Gregory YH Lip, MD, FRCPE, FESC, FACC
Freek Verheugt, MD, FACC, FESC
Christopher P Cannon, MD
Gordon M Saperia, MD, FACC
INTRODUCTION — In some patients with an acute coronary syndrome (see “Criteria for the diagnosis of acute myocardial infarction”, section on ‘Acute coronary syndrome’), chronic oral anticoagulation is required to lower the risk of systemic (arterial) thromboembolism, such as those with atrial fibrillation, left ventricular systolic dysfunction or thrombus, or prosthetic heart valves. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Indications for anticoagulation in heart failure” and “Left ventricular thrombus after acute myocardial infarction”, section on ‘Prevention of LV thrombus’ and “Antithrombotic therapy in patients with prosthetic heart valves”.)
Acute coronary syndrome (ACS) patients are routinely treated with aspirin and a P2Y12 receptor blocker (eg clopidogrel, prasugrel, or ticagrelor) to decrease the risk of recurrent events (See “Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction”, section on ‘Summary and recommendations’ and “Antiplatelet agents in acute ST elevation myocardial infarction”, section on ‘Summary and recommendations’.). Thus, those who also require oral anticoagulation are discharged on triple oral anticoagulant therapy (TOAT). (See “Triple antithrombotic therapy in patients with cardiovascular disease”.)
The issue of whether chronic anticoagulant therapy reduces the risk of recurrent cardiovascular events, such as myocardial infarction (MI) or cardiac death, after ACS has been evaluated in clinical trials. The rationale for a potential role of chronic anticoagulant therapy in this setting is based on the following two pieces of information:
- The high rates of recurrent ischemic events after ACS due, at least in part, to a persistent thrombotic risk within the coronary circulation. This thrombotic risk stems from heightened platelet reactivity, an increase in activity of some or all of the elements of the coagulation cascade, or both. (See “Overview of hemostasis”.)
- The proven efficacy of long term antithrombotic therapy with dual antiplatelet therapy in reducing recurrent ischemic events in most patients with an ACS. (See “Overview of the acute management of unstable angina and acute non-ST elevation myocardial infarction” and “Overview of the acute management of acute ST elevation myocardial infarction”.)
This topic will focus on the potential role of oral anticoagulation to prevent recurrent ischemic events in patients with ACS. The use of chronic anticoagulant therapy in ACS patients who have clear indications for it will be addressed briefly here, but is discussed in detail elsewhere. (See “Triple antithrombotic therapy in patients with cardiovascular disease”.)
BIOLOGIC PLAUSIBILITY — The rationale for possible benefit from chronic anticoagulant therapy for the prevention of recurrent ischemic events comes in part from the following observations:
- There is an ongoing thrombotic risk that may be due to progressive disease .
- There is persistent elevation of markers of thrombin generation for as long as six months after ACS .
- Serial angioscopy of culprit plaques (after MI) shows persistence of thrombus at 1, 6 and 18 months (64, 5, and 12 percent respectively) . (See “Pathology and pathogenesis of the vulnerable plaque”.)
- Vulnerable plaques are characterized by repeated plaque micro-ruptures, followed by subclinical thrombosis .
- In small angiographic follow-up studies of ACS patients treated with either aspirin or warfarin, lesion progression was significantly reduced in the warfarin group [1,5].
- Local synthesis of several functionally active coagulation proteins has been demonstrated in human atherosclerotic lesions. These proteins may be involved in atherogenesis, as indicated by increased thrombi-generating activity in early atherosclerotic lesions .
PATIENTS WITHOUT OTHER INDICATIONS FOR CHRONIC ANTICOAGULATION — The evidence presented in this section does not support the use of chronic oral anticoagulant therapy to reduce the incidence of ischemic events after an ACS when patients (without other indications for anticoagulation) are managed with current recommendations for dual antiplatelet therapy (DAPT) and myocardial revascularization . The occasional ACS patient who cannot take a P2Y12 receptor blocker (eg clopidogrel, prasugrel, or ticagrelor) may benefit from the addition of warfarin to aspirin.
