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INTRODUCTION — Some patients with cardiovascular disease have indications for anticoagulant and antiplatelet therapy. It is estimated that between 5 and 10 percent of patients scheduled for coronary artery stenting and who require dual antiplatelet therapy (DAPT) are receiving oral anticoagulation (OAC), most often for atrial fibrillation (AF) [1,2] (see "Long-term antiplatelet therapy after coronary artery stenting in stable patients"). The concomitant use of DAPT using aspirin and a platelet P2Y12 receptor blocker and OAC is referred to as triple oral antithrombotic therapy or triple therapy for short. While the use of three antithrombotic agents reduces the rate of ischemic events, the risk of bleeding is significantly increased compared with one or two antithrombotic agents. This topic will provide the clinician with a guide for choosing the antithrombotic regimen for patients with an indication for anticoagulant and antiplatelet therapy after percutaneous coronary intervention (PCI).
The periprocedural management of antithrombotic therapy is discussed elsewhere. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation undergoing percutaneous coronary intervention", section on 'Elective patients' and "Periprocedural bleeding in patients undergoing percutaneous coronary intervention", section on 'Risk factors' and "Periprocedural and long-term gastrointestinal bleeding in patients undergoing percutaneous coronary intervention" and "Periprocedural complications of percutaneous coronary intervention", section on 'Vascular complications' and "Antithrombotic therapy for prosthetic heart valves: Management of bleeding and invasive procedures", section on 'Cardiac catheterization'.)
ASSESSING PATIENT ISCHEMIC AND BLEEDING RISK — For patients who are candidates for triple oral antithrombotic therapy (triple therapy) (see 'Introduction' above), the first step in choosing antithrombotic therapy is to assess ischemic and bleeding risks. In most patients, the risk factors for each overlap significantly, making assessment of net benefit (or risk) difficult.
●Ischemic risk – The risk of an ischemic event (myocardial infarction [MI], stroke, need for repeat revascularization, or cardiovascular death) is increased in patients with recent acute coronary syndrome (ACS) or stroke, complicated coronary artery disease or a suboptimal result at the time of percutaneous coronary intervention (PCI), the need to prematurely stop antithrombotic therapy, age ≥65 years, and chronic kidney disease.
●Bleeding risk – Risk factors include age ≥65 years, prior history of bleeding, and hypertension. Risk prediction models are available (table 1). (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Risk factors' and "Management of warfarin-associated bleeding or supratherapeutic INR", section on 'Risk factors'.)
Each patient will fall somewhere in the spectrum between being high ischemic risk and not at increased risk (above that imparted by the antithrombotic therapy) of bleeding to being at relatively low ischemic risk and very high bleeding risk. The duration of triple therapy should take into account this assessment. (See 'Our approach' below.)
OUR APPROACH — This section will summarize our approach to starting triple oral antithrombotic therapy (triple therapy) for the two groups of patients who might need it: patients taking long-term oral anticoagulation (OAC) who require dual antiplatelet therapy (DAPT) after intracoronary stent placement and patients on DAPT who subsequently require initiation of OAC.
The evidence does not allow for firm conclusions regarding the optimal duration of triple therapy or the dose of non-vitamin K antagonist oral anticoagulant (NOAC) when chosen. In addition, if a NOAC is chosen, there is no evidence to suggest that any one agent should be preferred.
Thus, for all patients, recommendations need to be individualized based on careful consideration of patient characteristics as well as patient preferences. The patient's baseline ischemic and bleeding risks are particularly important in formulating an antithrombotic regimen for patients who are candidates for triple therapy. (See 'Efficacy' below and 'Assessing patient ischemic and bleeding risk' above.)
Our recommendations assume that the patient has a strong need for OAC. In an occasional patient, such as those with atrial fibrillation (AF) and a CHA2DS2-VASc score (table 2) of 1, the benefit-to-risk ratio for the OAC was close to one. In these patients, we consider it reasonable to stop OAC after stenting and treat with DAPT for up to six months, at which time the patient is restarted on OAC and aspirin. (See "Atrial fibrillation: Risk of embolization", section on 'Options for estimating risk in the individual patient'.)
