Version May 2024
INTRODUCTION — Some patients with coronary artery disease (CAD) have indications for intense antiplatelet therapy and anticoagulant therapy. The most common indications for oral anticoagulant are atrial fibrillation (AF), venous thromboembolism, and valvular heart disease. Indications for one or two antiplatelet agents include stable CAD (aspirin alone), recent acute coronary syndrome (ACS; aspirin plus a P2Y12 inhibitor), or recent coronary artery stent placement (aspirin plus a P2Y12 inhibitor). Individuals who require anticoagulant and antiplatelet therapy are a clinical challenge with regard to the need to balance the benefit and risk from intensive antithrombotic therapy.
The use of two antiplatelet agents is referred to as dual antiplatelet therapy (DAPT); DAPT plus anticoagulant has been referred to as "triple oral antithrombotic therapy" or "triple therapy" for short. The term "combined antithrombotic therapy" is also used. The use of three antithrombotic agents reduces the risk of cardiac ischemic events but also increases the risk of bleeding compared with one or two antithrombotic agents. While triple therapy has been the practice for many years, evidence supports the use of two antithrombotic agents (an oral anticoagulant plus a P2Y12 inhibitor) in most cases after initial short-term triple therapy of up to one week.
This topic will provide the clinician with a guide for choosing a reasonable antithrombotic regimen for CAD patients with an indication for combined antithrombotic therapy after coronary artery stenting. Patients with an ACS treated medically (no stenting) who need oral anticoagulation are discussed separately. (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)
Other related topics include:
ASSESSING PATIENT RISKS — In patients who are candidates for combined antithrombotic therapy, the first step in choosing the antithrombotic regimen is to assess thrombotic and bleeding risks and assign the patient to one of four groups, which are discussed below. The type and duration of combined antithrombotic therapy should take into account this assignment. (See 'Our approach' below.)
●Thrombotic risk – Risk factors for a thrombotic (or ischemic) event (eg, myocardial infarction [MI], stroke that is often secondary to AF, need for repeat revascularization, or resuscitated out of hospital cardiac arrest) after percutaneous coronary intervention (PCI) include recent acute coronary syndrome or stroke; complicated, multivessel CAD, particularly in patients with diabetes; a suboptimal result at the time of PCI; the need to prematurely stop antithrombotic therapy; age ≥65 years; prior stent thrombosis; and chronic kidney disease. In contrast, patients with stable disease, less complex coronary lesions, and optimal PCI results are felt to be at low risk of a subsequent thrombotic event.
●Bleeding risk – All patients taking oral anticoagulants (OAC) are at relatively high bleeding risk. We use the terms "low bleeding risk" and "high bleeding risk" to subdivide patients who are taking OAC.
Risk factors that increase the bleeding risk from high to very high after PCI include age ≥65 years, prior history of bleeding, and hypertension. (See "Risks and prevention of bleeding with oral anticoagulants" and "High bleeding risk patients undergoing percutaneous coronary intervention", section on 'Definition of high bleeding risk'.)
Assessing the bleeding risk in patients with concomitant antiplatelet therapy and OAC is an important part of care. Risk prediction models are available to help categorize the patient [1]. Bleeding risk is discussed in detail elsewhere. (See "High bleeding risk patients undergoing percutaneous coronary intervention", section on 'Assessing individual patient risk'.)
In an analysis of the ISAR TRIPLE population [2], an enhanced platelet inhibition delivered by clopidogrel is associated with an increased risk for major bleeding and death in patients with concomitant antiplatelet and anticoagulation therapy [3]. The role of platelet function testing to help identify those with a high bleeding risk where a less aggressive antithrombotic therapy is needed remains uncertain, and we do not think is routinely indicated. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Summary and recommendations'.)
Based on an evaluation of thrombotic and bleeding risk, the patient taking OAC should be assigned to one of the following groups:
●Low thrombotic risk and low bleeding risk
●Low thrombotic risk and high bleeding risk
●High thrombotic risk and low bleeding risk
●High thrombotic risk and high bleeding risk
Some patients will not fit easily into one of these four broad categories, and the clinician should use clinical judgement and patient preferences to guide the choice of antithrombotic therapy. (See 'Our approach' below.)
