Short- and long-term anticoagulation are integral parts of the treatment of many cardiovascular conditions, including acute coronary syndromes, stroke, peripheral arterial disease, and venous thromboembolic disease. These conditions are discussed in other chapters. Long-term anticoagulation will be discussed in this chapter for the following conditions: atrial fibrillation, native valvular heart disease, prosthetic heart valves, left ventricular thrombus with acute myocardial infarction, remote myocardial infarction, left ventricular aneurysm, dilated cardiomyopathy, atherosclerotic sources of emboli, paradoxical emboli associated with a patent foramen ovale, and intracardiac devices.
Guidelines have been written by a number of organizations, including the American Heart Association (AHA), American College of Cardiology (ACC), American College of Chest Physicians (ACCP), and ESC for the management of anticoagulation in a number of conditions. These guidelines vary in their content and format; however, their recommendations are mostly in agreement.
Atrial fibrillation can result in atrial thrombus formation (most often seen in the left atrial appendage [see Figure 4–3]), which can subsequently result in embolization (most often recognized clinically to the brain resulting in ischemic stroke). The incidence of stroke in patients with atrial fibrillation not related to rheumatic mitral valve disease is 4–5% per year, 4–5 times greater than in similar patients who do not have atrial fibrillation. The incidence of stroke with atrial fibrillation is age related. For those age 50–59 years, the incidence is about 1.5% per year, but this increases to > 10% per year for those 80 years of age and older.
AHA/ACC/ESC has recommended classifying atrial fibrillation as (1) first episode, (2) paroxysmal, (3) persistent, and (4) permanent. Acute atrial fibrillation is that which occurs for the first time. Chronic atrial fibrillation can be paroxysmal, persistent, or permanent. In paroxysmal atrial fibrillation, episodes spontaneously convert to normal sinus rhythm usually within 7 days. In persistent atrial fibrillation, episodes last longer than 7 days and/or conversion to normal sinus rhythm requires cardioversion, either chemical or electrical. In permanent atrial fibrillation, normal sinus rhythm can no longer be restored, and/or the patient and physician no longer attempt to restore or maintain normal sinus rhythm. The risk of stroke is considered the same for all three categories of chronic atrial fibrillation.
Atrial flutter is much less common than atrial fibrillation; however, these two arrhythmias are often seen in the same individual. Patients with atrial flutter are also at risk for thromboembolism, and therefore, the two arrhythmias are treated the same in terms of anticoagulation.
Chronic Atrial Fibrillation (Nonvalvular)
The efficacy of long-term therapy with oral anticoagulants (warfarin) for primary and secondary prevention of stroke in patients with nonvalvular atrial fibrillation has been clearly shown in randomized, placebo controlled trials.
The risks of anticoagulant therapy in this particular patient population are considerable. ICH increases significantly with age greater than 75 years and INRs greater than 4.0.
Randomized studies have also evaluated the effects of aspirin in reducing the incidence of stroke in patients with nonvalvular atrial fibrillation. These studies showed little benefit of aspirin, much less than with dose-adjusted warfarin. The combination of aspirin and fixed, low-dose warfarin has been compared with dose-adjusted warfarin and was not as effective in lowering the incidence of stroke. Aspirin plus clopidogrel was more efficacious than aspirin alone for stroke prevention in nonvalvular atrial fibrillation patients, but inferior to dose-adjusted warfarin despite a similar risk of bleeds.
Anticoagulant therapy in atrial fibrillation reduces the incidence of stroke by > 60%. The usually accepted target INR for the prevention of stroke with warfarin is 2.0–3.0, and the time patients are within this range (time in target range) is predictive of the efficacy of anticoagulation—the best results are when patients are in this range > 65% of the time. Its efficacy is diminished if the INR is less than 2.0, and INRs greater than 4.0 are associated with a higher risk of bleeding, including ICH. In view of the higher risk of anticoagulation in the very elderly, the target INR is at times lowered to 2.0–2.5. The newer oral anticoagulants are more effective in maintaining continuous effective anticoagulation.
In patients with atrial fibrillation and coronary artery disease, antiplatelet drugs may be added to warfarin in certain situations. The ACCP guidelines suggest that patients with stable coronary disease (no acute coronary syndrome in the last year) and atrial fibrillation (requiring anticoagulant therapy) should receive warfarin without antiplatelet agents. For atrial fibrillation patients with an acute coronary syndrome, who are not treated with coronary stent(s), anticoagulant therapy with warfarin and a single antiplatelet agent for 1 year is advised. Atrial fibrillation patients at high risk for thromboembolism, in particular those with previous thromboembolism or an acute coronary syndrome, who do not receive a stent should be treated with warfarin and dual antiplatelet agents (aspirin and clopidogrel) for 12 months. After that time, warfarin alone is advised, just as for patients with atrial fibrillation and stable coronary disease. For atrial fibrillation patients requiring anticoagulant therapy who develop an acute coronary syndrome treated with stent(s), the ACCP guidelines advise warfarin and dual antiplatelet therapy for 1 month for bare metal stents and 3–6 months for drug-eluting stents. After these time periods, warfarin and single antiplatelet therapy (frequently clopidogrel) is advised for the remainder of the first year, followed by warfarin alone, just as for atrial fibrillation and stable coronary artery disease. Patients who require long-term anticoagulation with warfarin are preferably treated with a bare metal stent, rather than a drug-eluting stent if possible, to lower the time of exposure to triple therapy and its risk of bleeding complications. Guideline recommendations for the combination of warfarin and antiplatelet agent(s) vary considerably.