Patients on long-term OAC — The following is our approach to triple therapy in patients receiving long-term oral anticoagulation (OAC):
●For patients taking warfarin whose international normalized ratio (INR) has been relatively easy to maintain, we suggest continuing with warfarin. During the period of triple therapy, the INR should be monitored closely and kept within the 2.0 to 2.5 range.
●For patients taking NOACs without difficulty, we suggest continuing the NOAC rather than switching to warfarin. For patients previously on warfarin 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 NOAC is reasonable. A patient who has difficulty having blood drawn is an example. The choice of NOAC should be determined by factors such as practitioner familiarity, cost, availability, and dosing frequency. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Select an anticoagulant'.)
●We prefer aspirin 75 to 100 mg daily and clopidogrel 75 mg daily as the (dual) antiplatelet part of the triple therapy regimen. We do not prescribe the more potent antiplatelet agents ticagrelor or prasugrel in this setting. (See 'Alternatives to clopidogrel' below.)
●The decision regarding the duration of triple therapy is based on an assessment of the benefit (reduction in ischemic events) to risk (increase in bleeding events) ratio for each patient (see 'Assessing patient ischemic and bleeding risk' above).
In many patients, we now treat for one to three months with triple therapy and then omit aspirin. We generally recommend shorter-duration therapy for patients at high (or very high) bleeding risk/average ischemic risk and longer therapy for patients at higher ischemic risk/not increased bleeding risk. (See 'Duration' below.)
Our United States contributors generally choose the longer duration of therapy within the following time frames, while our European contributors tend to choose the shorter duration:
•High (or very high) bleeding risk and average ischemic risk: one to three months of triple therapy. It is reasonable to consider 12 months of oral anticoagulant plus clopidogrel (omit aspirin) for these patients. (See 'Efficacy' below.)
•Low bleeding risk and increased ischemic risk: 3 to 12 months of triple therapy.
The above time frames apply to patients who have had drug-eluting stents (DES) placed (they are used in the majority of cases). For patients in whom bare-metal stents (BMS) have been placed, one month of triple therapy irrespective of ischemic or bleeding risk is reasonable.
Patients on DAPT after stent placement — The following approach applies to patients taking dual antiplatelet therapy (DAPT) for recent stent placement who need to be started on OAC, usually for the development of AF. We start either warfarin or NOAC. The duration of triple therapy will be determined, in large part, by the amount of time they have already been on DAPT.
In practice, we subtract the length of time the individual has been on DAPT prior to starting OAC from the suggested duration of triple therapy, given in the bullets directly above, and tell the patient to stay on triple therapy for that length of time. The one variation on this approach is the patient with a DES who is at average ischemic risk and low bleeding risk. This individual may have initially been recommended 12 months of DAPT and may have passed the six-month mark. Such an individual may now have one antiplatelet agent stopped.
Nonstented ACS patients requiring OAC — Our recommendations for antithrombotic therapy in acute coronary syndrome (ACS) patients who have not undergone stenting are found elsewhere. (See "Chronic anticoagulation after acute coronary syndromes", section on 'Patients with indications for chronic anticoagulation'.)
EFFICACY — For many patients undergoing percutaneous coronary intervention (PCI) with stenting who require chronic anticoagulation, we prefer triple therapy for one to three months rather than oral anticoagulation (OAC) plus one antiplatelet agent or to dual antiplatelet therapy (DAPT) during this time period. However, the evidence to support this recommendation is weak. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration'.)
The issue of whether OAC plus a single antiplatelet agent is as efficacious as triple therapy was evaluated in the open-label, randomized WOEST trial, which randomly assigned 573 patients who were receiving long-term OAC and undergoing PCI to clopidogrel alone or clopidogrel plus aspirin (triple therapy) . Approximately 25 percent of patients had an acute coronary syndrome (ACS). In the triple therapy group, patients received aspirin 80 mg daily and clopidogrel 75 mg daily for at least one month after bare-metal stenting (BMS) and for at least one year after drug-eluting stenting (DES). In the OAC and clopidogrel group, patients received clopidogrel 75 mg daily for at least one month after BMS (up to one year for patients with ACS) and for at least one year after DES. Antithrombotic therapy with prasugrel, ticagrelor, dabigatran, apixaban, or rivaroxaban was not used. The indication for anticoagulant was atrial fibrillation (AF) in 69 percent of patients.
