Anticoagulation for Valvular Heart Disease

Introduction

Valvular heart disease (VHD) is a common contributor to cardiac morbidity and mortality.1-3 Current data estimate the overall prevalence of VHD in the United States to be 2.5%, with prevalence estimates in those over the age of 75 to be as high as 13.3%.4

Surgical repair of VHD with either a mechanical or bioprosthetic valve is a common solution with ever-improving operative outcomes.5,6 Observational data indicate a steady increase in the use of bioprosthetic valves, with a concurrent decrease in the use of mechanical prostheses.5,6 This may be attributable to the advancing technology in bioprosthetic device development, and the increasing rate of valve replacement surgery in the elderly, in whom bioprosthetic devices are preferred.7

Thrombotic and embolic complications and anticoagulation-related bleeding are by far the most prevalent contributors to morbidity and mortality after surgery for VHD.8,9 The risk of thromboembolic complications is greatest during the first three months after surgery for both mechanical and bioprosthetic devices, with persistent life-long risk for patients with mechanical valves.10,11 Furthermore, the presence of atrial fibrillation, a common arrhythmia in patients with VHD (especially if involving the mitral valve), also requires lifelong anticoagulation in the majority of patients. These considerations underscore the importance of addressing proper anticoagulation techniques to minimize postoperative thrombotic complications, while maintaining acceptable levels of risk related to bleeding.

Mechanical Valve Replacement

After valve repair with a mechanical device, the American College of Chest Physicians (ACCP) and the American College of Cardiology (ACC)/American Heart Association (AHA)12,13 provide fairly similar recommendations regarding the use of anticoagulation (Tables 1 and 2). The mainstay of treatment in both guidelines remains indefinite anticoagulation with a vitamin K antagonist (VKA). The benefits of VKA therapy after mechanical valve placement are marked. When compared with no antithrombotic therapy in a 1994 meta-analysis, VKA therapy showed statistically significant reductions in the rate of major systemic embolization (from 4.0 to 1.0 events per 100 patient-years), total thromboembolism risk (from 8.6 to 1.8 events per 100 patient-years), and risk of valve thrombosis (from 1.8 to 0.2 events per 100 patient-years).14 VKA therapy was also superior to aspirin therapy alone for total thromboembolism risk (1.8 events per 100 patient-years; 95% confidence interval [CI], 1.7 to 1.9 versus 7.5 events per 100 patient-years; 95% CI, 5.9 to 9.4) and risk of valve thrombosis (0.2 events per 100 patient-years; 95% CI, 0.2 to 0.2 versus 1.0 events per 100 patient-years; 95% CI, 0.4 to 1.7).14 The risk of major bleeding in patients with mechanical valves treated with VKA therapy was found to be 1.2 to 2.6 events per 100 patient-years.14,15

Table 1: ACCP Recommendations for Antithrombotic Therapy in Patients With Mechanical Heart Valves12

 VKA Therapy

  • VKA therapy is recommended over no VKA therapy for long-term management (Grade 1B recommendation)
  • With mechanical aortic valve, VKA therapy with a target INR of 2.5 (range 2.0 to 3.0) is recommended (Grade 1B recommendation)
  • With mechanical mitral valve, VKA therapy with a target INR of 3.0 (range 2.5 to 3.5) is recommended (Grade 2C recommendation)
  • With mechanical valves in both the aortic and mitral position, a target INR of 3.0 (range 2.5 to 3.5) is recommended (Grade 2C recommendation)

 Antiplatelet Therapy

  • With mechanical mitral or aortic valve at low risk of bleeding, an antiplatelet agent such as low-dose aspirin (50 to 100 mg/day) is recommended in addition to long-term VKA therapy (Grade 1B recommendation)
ACCP = American College of Chest Physicians; VKA=Vitamin K Antagonist; INR = International Normalized Ratio

Table 2: ACC/AHA Recommendations for Antithrombotic Therapy in Patients With Mechanical Heart Valves13