Warfarin — DAPT (aspirin and a platelet P2Y12 receptor blocker) is recommended to most patients after ACS, with or without stent implantation. As there are no studies comparing warfarin plus DAPT to DAPT alone or to warfarin plus a single antiplatelet agent, the applicability to current practice of the studies presented below is limited. (See “Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction”, section on ‘Summary and recommendations’ and “Antiplatelet agents in acute ST elevation myocardial infarction”, section on ‘Summary and recommendations’ and “Coronary artery stent thrombosis: Prevention and management”, section on ‘Summary and recommendations’.)
Keeping this limitation in mind, efficacy and safety outcomes have been evaluated in ACS patients treated with warfarin alone, aspirin alone, and therapy with both. The available evidence suggests that combined therapy may reduce the risk of ischemic events compared to aspirin alone when the International Normalized Ratio (INR) is strictly maintained between 2.0 and 3.0. As combined therapy also increases the risk of bleeding compared to monotherapy, the benefit with warfarin is partially offset. (See “Triple antithrombotic therapy in patients with cardiovascular disease”, section on ‘Bleeding’.)
Meta-analyses — Two meta-analyses of trials that compared aspirin plus warfarin to aspirin alone came to a similar conclusion: among ACS patients at low or intermediate risk for bleeding, the benefits of adding warfarin to aspirin outweigh the bleeding risks only when the attained INR was 2.0 to 3.0 [7,8].
The larger meta-analysis evaluated 14 trials with follow-up from three months to five years and involving over 25,000 patients with an ACS . When evaluating the findings, it should be kept in mind that two of the major contributing trials, CHAMP and CARS, had median INR less than 2.0.
The following findings were noted with warfarin plus aspirin compared to aspirin alone:
- No significant difference in the overall risk of major adverse events (all cause death, nonfatal MI, and nonfatal thromboembolic stroke)
- A significant increase in major bleeding (odds ratio 1.77, 95% CI 1.47-2.13)
- In trials with a goal INR of 2.0 to 3.0, combination therapy was associated with a significant reduction in the risk of major adverse events (odds ratio 0.73, 95% CI 0.63-0.84)
Randomized trials — In individual randomized trials included in the meta-analyses, the comparator therapy (warfarin, warfarin plus aspirin, or aspirin), the intensity of warfarin therapy, or both has varied [7-20]. The intensity of warfarin therapy has varied from low (INR ≤1.5) , to moderate (INR 1.5 to 2.5) [15,17-19], to high (INR 2.5 to 4.8) [11-16]. In addition the trials varied significantly in the percent of patients with ST elevation MI, non-ST elevation MI, and unstable angina. These differences in trial design limit the ability to compare outcomes from one trial to another.
The following trials account for most of the patients included in the above meta-analysis. In the first five, the majority of ACS patients had either ST elevation or non-ST elevation MI:
- The CHAMP trial randomly assigned 5059 patients to either aspirin alone (81 mg/day) or a combination of aspirin (81 mg/day) and warfarin, titrated to an INR of 1.5 to 2.5 (mean 1.8) . After a 2.7 year follow-up there was no difference in mortality (17.3 versus 17.6 percent respectively), nonfatal infarction (13.1 versus 13.3 percent), or nonfatal stroke (3.5 versus 3.1 percent) between the two groups.
- The WARIS II trial randomly assigned 3630 patients to aspirin (160 mg/day) alone, warfarin alone (target INR 2.8 to 4.2, mean attained INR 2.8), or combination therapy at lower dose (aspirin 75 mg/day and target INR 2.0 to 2.5, mean attained INR 2.2) . After a mean follow-up of four years, the incidence of the combined primary outcome of death, nonfatal reinfarction, or thromboembolic stroke was significantly less with combination therapy compared with aspirin alone (15 versus 20 percent, risk reduction 29 percent) and with warfarin alone compared to aspirin alone (16.7 versus 20.0 percent, risk reduction 19 percent).
