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Antithrombotic Therapy in Valvular Heart Disease—Native and Prosthetic

The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy

Correspondence to: Deeb N. Salem, MD, FCCP, Chair, Tufts New England Medical Ctr, 750 Washington St, Boston, MA 02111; e-mail: dsalem{at}tufts.org

	Abstract

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
This chapter about antithrombotic therapy in native and prosthetic valvular heart disease is part of the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy: Evidence Based Guidelines. Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading see Guyatt et al, CHEST 2004; 126:179S–187S). Among the key recommendations in this chapter are the following: For patients with rheumatic mitral valve disease and atrial fibrillation (AF), or a history of previous systemic embolism, we recommend long-term oral anticoagulant (OAC) therapy (target international normalized ratio [INR], 2.5; range, 2.0 to 3.0) [Grade 1C+]. For patients with rheumatic mitral valve disease with AF or a history of systemic embolism who suffer systemic embolism while receiving OACs at a therapeutic INR, we recommend adding aspirin, 75 to 100 mg/d (Grade 1C). For those patients unable to take aspirin, we recommend adding dipyridamole, 400 mg/d, or clopidogrel (Grade 1C). In people with mitral valve prolapse (MVP) without history of systemic embolism, unexplained transient ischemic attacks (TIAs), or AF, we recommended against any antithrombotic therapy (Grade 1C). In patients with MVP and documented but unexplained TIAs, we recommend long-term aspirin therapy, 50 to 162 mg/d (Grade 1A). For all patients with mechanical prosthetic heart valves, we recommend vitamin K antagonists (Grade 1C+). For patients with a St. Jude Medical (St. Paul, MN) bileaflet valve in the aortic position, we recommend a target INR of 2.5 (range, 2.0 to 3.0) [Grade 1A]. For patients with tilting disk valves and bileaflet mechanical valves in the mitral position, we recommend a target INR of 3.0 (range, 2.5 to 3.5) [Grade 1C+]. For patients with caged ball or caged disk valves, we suggest a target INR of 3.0 (range, 2.5 to 3.5) in combination with aspirin, 75 to 100 mg/d (Grade 2A). For patients with bioprosthetic valves, we recommend vitamin K antagonists with a target INR of 2.5 (range, 2.0 to 3.0) for the first 3 months after valve insertion in the mitral position (Grade 1C+) and in the aortic position (Grade 2C). For patients with bioprosthetic valves who are in sinus rhythm and do not have AF, we recommend long-term (> 3 months) therapy with aspirin, 75 to 100 mg/d (Grade 1C+).

Key Words: antithrombotic • aspirin • heart disease • heart valves • prophylaxis

	Introduction

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
Few complications of valvular heart disease can be more devastating than systemic embolism. Antithrombotic therapy can reduce, although not eliminate, the likelihood of this catastrophe. If this therapy were risk free, and of no cost, all patients with significant valvular heart disease should be treated. Unfortunately, antithrombotic therapy, particularly with coumarin 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 therapy are greater in patients with endocarditis, pregnancy, and bleeding diatheses.

This review will examine the risks of thromboembolism in various forms of native valvular heart disease as well as mechanical and bioprosthetic heart valve replacements, and suggest 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. Table 1 presents eligibility criteria for the questions addressed in this chapter.

	1.0 Rheumatic Mitral Valve Disease

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
The incidence of systemic embolism is greater in rheumatic mitral valve disease than in any other common form of valvular heart disease. While surgery and the frequent use of long-term anticoagulant therapy have altered the natural history of this disease during the past 40 years, Wood² cited a prevalence of systemic emboli of 9 to 14% in several large early series of mitral stenosis; in 1961, Ellis and Harken³ reported that 27% of 1,500 patients undergoing mitral valvuloplasty had a history of clinically detectable systemic emboli. Among 754 patients followed up for 5,833 patient-years, Szekely⁴ observed an incidence of emboli of 1.5%/yr, while the number was found to vary from 1.5 to 4.7%/yr preoperatively in six reports of rheumatic mitral valve disease.⁵ 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 detectable systemic embolus during the course of the disease.⁶