 VKA Therapy

  • With mechanical aortic valve, VKA therapy with a target INR of 2.5 if no risk factors (atrial fibrillation, prior thromboembolism, left ventricular dysfunction, or hypercoagulable state) are present (Class I recommendation; Level of evidence: B)
  • VKA therapy with a target INR of 3.0 after:
    • Mechanical aortic valve replacement if risk factors are present (Class I recommendation; Level of evidence: B)
    • Mechanical aortic valve replacement with Starr-Edwards or disc valves other than Medtronic Hall if no risk factors are present (Class I recommendation; Level of evidence: B)
    • Mechanical mitral valve replacement with any type of valve (Class I recommendation; (Level of evidence: B)

 Antiplatelet Therapy

  • At a dose of 75 to 100 mg/day in addition to warfarin in all patients with mechanical valves (Class I recommendation; Level of evidence: A)
ACC/AHA = American College of Cardiology/American Heart Association; VKA = Vitamin K Antagonist; INR = International Normalized Ratio

Subsequent studies have shown the addition of aspirin to VKA therapy in patients with mechanical valves leads to reduction in risk of thromboembolism and mortality when compared to VKA therapy alone (65% observed risk reduction in major systemic embolism or death in the aspirin plus VKA group).16,17 The addition of at least 50 to 75 mg/day of aspirin is, therefore, recommended in the current ACC/AHA and ACCP guidelines for all patients with mechanical valves, though consideration must be given to an individual patient's bleeding risk.12,13

Attempts to broaden options for anticoagulation in patients with mechanical valves have been unsuccessful. Investigators in the Dabigatran versus Warfarin in Patients with Mechanical Heart Valves (RE-ALIGN )trial randomized patients who had undergone aortic or mitral valve replacement within seven days or ≥ three months to receive either dabigatran dosed by renal function (150 mg twice-daily for creatinine clearance < 70 mL/min, 220 mg twice-daily for creatinine clearance 70 to 109 mL/min, or 300 mg twice-daily for creatinine clearance ≥100 mL/min), or warfarin (international normalized ratio [INR] range 2.0 to 3.0 or 2.5 to 3.5 based on thromboembolic risk). The trial was terminated prematurely because of an excess of both thromboembolic events (hazard ratio [HR] 1.94; 95% CI, 0.64 to 5.86; P = 0.24) and bleeding events (HR 2.45; 95% CI, 1.23 to 4.86; P = 0.01) among patients in the dabigatran group.18

Therefore, the ACCP recommends VKA therapy with a target INR of 2.5 (range 2.0 to 3.0) for mechanical aortic valves and target INR of 3.0 (range 2.5 to 3.5) for mechanical mitral valves (Table 1). For patients who are at low risk of bleeding, the ACCP recommends adding an antiplatelet agent such as low-dose aspirin (50 to 100 mg/day) to VKA therapy.

The ACC/AHA Guidelines for the Management of Patients with Valvular Heart Disease recommend VKA therapy with a target INR of 2.5 for patients with mechanical aortic valves, if no additional risk factors are present (Table 2). Additional risk factors are defined as atrial fibrillation, prior thromboembolism, left ventricular dysfunction, or hypercoagulable state. For patients with mechanical mitral valves, older generation mechanical aortic valves, or risk factors in addition to any type of mechanical aortic valve, a target INR of 3.0 is recommended. Antiplatelet therapy at a dose of 75 to 100 mg/day is recommended in addition to warfarin for all patients with mechanical valves.

Bioprosthetic Valve Replacement

The optimal antithrombotic regimen and duration after placement of a bioprosthetic device is less clear. Studies have demonstrated that bioprosthetic devices do confer an increased risk for thrombotic complications during the first three months after surgery,11,19 albeit a lower risk than that associated with mechanical valves.8 Thromboembolic stroke rates after valve repair with a bioprosthetic device have been reported to range from 0.2% to 3.3% per year, with disproportionately higher risk for valves in the mitral position compared to valves in the aortic position.12,11,20 Stroke rates are even lower (0.2% to 0.7% per year) for patients in normal sinus rhythm.13 Investigators have theorized that the early thrombogenicity of bioprosthetic valves is attributable to the lack of complete endothelialization of the suture zone in the early postoperative period.21 For this reason, it is generally accepted that some degree of antithrombotic and/or antiplatelet therapy is indicated at least in the short-term following bioprosthetic valve replacement.