Balancing the Risk of Stroke and Anticoagulation in Patients with Nonvalvular Atrial Fibrillation
In choosing long-term anticoagulation for patients with nonvalvular atrial fibrillation, the balance between risks and benefits should be considered. The Stroke Prevention in Atrial Fibrillation (SPAF) investigators, the Atrial Fibrillation Investigators, the AHA/ACC/ECS, and the ACCP have determined risk factors for stroke in patients with atrial fibrillation. Assessment of patients for these risk factors is helpful in determining antithrombotic therapy. CHADS2 is a modified stroke risk classification that integrates the above schemes (Table 4–2, left column). Congestive heart failure (C), hypertension (H), age greater than 75 years (A), and diabetes (D) are each assigned 1 point. Patients with previous stroke (S) are assigned 2 points. The CHADS2 risk score assists in determining the approach to antithrombotic treatment (Table 4–3, left column). Lowest risk patients have a score of 0 and do not require warfarin. Intermediate-risk patients have a score of 1 and may be treated with anticoagulant or aspirin when the net clinical benefit is considered (stroke risk reduction with anticoagulant versus risk of major bleeding with anticoagulant). High-risk patients have a score of 2 or greater and derive the most benefit from anticoagulants. Patients with atrial fibrillation who have had a previous stroke should receive anticoagulation therapy unless there is a contraindication.
Table 4–2. CHADS2 and CHA2DS2-Vasc Risk Assessment for Anticoagulation in Nonvalvular Atrial Fibrillation ||Download (.pdf)
Table 4–2. CHADS2 and CHA2DS2-Vasc Risk Assessment for Anticoagulation in Nonvalvular Atrial Fibrillation
Age > 75
Stroke or TIA
Stroke or TIA
Table 4–3. Anticoagulation for Chronic Nonvalvular Atrial Fibrillation by CHADS2 and CHA2DS2-Vasc Risk ||Download (.pdf)
Table 4–3. Anticoagulation for Chronic Nonvalvular Atrial Fibrillation by CHADS2 and CHA2DS2-Vasc Risk
Recently, an alternative risk stratification scheme has been proposed to take into account the importance of age, gender, and coexisting vascular disease. This risk assessment scheme is CHA2DS2-Vasc (see Table 4–3, right column). This acronym is defined similar to CHADS2 with Vasc defined as vascular disease (peripheral or coronary artery disease or atheroma on TEE) and a sex category. Hypertension is defined as a systolic blood pressure greater than 160 mm Hg on treatment. A potential advantage of this scheme is that those with low scores (CHA2DS2-Vasc = 0 or 1) have a very low incidence of stroke if not anticoagulated and may be treated with no antithrombotic or low-dose aspirin. A decision to treat with oral anticoagulants can be based on CHADS2 risk factors complimented by CHA2DS2-Vasc. Patients who have a CHADS2 score of 1 can be reevaluated with CHA2DS2-Vasc. If their CHA2DS2-Vasc score is 1, they are considered intermediate risk and can be treated with either aspirin or dose-adjusted warfarin. If they have a CHA2DS2-Vasc score of 2 or greater, therapeutic anticoagulation should be recommended. Importantly, neither CHADS2 nor CHA2DS2-Vasc has high predictive value, and both serve to guide rather than mandate antithrombotic therapy.
The risk of stroke is similar for patients with chronic paroxysmal, persistent, and permanent atrial fibrillation.
Risk stratification has also been developed for bleeding on anticoagulant therapy with warfarin. Several schemas (HEMOR2RAGE, HAS-BLED, RIETE, and ATRIA) were derived from nonvalvular atrial fibrillation patients. The definitions of clinical risk factors and of major bleeding vary for these schemas, and none has become the standard. However, the HAS-BLED score has the virtue of simplicity (Table 4–4). Just as for stroke risk standard schemas, the predictive value for hemorrhage with these schemas is not high. Disturbingly, many of the clinical risks for stroke are the same as those for bleeding on warfarin, leading to a clinical conundrum regarding therapeutic anticoagulation. The clinical result of a cardioembolic stroke can be devastating, and this frequently justifies acceptance of the bleeding risk for many patients.
Table 4–4. Bleeding Risk in Chronic Nonvalvular Atrial Fibrillation by the HAS-BLED Score ||Download (.pdf)
Table 4–4. Bleeding Risk in Chronic Nonvalvular Atrial Fibrillation by the HAS-BLED Score
Renal disease (Cr > 2.6 mg/dL)
Liver disease (bilirubin 2× normal)
Prior major bleeding
Age ≥ 65
Recently, three new anticoagulants have been developed and compared with warfarin for stroke prevention in nonvalvular atrial fibrillation (Figure 4–6). In contrast to warfarin, which targets all vitamin K–dependent coagulation factors, these agents specifically target just one component of the coagulation cascade with more predictable effects.
Primary efficacy of stroke or systemic embolism and safety of major bleeding end points for new anticoagulants compared with dose-adjusted warfarin. (Data from De Caterina R, et al. New oral anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on Thrombosis-Task force on Anticoagulants in Heart Disease position paper. J Am Coll Cardiol. 2012;59:1413–25.)
Dabigatran is a direct thrombin inhibitor. Dabigatran reaches the colon and may be associated with lower gastrointestinal bleeding, but whether those with previous lower gastrointestinal bleeds are more likely to bleed has not been shown. Dabigatran has, on meta-analysis of studies that included patients with nonvalvular atrial fibrillation and other conditions requiring long-term anticoagulation, been reported to have an increased incidence of acute coronary syndromes in comparison with dose-adjusted warfarin. The increase is not high, however, and may be offset by stroke protection. The anticoagulant effect of dabigatran cannot be precisely determined by routine laboratory tests, although its effects are reflected in the aPTT. There is no specific agent to reverse its anticoagulant effect, but accidental overdose may be treated with activated charcoal to absorb the drug from the stomach. Hemodialysis is effective in reducing its concentration and protein complex concentrate may also be given.