The incidence of systemic emboli increases dramatically with the development of atrial fibrillation (AF). Szekely⁴ reported that the risk of embolism was seven times greater in patients with rheumatic mitral valve disease and AF than in those with normal sinus rhythm; among patients with mitral valve disease with AF, Hinton et al⁷ found a 41% prevalence of systemic emboli at autopsy. Three fourths of the patients with mitral stenosis and cerebral emboli described by Harris and Levine⁸ and by Wood² had AF. Among 839 patients with mitral valve disease described by Coulshed and associates,⁹ 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. Wood² confirmed that emboli occur 1.5 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^10111213 and those with lower cardiac indexes,¹⁰ but appears to correlate poorly with mitral calcification,⁹ mitral valve area,¹⁰ or clinical classification.²⁹¹⁰¹⁴ Indeed, several investigators have pointed out that patients with mitral valve disease with emboli frequently are found to have minor valve disease, and Wood² 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. Early studies²⁹¹⁴ of rheumatic mitral valve disease reported a weak correlation. While some reports,¹⁵¹⁶¹⁷ primarily in patients with nonvalvular AF, suggest that left atrial size is an independent risk factor for thromboembolism, another study¹⁸ describing 1,066 patients with AF found no such relationship.

In a prospective study of > 500 patients with mitral stenosis, Chiang et al¹⁹ identified risk factors for systemic embolism in patients with AF or sinus rhythm. Nine clinical and 10 echocardiographic variables were assessed for prediction of systemic embolism over a mean follow-up of 36.9 ± 22.5 months (± SD). Predictors of embolization for patients in sinus rhythm were age, the presence of a left atrial thrombus, and significant aortic regurgitation. In contrast to previous studies, mitral valve area was related to an increased risk of embolization. A correlation between left atrial thrombus and systemic thromboembolism for patients in sinus rhythm was confirmed by this study, and supports the use of anticoagulation in this group. Previous embolism was associated with subsequent embolism in patients in AF. Percutaneous balloon mitral commissurotomy decreased the risk of systemic embolism in patients with mitral stenosis who were in AF. This suggests benefits from early use of this procedure.

Among patients with valvular disease who suffer a first embolus, recurrent emboli occur in 30 to 65% of cases,²⁶²⁰²¹ of which 60 to 65% are within the first year,²⁰²¹ and most occur within 6 months. Mitral valvuloplasty does not appear to eliminate the risk of thromboembolism.⁵⁹ Thus, a successful mitral valvuloplasty does not eliminate the need for anticoagulation in patients who required long-term anticoagulation prior to the procedure, and 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 heart disease patients and to the widespread use of long-term anticoagulant therapy in these patients.

1.1 Rheumatic mitral valve disease with AF or a history of systemic embolism
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 an observational study,⁴ the incidence of recurrent embolism in patients with mitral valve disease who received warfarin was 3.4%/yr, while in the nonanticoagulation group it was 9.6%/yr. Adams et al²² followed up 84 patients with mitral stenosis and cerebral emboli for up to 20 years, half of whom received no anticoagulant therapy (1949 to 1959), and half of whom received warfarin (1959 to 1969). 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 4 deaths in the treated group. Fleming¹⁴ found a 25% incidence of emboli among 500 untreated 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% per patient-year. In a retrospective study of 254 patients with AF, an embolic rate of 5.46%/yr was reported for patients not receiving anticoagulation, vs 0.7%/yr for those receiving long-term warfarin therapy.²³ Long-term anticoagulant therapy in patients with mitral stenosis who were found to have left atrial thrombus by transesophageal echocardiography (TEE) can result in the disappearance of left atrial thrombus. In a study²⁴ of 108 patients with mitral stenosis and left atrial thrombus, there was a 62% disappearance rate of left atrial thrombus with warfarin therapy over an average period of 34 months. Smaller size of the thrombus and a lower New York Heart Association functional class were independent predictors of thrombus disappearance.²⁴

Perhaps the strongest evidence supporting the utility of anticoagulation for the prevention of thromboembolism in mitral valve disease comes from extrapolation of the results of four, large, randomized studies^25262728 in patients with nonvalvular AF. Each of these studies demonstrated that warfarin was effective in reducing stroke in patients with nonvalvular AF. An additional Canadian multicenter trial²⁹ was terminated prematurely when its results developed a trend consistent with the data reported in the four earlier trials. More recently, a meta-analysis that included six published, randomized trials with a total of 4,052 patients has provided further confirmation that warfarin was superior to aspirin in decreasing the risk of stroke in patients with nonvalvular AF.³⁰ Evidence is also mounting that supports the use of long-term anticoagulation for patients with AF who are treated with antiarrhythmic medications to maintain sinus rhythm.³¹³² Singer et al, in this Supplement, review in detail the evidence regarding anticoagulation in patients with nonvalvular AF.

