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Acute coronary syndrome: Oral anticoagulation in medically treated patients

Acute coronary syndrome: Oral anticoagulation in medically treated patients
Literature review current through: Jan 2024.
This topic last updated: May 15, 2023.

INTRODUCTION — All patients with an acute coronary syndrome (ACS) (see "Diagnosis of acute myocardial infarction", section on 'Definitions'), irrespective of whether or not percutaneous coronary intervention (PCI) with stenting is performed, benefit from antiplatelet therapy with aspirin and a P2Y12 inhibitor. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Duration' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Duration of dual antiplatelet therapy'.)

This topic will address two clinically important questions for ACS patients who are treated medically (no PCI) and are discharged from the hospital:

Does chronic oral anticoagulant therapy (OAC), with or without antiplatelet therapy, have a role?

In ACS patients who are receiving long-term OAC for an indication such as atrial fibrillation (AF) or deep vein thrombosis, what is the optimal antithrombotic regimen?

The approach to combined antithrombotic therapy in patients receiving OAC who have undergone PCI is discussed elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy".)

The use of parenteral anticoagulants at the time of presentation for ACS is discussed elsewhere. (See "Acute ST-elevation myocardial infarction: Management of anticoagulation", section on 'Summary and recommendations' and "Anticoagulant therapy in non-ST elevation acute coronary syndromes", section on 'Summary and recommendations'.)

POTENTIAL ROLE OF ORAL ANTICOAGULANTS IN UNSTENTED ACUTE CORONARY SYNDROME PATIENTS — The rationale for possible benefit from chronic anticoagulant therapy for the prevention of recurrent ischemic events comes in part from the following observations:

The high rates of recurrent ischemic events after ACS are 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 [1]. (See "Overview of hemostasis".)

There is persistent elevation of markers of thrombin generation for as long as six months after ACS [2].

Serial angioscopy of culprit plaques (after myocardial infarction [MI]) shows persistence of thrombus at 1, 6, and 18 months (64, 5, and 12 percent, respectively) [3]. (See "Mechanisms of acute coronary syndromes related to atherosclerosis".)

Vulnerable plaques are characterized by repeated plaque microruptures, followed by subclinical thrombosis [4].

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 [4].

Evidence — Available oral anticoagulants include warfarin and four direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]): rivaroxaban, dabigatran, edoxaban, and apixaban. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects".)

Among the OACs, only rivaroxaban has been shown to reduce the risk of recurrent ischemic events, including mortality, when added to dual antiplatelet therapy (DAPT) in patients with ACS who have not undergone percutaneous coronary intervention (PCI) with stenting. However, there is an important increase in major bleeding risk.

Rivaroxaban — Adding low-dose rivaroxaban to aspirin and clopidogrel in patients with ACS who are not at high risk of bleeding is a reasonable strategy based primarily on the ATLAS 2 ACS-TIMI 51 trial presented below. In that study, rivaroxaban at a dose of 2.5 mg twice daily improved mortality in patients with recent ACS when added to aspirin and clopidogrel. However, such therapy significantly increases the risk of major bleeding and intracranial hemorrhage.

It should be kept in mind that the level of anticoagulation achieved with either a 2.5 or 5 mg twice-daily dose is less than that seen with the 20 mg once-daily dose, as is used in patients with AF (or 15 mg in those on triple therapy). Thus, at this dose, it is not strictly "anticoagulation" but rather low-dose factor Xa inhibition.  

The ATLAS 2 ACS-TIMI 51 trial randomly assigned 15,526 patients with recent ACS to either twice-daily doses of 2.5 mg or 5 mg ("very low" and "low dose," respectively) of rivaroxaban or placebo [6]. These doses are one-quarter and one-half of the full anticoagulation dose. All patients were intended to receive DAPT with aspirin and either clopidogrel or ticlopidine (ticagrelor and prasugrel were not prescribed); 93 percent of patients ultimately received DAPT. Approximately 40 percent of patients did not undergo revascularization. The primary efficacy endpoint was a composite of death from cardiovascular causes, MI, or stroke. The following outcomes (comparing drug with placebo) were seen after a mean duration of treatment of 13.1 months:

Rivaroxaban (both doses combined) significantly reduced the rate of primary efficacy endpoint (8.9 versus 10.7 percent; hazard ratio [HR] 0.84, 95% CI 0.74-0.96). These rates for the 2.5 mg and 5 mg doses of rivaroxaban were 9.1 and 8.8 percent, respectively.

