foramen Ovale and Atrial Septal Aneurysm of The incidence paradoxical embolism is unknown. In recent years, however, the role of developmental and acquired disease of the interatrial septum as a cause of cryptogenic stroke has received considerable attention. Paradoxical embolism through a patent foramen ovale (PFO) is well documented and thrombus on the arterial side of an atrial septal aneurysm has been reported at autopsy, during surgery, and by TEE.89 Much of the uncertainty about the incidence of paradoxical embolism lies in the fact that 27 to 29% of normal hearts have demonstrable PFOs at autop¬ the specificity of this finding as a marker of sy,90,91 and thus embolism is low. However, the demonstration by paradoxical TTE that 10 to 18% of normal people exhibit right-to-left shunting through a PFO during cough or Valsalva's maneu¬ ver,92,93 (by TEE the incidence approaches the anatomic data98), and the observation that 57% of patients with PFOs and suspected paradoxical embolism were found to have venous thrombosis by venography,94 provides support for the thesis that paradoxical embolism may be more common than believed. generally A number of studies have demonstrated a strong associ¬ ation between PFO and stroke.9395"97 The evidence for this association is particularly apparent in younger patients where the likelihood of atherosclerotic embolic disease is less in a thoughtful review of this compelling. Nevertheless, al98 that the role of "para¬ Movsowitz et conclude subject, doxical embolism through a PFO remains controversial." It is generally agreed that contrast TEE is the diagnostic technique of choice for demonstrating a PFO. However, because the sensitivity of contrast TEE is greater than that of contrast TTE, the question may be asked whether the smaller PFOs identified only by TEE are likely to be clin¬ ically relevant to the true incidence of paradoxical embolism. Fourth ACCP Consensus Conference on Antithrombotic Therapy Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 A strong association between atrial septal aneurysm and stroke has also been reported.89'99 The former condition has been identified in 1% of autopsies and in 3 to 4% of nonstroke patients examined by TEE.89,99 Because of a high incidence of PFO in patients with atrial septal aneurysm (70 to 83%) and anecdotal reports of clot within the aneurysm, there are two potential sources of systemic embolism in this condition; namely paradoxical embolism and arterial throm¬ boembolism from the left side of the atrial septal aneurysm. In both isolated PFO and in atrial septal aneurysm, the indications for antithrombotic therapy remain problematic. In patients with unexplained cerebral ischemia or stroke, the demonstration of right-to-left shunting through a PFO war¬ rants a search for deep vein thrombosis. In this circumstance, evidence for venous thrombosis (or pulmonary embolism) together with systemic embolism and a PFO provides a strong indication for long-term anticoagulation, venous interruption, or in some cases closure of the PFO. In the absence of evidence for venous thromboembolism, the threshold for these interventions is higher and must be made on a case-by-case basis. Certainly, long-term anticoagulation would not be recommended for asymptomatic PFOs or atrial aneurysms, although low-dose aspirin therapy would septal seem prudent therapy to reduce the likelihood of thrombo¬ sis on the arterial side of an atrial septal aneurysm. While role of PFO in patients with subsequent studies of thebroaden the indications for longstroke may cryptogenic term warfarin therapy, the low specificity of PFO shunting as a risk factor for stroke and the known risks of long-term apply cautionsus¬in anticoagulation therapy mandate that we for life-long anticoagulation patients recommending of paradoxical embolism, unless the diagnostic pected evidence is quite convincing or alternate causes for stroke in themselves would justify this therapy. Decision analysis may be helpful in guiding therapy in the more difficult cases. Infective Endocarditis With the advent of effective antimicrobial therapy, the incidence of systemic emboli in patients with infective endocarditis has decreased. In the preantibiotic era, clini¬ to 97% of patients cally detectable