After a median follow-up of 358 days, the following findings were noted:
●The combined secondary end point of death (myocardial infarction [MI], stroke, target-vessel revascularization, and stent thrombosis) was lower with clopidogrel and OAC (11.1 versus 17.6 percent; adjusted hazard ratio [HR] 0.56, 95% CI 0.35-0.91), as was the secondary end point of all-cause death (2.5 versus 6.3 percent; adjusted HR 0.39, 95% CI 0.16-0.93). However, the finding of such a large mortality difference in a relatively small trial is unlikely to be repeated.
●The primary end point of bleeding was significantly higher with triple therapy. This issue is discussed in detail below. (See 'Bleeding' below.)
WOEST suggests that for many patients who require anticoagulant and antiplatelet therapy, aspirin may not be necessary and perhaps may be harmful. However, the WOEST trial was small (only 279 patients received OAC plus clopidogrel and, of these, only approximately 180 received a DES) and not designed or powered to detect stent thrombosis risk. Since it is possible that the omission of aspirin may lead to an increased risk of stent thrombosis, we remain concerned about this issue. Larger randomized trials are needed. Another concern is that those patients who are resistant to the antiplatelet effect of clopidogrel might have little protection against stent thrombosis. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'HPR and thrombotic events'.)
Until further evidence is available to help guide decision making, we believe initial triple therapy for a few (one to three) months and then switching to dual therapy with an OAC plus clopidogrel, rather than starting with dual therapy, should be recommended for patients with stent placement and an indication for OAC. This recommendation is based on our concern about the potential for coronary artery stent thrombosis. However, for patients at very high bleeding risk, we believe it is reasonable to omit aspirin during the first month based on results from the WOEST and PIONEER AF-PCI trials. (See 'Alternatives to clopidogrel' below and "Long-term antiplatelet therapy after coronary artery stenting in stable patients" and 'Alternatives to warfarin' below.)
Triple therapy has been compared with DAPT in stented patients requiring OAC in observational studies, each with significant limitations [4-7]. In the aggregate, these studies suggest that major adverse cardiovascular outcomes may be worse in patients with an indication for OAC who undergo PCI and are discharged on DAPT without anticoagulant. The studies do not exclude the possibility that patients at low risk for thromboembolic events, such as those with AF and a CHA2DS2-VASc score (table 2) of less than 2, could have OAC discontinued with reasonable safety during the period of DAPT (see "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Potential alternatives to anticoagulant monotherapy'). In addition, most of the patients on triple therapy included in the above studies had AF as the reason for OAC. There is little evidence upon which decisions can be made for patients on OAC with other diagnoses, such as valvular heart disease.
DURATION — The available evidence does not allow for firm conclusions regarding the optimal duration of triple oral antithrombotic therapy (triple therapy). Our United States contributors generally choose the longer duration of therapy within the following time frames, while our European contributors tend to choose the shorter duration (see 'Efficacy' above):
●High (or very high) bleeding risk and average ischemic risk: one to three months of triple therapy. It is reasonable to consider 12 months of oral anticoagulant (OAC) plus clopidogrel (omit aspirin) for these patients. This regimen was evaluated in the WOEST and PIONEER AF-PCI trials. (See 'Efficacy' above and 'Alternatives to warfarin' below.)
●Low bleeding risk and increased ischemic risk: 3 to 12 months of triple therapy.
●Many patients may not easily fit into one of the two categories (above), such as those at some level of intermediate bleeding risk and intermediate ischemic risk. Our approach is to individualize decision making, particularly in these patients.
Shorter therapy may be appropriate for patients at high bleeding risk and those who have had bare-metal stents (BMS) placed. Patients with an increased risk of a recurrent ischemic event, such as those with an acute coronary syndrome (ACS), may be considered for longer therapy (up to 12 months) if they are not at high (or very high) bleeding risk.