- The ASPECT-2 trial randomly assigned 999 patients to one of three regimens: low dose aspirin (80 mg/day); high intensity oral anticoagulation (target INR 3 to 4, mean attained value 3.2); or low dose aspirin plus moderate intensity anticoagulation (target INR 2 to 2.5, mean attained value 2.4) . At a median follow-up of 12 months, the incidence of the primary end point of MI, stroke, or death was significantly lower in the two warfarin plus aspirin groups than in the aspirin alone group (5 versus 5 versus 9 percent respectively). However, almost 20 percent of the warfarin and combined therapy groups discontinued treatment, and only about 40 percent of patients receiving warfarin remained in the therapeutic range.
- The CARS trial randomly assigned 8803 patients to aspirin 160 mg, warfarin 3 mg with aspirin 80 mg, or warfarin 1mg with aspirin 80 mg daily. There was no significant difference in the combined primary outcome of reinfarction, non-fatal ischemic stroke, or cardiovascular death at one year .
- The LoWASA study randomly assigned 3300 patients to warfarin 1.25 mg plus aspirin 75 mg or aspirin 75 mg daily. After a median follow-up of 5 years, there was no significant difference in the combined primary outcome of cardiovascular death, reinfarction or stroke (28.1 versus 28.8 percent respectively) .
- The international OASIS-2 trial, randomly assigned 3712 patients (87 percent had unstable angina) to either oral anticoagulation (target INR of 2.5) in addition to aspirin or aspirin alone . At five months, patients from countries in which there was good compliance to anticoagulation (INR ≥2) had a significant reduction in the primary end point or cardiovascular death, myocardial infarction, or stroke (6.1 versus 8.9 percent, relative risk 0.68, 95% CI 0.48-0.95). No such benefit was seen in patients from countries with poor INR compliance.
As pointed out in the discussion of the meta-analyses above, the inconsistent outcomes in the above trials may have resulted from either differing intensity of oral anticoagulant therapy or relatively high dropout rates in some.
Two additional limitations question the applicability of these trials to current practice:
- They were performed before the current era in which the great majority of patients with both non-ST elevation and ST elevation acute coronary syndromes are treated with an early invasive strategy using percutaneous coronary intervention with stenting (PCI) . (See “Coronary arteriography and revascularization for unstable angina or non-ST elevation acute myocardial infarction” and “Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome”.)
- They were performed before the current era in which most patients with an acute coronary syndrome are treated dual antiplatelet therapy with aspirin plus a platelet P2Y12 receptor blocker. (See “Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction”, section on ‘Platelet P2Y12 receptor blockers’ and “Antiplatelet agents in acute ST elevation myocardial infarction”, section on ‘P2Y12 receptor blockers’.)
These two limitations render the evidence of benefit from warfarin (when added to aspirin) demonstrated in the meta-analyses above applicable to only a small portion of patients with ACS, as most individuals receive dual antiplatelet therapy and many receive revascularization.
Dabigatran — Dabigatran is a direct thrombin inhibitor that has been approved for use for the prevention and treatment of venous and arterial thromboembolic disorders. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Dabigatran’ and “Treatment of lower extremity deep vein thrombosis”, section on ‘Dabigatran and rivaroxaban’.)
Dabigatran has not been evaluated for efficacy in the setting of ACS and thus we do not recommend its use. With regard to safety, the phase II RE-DEEM trial randomly assigned 1861 MI patients on dual antiplatelet therapy to dabigatran or placebo. There was a significant dose-dependent increase in the risk of major or clinically relevant minor bleeding during the six month treatment period .
Apixaban — Apixaban is an oral factor Xa inhibitor that has been studied for the prevention of venous thromboembolism in postoperative patients and prevention of systemic embolic events in patients with atrial fibrillation. (See “Anticoagulants other than heparin and warfarin”, section on ‘Apixaban’ and “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Apixaban’.)