Rivaroxaban is a factor Xa inhibitor and in a dose of 20 mg daily was superior to warfarin for stroke prevention with similar rate of major bleeds in a study of very-high-risk (average CHADS2 score of 3.46) nonvalvular atrial fibrillation patients. Drug and diet interactions are, in general, minimal. It is metabolized in the liver through CYP-dependent and -independent mechanisms and is not recommended for those receiving inhibitors of both CYP3A4 and P-glycoprotein, including azole antimycotics and HIV protease inhibitors. The anticoagulant effect of this drug is not easily measured clinically, and no specific agent is available to reverse its effect. Accidental overdose may be treated with activated charcoal to absorb the drug from the stomach. Hemodialysis is not effective in reducing its concentration because it is highly protein bound. Its anticoagulant effect can be reversed in vitro with prothrombin complex concentrate, but this has not been demonstrated clinically.
Apixaban is also a factor Xa inhibitor and, in a dose of 5 mg bid, was superior to warfarin for prevention of stroke with fewer bleeds. Apixaban is metabolized in the liver via CYP3A4-dependent and -independent mechanisms, and about one-quarter is excreted in the urine. It is not recommended for patients with impaired renal function defined as a CrCl < 15 cc/min or in those receiving HIV protease inhibitors. There is no easy way to monitor the anticoagulant effect of apixaban clinically, and there is no specific reversal agent. Accidental overdose may benefit from activated charcoal to absorb the drug from the stomach. The use of prothrombin complex concentrate and/or factor VIIa may be helpful in uncontrolled bleeding, but there is no clinical evidence of efficacy.
Potential disadvantages of these agents are that their anticoagulation effect cannot be easily measured or reversed if hemorrhage occurs. Other potential limitations are that these agents have only been studied in patients who are “warfarin eligible,” and extrapolation to “non–warfarin eligible” patients cannot be advised. In addition, risk factors for major bleeds with these agents have not been determined or validated. There are also no guidelines for the combination of these agents with antiplatelet agents.
An attractive strategy for stroke prevention in nonvalvular atrial fibrillation is rhythm control (ie, convert and maintain normal sinus rhythm with the aim of eliminating atrial fibrillation and hence stroke risk). Several studies have compared the outcomes of patients with atrial fibrillation treated with rate versus rhythm control. The incidence of stroke was similar for both strategies. Importantly, most strokes in these studies occurred in patients not taking anticoagulants or those who had subtherapeutic INRs. In some of these studies, patients in the rhythm control strategy could be taken off anticoagulants if they symptomatically remained in normal sinus rhythm for at least 1 month. Patients may not always be accurate when self-reporting the occurrence of atrial fibrillation based on symptoms. Hence, anticoagulation may have been discontinued when atrial fibrillation persisted, exposing these patients to thromboembolic risk. Recommendations regarding discontinuing anticoagulants when a patient is no longer in atrial fibrillation are somewhat vague. (See later discussion of anticoagulation in regard to cardioversion in atrial fibrillation.) The decision to stop warfarin in patients who are no longer in atrial fibrillation should consider risk factors for stroke and anticoagulation.
Catheter ablation is increasingly used in the treatment of highly symptomatic patients primarily with paroxysmal atrial fibrillation. Initial reports of those with long-term success at maintaining sinus rhythm have been encouraging, but whether this lowers the thromboembolic risk and hence indication for anticoagulation has not been determined. This technique should not, at this time, be considered for the purpose of avoiding anticoagulation in patients with nonvalvular atrial fibrillation.
Cardioversion of Atrial Fibrillation
Restoration of sinus rhythm can occur spontaneously or as the result of chemical or electrical cardioversion. Conversion to sinus rhythm can result in systemic emboli through two potential mechanisms. The first is embolization of existing left atrial appendage thrombus, as the mechanical function of the atrium returns following conversion. The second is the development of left atrial appendage thrombus during the postconversion period, when the atrium is mechanically stunned. Embolization of the newly formed thrombus may then occur several days to weeks following conversion, as the mechanical function of the atrium returns. Retrospective studies have shown up to a 5% incidence of embolic events in patients with atrial fibrillation of unknown duration that were not anticoagulated before cardioversion, compared with less than 1% in those given anticoagulants.
There are two approaches to elective cardioversion to minimize stroke risk: the conventional approach and the TEE-guided approach (Figure 4–7). A randomized study showed that these two approaches were equal in terms of stroke risk. In the conventional approach, patients with atrial fibrillation of unknown or greater than 48 hours duration are treated with warfarin to achieve an INR of 2.0–3.0 or one of the new oral anticoagulants for at least 3 weeks before and at least 4 weeks after successful cardioversion. This recommendation applies regardless of stroke risk factors (CHADS2 or CHA2DS2-Vasc scores). Continuation of anticoagulation beyond 4 weeks depends, however, on stroke risk factors and whether there have been previous episodes of atrial fibrillation. In the TEE-guided approach, patients with atrial fibrillation of unknown or greater than 48 hours duration are therapeutically anticoagulated with UFH to maintain an aPTT of 50–70 seconds, warfarin to maintain an INR of 2.0–3.0, or one of the new anticoagulants and then undergo a TEE. If no left atrial or left atrial appendage thrombus is seen, cardioversion is performed. If sinus rhythm is restored, anticoagulation with warfarin or one of the new anticoagulants should be continued for at least 4 weeks or longer, depending on stroke risk factors. If a left atrial thrombus is seen on TEE, cardioversion should not be performed. These patients should be treated with oral anticoagulant. After 3–4 weeks of therapeutic anticoagulation with warfarin (INR 2.0–3.0) or a newer anticoagulant, TEE can be repeated. If no thrombus is seen, cardioversion can be performed followed by at least another 4 weeks of oral anticoagulant.