OUR APPROACH — In this section, we provide an approach to choosing an antithrombotic regimen in patients who require long-term oral anticoagulant as well as antiplatelet therapy consequent to percutaneous coronary intervention (PCI).
In all patients, decision making must be individualized after careful consideration of patient characteristics, as well as patient preferences. Many patients will fall between the ends of the benefit and risk spectrums for thrombosis and bleeding.
The relevant studies (see 'Efficacy and safety' below) provide a framework on which recommendations are made. However, differences between studies and individual study limitations prevent us from being able to make strong recommendations, particularly with regard to the duration of any antithrombotic combination, as well as the specific antithrombotic drugs.
There are three time periods that are discussed directly below: procedure to one month, discharge to 12 months, and after 12 months.
Procedure to one month — For patients who are on triple therapy, we discontinue aspirin, usually within the first week to one month following PCI.
Discharge to 12 months — The first step in choosing the antithrombotic regimen at the time of discharge is to assess thrombotic and bleeding risks and assign the patient to one of the following four groups. (See 'Assessing patient risks' above.)
The following points apply to most patients:
●We discharge patients on a direct-acting oral anticoagulant (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) plus a P2Y12 inhibitor plus aspirin. In most patients, we continue aspirin for up to one week based on how the randomized trials discussed below were carried out.
●During the first 12 months, any new ischemic or bleeding episode (or change in bleeding risk) should lead to a reevaluation of antithrombotic therapy in all four of the groups below.
●In the four patient groups below, we usually choose clopidogrel as the P2Y12 inhibitor. (See 'Antiplatelet specifics' below.)
●At 12 months, antithrombotic therapy should be reevaluated. (See 'After 12 months' below.)
Low thrombotic risk and low bleeding risk — We discharge patients not at the highest bleeding risk on a DOAC plus clopidogrel plus aspirin. We continue aspirin for up to one week. This recommendation to continue aspirin after discharge is based on a high risk for early stent thrombosis in patients who discontinue aspirin early after PCI. Subsequently, we continue DOAC plus clopidogrel for 12 months. It is important to remember that early stent thrombosis should tip people off to the fact that there was residual disease not optimally treated by the stent.
Low thrombotic risk and high bleeding risk — For these patients at high bleeding risk, we prefer to continue aspirin for up to one week after discharge but consider discontinuing it at discharge in patients at highest risk of bleeding, provided that the angiographic result is optimal. Subsequently, we generally treat with DOAC plus clopidogrel for 12 months. In patients at the very highest bleeding risk, we consider stopping the P2Y12 inhibitor at six months. It should be noted that a consensus document from the American College of Cardiology allows for discontinuation of the P2Y12 inhibitor at three months; in most cases, we are reluctant to stop the P2Y12 inhibitor at three months [4]. (See 'Recommendations of others' below.)
High thrombotic risk and low bleeding risk — We discharge most patients on DOAC plus clopidogrel plus aspirin. We usually continue aspirin for one month, at which time it is discontinued. We treat with DOAC plus clopidogrel for a total of 12 months after discharge. (See 'After 12 months' below.)
High thrombotic risk and high bleeding risk — We discharge these patients on DOAC plus clopidogrel and aspirin and continue the aspirin, if possible, for one month. We then continue DOAC plus clopidogrel for 12 months after discharge. However, it is difficult to make a single recommendation regarding the duration of antiplatelet therapy for patients in this group, as there is a tension between the two risks. Individualized patient decision-making is essential. The consensus document from the American College of Cardiology allows for treatment with DOAC plus clopidogrel for six months and then discontinuation of clopidogrel; we believe stopping clopidogrel at six months is too early. (See 'After 12 months' below.)
After 12 months — Most patients in the four groups discussed above will be treated with clopidogrel plus DOAC for one year after percutaneous coronary intervention (PCI). After that time, antithrombotic therapy should be reevaluated and a long-term antithrombotic strategy put in place.
Although the AFIRE trial presented below argues for DOAC monotherapy, we think that either DOAC monotherapy or DOAC plus a single antiplatelet agent (either aspirin or clopidogrel) is a reasonable strategy after one year. We would like to see additional evidence to support the use of DOAC monotherapy before we make a broad recommendation for its use. (See 'Long-term therapy studies' below.)