In view of these data, as a general rule, all patients with rheumatic mitral valve disease and AF (paroxysmal or chronic), or who have demonstrated their high risk by previous systemic embolism, should be offered treatment with long-term oral anticoagulant (OAC) therapy. Exceptions that require detailed tradeoff 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 international normalized ratio (INR).

In a randomized study³³ of patients with prosthetic heart valves, the addition of dipyridamole to warfarin therapy proved effective in reducing the incidence of systemic emboli. Similar findings were reported in a study by Cheseboro et al.³⁴ Dale and associates³⁵ performed a randomized trial of aspirin (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 complications, including bleeding, were encountered more often in the patients receiving aspirin. At the completion of the study, all patients were treated with aspirin alone and had unsatisfactory control of embolic events. Turpie et al³⁶ reported that the addition of aspirin (100 mg/d) to warfarin (INR 3.0 to 4.5) reduced mortality and 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 antiplatelet therapy have since been confirmed in a nonrandomized prospective study of patients with St. Jude Medical (St. Paul, MN) valve prostheses.³⁷

Thus, there is evidence that dipyridamole 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 vitamin K antagonists therapy will reduce the incidence of thromboembolism in patients with prosthetic valves. However, until these findings are confirmed and the effectiveness of platelet-active drugs compared with that of OACs in randomized trials, patients with rheumatic mitral valve disease considered to be at risk for thromboembolism should be administered OACs unless the risk of bleeding is unusually high. If this therapy should fail, a platelet-active agent should be added; or, if OACs are contraindicated, antiplatelet therapy might be a reasonable, albeit uncertain, alternative. Until there are further clinical studies supporting the use of dipyridamole in the setting of valvular heart disease, the role of dipyridamole will remain unclear. There is some evidence that the drug offers little beyond the effect of aspirin administered concomitantly.³⁸

	Recommendations

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
For patients with rheumatic mitral valve disease and AF, or a history of previous systemic embolism:

1.1.1. We recommend long-term OAC therapy (target INR, 2.5; range, 2.0 to 3.0) [Grade 1C+].

For patients with rheumatic mitral valve disease and AF, or a history of previous systemic embolism:

1.1.2. We suggest clinicians not use concomitant therapy with an OAC and an antiplatelet agent (APA) [Grade 2C].

Underlying values and preferences: This recommendation places a relatively high value on avoiding the additional bleeding risk associated with concomitant OAC and antiplatelet therapy.

1.1.3. For patients with rheumatic mitral valve disease with AF or a history of systemic embolism who suffer systemic embolism while receiving OACs at a therapeutic INR, we recommend adding aspirin, 75 to 100 mg/d (Grade 1C). For those patients unable to take aspirin, we recommend adding dipyridamole, 400 mg/d, or clopidogrel (Grade 1C).

1.2 Patients with mitral valve disease in sinus rhythm
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 possible candidate for long-term OAC therapy. This is particularly true if the patient has had prior AF or is being treated with antiarrhythmic medications to maintain sinus rhythm.³¹³² It is not yet clear whether periodic echocardiography to detect atrial thrombus is indicated in older patients with mitral stenosis who remain in sinus rhythm. 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 the rheumatic mitral disease patient with a very large atrium, some authorities suggest that patients in normal sinus rhythm with a left atrial diameter > 55 mm should receive anticoagulant therapy.³⁹

	Recommendations

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
1.2.1. In patients with rheumatic mitral valve disease and normal sinus rhythm with a left atrial diameter > 5.5 cm, we suggest long-term OAC therapy (target INR, 2.5; range, 2.0 to 3.0) [Grade 2C].

Underlying values and preferences: This recommendation places a relatively high value on avoiding systemic embolism and its consequences, and a relatively low value on avoiding the bleeding risk and inconvenience associated with OAC therapy.

1.2.2. In patients with rheumatic mitral valve disease and normal sinus rhythm with a left atrial diameter < 5.5 cm, we suggest clinicians not use antithrombotic therapy (Grade 2C).