Formulating recommendations for the duration of antithrombotic therapy in patients with indications for triple therapy is a complicated process, in part because there is a broad range for the benefit (prevention of ischemic events) to risk (bleeding) ratio. Since the evidence base upon which recommendations can be made is weak, our recommendations represent consensus of our experts in some cases and a range of approaches in others.
Our recommendations take into account the following:
●In most patients who have received an intracoronary stent but who do not require anticoagulation, we prescribe dual antiplatelet therapy (DAPT) for 6 to 12 months, and then reevaluate the benefits and risks of longer therapy. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration'.)
●The risk of stent thrombosis is highest in the early phase after percutaneous coronary intervention (PCI) and declines over time , and the risk of bleeding increases with length of therapy [9,10]. For patients who have had BMS placed, the risk of stent thrombosis is greatest in the first 14 to 30 days. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Bare metal stents'.)
The study that best directly addresses the issue of duration is the ISAR-TRIPLE trial . This study randomly assigned 614 patients taking aspirin plus warfarin to treatment with clopidogrel for six weeks or six months after placement of a drug-eluting stent (DES). The indication for OAC was atrial fibrillation (AF) in 84 percent of patients. Ninety-eight percent of patients underwent catheterization using femoral access. The majority of patients received new-generation DES. Approximately one-third of patients had an ACS. Antithrombotic therapy with prasugrel, ticagrelor, dabigatran, apixaban, or rivaroxaban was not used. After completion of the study, most patients continued on OAC and aspirin.
After a follow-up of nine months, the following findings were noted:
●The primary end point of death (myocardial infarction [MI], definite stent thrombosis, stroke, or Thrombolysis in Myocardial Infarction [TIMI] major bleeding (table 3)) occurred in 9.8 percent patients in the six-week group compared with 8.8 percent patients in the six-month group (hazard ratio [HR] 1.14, 95% CI 0.68-1.91) at nine months.
●The combined ischemic end point of cardiac death (MI, definite stent thrombosis, or ischemic stroke) was 4.0 percent patients in the six-week group and in 4.3 percent patients in the six-month group (HR 0.93, 95% CI 0.43-2.05). There was no difference in TIMI major bleeding between the two groups (5.3 versus 4.0 percent; HR 1.35; 95% CI 0.64-2.84).
●There was no difference in the rate of any Bleeding Academic Research Consortium (BARC) bleeding (table 4) between the six-week and six-month groups. This is discussed in detail above. (See 'Bleeding' below.)
The ISAR-TRIPLE trial did not show that six weeks of triple therapy was superior to six months with regard to the net clinical outcome. Shortening the duration of triple therapy did not increase the incidence of ischemic events, and the longer therapy did not increase the incidence of major bleeding. The results of ISAR-TRIPLE suggest that clinicians must weigh the trade-off between ischemic and bleeding risks when choosing the duration of triple therapy.
There is very little additional relevant evidence from observational studies that can be used to formulate a recommendation for the use of triple therapy. In most cases, guideline recommendations have been based on expert opinion. (See 'Recommendations of others' below.)
NEWER ANTITHROMBOTIC AGENTS
Alternatives to clopidogrel — For most patients who will require some period of triple oral antithrombotic therapy (triple therapy), we prefer clopidogrel to one of the more potent P2Y12 receptor blockers (prasugrel or ticagrelor), including patients who are being treated for an acute coronary syndrome (ACS). Most of the patients enrolled in the relevant trials were treated with clopidogrel.
There are limited data on the role of newer P2Y12 inhibitors as part of triple therapy. In a prospective, observational study of 377 patients who underwent drug-eluting stent (DES) placement and who had an indication for oral anticoagulation, 5.6 percent received prasugrel and the rest clopidogrel . All patients were treated with triple therapy for at least six months. The primary end point of Thrombolysis in Myocardial Infarction (TIMI) major and minor bleeding occurred more often in the prasugrel group (28.6 versus 6.7 percent; adjusted hazard ratio [HR] 3.2, 95% CI 1.1-9.1). There was no significant difference in the composite secondary end point (death, myocardial infarction [MI], ischemic stroke, or definite stent thrombosis). In most patients, the indication for prasugrel was high platelet reactivity.