In patients at the end of the spectrum where bleeding risk is high and ischemic risk is low, long-term DOAC monotherapy is reasonable. On the other hand, for patients at high ischemic risk and low bleeding risk, DOAC plus a single antiplatelet agent makes sense. For those patients committed to DOAC plus a single antiplatelet agent, the choice between aspirin and clopidogrel is also determined by consideration of bleeding and ischemic risks.
Anticoagulant specifics — For most patients who require combined anticoagulant and antiplatelet therapy, we choose a DOAC rather than warfarin; an exception is for patients that have a mechanical value and who are taking warfarin. This choice is based on studies in the broad population of patients with AF for whom DOACs are preferred to warfarin for stroke prevention and the recent trials in which patients received DOAC in one arm and warfarin in the other [5] (see 'Efficacy and safety' below). The rates of major bleeding and intracranial hemorrhage in particular are lower for all DOACs compared with warfarin, including studies of patients with AF post-PCI. (See "Atrial fibrillation in adults: Use of oral anticoagulants".)
Our preference for DOAC rather than warfarin may necessitate that some patients will need to have their OAC switched. In these patients, more detailed education is important to avoid confusion. From a clinical standpoint, some patients still need to switch from one DOAC to another because of their insurance coverage and deductibles. (See 'Discharge to 12 months' above.)
The following are specific anticoagulant recommendations:
●We prefer DOAC rather than warfarin for most patients. For patients taking warfarin whose international normalized ratio (INR) has been relatively easy to maintain and who prefer to continue warfarin after having heard an explanation of the potential benefits of DOACs, it is reasonable to continue taking warfarin. In these patients, consideration should be given to home monitoring of INR to reduce variability in INR.
For these patients taking warfarin and antiplatelet therapy, the INR should be monitored closely and ideally kept within the 2.0 to 2.5 range. For patients whose INRs have been difficult to manage for reasons other than compliance or in whom the risk of bleeding is thought to be high, switching to a DOAC is reasonable. A patient who has difficulty having blood drawn is an example.
●When a DOAC is chosen, most of our experts use a dose or doses tested in randomized trials and approved by regulatory agencies. These trials are presented below (see 'Efficacy and safety' below). For all agents, attention to dose adjustment based on renal function, weight, and age is important. The specific DOAC chosen varies depending on patient characteristics, availability, and cost of the specific drug. Avoiding an incorrectly too-low dose is important as it leads to decreased efficacy, often without improving bleeding.
•For dabigatran, this includes both the 150 mg twice daily dose and the 110 mg twice daily dose. However, the 110 mg option is not approved for this indication in the United States but is approved and widely used in other countries. Outside the United States, for patients over the age of 80, the 110 mg twice daily dose is mandated in the label.
•The dose of apixaban is 5 mg twice daily as studied in the AUGUSTUS trial. Dose reduction of apixaban to 2.5 mg twice daily may be necessary in patients with at least two of the following characteristics: age ≥80 years, body weight ≤60 kg, or serum creatinine ≥1.5 mg/dL.
•For rivaroxaban, some experts recommend 15 mg daily (the dose tested in the PIONEER-AF PCI trial) while others recommend the full dose of 20 mg daily, as approved for stroke prevention [6]. While a lower dose of rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor appears to be a rational choice, the PIONEER AF-PCI trial was underpowered to exclude an increased risk for stroke [7]. If rivaroxaban 15 mg has been selected as the anticoagulant, it is increased to 20 mg when clopidogrel is discontinued.
•Edoxaban 60 mg once daily, as used in the ENTRUST-AF PCI trial, is an option. However, it was not shown to have a reduced risk of bleeding in a dual therapy regimen compared with warfarin triple therapy, whereas other NOACs all did have lower bleeding. Dose reduction to 30 mg daily may be necessary for some patients with chronic kidney disease.