emboli occurred in 70since that time, the with infective endocarditis,100 while, Emboli to 40%.101"106 to be 12 has been reported prevalence occur more frequently in patients with acute endocarditis than in those with subacute disease,107 and the incidence of emboli in right-sided endocarditis is particularly pulmonary Cerebral emboli are considerably more common high.103108 in patients with mitral valve endocarditis than in those with infection of the aortic valve; interestingly, this observation is not explained by the occurrence of AF.104 While embolic rate (in terms of events per patient-week) has not been re¬ in endocarditis, considering the relatively short ported course of the disease, an unusually high event per unit time may be inferred. The use of anticoagulant therapy in patients with infective endocarditis was initially introduced in the sulfonamide era, not as a means of preventing thromboembolism but to im¬ prove the penetration of antibiotic into the infected vegeta¬ tions.109 While complications ofthis therapy were not always encountered,110111 most workers reported an alarming incidence of cerebral hemorrhage,112"114 and it was sug¬ gested that the routine use of anticoagulant therapy in pa¬ tients with endocarditis be abandoned.113115,116 However, the issue remained controversial. While reference to the early adverse experience of anticoagulant therapy in patients with endocarditis frequently has been made, Lerner and Weinstein103 concluded that anticoagulants were "probably contraindicated" in patients with infective endocarditis. With the advent of echocardiography, means of identify¬ ing the patient at risk for embolization have been proposed, and a high correlation between echocardiographically de¬ monstrable vegetations and embolism has been report¬ ed.108117"119 However, in a review of this subject, O'Brien and Geiser120 report that 80% of patients with infective en¬ docarditis have vegetations detected by echocardiography while only one third have systemic emboli. TEE has added a further dimension to the diagnostic accuracy of endocardi¬ tis. Indeed, Popp121 concludes that "the current state of the art in transesophageal echocardiographic imaging makes the likelihood of endocarditis low in patients without demon¬ strated vegetations." However, the ability of these tech¬ niques to identify the patient at risk for embolism is low. Further, there is no convincing evidence that prophylactic of emboli in therapy reduces the incidence anticoagulant it is generally and valve with native endocarditis, patients believed that the routine use of anticoagulant drugs is not in this circumstance. In a study of the rate of cere¬ justified bral embolic events in relation to antibiotic and anticoagu¬ lant therapy in patients with infective endocarditis, a prompt reduction in emboli was observed soon after antibiotic while the incidence of emboli was the therapy was started, same among those who did or did not receive anticoagulant therapy.122 However, in the patient with a special indication, eg, the patient with mitral valve disease and the recent on¬ set of AF, appropriate anticoagulant therapy should not be withheld. The patient with prosthetic valve endocarditis deserves With the exception of those patients with special comment. sinus rhythm, patients with pros¬ in normal bioprostheses thetic valves are at constant risk of thromboembolism and there are important reasons not to interrupt anticoagulant The risks of thromboembolic therapy in this circumstance. events in patients with prosthetic valve endocarditis are than in those with native valve endocarditis; emboli higherbeen have reported in 50 to 88% of patients with prosthetic valve endocarditis.104"106123,124 However, opinion is divided on the effectiveness of anticoagulation in reducing the number of embolic events associated with prosthetic valve endocarditis. Wilson et al124 reported CNS complications in endocarditis who only 3 of 38 patients with prosthetic valvewhile events were received adequate anticoagulant therapy, observed in 10 to 14 patients who received either inadequate or no anticoagulation (level IV). However, Yeh et al125 found that adequate anticoagulation failed to control emboli dur¬ ing prosthetic valve endocarditis, and the