The rates of death from cardiovascular cause or any cause were significantly reduced with the 2.5 mg dose (2.7 versus 4.1 and 2.9 versus 4.5 percent, respectively). This survival benefit was not seen with the 5 mg dose. Both doses of rivaroxaban significantly reduced the rate of stent thrombosis by about 31 percent.

Rivaroxaban significantly increased the rate of TIMI major bleeding not related to coronary artery bypass grafting (2.1 versus 0.6 percent; HR 3.96, 95% CI 2.46-6.38). These rates for the 2.5 mg and 5 mg doses of rivaroxaban were 1.8 and 2.4 percent, respectively. Rivaroxaban also increased the rate of intracranial hemorrhage (0.6 versus 0.2 percent; p = 0.009).

The smaller GEMINI-ACS-1 trial randomly assigned 3037 ACS patients to either aspirin 100 mg daily or rivaroxaban 2.5 mg twice daily within 10 days of hospitalization; both groups had received aspirin plus a P2Y12 receptor blocker (clopidogrel or ticagrelor), and both groups continued after randomization with the latter [7]. After a median treatment duration of 291 days, TIMI non-coronary artery bypass graft clinically significant bleeding was similar in the two groups (5 percent; HR 1.09, 95% CI 0.80-1.50). The study was not powered to assess efficacy.

Apixaban — The APPRAISE-2 trial randomly assigned 7392 patients with an ACS to either apixaban 5 mg twice daily (the full anticoagulant dose) or placebo in addition to aspirin or DAPT. Over 50 percent of patients did not undergo PCI with stenting. The trial was stopped early due to a significant increase in the rate of major bleeding in the apixaban group [8]. At a median follow-up of 241 days, the primary endpoint 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 TIMI major bleeding occurred significantly more often in the group that received apixaban (1.3 versus 0.5 percent) [9]. These findings were consistent in all subgroups, including those stratified by use of revascularization (55 percent of patients underwent medical management without revascularization).

Dabigatran — We do not recommend the addition of dabigatran to antiplatelet therapy in ACS patients who did not undergo stenting. 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 DAPT 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 [10].

Edoxaban — Edoxaban has not been evaluated in ACS patients who have not undergone PCI with stenting.

Warfarin — There are no studies comparing warfarin plus DAPT with DAPT alone or with warfarin plus a single antiplatelet agent. The evidence presented below regarding the role of warfarin in ACS patients has limited applicability to current practice for the following reasons:

They were performed before the current era in which the great majority of patients with ACS are treated with an early invasive strategy PCI with stenting [11]. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization" 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 ACS are treated with DAPT with aspirin plus a platelet P2Y12 inhibitor. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'P2Y12 use' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving fibrinolytic therapy'.)

Keeping these limitations 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 with aspirin alone when the international normalized ratio (INR) is strictly maintained between 2 and 3. As combined therapy also increases the risk of bleeding compared with monotherapy, the benefit with warfarin is partially offset. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Bleeding'.)

Two meta-analyses of trials that compared aspirin plus warfarin with aspirin alone came to a similar conclusion: Among ACS patients at low or intermediate risk for bleeding, the benefits (reduction in ischemic events) of adding warfarin to aspirin outweigh the bleeding risks only when the attained INR is 2 to 3 [11,12].