Antiplatelet specifics — The choice of P2Y12 inhibitor (clopidogrel, ticagrelor, or prasugrel) should take into consideration the indication for the procedure (stable or unstable disease):
●For stable patients, we prefer clopidogrel to one of the more potent P2Y12 inhibitors (prasugrel or ticagrelor) for two reasons:
•Clopidogrel is preferred to ticagrelor or prasugrel in stented patients who do not require OAC;
•Clopidogrel was used in most of the relevant randomized trials of patients who were taking OAC. (See 'Post-discharge studies' below and "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Early postprocedural decisions'.)
The dose of clopidogrel is 75 mg daily.
●For patients with an acute coronary syndrome, there is some evidence that either clopidogrel or ticagrelor is a reasonable choice in patients also taking OAC [8,9]. If ticagrelor is chosen, the dose should be 90 mg twice daily.
However, bleeding rates will be higher with ticagrelor, given the higher level of antiplatelet effect than clopidogrel. Most of our experts switch from ticagrelor to clopidogrel at the time of discharge in this setting, unless the patient is at very high risk for a thrombotic event, particularly if they have had a prior ischemic event while on clopidogrel.
●If aspirin is used, the dose is 75 to 100 mg daily. (See 'High thrombotic risk and low bleeding risk' above.)
Patients with prior stent placement — The following approach applies to patients taking dual antiplatelet therapy (DAPT) for recent stent placement or acute coronary syndrome who need to be started on OAC, usually for the development of AF or new deep vein thrombosis or pulmonary embolism. As a reminder, in the general population of patients who have received an intracoronary stent and who do not require anticoagulation, we prescribe DAPT for 6 to 12 months. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Summary and recommendations'.)
We prefer DOAC to warfarin and we choose dabigatran, rivaroxaban, or apixaban in preference to edoxaban, as they have been shown to reduce bleeding events in the setting of combined DOAC and P2Y12 inhibitor therapy. (See 'Anticoagulant specifics' above.)
The duration of combined antiplatelet plus anticoagulant therapy will be determined, in large part, by the length of time they have been treated with antiplatelet therapy.
In practice, we subtract the length of time the individual has been on DAPT prior to starting OAC from the suggested duration of intense antithrombotic therapy in the four broad groups of patients discussed in detail above (see 'Discharge to 12 months' above). The following is an example. A patient underwent coronary artery stenting on January 1st and was discharged on aspirin and clopidogrel. On July 1st, he was diagnosed with new onset AF and determined to need long-term OAC. Aspirin was stopped, and the patient was treated with OAC plus clopidogrel until January 1st of the following year, at which time antithrombotic therapy was reevaluated.
EFFICACY AND SAFETY — The studies presented below support our approach to the use of antithrombotic therapy in patients with who require both anticoagulant and antiplatelet therapy. (See 'Our approach' above.)
Post-discharge studies — The two most rational options for initial antithrombotic regimen include oral anticoagulant (OAC) plus two antiplatelet agents (triple therapy) or OAC plus one antiplatelet agent. A third option, the use of dual antiplatelet therapy (DAPT) without anticoagulant, was evaluated in observational studies, each with significant limitations [10-13], and the ACTIVE W trial [14]. In the aggregate, these studies suggest that major adverse cardiovascular outcomes may be worse in patients with an indication for OAC who undergo percutaneous coronary intervention (PCI) and are discharged on DAPT without anticoagulant.
Until 2016, antithrombotic therapy with three oral agents (triple therapy) was recommended as initial therapy for some period of time in most stented patients taking long-term anticoagulation. Based on the results of randomized trials (discussed below), which found that OAC plus P2Y12 inhibitor therapy (without aspirin) leads to a lower rate of bleeding, and intracranial hemorrhage in particular and equivalent efficacy outcomes, we stop aspirin at the time of hospital discharge after PCI in many patients who are receiving anticoagulant therapy. However, some patients at high ischemic/thrombotic risk are treated with aspirin for one month post-PCI in this setting. (See 'Discharge to 12 months' above.)