Anticoagulation strategies for elective cardioversion of atrial fibrillation of unknown duration or lasting longer than 48 hours. INR, international normalized ratio; New OAC, new oral anticoagulant; PTT, partial thromboplastin time.
For patients with atrial fibrillation of known duration less than 48 hours, according to ACC/AHA/ESC guidelines, anticoagulation is optional prior to and following cardioversion. Whether or not to anticoagulate for the 4 weeks following cardioversion is controversial. The ACCP recommends UFH prior to cardioversion and routine therapeutic anticoagulation for 4 weeks following cardioversion, but the ACC/AHA/ESC recommendations are less directive. These anticoagulation decisions could be based on risk factors and whether there had been previous episodes of atrial fibrillation. For emergency cardioversion (patients with unstable hemodynamics, uncontrolled angina, or congestive heart failure), UFH should be given and the patient treated with oral anticoagulant, either warfarin or one of the new anticoagulants, for 4 weeks or longer, depending on stroke risk factors.
Problems in Prescribing Anticoagulation for Atrial Fibrillation
A number of studies have shown that warfarin is not prescribed as often as expected for patients with nonvalvular atrial fibrillation given their hemorrhagic risks, particularly elderly patients. Elderly patients are at high risk for stroke but also at high risk for bleeding complications from warfarin. Often-cited reasons for not prescribing warfarin in those who meet usual criteria for its use include risk of falls, poor compliance, concurrent illnesses, frail state, and history of substance abuse. Applying the results of the placebo-controlled randomized studies to clinical practice is difficult. Patients included in these clinical trials were quite select; in fact, they accounted for less than 10% of those screened. In addition, most studies included very few patients 80 years of age or older. Patients at high risk for bleeding, such as those with recent gastrointestinal tract bleeding, previous ICH, recent stroke, and renal insufficiency, were not included in these studies. It is also important to note that trial protocols required closer monitoring of patients than is usually done in clinical practice. Also, patients included in these studies may be more motivated and compliant than those usually seen in clinical practice. Applying the recommendations derived from these randomized studies requires judgment, and clinicians must consider issues of compliance, risk of trauma and bleeding, and adequacy of follow-up.
The newer anticoagulants offer certain advantages, including the lack of routine monitoring of effect and fewer drug and dietary interactions. The efficacy of these drugs for prevention of stroke was shown to be the same as or better than warfarin (see Figure 4–6), but it is important to remember that these studies were performed in, and hence their results apply to, warfarin-eligible patients; extrapolation to patients not otherwise warfarin candidates cannot be advised.
Native Valvular Heart Disease
Thromboembolic complications may occur with a number of valvular conditions. Rheumatic mitral valve disease, particularly when accompanied by atrial fibrillation, has a very high incidence of embolic events. In contrast, patients with mitral valve prolapse and calcific aortic and mitral valve disease (except when atrial fibrillation is also present) are at low risk for embolic events.
Rheumatic Mitral Valve Disease
The risk of thromboembolism with mitral stenosis and atrial fibrillation is 18 times greater than matched controls. Patients with rheumatic mitral valve stenosis have at least one chance in five of having a clinically detectable embolic event during their lifetime. Atrial fibrillation is common in patients with rheumatic mitral stenosis, but thromboembolic complications can also occur in patients with rheumatic mitral stenosis who are in sinus rhythm. The ACCP recommends that all patients with rheumatic mitral valve disease and atrial fibrillation or a previous embolic event receive warfarin with a target INR of 2.0–3.0. If an embolic event occurs while a patient is receiving therapeutic anticoagulant therapy, daily aspirin 75–100 mg, dipyridamole 400 mg (in divided doses), or clopidogrel 75 mg should be added. In patients in sinus rhythm with rheumatic mitral stenosis and a left atrial diameter of greater than 5.5 cm by echocardiography, treatment with warfarin with a target INR of 2.0–3.0 had been recommended in the past but currently is not recommended by ACC/AHA guidelines. For patients with rheumatic mitral stenosis undergoing balloon valvuloplasty, warfarin should be given for 3 weeks before and 4 weeks after the procedure.
Balloon valvuloplasty should not be performed on patients with left atrial/appendage thrombus.
Patients with pure rheumatic mitral regurgitation may be at less risk for thromboembolism than those with mitral stenosis because flow through the left atrium is increased due to mitral regurgitation and may lessen the likelihood of thrombus formation. There are no specific recommendations for anticoagulation of patients with rheumatic mitral regurgitation in sinus rhythm. Most patients with rheumatic mitral regurgitation, however, also have some degree of mitral stenosis, and recommendations for anticoagulation for mitral stenosis apply to these patients.
Nonrheumatic Mitral Regurgitation
The routine use of antithrombotic therapy for primary prevention of stroke or systemic embolus in nonrheumatic mitral regurgitation is not recommended. Secondary prevention with warfarin with a target INR of 2.0–3.0 is, however, recommended for those with previous thromboembolism or atrial fibrillation.
A very small number of patients with mitral valve prolapse experience stroke or transient ischemic attacks despite no other identifiable cause. The mechanism for thromboembolism in mitral prolapse is thought to be fibrinous exudates on the myxomatous valve itself or in the left atrium at the angle formed by the posterior mitral valve leaflet and left atrial wall. No antithrombotic measures are recommended for primary prevention of thromboembolism. Secondary prevention, however, is recommended. The ACCP recommends that patients with mitral valve prolapse who have had documented but unexplained transient ischemic attack or stroke receive long-term treatment with aspirin (50–162 mg daily). For patients with mitral valve prolapse who have had systemic emboli or recurrent transient ischemic attacks despite aspirin therapy, long-term treatment with warfarin, with a target INR of 2.0–3.0, is recommended.