Alternatives to warfarin — For many of our patients who require some period of triple therapy (most of these patients will have atrial fibrillation as the reason for long-term oral anticoagulation), we prescribe one of the non-vitamin K antagonist oral anticoagulants (NOACs). If chosen, there is no high-quality evidence to support the use of one over another, nor is the optimal dose known.
The PIONEER AF-PCI trial randomly assigned 2124 patients with nonvalvular atrial fibrillation (AF) who had undergone percutaneous coronary intervention (PCI) with stenting 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 dual antiplatelet therapy (DAPT) for 1, 6, or 12 months; or standard therapy with a dose-adjusted vitamin K antagonist plus DAPT for 1, 6, or 12 months . Clopidogrel was the P2Y12 inhibitor in approximately 98 percent of patients. The primary safety outcome was clinically significant bleeding, which was a composite of major or minor bleeding according to TIMI criteria, or bleeding requiring medical attention, defined as a bleeding event that requires medical treatment, surgical treatment, or laboratory evaluation and does not meet criteria for a major or minor bleeding event.
The following findings were noted:
●The primary safety outcome 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). This finding was consistent across multiple subgroups. The bleeding end point was mainly triggered by "bleeding requiring medical attention," while there was no significant difference regarding TIMI major or TIMI minor bleeding.
●The rates of death from cardiovascular causes, MI, or stroke were similar in the three groups (6.5, 5.6, and 6.0 percent, respectively), as were the rates for each of the components. However, there were broad confidence intervals among the three treatment groups due to the small number of end points. Furthermore, this trial was not powered for ischemic events, and we do not draw firm conclusions regarding efficacy from these data.
The very low dose of rivaroxaban (2.5 mg twice daily), as used in PIONEER AF-PCI trial, is not approved for use in this setting in the United States. We prescribe rivaroxaban 15 mg daily with a P2Y12 receptor blocker.
The rationale for considering their use comes from studies in the broad population of patients for whom NOACs are preferred to warfarin for stroke prevention. Indirect evidence to support their use comes from subgroup analysis of the RE-LY trial, which compared dabigatran with warfarin in patients with AF. The advantages of dabigatran over warfarin were preserved in the 38 percent of patients taking concomitant antiplatelet therapy, including 4.5 percent taking DAPT . (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Select an anticoagulant'.)
When a NOAC is chosen as part of triple therapy, some of our experts use a dose or doses tested in randomized trials and approved by regulatory agencies. For example, dabigatran 150 mg twice daily, dabigatran 110 mg twice daily, edoxaban 60 mg once daily, apixaban 5 mg twice daily, and rivaroxaban 20 mg once daily are used by some experts in patients without factors that might lead to a lower dose or avoidance of NOACs altogether, such as age >75 years, reduced renal function, body weight <60 kg, and/or receiving an interacting medication.
Dabigatran 110 mg twice daily is another possible option as it has been tested in the RE-LY trial; however, the 110 mg option is NOT approved for this indication in the United States but widely available in other countries. Specific recommendations are available in the individual drug monographs. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects".)
However, many of our experts do not use these higher doses out of concern that they may lead to an unacceptable rate of major bleeding when given with DAPT. The following are lower doses used by some of our expert contributors:
●Some of our experts no longer use rivaroxaban 20 mg daily plus DAPT, as the PIONEER AF-PCI trial suggests outcomes with rivaroxaban and a P2Y12 receptor blocker are comparable to warfarin plus DAPT or very low-dose rivaroxaban plus DAPT. (See 'Newer antithrombotic agents' above.).
While a lower dose of rivaroxaban (15 mg once daily) plus a P2Y12 receptor blocker appears to be a rational choice, the PIONEER AF-PCI trial was underpowered to exclude an increased risk for stroke .
●Dabigatran 110 mg twice daily is another possible option as it has been tested in the RE-LY trial; however, the 110 mg option is NOT approved for this indication in the United States but widely available in other countries.