A 2019 meta-analysis evaluated the results of the WOEST (2013), ISAR-TRIPLE (2015), PIONEER AF-PCI (2016), RE-DUAL PCI (2017), and AUGUSTUS (2019) randomized trials [5]. Each trial compared differing antithrombotic regimens in patients who required long-term OAC (mostly due to AF) and underwent PCI. Compared with a regimen of vitamin K antagonist (VKA) plus DAPT, the odds ratios for Thrombolysis in Myocardial Infarction (TIMI) major bleeding were 0.58 (95% CI 0.31-1.08) for VKA plus P2Y12 inhibitor, 0.49 (95% CI 0.30-0.82) for direct-acting oral anticoagulant (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) plus P2Y12 inhibitor, and 0.70 (95% CI 0.38-1.23) for DOAC plus DAPT. The individual trials were not powered for ischemic events. A few details of each of the major trials that evaluated patients requiring both OAC and antiplatelet therapy are as follows:
●The WOEST trial randomly assigned 573 patients to clopidogrel alone or clopidogrel plus aspirin [15]. Approximately 25 percent of patients had an acute coronary syndrome (ACS). After a median follow-up of 358 days, the primary endpoint of bleeding was significantly lower with DAPT. (See 'Bleeding' below.)
●The ISAR-TRIPLE trial randomly assigned 614 PCI patients to aspirin plus warfarin plus clopidogrel for either six weeks or six months [2]. Approximately one-third of patients had an ACS. After a follow-up of nine months, the primary endpoint of death (MI, definite stent thrombosis, stroke, or TIMI major bleeding (table 1)) occurred in 9.8 percent of patients in the six-week group compared with 8.8 percent of patients in the six-month group (hazard ratio [HR] 1.14, 95% CI 0.68-1.91) at nine months.
●The PIONEER AF-PCI trial randomly assigned 2124 stented patients to one of three antithrombotic regimens in a 1:1:1 ratio: low-dose rivaroxaban (15 mg daily) plus a P2Y12 inhibitor for 12 months; very low-dose rivaroxaban (2.5 mg twice daily) plus DAPT for 1, 6, or 12 months; or standard therapy with a dose-adjusted VKA plus DAPT for 1, 6, or 12 months [6].
The primary safety outcome of clinically significant bleeding occurred less often in the two groups receiving rivaroxaban (16.8, 18.0, and 26.7 percent, respectively; HRs 0.59, 95% CI 0.47-0.76 and 0.63, 95% CI 0.50-0.80, respectively). The bleeding endpoint was mainly triggered by "bleeding requiring medical attention," while there was no significant difference regarding TIMI major or TIMI minor bleeding. The three groups had similar efficacy rates (6.5, 5.6, and 6.0 percent, respectively).
●The RE-DUAL PCI trial randomly assigned 2725 AF patients to warfarin plus a P2Y12 receptor inhibitor (clopidogrel or ticagrelor) and aspirin for one to three months or dabigatran (110 or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) [9]. Therapy was continued for at least six months (average 14 months). ACS was the indication for PCI in about 50 percent of cases. The primary endpoint of a major or clinically relevant nonmajor bleeding event occurred less often in the 110 mg (15.4 versus 26.9 percent; HR 0.52, 95% CI 0.42-0.63) and 150 mg (20.2 versus 25.7 percent; HR 0.72, 95% CI 0.58-0.88) dual therapy groups.
In 2019, subsequent to the meta-analysis of the above trials, AUGUSTUS and ENTRUST-AF PCI were published and support the concept that DOAC plus a P2Y12 inhibitor is preferred to an OAC plus two antiplatelet agents in most cases:
●The AUGUSTUS trial used a two-by-two factorial design and randomly assigned 4614 patients with AF who had an ACS or had undergone PCI and were planning to take a P2Y12 inhibitor to apixaban or a VKA and to aspirin or matching placebo for six months [16]. Patients taking long-term anticoagulant therapy for reasons other than AF were excluded. In more than 90 percent of patients, clopidogrel was the P2Y12 inhibitor chosen. The dose of apixaban was 5 mg twice daily and was adjusted to 2.5 mg twice daily according to the label criteria if a patient had two of three criteria, age was 80 years or greater, the weight was no more than 60 kg, or the creatinine level was 1.5 mg per deciliter (133 micromol per liter) or higher. The mean time from randomization to the index event was six days.