Calcific Mitral and Aortic Valve Conditions
Calcification of the mitral valve annulus and aortic valve occur commonly in elderly individuals. The incidence of stroke in patients with mitral annular calcification is increased. Embolic events associated with fibrocalcific mitral annular disease occur particularly in those with chronic kidney disease. In addition to thromboembolism, calcified spicules can be dislodged from ulcerated calcific plaques. It may not be possible to differentiate thromboembolism from calcific emboli, although occasionally, calcific emboli may be seen on fundoscopic examination. The ACCP recommends that in the absence of atrial fibrillation, patients with mitral annular calcification complicated by systemic emboli, not documented to be due to calcific emboli, be treated with aspirin 50–100 mg/day. If recurrent thromboembolism is documented on aspirin therapy, dose-adjusted warfarin with a target INR of 2.0–3.0 is recommended. For documented systemic calcific embolism, no specific recommendation is given, although aspirin 50–100 mg daily and statin therapy should be considered. Individuals with calcified aortic valves do not have an increased incidence of strokes compared to controls, although they may be at risk for calcific emboli. Patients with calcification of the aortic valve should not receive warfarin unless they have other indications. For documented calcific embolism, therapy with aspirin 50–100 mg daily and statin therapy should be considered.
The incidence of embolic events in infective endocarditis is quite high. In the preantibiotic era, clinically detected emboli occurred in 70–90% of patients. Currently, the incidence of emboli is 12–40%. In the sulfonamide era, anticoagulant therapy was used to improve penetration of antibiotics into the vegetations. This resulted in a high incidence of cerebral hemorrhage, and the routine use of anticoagulants was abandoned.
Infective endocarditis may occur in patients who have been receiving long-term anticoagulant therapy. If endocarditis develops in a patient with a mechanical prosthetic valve, warfarin should be stopped at the time of initial presentation, until it is clear that invasive procedures will not be required and there are no signs of central nervous system (CNS) involvement. Therapeutic anticoagulation should be restarted when it is clear that the patient does not require interventional procedures or have CNS involvement.
Nonbacterial thrombotic endocarditis (marantic endocarditis) is a condition in which fibrin thrombi are deposited superficially on normal or degenerated cardiac valves. This usually occurs in malignancies, chronic debilitating conditions, and acute fulminant diseases such as septicemia and disseminated intravascular coagulation. The reported incidence of systemic emboli in this condition varies from 14% to 91%. Treatment of nonbacterial thrombotic endocarditis should be directed at the underlying condition. The ACCP recommends UFH for patients with nonbacterial endocarditis with systemic or pulmonary emboli.
Prosthetic heart valves may be either mechanical or bioprosthetic. Mechanical valves require lifelong anticoagulation, whereas bioprosthetic valves usually do not. A mechanical valve prosthesis is more durable than a bioprosthesis, and therefore, it is less likely to require repeat valve surgery. Therefore, it is important to evaluate patients for hemorrhagic risk and likelihood for repeat surgery when choosing the type of prosthetic valve. For older patients, the risk of anticoagulation may be greater than the risk of another operation to replace a bioprosthetic valve. For women of childbearing age, the risks of anticoagulation during pregnancy should be considered in selecting the type of prosthetic heart valve.
Mechanical Prosthetic Heart Valves
Mechanical prosthetic heart valves include caged-ball, unileaflet tilting-disk, and bileaflet tilting-disk prosthesis. Caged-ball prosthetic valves are no longer implanted, and patients with these valves are rarely seen. Although flow characteristics vary, all prosthetic valves are foreign material (the sewing ring and the mechanical portions of the prosthesis) placed in the central circulation, providing a potential nidus for thrombus formation. The underlying pathologic process, as well as atrial fibrillation and decreased systolic performance of the left ventricle, are important risk factors for postimplant thromboembolism. The risk of thromboembolism varies for the different types of mechanical prosthetic valves. The lowest risk is for the bileaflet tilting-disk valves and the highest risk is for the caged-ball valves.
The thromboembolic rate of patients with mechanical valves treated with moderate- or high-intensity anticoagulation is similar. However, the hemorrhagic risk is much higher for those receiving high-intensity anticoagulation. Antiplatelet agents may be used in combination with warfarin; the combination has been shown to lower the incidence of thromboembolism, but with an increase in hemorrhagic complications.
Current ACCP recommendations for anticoagulant therapy in patients with a mechanical heart valve are as follows: (1) For patients who have had an aortic valve replacement with a St. Jude or CarboMedics bileaflet valve or a Medtronic Hall unileaflet valve, warfarin with a target INR of 2.0–3.0 should be given. (2) For patients who have had a mitral valve replacement with either a unileaflet or bileaflet valve, warfarin should be given with a target INR of 2.5–3.5. Aspirin in doses of 75–100 mg should be added for patients with high-risk factors for thromboembolism, such as atrial fibrillation, myocardial infarction, low left ventricular ejection fraction, or previous systemic embolism despite warfarin with therapeutic INRs.
The AHA/ACC guidelines differ slightly. They recommend aspirin in addition to warfarin for all patients with mechanical valve prosthesis. In patients with bileaflet tilting-disk valves, warfarin with a target INR of 2.5–3.5 is recommended for the first 3 months after aortic valve replacement. Subsequently, the target INR should be 2.0–3.0. There is less certain evidence for high-risk patients who cannot take aspirin that clopidogrel, 75 mg daily, may be substituted or that warfarin be increased to a target INR of 3.0–4.0.