1.3 Patients undergoing mitral valvuloplasty
With the advent of percutaneous balloon mitral valvuloplasty, clinicians face a small chance that the catheter will dislodge the left atrial clot during the procedure. Accordingly, some centers have made it a practice to treat all such patients with OACs for a minimum of 3 weeks before the balloon valvuloplasty, regardless of the presence or absence of AF. An alternate strategy might be to perform TEE just prior to balloon mitral valvuloplasty and withhold anticoagulation prior to valvuloplasty if the examination does not reveal a left atrial clot.⁴⁰⁴¹

Recently, Abraham et al⁴² reported on performing percutaneous transvenous mitral valvuloplasty on 629 relatively young patients (mean age, 29.51 ± 9.9 years [± SD]) with rheumatic mitral stenosis, normal sinus rhythm, no history of embolism, or echocardiographic evidence of clot without anticoagulation prior, during, or after the procedure. No patient had an embolism in the immediate postprocedure period or during a median follow-up of 3 months. However, until this study is reproduced, based on experience with patients undergoing cardioversion of AF, the absence of atrial clot by TEE at the time of the procedure does not preclude the need for prompt anticoagulation after cardioversion to prevent thromboembolism. Indeed, one can make a good case for anticoagulation therapy in most patients after balloon mitral valvuloplasty for at least 4 weeks.⁴¹ Kang et al⁴³ reported on 49 patients with mitral stenosis with left atrial appendage thrombi who were otherwise candidates for percutaneous mitral valvuloplasty (PMV).⁴³ Twenty-five patients underwent PMV after being treated with warfarin to achieve an INR of 2.0 to 3.0. PMV was performed after the resolution of left atrial appendage thrombi (mean resolution time, 5 ± 3 months [± SD]). There were no procedure-related complications reported during or after PMV.

	Recommendation

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
1.3.1. For patients undergoing mitral valvuloplasty, we suggest anticoagulation with vitamin K antagonists with a target INR of 2.5 (range, 2.0 to 3.0) for 3 weeks prior to the procedure and for 4 weeks after the procedure (Grade 2C).

	2.0 Mitral Valve Prolapse

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
Mitral valve prolapse (MVP) is the most common form of valve disease in adults.⁴⁴ While generally innocuous, it is sometimes annoying, and serious complications can occur. During the past 20 years, embolic phenomena have been reported in several patients with MVP in whom no other source for emboli could be found. In 1974, Barnett⁴⁵ observed four 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.⁴⁶ Similar observations have been made by other investigators,⁴⁷⁴⁸⁴⁹ and as many as nine such patients have been reported from a single center.⁴⁹

Earlier evidence linking MVP to stroke was provided by the case-control study of Barnett and associates.⁵⁰ Among 60 patients < 45 years old who had TIAs or partial stroke, MVP was detected in 40%; in 60 age-matched control subjects, the incidence was 6.8% (p < 0.001); and in 42 stroke patients > 45 years old, MVP was found in 5.7%, an incidence comparable to that in the general population.⁵⁰ More recently, with the use of two-dimensional echocardiography, the criteria for the diagnosis of MVP have changed resulting in a lower prevalence than previously believed. In fact, in a study by Gilon at al,⁵¹ MVP was found to be less common than previously reported among young patients with stroke or TIA. In this case-control study of young stroke patients (age 45 years), 4 of 213 patients (1.9%) had MVP as compared with 7 of 263 control subjects (2.7%). Seventy-one of 213 patients had unexplained stroke: no identifiable or recognized cause of stroke or TIA. Of this subgroup, two patients (2.8%) had prolapse. This rate was not significantly different than the control group. Evaluation of the Framingham Heart Study⁵² offspring cohort has yielded similar results, with MVP in only 2.4% of this cohort. In the Framingham cohort,²⁵ no significant difference was found in the prevalence of stroke or TIA in individuals with MVP as compared to those without MVP.

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 that 6% of the female and 4% of the male population have MVP, the incidence of thromboembolism in these > 12 million Americans must be extraordinarily low. Indeed, it has been estimated that the risk of stroke in young adults with MVP is only 1 in 6,000/yr.⁵³ As suggested by Cheitlin,⁵⁴ informing the patients with MVP of this risk is not indicated, "nor is it 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 therapy. Since repeated ischemic episodes are not uncommon,^47505556 long-term aspirin therapy appears indicated as in many patients with TIAs and no MVP.⁵⁷ No studies of antithrombotic therapy in this disease have been reported (to our knowledge), so guidelines for therapy are at best empiric and drawn from experience with other thromboembolic conditions. Although there is no evidence, long-term anticoagulation should be considered 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 al⁵⁸ 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. Since myxomatous degeneration and denudation of the mitral endothelium are likely to be critical in the thrombogenic process, patients with "secondary" MVP,⁵⁹ 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 patients represent a subpopulation without increased risk of thromboembolism. However, past observations indicate otherwise, as most MVP patients with cerebral ischemia are found to have normal results of physical examination.⁶⁰

In a prospective study of 237 patients with MVP, Nishimura et al⁶¹ concluded that those with a redundant mitral valve on echocardiography constituted a subgroup of patients at high risk for MR, infectious endocarditis, sudden death, and cerebral embolic events. Most of these observations were confirmed in a retrospective study by Marks et al,⁶² except that the risk of stroke was not correlated 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 ischemic events.