risk of bleeding appears to be greater among patients with infected prostheses (level IV).105 Pruitt and associates104 found that 23% of the hemorrhagic events occurred in the 3% of patients receiving anticoagulants and a 50% incidence of hemorrhage was observed by Johnson126 in patients with prosthetic valve endocarditis treated with anticoagulants. Other workers, too, have reported a high incidence of intracranial hemorrhage not CHEST /108 / 4 / OCTOBER, 1995 / Supplement Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 365S ovale in young stroke patients. Lancet 1988; 2:11-12 RL, Gopal A, et al. Patent foramen ovale as a risk factor for cryptogenic stroke. Ann Intern Med 1992; 117:461-65 DeBelder MA, Tourikis L, Leech G, et al. Risk of patent fora¬ men ovale for thromboembolic events in all age groups. Am J Cardiol 1992; 69:1316-20 Movsowitz C, Podolsky LA, Meyerowitz CB, et al. Patent fora¬ men ovale: a nonfunctional embryological remnant or a poten¬ tial cause of significant pathology? J Am Soc Echocardiogr 1992; 5:257-70 Pearson AC, Nagelhout D, Castello R, et al. Atrial septal aneu¬ rysm and stroke: a transesophageal echocardiographic study. J Am Coll Cardiol 1991; 18:1223-29 Weinstein L. Infective endocarditis. In: Braunwald E, ed. Heart disease. Philadelphia: WB Saunders, 1984 Cates JE, Christie RV. Subacute bacterial endocarditis: a review of 442 patients treated in 14 centers appointed by the penicillin trials committee of the MRC. Q J Med 1951; 20:93 Brunson JG. Coronary embolism in bacterial endocarditis. Am J Pathol 1953; 26:689 Lerner PI, Weinstein L. Infective endocarditis in the antibiotic era. N Engl J Med 1966; 274:323-93 Pruitt AA, Rubin RH, Karchmer AW, et al. Neurologic compli¬ cations of bacterial endocarditis. Medicine 1978; 57:329-43 Carpenter JL, McAllister CK. Anticoagulation in prosthetic valve endocarditis. South Med J 1983; 76:1372-75 Garvey CJ, Neu HC. Infective endocarditis: an evolving disease. Medicine 1979; 57:105-26 Morgan WL, Bland EF. Bacterial endocarditis in the antibiotic era. Circulation 1959; 19:753-59 Ginzton LE, Siegel RJ, Criley JM. Natural history of tricuspid valve endocarditis: a two-dimensional echocardiographic study. Am J Cardiol 1982; 49:1853-59 Friedman M, Katz LN, Howell K. Experimental endocarditis due to streptococcal viridans. Arch Intern Med 1938; 61:95 Loewe L, Rosenblatt P, Greene HJ, et al. Combined penicillin and heparin therapy of subacute bacterial endocarditis. JAMA 96 DiTullio M, Sacco 97 98 99 100 101 102 103 104 105 106 107 108 109 110 Roy P, Tajik AJ, Guiliani ER, et al. Spectrum of echocardio¬ graphic findings in bacterial endocarditis. Circulation 1976; 53:474-82 119 Stuart JA, Silimperi D, Harris P, et al. Echocardiographic doc¬ umentation of vegetative lesion in infective endocarditis: clinical implications. Circulation 1980; 61:374-80 120 O'Brien JT, Geiser EA. Infective endocarditis and echocardi¬ ography. Am Heart J 1984; 108:386-94 121 Popp RL. Echocardiography. N Engl J Med 1990; 323:165-72 122 Paschalis C, Pugsley W, John R, et al. Rate of cerebral embolic events in relation to antibiotic and anticoagulant therapy in pa¬ tients with bacterial endocarditis. Eur Neurol 1990; 30:87-9 123 Block PC, DeSanctis RW, Weinberg AN. Prosthetic valve en¬ docarditis. J Thorac Cardiovasc Surg 1970; 60:540-48 124 Wilson WR, Geraci JE, Danielson GK, et al. Anticoagulant therapy and central nervous system complications in patients with prosthetic valve endocarditis. Circulation 1978; 57:1004-07 125 Yeh TJ, Anabtaw I, Cornet VE, et al. Influence of rhythm and anticoagulation upon the essence of embolization associated with Starr-Edwards prostheses. Circulation 1967; 35:77-81 126 Johnson WD Jr. Prosthetic valve endocarditis. In: Kay E, ed. 118 Infective endocarditis. Baltimore: 129 127 Lieberman A, Hass WE, Pinto R, et al. Intracranial hemorrhage and infarction in anticoagulated patients with prosthetic heart valves. Stroke 1978; 9:18-24 128 Scott WR, New PFJ, Davis KR, et al. Computerized axial tomography of intracerebral and intraventricular hemorrhage. Radiology 1974; 112:73-80 129 Cerebral Embolism Study Group. Immediate anticoagulation of embolic stroke: a randomized trial. Stroke 1983; 14:668-76 130 Cerebral Embolism Study Group. Immediate