The ESC recommends warfarin therapy for mechanical valves based on the thrombogenicity of the different types of valves. For low-risk valves (bileaflet tilting-disk), they recommend a target INR of 2.0–3.0. For intermediate-risk valves (unileaflet tilting-disk), they recommend a target INR of 2.5–3.5. For high-risk valves (caged-ball), they recommend a target INR of 3.0–4.0 without other risk factors and 3.5–4.5 if there are other risk factors. They recommend the addition of antiplatelet therapy for concurrent arterial disease, coronary artery stenting, recurrent thromboembolism despite treatment of other risk factors, and optimization of anticoagulation for caged-ball valves. Table 4–5 summarizes anticoagulation recommendations for mechanical prosthetic heart valves.
Table 4–5. Anticoagulation for Mechanical Prosthetic Valves ||Download (.pdf)
Table 4–5. Anticoagulation for Mechanical Prosthetic Valves
Type of Mechanical Prosthetic Valve
Goal of Anticoagulation1
Aortic bileaflet tilting disk
Aortic unileaflet tilting disk
Mitral bileaflet tilting disk
Mitral unileaflet tilting disk
Anticoagulation with UFH should be started in the postoperative period when adequate hemostasis is achieved and continued until therapy with warfarin is in the therapeutic range for the specific mechanical prosthesis implanted.
An embolic event is the most common adverse consequence seen as a result of thrombosis of a mechanical prosthetic heart valve, but hemodynamic compromise can also occur and be insidious or acutely life-threatening. Thrombi affecting mechanical prosthetic valves can either obstruct or prevent closure of the valve. Fluoroscopic imaging of prosthetic valve motion can be useful for detecting obstruction by showing reduction in excursion of prosthetic valve leaflet(s). TTE and TEE are the most sensitive and specific diagnostic tests for detecting thrombus complicating a prosthetic valve. According to ACCP guidelines, emergency surgery is reasonable for patients with a thrombosed left-sided prosthetic valve with functional class III–IV symptoms or a large clot burden. Thrombolytic therapy may be considered as first-line therapy for patients with a thrombosed left-sided prosthetic valve and functional class I–II symptoms. Thrombolytic therapy may be considered as first-line therapy in any patient with a left-sided prosthetic valve if emergency surgery is considered to be too high risk or is not available. Thrombolytic therapy is reasonable for a thrombosed right-sided prosthetic heart valve in a patient with functional class III–IV symptoms. UFH is an alternative to thrombolytic therapy in a patient with a thrombosed prosthetic valve with a low clot burden and functional class I–II symptoms. Pannus formation on the sewing ring of the prosthetic valve can cause similar hemodynamic compromise and may be a nidus for thrombus.
Bioprosthetic Heart Valves
Despite the advantages of bioprosthetic valves in terms of central flow and less thrombogenic valve material, thromboembolic complications do occur, particularly in the early postoperative period. The presumed mechanism in this setting is thrombus formation on the sewing ring. A randomized trial of two intensities of anticoagulation following bioprosthetic valve replacement showed similar rates of thromboembolism but fewer hemorrhagic complications for low-intensity anticoagulation.
In the first 3 months following mitral bioprosthetic valve replacement, warfarin is recommended with a target INR of 2.0–3.0. UFH or LMWH should be given postoperatively until the INR is therapeutic for 2 days. Long-term treatment with warfarin is not necessary following bioprosthetic valve replacement in patients who are in sinus rhythm, but long-term therapy with aspirin is recommended. If atrial fibrillation is present, these patients should receive long-term warfarin, as the rate of thromboembolism is high without its use. The AHA/ACC guidelines recommend that patients with a mitral bioprosthesis and risk factors (atrial fibrillation, prior thromboembolic event, left ventricular dysfunction, and a hypercoagulable state) should receive warfarin with a target INR goal of 2.0–3.0. It is also recommended that patients with a bioprosthetic valve receive aspirin in addition to warfarin, if high-risk factors are present.
For the first 3 months following mitral valve repair with an annuloplasty ring, warfarin has been recommended by the ESC and considered reasonable by the ACC/AHA. It is not recommended by the ACCP, provided the patient is in normal sinus rhythm.
For aortic bioprosthetic valves, the ACCP does not recommend long-term warfarin unless high-risk factors are present. Aspirin 50–100 mg should be given during the first 3 months following surgery. Warfarin is not currently recommended for transcatheter aortic bioprosthesis. Instead, aspirin and clopidogrel are recommended for the first 3 months following implant. Table 4–6 summarizes general recommendations for anticoagulants with bioprosthetic valves.
Table 4–6. Anticoagulation for Bioprosthetic Valves ||Download (.pdf)
Table 4–6. Anticoagulation for Bioprosthetic Valves
For first 3 months after surgery
Warfarin INR 2–3
After 3 months
No atrial fibrillation
Aspirin, 325 mg/day
Aortic + atrial fibrillation
Warfarin, INR 2.0–3.01
Mitral + atrial fibrillation
Warfarin, INR 2.0–3.01
Left Ventricular Thrombus
Left ventricular thrombi can complicate myocardial infarction and nonischemic dilated cardiomyopathy. In acute and remote myocardial infarction, the risk factors for ventricular thrombus include anterior myocardial infarction, apical wall motion abnormality, and left ventricular ejection fraction < 40%. No or ineffective reperfusion in acute anterior myocardial infarction is the major risk factor. In dilated cardiomyopathy, left ventricular ejection fraction < 35% is a risk factor for left ventricular thrombus and embolization. Risk factors for embolization of left ventricular thrombus include protrusion into the left ventricle and mobility, a low left ventricular ejection fraction (< 35%), and within 3 months of acute infarction.