Our approach — For patients with ACS who have been managed medically (without intracoronary stenting) and who do not have other indications for chronic anticoagulant therapy, there are two reasonable options for antithrombotic therapy based on the evidence presented above:

The established approach with aspirin and ticagrelor for one year followed by aspirin alone. Prasugrel has not been shown to improve outcomes in this setting. In patients at higher bleeding risk, clopidogrel can be used instead of ticagrelor. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients not reperfused' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Ischemia-guided management'.)

After one year, we continue with aspirin. In patients at high thrombotic risk, such as those with multiple myocardial infarctions, left main stenting, or multiple stents, we consider extending aspirin and ticagrelor 60 mg twice daily for an additional 18 months as was evaluated in the PEGASUS 54 trial. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients".)

Rivaroxaban 2.5 mg twice daily in addition to aspirin and clopidogrel 75 mg daily for about one year in patients at high thrombotic risk and not at high bleeding risk. High-bleeding-risk patients should not receive rivaroxaban in this setting if one of the following are present: age >75 years, history of stroke or gastrointestinal bleeding, hepatic or renal disease, malignancy, or excessive fall risk. This regimen has not been approved by the U S Food and Drug administration. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Anticoagulant therapy' and 'Rivaroxaban' above.)

After one year, we omit clopidogrel and continue with rivaroxaban 2.5 mg twice daily and aspirin (see 'Rivaroxaban' above). Other factors such as baseline anemia or hypertension are relative contraindications that become absolute as their severity worsens. We are uncertain as to how to properly identify which moderate-bleeding-risk patients might benefit from rivaroxaban. Practitioners should have a detailed discussion about the relative benefits and risks of adding rivaroxaban to aspirin plus clopidogrel with potential candidates. After one year, we reassess the relative ischemic and bleeding risks. Some patients are candidates for long-term therapy with rivaroxaban and aspirin while in others it may be appropriate to consider only aspirin.

Some ACS patients will not receive 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. (See "NSAIDs (including aspirin): Allergic and pseudoallergic reactions", section on 'Management' and "Diagnostic challenge and desensitization protocols for NSAID reactions" and "Aspirin-exacerbated respiratory disease" and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Problems with clopidogrel use'.)

For patients who cannot receive DAPT, we make the following recommendations:

For those patients who cannot take a platelet P2Y12 inhibitor and those in whom the risk of bleeding (table 1) due to long-term therapy with both antiplatelet and anticoagulant drugs is acceptable, we believe the addition of low-dose rivaroxaban to aspirin is reasonable. This is based on the small portion of patients in the ATLAS 2 ACS-TIMI 51 trial (see 'Rivaroxaban' above) who did not receive DAPT.

For the uncommon patient who cannot take aspirin, we use clopidogrel alone, as was carried out in the CAPRIE trial. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease", section on 'Alternatives to aspirin'.)  

Patients who have had no recurrent ischemic episodes through one year are considered to have stable coronary artery disease. We continue rivaroxaban monotherapy based on the AFIRE trial. This issue is discussed in detail elsewhere. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Long-term therapy studies'.)

BLEEDING RISK — For patients who require oral anticoagulant plus antiplatelet (aspirin and/or P2Y12 receptor blocker) therapy, the bleeding risk is increased significantly compared with either therapy alone. This issue is discussed in detail separately. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Bleeding'.)

PATIENTS WHO REQUIRE ORAL ANTICOAGULANT — The optimal antithrombotic approach in ACS patients with a long-term indication for oral anticoagulants (OAC), such as those with atrial fibrillation (AF) or deep vein thrombosis, who are treated medically (no percutaneous coronary intervention) is not known.

We discharge these patients on OAC plus clopidogrel 75 mg daily and treat for one year. In patients at very high thrombotic risk who are not at high bleeding risk, we consider adding aspirin for one month.

We prefer DOACs to warfarin and we use full-dose DOAC rather than low-dose rivaroxaban in this setting. Clopidogrel is the only P2Y12 inhibitor we use with full-dose OAC, as there would be a very high risk of a bleeding complication if prasugrel or ticagrelor were used instead of clopidogrel. OAC plus aspirin for one year is a reasonable alternative to OAC plus clopidogrel.