anticoagulation of 131 132 1944; 124:144-49 111 Thill CJ, Meyer OO. Experiences with penicillin and dicouma¬ rol in the treatment of subacute bacterial endocarditis. Am J Med Sci 1947; 213:300 112 McLean J, Meyer BBM, Griffith JM. Heparin in subacute bac¬ terial endocarditis: report of a case and critical review of litera¬ ture. JAMA 1941; 117:1870-79 113 Katz LN, Elek SR. Combined heparin and chemotherapy in subacute bacterial endocarditis. JAMA 1944; 124:149-52 114 Kanis JA. The use of anticoagulants in bacterial endocarditis. Postgrad Med J 1974; 50:312-13 115 Finland M. Current status of therapy in bacterial endocarditis. JAMA 1959; 166:364-73 116 Priest WS, Smith JM, McGee CJ. The effect of anticoagulants on the penicillin therapy and the pathologic lesion of subacute bacterial endocarditis. N Engl J Med 1946; 235:699-706 117 Wann LS, Dillon JC, Weyman AE, et al. Echocardiography in bacterial endocarditis. N Engl J Med 1976; 295:135 370S University Park Press, 1979; 133 134 135 136 embolic stroke: brain hemorrhage and management options. Stroke 1984; 15:779-89 Cohn LH, Mudge GH, Pratter F, et al. Five to eight year fol¬ low-up of patients undergoing porcine heart valve replacement. N Engl J Med 1982; 304:258-62 Davenport J, Hart RG Prosthetic valve endocarditis 1976-87: antibiotics, anticoagulation and stroke. Stroke 1990; 21:993-99 Lopez JA, Ross RS, Fishbein MC, et al. Non-bacterial throm¬ botic endocarditis: a review. Am Heart J 1987; 113:773-84 Angrist A, Marquiss J. The changing morphologic picture of endocarditis since the advent of chemotherapy and antibiotic agents. Am J Pathol 1954; 30:39-63 Sack GH, Levin J, Bell WR. Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic and therapeutic fea¬ tures. Medicine 1977; 56:1-37 Rogers LR, Cho ES, Kempin S, et al. Cerebral infarction from non-bacterial thrombotic endocarditis: clinical and pathological study including the effects of anticoagulation. Am J Med 1987; 83:746-56 137 Lopez JA, Fishbein MC, Siegel RJ. Echocardiographic features of non-bacterial thrombotic endocarditis. Am J Cardiol 1987; 59:478-80 Fourth ACCP Consensus Conference on Antithrombotic Therapy Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 Recommendations Rheumatic Mitral Valve Disease 1. It is strongly recommended that long-term warfarin sufficient to prolong the INR to 2.0 to 3.0 be used therapy in patients with rheumatic mitral valve disease who have ei¬ ther a history of systemic embolism or who have paroxysmal or chronic atrial fibrillation, This recommendation is based on three level IV studies16,26,32 demonstrating efficacy in patients with mitral valve disease and five level I studies showing efficacy in subjects with nonvalvular atrial fibrilla¬ tory of thromboembolism or AF. This grade C recommen¬ dation is based on the relatively low incidence of throm¬ boembolism in patients with this common disorder.76,79 2. It is recommended that long-term warfarin therapy (INR, 2.0 to 3.0) be considered in patients with rheumatic Patent Foramen Ovale and Atrial Septal Aneurysm 1. It is strongly recommended that anticoagulant therapy not be given to patients with asymptomatic PFOs or atrial aneurysms. This grade C recommendation is made septal because of the high incidence of demonstrable PFOs in the tion.9^ mitral valve disease and normal sinus rhythm, if the left atrial diameter is in excess of 5.5 cm. This recommendation is based on the belief that the likelihood of developing AF in such cases will be high. Furthermore, since it is recognized that the risk of thromboembolism may be substantial in some patients with rheumatic mitral valve disease and normal si¬ nus rhythm, it is recommended that the decision to use warfarin be adjudicated on the basis of comorbid risk factors, left atrial size, age, and the hemodynamic particularly severity of the lesion. These grade C recommendations are not based on published studies. 