Clinicians can consider patients with documented but unexplained TIAs in the same way they would other patients with unexplained TIAs. As documented in the guideline chapter on prevention of stroke (see the article by Albers et al in this Supplement), randomized trials have consistently shown that aspirin reduces stroke risk in such patients.

	Recommendations

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
2.0.1. In people with MVP who have not experienced systemic embolism, unexplained TIAs, or AF, we recommended against any antithrombotic therapy (Grade 1C).

2.0.2. In patients with MVP who have documented but unexplained TIAs, we recommend long-term aspirin therapy, 50 to 162 mg/d (Grade 1A).

2.0.3. In patients with MVP who have documented systemic embolism or recurrent TIAs despite aspirin therapy, we suggest long-term vitamin K antagonist therapy (target INR, 2.5; range 2.0 to 3.0) [Grade 2C].

	3.0 Mitral Annular Calcification

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
The clinical syndrome of mitral annular calcification (MAC), first clearly described in 1962,⁶³ 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 MAC. While the true incidence of systemic emboli in this condition is not known, embolic events appear conspicuous with or without associated AF.^636465666768 Four of the 14 original patients described by Korn et al⁶³ had cerebral emboli, and 5 of 80 patients described by Fulkerson et al⁶⁵ had systemic emboli, only 2 of whom had AF. More recently, 16 of 142 patients with MAC were found to have systemic calcareous emboli.⁶⁹ In autopsy specimens, thrombi have been found on heavily calcified annular tissue,⁷⁰ and echogenic densities have been described in the left ventricular outflow tract in this condition among patients with cerebral ischemic events.⁶⁶ Perhaps the best estimate of the thromboembolic potential of MAC comes from the Framingham Heart Study.⁶⁸ Among 1,159 subjects with no history of stroke at the index echocardiographic examination, the relative risk of stroke in those with MAC was 2.10 times that without MAC (p = 0.006), independent of traditional risk factors for stroke. Even in those subjects 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.⁶⁵⁶⁷⁷¹ While the relative frequency of calcific emboli and thromboembolism is unknown, it is likely that the incidence of the former problem 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.⁶⁵⁷² Since there is little reason to believe that anticoagulant therapy would be effective in preventing calcific emboli, the rationale for using antithrombotic drugs in patients with MAC rests primarily on the frequency of true thromboembolism. In the Framingham study, the incidence of AF was 12 times greater in patients with MAC than in those without this lesion,⁷³ and 29% of the patients with annular calcification described by Fulkerson et al⁶⁵ had AF. In addition, left atrial enlargement is not uncommon, even in those with normal sinus rhythm. MAC has also been associated with diffuse atherosclerotic disease, including aortic and carotid artery atheromas.⁷⁴⁷⁵ Thus, the many factors contributing to the risk of thromboembolism in MAC include AF, the hemodynamic consequences of the mitral valve lesion itself (stenosis and regurgitation), fragmentation of calcific annular tissue, and diffuse vascular atherosclerosis. 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 to 75 years),⁶¹⁶⁵ the risks of anticoagulation with vitamin K antagonists 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 anticoagulation may outweigh the benefit of OAC therapy in patients without AF. Certainly the clinician should be discouraged from initiating anticoagulant therapy merely on the basis of radiographic evidence of MAC. Antiplatelet drugs might represent an uncertain compromise for those with advanced lesions, although to our knowledge no studies indicate that this therapy is effective in preventing thromboembolism in MAC. For patients with repeated embolic events despite OAC therapy or in whom multiple calcific emboli are recognized, valve replacement should be considered.

	Recommendation

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
3.0.1. In patients with MAC complicated by systemic embolism, not documented to be calcific embolism, we suggest treatment with long-term OAC therapy with a target INR of 2.5 (INR range, 2.0 to 3.0) [Grade 2C].