The APPRAISE-2 trial, which randomly assigned 7392 patients with an acute coronary syndrome (ACS) to either apixaban 5 mg twice daily or placebo in addition to aspirin or dual antiplatelet therapy, was stopped early due to a significant increase in the rate of major bleeding in the apixaban group . Patients included those with either MI or unstable angina (19 percent) within the previous seven days and at least two high risk features for a recurrent event (age ≥65 years, diabetes mellitus, MI within 5 years, history of either cerebrovascular or peripheral artery disease, heart failure or a left ventricular ejection fraction <40 percent, impaired renal function, or no revascularization for the index event).
At a median follow-up of 241 days, the primary end point of cardiovascular death, MI, or ischemic stroke occurred in a similar percent of patients in the apixaban and placebo groups (7.5 versus 7.9 respectively), while the primary safety outcome of Thrombolysis in Myocardial Infarction (TIMI) major bleeding occurred significantly more often in the group that received apixaban (1.3 versus 0.5 percent) . These findings were consistent in all subgroups, including those stratified by use of revascularization (55 percent of patients underwent medical management without revascularization).
Rivaroxaban — Rivaroxaban is an oral factor Xa inhibitor that has been studied for the prevention of venous thromboembolism in postoperative patients and prevention of systemic embolic events in patients with atrial fibrillation. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Anticoagulants other than heparin and warfarin”, section on ‘Rivaroxaban’ and “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation”, section on ‘Rivaroxaban’.)
The phase II ATLAS ACS-TIMI 46 dose ranging trial randomly assigned over 3000 ACS patients to either rivaroxaban (at multiple doses) or placebo . All patients received aspirin, while a thienopyridine was given at the investigator’s discretion. There was no significant difference in the rates of the primary efficacy endpoint (5.6 versus 7.0 percent respectively; hazard ratio 0.70, 95% CI 0.60-1.05). Bleeding was increased with rivaroxaban in a dose dependent manner. The results of the phase III ATLAS-2 ACS TIMI 51 trial, which compared to rivaroxaban to placebo in ACS patients, will be presented at the American Heart Association Scientific Sessions in November 2011 .
Summary — We do not recommend chronic oral anticoagulation for ACS patients (without other indications) who are treated with current recommended therapies (including dual antiplatelet therapy) unless they meet other criteria for the use of anticoagulant therapy. This recommendation is based not only on an absence of evidence of benefit, but also the concern for the increase in bleeding risk associated with the combination of aggressive antiplatelet therapy plus anticoagulation. (See “Triple antithrombotic therapy in patients with cardiovascular disease”, section on ‘Bleeding’.)
Some ACS patients will not receive dual antiplatelet therapy (DAPT), usually due to allergy to either aspirin or platelet P2Y12 receptor blocker. We suggest referral to a specialist (often an allergist) familiar with the management of these patients. There are several types of aspirin hypersensitivity syndromes, which can usually be distinguished by the nature of the patient’s past reactions and the presence of certain characteristic underlying conditions (eg, chronic urticaria, asthma, chronic sinus disease). The different types of aspirin hypersensitivity and desensitizations protocols are reviewed separately. (See “NSAIDs (including aspirin): Allergic and pseudoallergic reactions”, section on ‘Management’ and “Antithrombotic therapy for intracoronary stent implantation: General use”, section on ‘Hypersensitivity’ and “Diagnostic challenge and desensitization protocols for NSAID reactions” and “Aspirin exacerbated respiratory disease”.)