3. It is recommended that if recurrent systemic embolism occurs despite adequate warfarin therapy, that the addition of aspirin (80 to 100 mg/d) be considered,47 For those pa¬ tients unable to take aspirin, alternative strategies would be to increase the warfarin dose sufficient to prolong the PT to an INR of 2.5 to 3.5, add dipyridamole, 400 mg/d, or add ticlopidine, 250 mg twice daily. Aortic Valve Disease 1. It is strongly recommended that long-term antithrom¬ botic therapy not be given to patients with aortic valve dis¬ ease unless they also have concomitant mitral valve disease, AF, or a history of systemic embolism. This grade C recom¬ mendation is made because of the low incidence of clinically detectable systemic thromboembolism in these patients. Mitral Valve Prolapse 1. It is strongly recommended that long-term antithrom¬ botic therapy not be given to patients with MVP who have not experienced systemic embolism, unexplained TIAs, or AF. This grade C recommendation is based on the low in¬ cidence of systemic embolism in patients with this common disorder.53,66 2. It is recommended that patients with MVP who have documented but unexplained TIAs be treated with longterm low-dose aspirin therapy. The dose currently recom¬ mended is 160 to 325 mg/d (see article on cerebrovascular disease by Sherman et al, pp 444S-456S in this supplement). 3. It is recommended that patients with MVP who have (1) documented systemic embolism, (2) chronic or paroxys¬ mal AF, or (3) recurrent TIAs despite aspirin therapy be treated with long-term warfarin therapy (INR, 2.0 to 3.0). Mitral Annular Calcification 1. It is recommended that long-term antithrombotic therapy not be given to patients with MAC who lack a his¬ 2. It is recommended that patients with MAC compli¬ cated by (1) systemic embolism not documented to be cal¬ cific embolism or (2) associated AF be treated with longterm warfarin therapy (INR, 2.0 to 3.0). This grade A recommendation is based on the high incidence of systemic embolism in older AF patients and the demonstrated efficacy of anticoagulant therapy in patients with nonvalvu¬ lar atrial fibrillation.9-13 at large. population 2. It is strongly recommended that patients with unex¬ plained systemic embolism or TIAs and demonstrable venous thrombosis or pulmonary embolism and either PFO or atrial septal aneurysm be treated with long-term warfarin or closure of the PFO is therapy, unless venous interruption considered preferable therapy. In the case of atrial septal aneurysm, the possibility of both paradoxical embolism and systemic embolism from the arterial side of the aneurysm should be considered in choosing therapy. Infective Endocarditis 1. It is strongly recommended that anticoagulant therapy be given to patients in normal sinus rhythm with endocarditis involving a native valve uncomplicated infective or a bioprosthetic valve. This grade C recommendation is not based on the increased incidence of hemorrhage in these lack of demonstrated efficacy of an¬ patients112-114 and thein this setting.122132 ticoagulant therapy 2. It is recommended that long-term warfarin therapy be continued when endocarditis occurs in patients with a me¬ chanical prosthetic valve unless there are specific contrain¬ dications. This grade C recommendation is based on the high of systemic thromboembolism in these pa¬ frequency tients.104"106123,125 However, it is to be noted that the risk of intracranial hemorrhage is substantial.104105'127 3. The indications for anticoagulant therapy when sys¬ temic embolism occurs during the course of infective endocarditis involving a native or bioprosthetic heart valve are uncertain. The therapeutic decision should consider co¬ morbid factors, including AF, evidence of left atrial throm¬ bus, evidence and size of valvular vegetations, and particu¬ larly the success of antibiotic therapy in controlling the infective endocarditis. Nonbacterial Thrombotic Endocarditis 1. It is recommended that patients with NBTE and sys¬ temic or pulmonary emboli be treated with heparin. This grade C recommendation is based on a strong association between NBTE and disseminated intravascular coagulation and uncontrolled studies demonstrating efficacy in hospi¬ talized patients.133135,136 2. It is recommended that heparin therapy be considered for patients with disseminated cancer or debilitating disease CHEST /108 / 4 / OCTOBER, 1995 / Supplement Downloaded From: http://publications.chestnet.org/pdfaccess.ashx?url=/data/journals/chest/21723/ on 05/04/2017 367S who are found to have aseptic vegetations on echocardio¬ graphic study. 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