Comparisons were made of apixaban versus warfarin and of aspirin versus placebo. One comparison of the four groups was made for the primary bleeding endpoint. Comparing apixaban with VKA:
•Major or clinically relevant nonmajor bleeding (the primary endpoint) was found in 10.5 percent of patients receiving apixaban compared with 14.7 percent of those receiving a VKA (HR 0.69, 95% CI 0.58-0.81).
Stated another way, the event rates (primary outcome) per 100 patient-years for VKA plus aspirin, apixaban plus aspirin, VKA plus placebo, and apixaban plus placebo were 49.1, 33.6, 26.7, and 16.8, respectively.
•The rate of death or hospitalization, a secondary endpoint, was lower with apixaban (23.5 versus 27.4 percent; HR 0.83, 95% CI 0.74-0.93)
•There was no significant difference in the rate of ischemic events (the composite of death or hospitalization and the composite of death or ischemic events [stroke, MI, stent thrombosis (definite or probable)], or urgent revascularization) comparing apixaban with VKA or comparing aspirin with placebo, and no difference in the rate of stent thrombosis.
Comparing aspirin with placebo (ie, triple versus double therapy, pooling for type of anticoagulant):
•Major or clinically relevant nonmajor bleeding (the primary endpoint) was 16.1 percent of those receiving aspirin compared with 9.0 percent of those receiving placebo (HR 1.89, 95% CI 1.59-2.24).
•There was no significant difference in the rate of overall ischemic events (the composite of death or hospitalization and the composite of death or ischemic events [stroke, MI, stent thrombosis (definite or probable)], or urgent revascularization) comparing aspirin with placebo.
•The study was underpowered for assessing differences in individual ischemic events. However, it should be mentioned that there was numerical twofold increase in stent thrombosis rates in patients with placebo compared with aspirin.
●The ENTRUST-AF PCI trial randomly assigned 1506 patients with AF requiring anticoagulation who had a PCI for stable or unstable CAD to edoxaban plus a P2Y12 inhibitor for 12 months or to VKA in combination with a P2Y12 inhibitor plus aspirin for 1 to 12 months [17]. The primary endpoint of major or clinically relevant nonmajor bleeding within 12 months was not significantly reduced (17 versus 20.7 percent of patients, respectively; HR 0.83, 95% CI 0.65-1.05). There was no significant difference in the rate of ischemic events.
Two meta-analyses that included AUGUSTUS, ENTRUST AF-PCI, PIONEER AF-PCI, and RE-DUAL PCI have been published and came to similar conclusions [18,19]. It should be noted that the earlier of these two found a significant increase in the risk of stent thrombosis (RR 1.59, 95% CI 1.01-2.50) [18].
The following was noted in the more recent (2020) meta-analysis of four trials (7953 patients) at a median follow-up of one year [19]:
●Dual compared with triple antithrombotic therapy is associated with a significantly reduced risk for major bleeding (risk difference [RD] -0.013, 95% CI -0.025 to -0.002).
●No significant difference on the risks of all-cause mortality (RD 0.004, 95% CI -0.001 to 0.017) and myocardial infarction (RD 0.003, (95% CI -0.010 to 0.017).
Long-term therapy studies — The optimal antithrombotic regimen for stented patients who have completed 12 months of combined antithrombotic therapy with an OAC and a P2Y12 inhibitor had not been well studied until the OAC-ALONE and AFIRE randomized trials were published in 2019. Prior to these two trials, we advised OAC plus aspirin based on the observation of an ongoing risk of stent thrombosis after one year and the lack of evidence that anticoagulation alone is an effective preventive strategy. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration and Type of Antiplatelet Treatment'.)
In the OAC-ALONE trial, 696 stable patients with AF who had undergone PCI with stenting more than one year before were randomly assigned to either OAC (either warfarin or DOAC) alone or to OAC plus a single antiplatelet agent (either aspirin or clopidogrel) [20]. The study was terminated prematurely due to slow enrollment. During a median follow-up of 2.5 years, there was no difference in the primary composite endpoint of all-cause death, MI, stoke, or systemic embolism (HR 1.16, 95% CI 0.79-1.72), or the secondary endpoint of major bleeding (HR 0.73, 95% CI 0.44-1.20). There was a trend toward more ischemic events in the OAC-alone group in whom aspirin was omitted. This study was significantly underpowered to allow for any meaningful conclusions.