Several studies have addressed whether traditional anticoagulation with VKA therapy is needed after bioprosthetic valve replacement. In 2005, Sundt et al. retrospectively compared early anticoagulation with warfarin vs. no warfarin (independent of aspirin therapy) after bioprosthetic aortic valve replacement in 1,151 patients, and found no difference in the incidence of postoperative ischemic cerebrovascular accident.22 There was notably no difference between the two study groups with respect to bleeding complications. A similar retrospective cohort study of 4,075 patients compared warfarin with no warfarin treatment (independent of aspirin therapy) and showed statistically significant increases in the risk of stroke, thromboembolic events, and cardiovascular death within both 30 to 89 days after surgery, and 90 to 179 days after surgery among patients in the group without warfarin.23 Bleeding events were significantly increased in the group who had discontinued warfarin between postoperative days 30 and 89 (adjusted incidence rate ratio [AIRR] 2.32; 95% CI, 1.28 to 4.22), which the authors attribute to the fact that patients who experienced bleeds and subsequently stopped warfarin were included in the group who discontinued warfarin therapy. As expected, bleeding rates were lower for those who discontinued warfarin after 365 days (AIRR 0.40; 95% CI, 0.22 to 0.73 for discontinuation between day 365 and 729). Given these conflicting data, clinicians are left without a clear consensus on the role of anticoagulation with a VKA in patients with bioprosthetic valves.

Another retrospective cohort study compared aspirin alone with aspirin plus warfarin in over 25,000 patients ≥ 65 years old.25 There was a significantly lower adjusted risk of death (risk ratio [RR] 0.80; 95% CI, 0.66 to 0.96) and embolic events (RR 0.52; 95% CI, 0.35 to 0.76), but a significantly higher risk of bleeding (RR 2.8; 95% CI, 2.18 to 3.6) in the aspirin plus warfarin group when compared to aspirin alone. Notably, the numbers needed to treat for mortality and embolic risk associated with warfarin plus aspirin were 153 and 212, respectively, while the number needed to harm with a bleeding event was 55. The majority of bleeding events in these patients required readmission to the hospital, which was associated with a 3.5% increase in absolute risk of mortality over the subsequent two weeks after admission.

When aspirin alone was compared with warfarin alone, Brennan et al. found no difference in the risk of death or embolic event.25 Interestingly, no additional risk of bleeding was found in the warfarin alone group when compared with aspirin alone.

Recommendations from the ACCP (Table 3) and ACC/AHA (Table 4) are somewhat incongruous regarding antithrombotic therapy after bioprosthetic valve replacement. The ACCP currently recommends VKA therapy with target INR 2.5 (range 2.0 to 3.0) for the first three months after bioprosthetic mitral valve replacement.12 For aortic valve replacement with a bioprosthetic device, the ACCP recommends aspirin (50 to 100 mg/day) over VKA therapy for the first three months after surgery, for patients in whom there is no other indication for anticoagulation (i.e., atrial dysrhythmias, history of thromboembolism, etc.). If the patient remains without a definitive indication for anticoagulation, the ACCP recommends the continuation of aspirin therapy without VKA therapy beyond the initial three-month postoperative period.

Table 3: ACCP Recommendations for Antithrombotic Therapy in Patients With Bioprosthetic Heart Valves12

 VKA Therapy

  • VKA therapy with a target INR of 2.5 (range 2.0 to 3.0) is suggested over no VKA therapy for the first three months after bioprosthetic mitral valve replacement therapy (Grade 2C recommendation)

 Antiplatelet Therapy

  • Aspirin (50 to 100 mg/day) is suggested over VKA therapy for the first three months after bioprosthetic aortic valve replacement in patients who are in sinus rhythm and have no other indication for VKA therapy (Grade 2C recommendation)
  • Aspirin is suggested over no aspirin therapy after the first three months following bioprosthetic valve replacement in patient in sinus rhythm (Grade 2C recommendation)
  • Aspirin (50 to 100 mg/day) plus clopidogrel (75 mg/day) is suggested over VKA therapy for the first three months after transcatheter aortic bioprosthetic valve replacement (Grade 2C recommendation)
ACCP = American College of Chest Physicians; VKA = Vitamin K Antagonist; INR = International Normalized Ratio

Table 4: ACC/AHA Recommendations for Antithrombotic Therapy in Patients With Bioprosthetic Heart Valves13

 VKA Therapy with target INR of 2.5 (range 2.0 to 3.0):