Acute Myocardial Infarction
Postmortem findings of patients with acute myocardial infarction before the reperfusion era indicated a high incidence of left ventricular thrombi, pulmonary and systemic emboli, and coronary artery thrombi. Although embolic events were uncommon, they were frequently devastating since most (> 80%) were to the CNS (87% occur between days 5 and 21 following infarction). The risk of systemic emboli can be decreased with long-term oral anticoagulation. Risk stratification, to identify high- and low-risk groups for the development of thrombus and embolism, can improve the efficacy of anticoagulation following infarction.
Echocardiographic studies have shown thrombus formation to be most common in patients with anterior rather than inferior myocardial infarction. Patients with anterior infarction and akinesia or dyskinesia of the apex are at highest risk. On the basis of clinical and echocardiographic data, there appears to be good rationale to consider long-term (3 months) treatment with oral anticoagulants following anterior infarction in patients who did not receive or achieve effective reperfusion therapy or have decreased left ventricular systolic performance and apical akinesis or dyskinesis. Significantly fewer left ventricular thrombi and embolic events develop in patients receiving therapeutic doses of UFH following acute anterior infarction than in those treated with low-dose or no UFH. Studies of long-term oral anticoagulation following infarction have documented that anticoagulant therapy reduces the incidence of stroke and systemic emboli, although most did not report results based on infarct location.
For patients with anterior STEMI, apical akinesis, or dyskinesis and reduced left ventricular function, who have not received reperfusion therapy, initial anticoagulation with UFH followed by warfarin to maintain an INR of 2.0–3.0 for at least 3 months, in addition to low-dose aspirin (81–162 mg/day) can be recommended. After that time, warfarin could be discontinued if no intracardiac thrombus is detected by echocardiography. Aspirin (325 mg/day) should be continued indefinitely.
Because the incidence of ischemic stroke is low in patients receiving prompt and effective reperfusion therapy, either with thrombolytic or direct percutaneous intervention, it is unclear whether the risk-benefit ratio favors short- or long-term anticoagulation therapy (3 months) to prevent thrombosis and embolization. A reasonable approach is clinical evaluation and echocardiography before the patient is discharged from the hospital. Those with inferior infarction or anterior infarction without akinesia or dyskinesia of the apex and preserved left ventricular systolic performance do not require treatment with warfarin and can be treated with aspirin alone. Patients with left ventricular thrombus on echocardiography are at high risk for thromboembolism, and oral anticoagulation with warfarin is recommended for a period of at least 3 months to maintain an INR of 2.0–3.0. If repeat echocardiography shows resolution of the thrombus at 3 months, oral anticoagulation can be stopped. Aspirin and clopidogrel are usually prescribed for patients who have undergone percutaneous coronary intervention (PCI) for acute STEMI with placement of a stent. For patients who had direct PCI with placement of a bare metal stent and were subsequently shown to have left ventricular thrombus, it is recommended that they receive warfarin in addition to aspirin and clopidogrel for 1 month, then warfarin and single antiplatelet therapy (usually clopidogrel) for the second and third month after infarct. If no thrombus is present after 3 months, warfarin can be stopped and treatment with dual antiplatelet therapy continued for 12 months after infarct. At that time, single antithrombotic therapy should be given and continued indefinitely. If a drug-eluting stent was placed and a left ventricular thrombus was subsequently detected, warfarin, aspirin, and clopidogrel are advised for the first 3–6 months following stent implant. Warfarin can be stopped at that time, and dual platelet therapy should be continued for the remainder of the first year if no left ventricular thrombus can be seen. At that time, a single platelet therapy can be used and continued indefinitely.
Remote Infarction with Thrombus
Antithrombotic management of remote myocardial infarction (> 3 months after the acute event) is controversial. Although traditional studies have not indicated a high risk of embolization, some reports indicate that thrombus detected at least 3 months following infarction still carries a risk for embolism. For patients with remote infarction and left ventricular thrombus seen on echocardiography, treatment with warfarin to maintain an INR of 2.0–3.0 is recommended, particularly if the thrombus is new. A repeat echocardiogram at 3 months can be used to determine whether treatment with warfarin should be continued.
Left Ventricular Aneurysm
Although an uncommon complication of myocardial infarction in the reperfusion era, left ventricular aneurysm provides the necessary substrate for thrombus formation. These aneurysms frequently contain thrombus, but systemic embolization is unusual. It is hypothesized that the low incidence of systemic emboli noted when left ventricular thrombus is flat or “mural” and contained within a discrete aneurysm (see Figure 4–1) relates to a smaller surface area of the clot being exposed to circulating blood. It is unclear whether patients with left ventricular aneurysm warrant long-term anticoagulant therapy for prevention of embolization if flat, mural thrombus is present. However, documented systemic embolization in patients with left ventricular aneurysm and thrombus should prompt therapeutic anticoagulation to maintain an INR of 2.0–3.0 for secondary prevention. Recurrent embolization despite therapeutic anticoagulation in this setting is an indication for left ventricular aneurysmectomy.
Dilated cardiomyopathy may be the end result of many types of heart disease. Characteristically, generalized four-chamber cardiac enlargement is present with right and left ventricular dysfunction that can cause stasis in any cardiac chamber. These patients have a significant incidence of intracardiac thrombi, particularly in the left ventricle and systemic emboli. In one clinical study, atrial fibrillation was shown to be the only independent predictor for thromboembolism in dilated cardiomyopathy. Another study stressed the importance of severe depression of left ventricular function as a predictor.
The characteristics and the embolic potential of left ventricular thrombi in dilated cardiomyopathy and those in left ventricular aneurysm seem to differ. In dilated cardiomyopathy, left ventricular thrombi may protrude and thus expose a greater surface area to circulating blood (see Figure 4–2). Several studies have indicated that thrombi that protrude into the left ventricular cavity or demonstrate free intracavitary motion are associated with a high risk of embolic events. Thrombi in left ventricular aneurysms are frequently mural and contained within the aneurysm (see Figure 4-1); exposure to circulating blood is minimal because of both their containment and flat shape; patients with these features are at low risk for embolization.