The larger AFIRE trial evaluated outcomes in individuals with AF who had undergone revascularization with either PCI with stenting or coronary artery bypass graft surgery or who had angiographically confirmed CAD not requiring revascularization more than one year earlier [21]. AFIRE randomly assigned 2236 patients to rivaroxaban (10 or 15 mg based on renal function) or rivaroxaban plus a single antiplatelet agent (either aspirin or a P2Y12 inhibitor). The 15 mg dose of rivaroxaban is a dose approved for use in a Japanese population and is likely similar to a 20 mg dose in a White population. The trial was stopped early due to increased mortality in the combination-therapy group. The median treatment duration was 23 months. The following was found:
●The event rates for the primary efficacy endpoint, a composite of stroke, systemic embolism, MI, unstable angina requiring revascularization, or death from any cause, were 4.14 and 5.75 percent per patient-year, respectively (HR 0.72, 95% CI 0.55-0.95).
●All-cause mortality was lower among patients receiving monotherapy with rates of 1.85 and 3.37 percent per patient-year, respectively (HR 0.55, 95% CI 0.38-0.81).
●The primary safety endpoint of major bleeding was 1.62 and 2.76 percent per patient-year in the two groups, respectively (HR 0.59, 95% CI 0.39-0.89).
OAC ALONE and AFIRE were studies in Asian populations for whom the relative risks for bleeding and thrombosis may be different than in some other populations.
BLEEDING — Major bleeding in patients receiving oral antithrombotic therapy is associated with a poor prognosis.
The rate of any bleeding ranges between approximately 15 and 40 percent per year, and the rate of major bleeding is in the range of 2 to 10 percent per year [2,6,15,22,23]. There is a two- to fivefold increase in bleeding risk with combined antithrombotic therapy with three agents compared with patients on dual antiplatelet therapy (DAPT) [22,24-26].
It should be kept in mind that bleeding definitions differ across all studies, with many using the major bleeding definition of the TIMI study group (intracranial bleeding or clinically significant overt signs of hemorrhage associated with >5.0 g/dL decrease in hemoglobin level) (table 1) [27]. Others incorporated the need for transfusion of two or more units of blood, the need for corrective surgery, or the occurrence of retroperitoneal hemorrhage into their bleeding definitions [10-12]. Another study defined major bleeding as a symptomatic event that was associated with a decrease in hemoglobin of at least 2.0 g/dL [28]. Some use the Bleeding Academic Research Consortium (BARC) definition (table 2).
Outcomes after bleeding — There is a strong relationship between 30-day bleeding after percutaneous coronary intervention and one-year mortality [29]. Bleeding events are not only a predictor of mortality but also have an impact on the compliance of patients with their medication. Even the occurrence of minimal bleeding events, such as easy bruising or bleeding from small cuts, is of high importance, as it has been demonstrated that the incidence of such "nuisance" bleeding is associated with clopidogrel therapy cessation in 11.1 percent of patients [30]. As premature discontinuation of clopidogrel is associated with an increased rate of stent thrombosis, discontinuation may contribute to the mortality risk associated with bleeding. (See "Periprocedural bleeding in patients undergoing percutaneous coronary intervention", section on 'Outcomes after bleeding'.)
Prevention — The risk of bleeding in patients on triple therapy can be reduced with dosing adjustment and the use of gastroprotective therapy.
Dosing of the administered antithrombotic drugs should be kept as low as possible:
●When used, aspirin should be given at a dose of 75 to 100 mg daily [31].
●Warfarin, when used as the anticoagulant, should be titrated to the lowest possible international normalized ratio (INR) level in patients receiving triple therapy [32,33]. One study demonstrated that aiming for a target INR of 2.0 to 2.5 leads to a significant decrease in bleeding events in patients treated with triple therapy as compared with INR levels >2.6. The patients treated with an INR level of 2.0 to 2.5 had similar bleeding events compared with DAPT [34]. We recommend that the frequency of laboratory tests should be increased to safely maintain the INR levels in this lower range. Home monitoring should be encouraged in these patients. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Importance of strict INR control'.)