	4.0 Aortic Valve and Aortic Arch Disorders

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
Clinically detectable systemic emboli in isolated aortic valve disease are distinctly uncommon. However, Stein et al⁷⁶ 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,⁷² and four cases of cerebral emboli were observed in patients with bicuspid aortic valves in whom no other source of emboli could be found.⁷⁷ 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 calcific aortic stenosis is that of Holley et al.⁷⁸ In this autopsy study¹⁷⁸ 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 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 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,⁷⁹ only 6 patients 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.⁸⁰ 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.⁸⁰ Boon et al⁸¹ prospectively compared the risk of stroke in 815 patients with aortic valve calcification with or without stenosis with 562 control subjects. These authors found no significant increase in strokes in patients with calcific aortic valve disorders compared with a matched control group. Otto et al⁸² evaluated 1,610 individuals with aortic sclerosis as well as 92 individuals with aortic stenosis enrolled in the Cardiovascular Health Study. No information on the presence or extent of aortic valve calcification was collected in this study. The authors found no significant increase in the incidence of stroke over a mean follow-up period of 5 years.⁸²

Thus, in the absence of associated mitral valve disease or AF, 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 they are 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 apparently outweigh the potential usefulness.

TEE of the aortic arch and ascending aorta have been used to identify plaque size and morphology as risk factors for ischemic stroke.⁸³⁸⁴ An evaluation of 382 patients enrolled in the Stroke Prevention in Atrial Fibrillation trial who underwent TEE found that 134 patients (35%) had complex aortic plaque > 4 mm; in these patients, the risk of stroke at 1 year was 12 to 20%; the risk of stroke in patients with AF alone and no aortic plaque was 1.2%.⁸⁵ In a prospective case-control study⁸⁶ of 250 patients with ischemic stroke, TEE revealed that 14.4% of patients with strokes had plaques 4 mm in thickness; this is in contrast to the control subjects (no ischemic event) who had a 2% occurrence of plaques of this size. Similarly, in patients with prior ischemic events, Amarenco and colleagues⁸⁷ found plaques 4 mm to be significant risk factors for recurrent ischemic events. These same researchers performed an analysis of 788 person-year follow-up to determine the affect of plaque morphology on the risk of ischemic disease. They determined that the only plaque morphology that increased the risk of ischemic events was the absence of plaque calcification.⁸⁸ Ulceration and hypoechoic plaques had no predictive value in evaluating vascular events. Overall, it was determined that aortic plaques 4 mm in thickness increased the risk of vascular events, and this risk is further increased by a lack of plaque calcification (RR = 10.3, lack vs presence of calcification). These authors hypothesized that the noncalcified plaques are probably lipid laden, and are thus unstable and prone to rupture and thrombosis. While calcified aortic plaques may be the cause of atheroemboli, particularly with aortic manipulation such as during bypass or catheter advancement, it is unlikely that antithrombotic therapy will be beneficial in this condition.⁸⁹

To study the effect of OACs on patients with atherosclerosis of the aorta, Ferrari et al⁹⁰ used TEE in a prospective cohort to compare treated vs nontreated patients. They found that patients treated with antiplatelet agent (APA) rather than OAC had more combined vascular events and a higher mortality rate (RR = 7.1), and that the more severe the aortic atheroma, the more frequent the vascular event rate. A ninefold-higher mortality risk was demonstrated for patients with aortic debris treated with APA as compared to patients treated with OACs. Patients with aortic plaques > 4 mm in thickness had almost a sixfold-higher risk for combined events when treated with APA vs OACs. This study did not provide information regarding patients who were receiving neither APA nor OAC therapy. Dressler et al⁹¹ found similar results in that patients with mobile aortic atheroma not receiving warfarin had a higher incidence of vascular events (27% had strokes) than those with warfarin treatment (0% had strokes). They also determined that the dimensions of the mobile component of the atheroma should not be used to assess the need for anticoagulation therapy, since small, medium, and large atheromas had similar outcomes.⁹¹ This is in contrast to current practice patterns, since studies reveal that 79% of patients with large or medium atheromas (medium diameter > 1 mm and area < 10 mm²) were prescribed warfarin, as opposed to 53% of patients with small plaques (defined as diameter < 1 mm). More recently, in a retrospective analysis by Tunick et al,⁹² a group of 519 patients with severe aortic plaque were evaluated for embolic events. In this study,⁹² individuals receiving statins for cholesterol lowering had significantly less embolic events than those not receiving statins (12% vs 29%). OAC and APA therapy did not significantly reduce the risk of embolic events. The authors concluded that this may be a beneficial effect of statins on plaque stability. Thus, patients with mobile atheroma should be considered for anticoagulation with OACs, while the role of the dimension of the plaque (ie, > 4 mm) in determining therapy is still not totally clear.