For patients who cannot receive dual antiplatelet therapy with aspirin plus platelet P2Y12 receptor blocker, such as those who are allergic to one or both, we make the following recommendations:
- For those patients who cannot take a platelet P2Y12 receptor blocker and in whom those in whom the risk of bleeding (table 1) due to long-term therapy with both antiplatelet and anticoagulant drugs is acceptable (see “Therapeutic use of warfarin”, section on ‘Bleeding’), we believe the addition of oral anticoagulant to aspirin is reasonable. This is based on a possible benefit from such therapy, as demonstrated in the meta-analyses discussed above in those patients in whom the INR on warfarin therapy can be consistently between 2.0 and 3.0. When therapy with warfarin plus aspirin is chosen after ACS, warfarin should be stopped at one year (unless there is another indication for warfarin, such as atrial fibrillation), as the patient is then considered to have stable coronary heart disease.
- For the uncommon patient who cannot take aspirin, options for antithrombotic therapy include a P2Y12 receptor blocker alone or in combination with warfarin. These two strategies have not been compared. Our authors and reviewers recommend, based on their experience, a potent P2Y12 receptor blocker (prasugrel or ticagrelor) alone or warfarin plus clopidogrel in combination for these patients. They have a preference for the former for the following reasons:
- Potent P2Y12 monotherapy avoids the inconvenience of routine international normalized ratio monitoring
- As P2Y12 receptor blockers are more effective at reducing the risk of cardiovascular events than aspirin (see “Benefits and risks of aspirin in secondary and primary prevention of cardiovascular disease”, section on ‘Comparison to thienopyridines’), they do not feel compelled to add warfarin for efficacy as in patients who cannot take P2Y12 inhibitors as discussed above.
- Our authors and reviewers do not use warfarin plus prasugrel or ticagrelor in this situation as this combination likely has a greater risk of bleeding compared to warfarin plus clopidogrel.
PATIENTS WITH INDICATIONS FOR CHRONIC ANTICOAGULATION — Although oral anticoagulation is not indicated to decrease the risk of ischemic events after ACS (as discussed above), some patients with ACS require oral anticoagulation for other reasons. As most patients with ACS are discharged on aspirin and a P2Y12 receptor blocker (eg, clopidogrel, prasugrel, or ticagrelor), patients who require oral anticoagulation may be discharged on triple oral antithrombotic therapy (TOAT). It is important to note that trials of TOAT used clopidogrel, but not ticagrelor or prasugrel. (See “Triple antithrombotic therapy in patients with cardiovascular disease”.)
The following conditions, which were exclusion criteria from many of the randomized trials discussed above, are indications for the simultaneous use of chronic oral anticoagulation and dual antiplatelet therapy, which is referred to as triple oral antithrombotic therapy (TOAT):
- Left ventricular (LV) thrombus or aneurysm. (See “Left ventricular thrombus after acute myocardial infarction” and “Left ventricular aneurysm and pseudoaneurysm following acute myocardial infarction”.)
- Left ventricular ejection fraction (LVEF) below 30 percent with or without heart failure. (See “Indications for anticoagulation in heart failure”, section on ‘Reduction in thromboembolic events or mortality’.)
- Chronic atrial fibrillation. (See “Antithrombotic therapy to prevent embolization in nonvalvular atrial fibrillation” and “Supraventricular arrhythmias after myocardial infarction”, section on ‘Atrial fibrillation’.)
- Prosthetic heart valves. (See “Antithrombotic therapy in patients with prosthetic heart valves”.)
- Prevention or treatment of venous thromboembolism, such as deep vein thrombosis and pulmonary embolism. (See “Anticoagulation in acute pulmonary embolism” and “Treatment of lower extremity deep vein thrombosis”.)
The available evidence supports the use of TOAT as opposed to dual antiplatelet therapy (DAPT) to decrease the risk of major adverse cardiovascular events in patients with ACS and an indication for chronic oral anticoagulant therapy. This topic is discussed in detail elsewhere. (see “Triple antithrombotic therapy in patients with cardiovascular disease”, section on ‘TOAT versus DAT’).