Support for this approach comes from the AUGUSTUS trial, which is discussed in detail separately. In AUGUSTUS, which used a two-by-two factorial design to compare apixaban (at a dose labelled for stroke prevention) with vitamin K antagonists and aspirin with placebo, 1097 patients (23.9 percent of the patients enrolled) had an acute coronary syndrome treated medically [13]. In this prespecified subgroup analysis, apixaban compared with vitamin K antagonist reduced major or clinically relevant nonmajor bleeding (hazard ratio [HR] 0.44, 95% CI 0.28-0.687), and there was a similar effect on the individual endpoints of death and ischemic events in both groups. Compared with placebo, aspirin had an almost significantly higher rate of bleeding than placebo (HR 1.49, 95% CI 0.98-2.26) and similar rates of ischemic events. These results were consistent with the main AUGUSTUS trial outcomes. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Post-discharge studies'.)

For patients who have completed the 12 months of antithrombotic therapy, long-term antithrombotic therapy with either OAC monotherapy or OAC plus an antiplatelet agent is reasonable. In patients at the end of the spectrum where bleeding risk is high and ischemic risk is low, long-term DOAC monotherapy makes sense. On the other hand, for patients at high ischemic risk and low bleeding risk, DOAC plus a single antiplatelet agent makes sense. The strategy of DOAC alone is supported by the AFIRE trial, which enrolled stable patients. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Long-term therapy studies'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Non-ST-elevation acute coronary syndromes (non-ST-elevation myocardial infarction)" and "Society guideline links: ST-elevation myocardial infarction (STEMI)" and "Society guideline links: Anticoagulation".)

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.)

Basics topics (see "Patient education: Choosing an oral medicine for blood clots (The Basics)" and "Patient education: Taking oral medicines for blood clots (The Basics)")

SUMMARY AND RECOMMENDATIONS

For patients with an acute coronary syndrome (ACS) who have been treated medically (no percutaneous coronary artery intervention with stenting), there are two clinical situations in which oral anticoagulant (OAC) therapy is either needed or may be useful:

Patients in whom the addition of OAC may improve clinical outcomes. (See 'Potential role of oral anticoagulants in unstented acute coronary syndrome patients' above.)

Patients with a long-term need for OAC. (See 'Patients who require oral anticoagulant' above.)

For ACS patients managed medically who do not have an indication for chronic OAC (the first group above), the following two strategies for the first year of antithrombotic therapy are reasonable. Patient preference may play an important role in deciding between the two (see 'Our approach' above):

Aspirin and ticagrelor. Prasugrel has not been shown to improve outcomes in this setting. In patients at higher bleeding risk, clopidogrel can be used instead of ticagrelor. Aspirin alone is given after one year.

Rivaroxaban 2.5 mg twice daily in addition to aspirin and clopidogrel 75 mg daily in patients not at high bleeding risk. If this approach is used, we continue aspirin alone after one year.

For ACS patients managed medically who are receiving long-term OAC for an indication such as atrial fibrillation (the second group above), we suggest full-dose non-vitamin K oral anticoagulant plus clopidogrel 75 mg daily for one year rather than warfarin plus clopidogrel 75 mg daily (Grade 2B). (See 'Patients who require oral anticoagulant' above.)

For patients who have completed the 12 months of antithrombotic therapy, long-term antithrombotic therapy with either OAC monotherapy or OAC plus an antiplatelet agent is reasonable. In patients at the end of the spectrum where bleeding risk is high and ischemic risk is low, long-term direct acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) monotherapy makes sense. On the other hand, for patients at high ischemic risk and low bleeding risk, DOAC plus a single antiplatelet agent makes sense. The strategy of DOAC alone is supported by the AFIRE trial, which enrolled stable patients. (See "Coronary artery disease patients requiring combined anticoagulant and antiplatelet therapy", section on 'Long-term therapy studies'.)

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