●We recommend gastroprotective therapy (eg, proton pump inhibitor) for patients taking a P2Y12 inhibitor and an oral anticoagulant to lower the risk of gastrointestinal bleeding. This issue is discussed separately. (See "Overview of the nonacute management of ST-elevation myocardial infarction", section on 'Gastrointestinal prophylaxis' and "Overview of the nonacute management of unstable angina and non-ST-elevation myocardial infarction", section on 'Gastrointestinal prophylaxis' and "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Early and late stent thrombosis' and "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Promotion of DAPT adherence' and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Reducing risk of bleeding' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity".)
CHOICE OF STENT — Newer (current) generation drug-eluting stents are the standard of care, rather than bare metal stents. (See "Percutaneous coronary intervention with intracoronary stents: Overview", section on 'Role for bare metal stents'.)
NONSTENTED ACUTE CORONARY SYNDROME PATIENTS — The management of non-stented acute coronary syndrome patients requiring oral anticoagulant is discussed separately. (See "Acute coronary syndrome: Oral anticoagulation in medically treated patients".)
PATIENTS WITH HEART VALVES — In patients with mechanical heart valves, all patients must be treated with vitamin K antagonists. Direct-acting oral anticoagulants (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) are contraindicated and cannot be used as alternatives to therapy with warfarin and should not be used. They have a black box warning (United States). Warfarin is also preferred in patients with mitral stenosis. (See "Antithrombotic therapy for mechanical heart valves", section on 'Approach to antithrombotic therapy' and "Rheumatic mitral stenosis: Overview of management", section on 'Prevention of thromboembolism'.)
In patients with surgical bioprosthetic heart valves, a DOAC is a reasonable choice. (See "Antithrombotic therapy for surgical bioprosthetic valves and surgical valve repair", section on 'Approach for surgical bioprosthetic valves'.)
RECOMMENDATIONS OF OTHERS — Guidelines or consensus statements which address the approach to patients who require long-term anticoagulant therapy for AF and antiplatelet therapy for intracoronary stenting are available [4,35-37].
Some of these were published prior to the results of the RE-DUAL PCI, AUGUSTUS, and ENTRUST-AF PCI trials. While our recommendations are generally in accord with those found in these guideline documents, differences are potentially attributable to their publication prior to the publication of important clinical trials. (See 'Efficacy and safety' above.)
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: Atrial fibrillation" and "Society guideline links: Percutaneous coronary intervention".)
SUMMARY AND RECOMMENDATIONS
●Assessing patient risk – For patients with coronary artery disease who undergo percutaneous coronary intervention (PCI) with stenting and who also require long-term oral anticoagulant (OAC) therapy for diagnoses such as atrial fibrillation, antithrombotic decision-making should be individualized, taking into account patient characteristics and preferences. (See 'Assessing patient risks' above.)
●Approach – Treatment during the first 12 months:
•After PCI, we discharge most patients on an OAC plus a P2Y12 inhibitor plus aspirin.
•The duration of aspirin therapy is determined by the patients thrombotic and bleeding risks. In patients at low thrombotic risk, we treat with aspirin for up to one week. For patients at high thrombotic risk, we treat with aspirin for up to one month. (See 'Our approach' above.)
•For most patients, we recommend a direct-acting oral anticoagulant (DOAC; also referred to as non-vitamin K oral anticoagulants [NOAC]) rather than warfarin (Grade 1B). (See 'Our approach' above and 'Anticoagulant specifics' above.)
When a DOAC is chosen, most of our experts use a dose or doses tested in randomized trials and approved by regulatory agencies. The specific DOAC chosen varies depending on patient characteristics, availability, and cost of the specific drug.
•For stable coronary artery disease patients who undergo PCI with stenting, we recommend clopidogrel as the P2Y12 inhibitor rather than prasugrel or ticagrelor (Grade 1A). (See 'Antiplatelet specifics' above.)
For patients with an acute coronary syndrome who undergo PCI with stenting, either clopidogrel or ticagrelor is a reasonable choice. We tend to use clopidogrel for patients at increased bleeding risk.
•We treat most patients with OAC plus P2Y12 inhibitor for 12 months. (See 'Discharge to 12 months' 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 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. (See 'After 12 months' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