	Recommendations

TOP Abstract Introduction 1.0 Rheumatic Mitral Valve... Recommendations Recommendations Recommendation 2.0 Mitral Valve Prolapse Recommendations 3.0 Mitral Annular Calcification Recommendation 4.0 Aortic Valve and... Recommendations 5.0 Prosthetic Heart... Recommendations 6.0 Prosthetic Heart... Recommendations Recommendations 7.0 Infective Endocarditis and... Recommendations 8.0 Withdrawal of... Summary References

 
4.0.1. In patients with aortic valve disease, we suggest that clinicians not use long-term vitamin K antagonist therapy unless they have another indication for anticoagulation (Grade 2C).

4.0.2. We suggest OAC therapy in patients with mobile aortic atheromas and aortic plaques > 4 mm as measured by TEE (Grade 2C).

	5.0 Prosthetic Heart Valves—Mechanical Prosthetic Heart Valves

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It is well established that patients with all types of mechanical valves require antithrombotic prophylaxis. Lack of prophylaxis in patients with St. Jude Medical bileaflet valves gave unacceptable results (embolism or valve thrombosis in 12%/yr with aortic valves and 22%/yr with mitral valves).⁹³ Among patients with the Bjork Shiley spherical disk valves who received no prophylaxis or prophylaxis with APAs alone, thromboemboli occurred in 23%/yr.⁹⁴ In the present consensus report, we continue to address literature that may permit a more refined assessment of the optimal level of INR for patients with modern mechanical prosthetic heart valves. We address whether low doses of aspirin or other antithrombotic drugs in combination with OACs may be beneficial. Investigations of low levels of warfarin are also assessed, particularly in newer valves. Investigations included in the present report are generally limited to those that report antithrombotic prophylaxis in terms of the INR. Much detailed information, particularly on the older valves, is given in the chapter on Antithrombotic Therapy in Prosthetic Heart Valves in the CHEST Supplement of 2001, and this will not be repeated.⁹⁵

Most results of antithrombotic prophylaxis are from nonrandomized case series without controls. The safety and efficacy of a given range of INR are usually reported on the basis of an intention-to-treat analysis rather than on the basis of the intensity of anticoagulation actually achieved. In some important investigations, less than half of the INRs were in the target range.³⁶⁹⁶ If failure to maintain tight control of the INR coupled with the failure to report the INRs at which events occurred, intention-to-treat analysis may yield misleading results about the safety or effectiveness of a given INR range. These limitations weaken the basis on which therapeutic recommendations can be made. They also indicate a need for further research in this area. Prospective studies that address risk factors among patients with each type and location of prosthetic valve, the level of anticoagulation actually achieved, and the level of anticoagulation at which complications occurred are needed before controversy regarding prophylaxis can be resolved.

The literature provide little data on the administration of heparin or low molecular weight heparin (LMWH) immediately after valve insertion. However, it is common practice to administer unfractionated heparin or LMWH as soon as it is safe to do so, and to continue such therapy until the INR is within the therapeutic range for 2 consecutive days. In a case series of 208 patients followed 2 weeks after insertion of a prosthetic heart valve, Montalescot and associates⁹⁷ found that therapeutic levels were more rapidly and more predictably achieved with LMWH than with unfractionated heparin. Major bleeding was the same in both groups. There was one stroke in the unfractionated heparin group and none in the LMWH group.

St. Jude medical bileaflet mechanical valve
Experience with St. Jude Medical bileaflet mechanical valves is shown in Table 2 .^9899100 Horstkotte and associates,¹⁰¹ among patients with St. Jude Medical valves in the aortic position, showed that less-intense anticoagulation, at an estimated INR of 1.8 to 2.8, in comparison to an estimated INR of 2.5 to 3.5, resulted in an increase in the rate of thromboemboli from 2.8 to 3.9%/yr, and a reduction in the rate of major bleeding from 1.25 to 0.4%/yr. These results formed the hypothesis for the randomized multicenter GELIA (German experience with low intensity anticoagulation) study,¹⁰² which enrolled 2,848 patients accounting for 8,061 follow-up years.¹⁰³ The GELIA data demonstrated no significant influence of the intensity of OAC (among patients randomized to target INR ranges of 3.0 to 4.5, 2.5 to 4.0, and 2.0 to 3.5) on the incidence of thromboemboli as well as bleeding.¹⁰⁴ However, all of the target range INRs overlapped, and frequently the INRs were out of target range.¹⁰⁴ Instability of OAC therapy was a strong predictor of major adverse events. Loss of atrial contraction had a pronounced effect on thromboembolic rates.¹⁰⁵ Among patients, 82% of whom had St. Jude Medical valves, and 96% of which were in the aortic position, thromboemboli were not more frequent at an INR of 2.0 to 3.0 than at an INR of 3.0 to 4.5, providing patients were in sinus rhythm with a normal size left atrium.¹⁰⁶

Baudet and associates⁹⁸ showed either thromboemboli or valve thrombosis in 1.06%/yr among patients with a St. Jude Medical valve in the aortic position, using an INR of 2.4 to 2.8. Emery and associates,⁹⁹ with an estimated INR of 1.8 to 2.0, observed thromboemboli in 0.69 to 0.80%/yr among patients with a St. Jude Medical valve in the aortic position. The higher value was among patients who underwent a coronary artery bypass graft as well.