MAJOR SOCIETY GUIDELINES — We generally agree with recommendations made in the 2004 American College of Cardiology/American Heart Association (ACC/AHA) guideline on ST elevation MI, the 2007 ACC/AHA focused update on STEMI, the 2011 American College of Cardiology Foundation/AHA focused update on the guideline for Unstable Angina/Non-ST Elevation Myocardial Infarction, and the 2008 American College of Chest Physicians (ACCP) guideline on the primary and secondary prevention of coronary artery disease:
- The 2011 ACCF/AHA focused update concluded that warfarin either without (INR 2.5 to 3.5) or with (INR 2.0 to 2.5) low-dose aspirin (75 to 81 mg per day) may be reasonable for patients (with unstable angina or NSTEMI) at high risk for (recurrent) thrombotic cardiac events and low bleeding risk who do not require or are intolerant of clopidogrel .
- The 2008 ACCP guideline came to a similar conclusion. In addition, this guideline felt that high-intensity warfarin (target INR 3.5, range 2.0 to 4.0) without concomitant aspirin was preferable to aspirin alone . It suggested that therapy with warfarin was reasonable for up to four years.
BLEEDING RISK — For patients who require oral anticoagulant plus antiplatelet (aspirin and/or P2Y12 receptor blocker) therapy, the bleeding risk is increased significantly compared to either therapy alone. This issue is discussed in detail separately. (See “Triple antithrombotic therapy in patients with cardiovascular disease”, section on ‘Bleeding’.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
- Beyond the Basics topic (see “Patient information: Warfarin (Coumadin®)”)
SUMMARY AND RECOMMENDATIONS — Most acute coronary syndrome (ACS) patients are treated with dual antiplatelet therapy (DAPT), irrespective of whether an intracoronary stent was placed (See “Antithrombotic therapy for intracoronary stent implantation: General use”, section on ‘Summary and recommendations’ and “Antiplatelet agents in unstable angina and acute non-ST elevation myocardial infarction”, section on ‘Summary and recommendations’.).
Some of these patients require chronic anticoagulation to lower the risk of systemic thromboembolism (such as those with atrial fibrillation). Recommendations for the use of triple oral antithrombotic therapy are discussed elsewhere. (See “Triple antithrombotic therapy in patients with cardiovascular disease”, section on ‘Summary and recommendations’.)
For ACS patients who do not have an indication for chronic anticoagulant therapy, we make the following recommendations regarding the addition of oral anticoagulant therapy to antiplatelet therapy to reduce the risk of subsequent ischemic events after an ACS (see ‘Patients without other indications for chronic anticoagulation’ above):
- For patients taking DAPT, we recommend not adding oral anticoagulant therapy to DAPT (Grade 1B). Patients taking DAPT plus anticoagulant therapy have higher bleeding rates than those taking DAPT alone. In addition evidence of benefit is lacking: in ACS patients taking dual antiplatelet therapy, warfarin has not been compared to placebo, full dose apixaban had worse outcomes compared to placebo (APPRAISE) (see ‘Apixaban’ above), and the results of ATLAS-2 TIMI 51, which compared two low doses of rivaroxaban to placebo, will be presented in late 2011. (See ‘Rivaroxaban’ above.)
- A few ACS patients may appear to not be candidates for DAPT due to allergy to either aspirin or platelet P2Y12 receptor blocker. These patients should be referred to a specialist (often an allergist) for an attempt at desensitization. For these patients taking antiplatelet monotherapy, we make the following recommendations:
- For patients taking aspirin but unable to take a P2Y12 receptor blocker and who are at low to intermediate bleeding risk (table 1), we suggest adding warfarin to aspirin monotherapy for one year (Grade 2B). This recommendation applies only if the INR can be maintained within the range of 2.0-3.0. (See ‘Summary’ above.)
- For patients taking P2Y12 receptor blocker but who are unable to take aspirin, we suggest antithrombotic monotherapy with either ticagrelor or prasugrel (no oral anticoagulant added to either) (Grade 2C). In patients for whom ticagrelor and prasugrel are not available, clopidogrel plus warfarin is a reasonable alternative. (See ‘Summary’ above.)
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