  • For the first 3 months after bioprosthetic aortic valve replacement (Class IIb recommendation; Level of evidence B)
  • For the first 3 months after bioprosthetic mitral valve replacement (Class IIa recommendation; Level of evidence C)

 Antiplatelet Therapy

  • After bioprosthetic aortic or mitral valve replacement at a dose of 75 to 100 mg/day (Class IIa recommendation; Level of evidence: B)
ACC/AHA = American College of Cardiology/American Heart Association; VKA = Vitamin K Antagonist; INR = International Normalized Ratio

There are no class I recommendations in the 2014 ACC/AHA guidelines supporting the use of VKA therapy in patients with bioprosthetic valves.13 The ACC/AHA does, however, offer a class IIa recommendation supporting VKA therapy for the first three months after bioprosthetic valve replacement at the mitral position and a class IIb recommendation supporting VKA therapy for the first three months after bioprosthetic valve replacement at the aortic position. Aspirin therapy at a dose of 75 to 100 mg/day is recommended in patients regardless of whether anticoagulation is employed. There are no specific recommendations offered in regards to duration of aspirin therapy in this population.

Recommendations from the ACC/AHA largely leave the choice of antithrombotic regimen in the setting of bioprosthetic valve replacement up to individual clinicians. Several factors that may influence a clinician's decision include institutionally-specific outcomes, likelihood for patient adherence to medication regimen, prior personal experience, regional convention, and personal preference. The duration and intensity of treatment with aspirin is also left up to the individual clinician's discretion. This lack of a clear consensus on optimal antithrombotic therapy after bioprosthetic valve replacement is reflected in the ACTION® Registry –GWTG™ survey results, which demonstrate a high degree of variability in postoperative treatment regimens across a variety of centers.26 Clinicians at 49 centers in 13 countries responded to a questionnaire that aimed at evaluating the variability in antithrombotic regimen after bioprosthetic valve replacement. Results showed that 43% of centers prescribe VKA, 33% prescribe aspirin, 20% prescribe VKA and aspirin, and 4% do not prescribe anything from discharge until month three. Variability in antithrombotic regimen differed not only among centers in different countries but also among centers within the same country and, in some cases, varied between individual clinicians within a single center.

In the current era of expanding strategies for anticoagulation, investigators have yet to establish the role for non-VKA oral anticoagulants (NOACs) in the setting of bioprosthetic valve replacement. To date, there are no large randomized clinical trials enrolling to answer this question. There is, however, a growing body of literature suggesting better safety profiles of the NOACs in head-to-head trials against warfarin for non-valvular atrial fibrillation.27-30 Notably, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) and Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) studies evaluating the safety and efficacy of apixaban and edoxaban allowed for the inclusion of patients with pre-existing bioprosthetic valves.28,30 Analyses of these data are eagerly awaited. A related question is whether the NOACs are safe and efficacious in patients in sinus rhythm early following placement of a bioprosthetic valve. Dedicated studies evaluating NOACs in this setting are unfortunately likely to be years away, thus leaving some degree of uncertainty regarding optimal antithrombotic therapy for the near future.

References

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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Clinical Topic Collection: Dyslipidemia, Geriatric Cardiology, Heart Failure and Cardiomyopathies, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and Heart Failure, Cardiac Surgery and VHD, Lipid Metabolism, Novel Agents

Keywords: Aged, American Heart Association, Anticoagulants, Aortic Valve, Aspirin, Atrial Fibrillation, Benzimidazoles, Cohort Studies, Confidence Intervals, Consensus, Creatinine, Embolism, Factor Xa, Fibrinolytic Agents, Heart Valve Diseases, Heart Valve Prosthesis, International Normalized Ratio, Longitudinal Studies, Mitral Valve, Myocardial Infarction, Numbers Needed To Treat, Odds Ratio, Patient Compliance, Patient Readmission, Platelet Aggregation Inhibitors, Prevalence, Pyrazoles, Pyridines, Pyridones, Questionnaires, Registries, Research Personnel, Retrospective Studies, Risk Factors, Risk Reduction Behavior, Stroke, Sutures, Thiazoles, Thromboembolism, Thrombosis, Ticlopidine, Uncertainty, Ventricular Dysfunction, Left, Vitamin K, Warfarin, beta-Alanine


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