Among patients with St. Jude Medical valves in the mitral position, rates of thromboemboli were somewhat higher than in the aortic position. With an estimated INR of 2.4 to 2.8, Baudet and associates⁹⁸ showed thromboemboli or valve thrombosis with the mitral valve at a rate of 2.2%/yr and a rate of 1.1%/yr thromboemboli or valve thrombosis in the aortic position. In the GELIA study,¹⁰⁴ linearized rates for bleeding (grade II, bleeding treated as an outpatient) were not statistically different with the treatment groups (INR 3.0 to 4.5, 2.5 to 4.0, or 2.0 to 3.5. However, the frequency of severe bleeding complications (grade III, requiring hospitalization) decreased with decreasing the target range without an increase in thromboembolic events.¹⁰⁴ If minor thromboembolic events (TIAs) and minor bleeding events (small hematomas, mild epistaxis, or gingival bleeding) usually not documented in studies with a less restrictive follow-up protocol than that of GELIA, were excluded, the rates for thromboembolic events were 0.78%/yr and bleeding events were 2.50%/yr.¹⁰⁹ Some studies showed comparable results with lower target ranges of INR of only 1.4,¹¹⁰ or 1.5,¹¹¹ but the actual range used was wide¹¹⁰ or not stated.¹¹⁰¹¹¹

Other bileaflet mechanical valves
Based on an analysis of published data, David and associates¹¹² concluded that there was no clinically important difference in the rate of systemic embolism among patients with the St. Jude Medical bileaflet valve and the CarboMedics (Austin, TX) bileaflet valve. Abe and associates,¹¹³ in patients with a CarboMedics bileaflet valve in the aortic position, mitral position, or both, showed approximately 1.1%/yr thromboemboli or thrombosis with an INR of 2.0 to 3.5. Wang and associates¹¹¹ used a target INR of 1.5 in patients with a CarboMedics valve in either the aortic or mitral position, and observed thromboemboli in 2.7%/yr. Others with the CarboMedics valve¹¹⁴ or the Duromedic (Baxter Healthcare, Edwards Division; Santa Ana, CA) valve¹¹⁵ used wider ranges of the target INR, so a safe lower value could not be assessed.

The Sorin bicarbon bileaflet valve (Sorin Biomedica Cardio; Saluggia, Italy), in patients with the valve in the aortic position, using an INR of 2.0 to 3.0, showed thromboemboli in 1.2%/yr.¹¹⁶ In the mitral position, using an INR of 3.0 to 4.0, thromboemboli were 0.7%/yr.

Monoleaflet or tilting disk valves
Among patients with an Omnicarbon monoleaflet valve (MedicalCV; Minneapolis, MN) in the aortic position, using an INR of 2.5 to 3.5, a rate of thromboemboli of 0.7%/yr was shown.¹¹⁷ Others, using a lower INR of 2.0 to 3.0 found the rate of thromboemboli to be no higher.¹¹⁸ In the mitral position, with an INR of 2.5 to 3.5,¹¹⁸ or 3.0 to 4.0,¹¹⁷ the rate of thromboemboli of was 0.9 to 1.1%/yr.

The Sorin Monostrut valve (Sorin Biomedica Cardio) showed more thromboemboli when in the mitral position than in the aortic position.¹¹⁹ The range of INR used in this case series (2.5 to 4.0) was too broad to assess whether a low INR would be effective.

Regarding the Bjork Shiley spherical disk valve,¹²⁰¹²¹ and the Bjork Shiley Convexo Concave valve,¹²¹ there are no investigations that use an INR of 2.0 to 3.0 or 2.5 to 3.5. Therefore, whether such levels of the INR can be used safely with these valves is undetermined (Table 3 ). However, in one case series that included 1,354 tilting disk valves, patients with tilting disk valves had the lowest rate of complications with an INR of 3.0 to 3.9, although an INR of 4.0 to 4.9 gave comparable results.¹⁰⁷