Unlike acute infarction, the natural history of left ventricular thrombus complicating dilated cardiomyopathy is unclear because no clinically apparent event marks the initiation of thrombus development. Studies of intracardiac thrombi complicating dilated cardiomyopathy have, in general, consisted of small numbers of patients, varying definitions of dilated cardiomyopathy, varying proportions of patients with coronary artery disease, and incomplete reporting of anticoagulation status. Aggregate analyses of these clinical and echocardiographic studies indicate that anticoagulation can reduce the thromboembolic rate. Anticoagulation following a thromboembolic event also appears effective as a secondary prevention measure.
Patients with dilated cardiomyopathy are at highest risk for thromboembolic complications if they have atrial fibrillation, severe left ventricular dysfunction, previous thromboembolism, or left ventricular thrombus documented by imaging techniques. For patients with these high-risk characteristics, therapeutic warfarin is recommended to maintain an INR of 2.0–3.0.
For patients with clinical heart failure and reduced left ventricular systolic performance (ejection fraction < 35%), the routine use of therapeutic anticoagulation with warfarin reduces the incidence of stroke but increases the risk of major bleeding, and there is no net clinical benefit. For patients with clinical heart failure and atrial fibrillation, previous thromboembolism, or left ventricular thrombus, therapeutic anticoagulation with warfarin (target INR 2.0–3.0) is recommended.
TEE is often performed in evaluation for a source of cardioembolism in the setting of stroke or transient ischemic attack and visualizes the ascending, transverse, and descending thoracic aorta. Aortic atheroma detected by this technique (see Figure 4-4) may be a cause of systemic embolus, including stroke. In the Stroke Prevention in Atrial Fibrillation Trial, patients who underwent TEE had a 35% incidence of complex aortic plaque greater than 4 mm thick. The risk of stroke at 1 year in these patients was 12–20%. The risk of stroke in patients with atrial fibrillation without complex aortic plaque was 1.2%. Studies have shown that plaque size greater than 4 mm in thickness and no calcification increase the risk of ischemic events.
Treatment of complex aortic plaque for the primary and secondary prevention of embolic stroke is controversial. While aspirin is generally recommended, warfarin has been reported to be efficacious in some series, particularly for secondary prevention. Patients with complex aortic plaques and embolic events treated with hydroxymethylglutaryl–coenzyme A (HMG-CoA) reductase inhibitors have a significantly lower risk of embolic events than those taking warfarin or aspirin, and HMG-CoA should be given for secondary prevention.
Paradoxical Emboli Associated with Patent Foramen Ovale
Intracardiac shunts have the potential to allow for venoarterial or paradoxical emboli (see Figure 4–5). These shunts are usually left to right, but there may also be right-to-left shunting under certain circumstances, such as cough or Valsalva maneuver. Patent foramen ovale is quite common, occurring in up to 15–20% of the population. Asymptomatic patent foramen ovale can be detected on TTE and TEE. The ACCP recommends that asymptomatic patients should not be treated with antithrombotics for primary prevention of systemic embolus. Patients with patent foramen ovale with right-to-left shunt and unexplained systematic embolism or transient ischemic attack should receive antiplatelet therapy for secondary prevention. If they also have venous thrombosis or pulmonary embolism, they will require long-term anticoagulation with warfarin to maintain an INR of 2.0–3.0. If there are recurrent events while on antiplatelet therapy, warfarin should be considered. Recurrent systemic embolus on anticoagulant therapy should prompt consideration for foramen ovale closure (either surgically or percutaneously).
Pacemakers, Implantable Cardioverter-Defibrillators, and Other Intracardiac Devices
Anticoagulant therapy is not usually considered for patients with pacemakers and implantable cardioverter-defibrillators (ICDs). However, a number of thromboembolic complications can occur. The intravascular and intracardiac leads used in these devices are foreign bodies that can act as a nidus for thrombus formation. On rare occasions, swelling of the arm on the side of implantation may develop. Ultrasound or venography may indicate obstruction of the subclavian vein. The treatment for subclavian vein thrombosis is UFH followed by oral anticoagulation. The duration of treatment with anticoagulants varies but is usually for at least 3 months. For extreme swelling and pain of the effected extremity, interventional procedures to restore flow in the subclavian vein should be considered. Thrombolytic therapy cannot be used in the immediate post-pacemaker implant period because of the risk of bleeding into the pacemaker pocket.
TEE performed for unrelated indications has demonstrated a high incidence of thrombi on pacing and ICD leads. Often these thrombi are highly mobile. Differentiation from infective endocarditis is mandatory, since the clinical approach and treatment will be affected. The risk for embolization to the pulmonary artery or systemically if there is a patent foramen ovale is unknown. There are no guidelines for treating these thrombi with anticoagulation or for removal of the device. If embolic events have occurred or there are other high-risk factors for thromboembolism, it seems reasonable to initially treat with oral anticoagulants. Follow-up TEE seems reasonable after at least 3 months of therapeutic anticoagulation to determine whether the thrombus has resolved. There is little evidence or experience to guide the duration of treatment.
Technologic advances are leading to the implantation of additional intracardiac devices. Since these devices are foreign bodies, they can act as a nidus for thrombus formation. Percutaneous closure devices for atrial septal defects are available. Current anticoagulation recommendations are for aspirin and clopidogrel for 3 months following the procedure. Warfarin is not recommended. Devices for percutaneous occlusion of the left atrial appendage are currently being investigated for use in nonvalvular atrial fibrillation. Although anticoagulation is required for this procedure, the strategy behind these devices is to avoid long-term anticoagulation. These devices are not yet clinically available.
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