As mentioned previously, the discussion directly above applies to patients with AF, the most common indication for long-term oral anticoagulant. The reader is referred to other topics for recommendations regarding the choice of oral anticoagulant in patients with native valvular heart disease, prosthetic heart valves, transcatheter aortic valve implantation, or deep vein thrombosis. (See "Direct oral anticoagulants and parenteral direct thrombin inhibitors: Dosing and adverse effects" and "Antithrombotic therapy for prosthetic heart valves: Indications" and "Venous thromboembolism: Anticoagulation after initial management", section on 'Agents for long-term anticoagulation' and "Transcatheter aortic valve implantation: Periprocedural management", section on 'Antithrombotic therapy'.)
In patients with mechanical heart valves, NOACs should not be considered alternatives to therapy with warfarin and should not be used. They are contraindicated and have a black box warning (United States).
BLEEDING — Major bleeding in patients receiving triple oral antithrombotic therapy (triple therapy) is associated with a poor prognosis. Up to 20 percent of hemorrhagic events in patients on triple therapy occur in the gastrointestinal tract . (See "Periprocedural and long-term gastrointestinal bleeding in patients undergoing percutaneous coronary intervention", section on 'Incidence and risk factors'.)
Rates — Information about the increase in absolute and relative rates of bleeding associated with triple therapy compared with other antithrombotic regimens comes from the WOEST and ISAR-TRIPLE trials (see 'Efficacy' above), as well as observational studies [2,4-7,16-22].
The following are reasonable estimates of bleeding risk for patients on triple therapy:
●There is a two- to fivefold increase in bleeding risk compared with patients on DAPT [2,20,21,23].
Estimating risk from observational studies is complicated by the fact that the comparator therapies varied widely in agent(s), duration, and dose; some of the studies included control groups that had no indication for oral anticoagulation (OAC). For instance, these studies present a broad range in the relative risk of bleeding for patients with triple therapy compared with those on dual antiplatelet therapy (DAPT), with as much as a 5 percent absolute decrease to an 11 percent absolute increase .
In addition, bleeding definitions differ across all studies, with many using the major bleeding definition of the Thrombolysis in Myocardial Infarction (TIMI) study group (intracranial bleeding or clinically significant overt signs of hemorrhage associated with >5.0 g/dL decrease in hemoglobin level) (table 3) . 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 [4-6]. Another study defined major bleeding as a symptomatic event that was associated with a decrease in hemoglobin of at least 2.0 g/dL . Some use the Bleeding Academic Research Consortium (BARC) definition (table 4).
The relative rates of bleeding in patients taking OAC and one antiplatelet agent are discussed in detail elsewhere. (See "Atrial fibrillation: Anticoagulant therapy to prevent embolization", section on 'Long-term antiplatelet therapy'.)
Outcomes — There is a strong relationship between 30-day bleeding after percutaneous coronary intervention (PCI) and one-year mortality . 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 . 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:
●Warfarin, when used as the anticoagulant, should be titrated to the lowest possible international normalized ratio (INR) level in patients receiving triple therapy [28,29]. 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 . We recommend that the frequency of laboratory tests should be increased to safely maintain the INR levels in this lower range. (See "Warfarin and other VKAs: Dosing and adverse effects", section on 'Importance of strict INR control'.)
The use of gastroprotective therapy to lower the risk of bleeding is discussed separately. (See "Overview of the non-acute management of ST elevation myocardial infarction", section on 'Gastrointestinal prophylaxis' and "Overview of the non-acute 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 'Prevention of treatment failure' and "Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding' and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity", section on 'Prevention strategies'.)
CHOICE OF STENT — With regard to stent choice, we prefer newer-generation, drug-eluting stent (DES), rather than bare-metal stent (BMS), for most patients. The use of BMS is limited to those patients with a low risk of restenosis for whom a very short duration of triple therapy is needed (eg, one month or less). (See "Coronary artery stent thrombosis: Incidence and risk factors", section on 'Late and one-year cumulative stent thrombosis'.)
Although there is no clear evidence to support the choice of BMS for patients who require a very short duration of triple therapy, we believe this is a reasonable approach in selected cases, such as those who are unlikely to comply with a recommendation for 6 to 12 months of dual antiplatelet therapy (DAPT). We estimate that in 2017, DES, rather than BMS, are placed in 70 to 95 percent of patients.
Data regarding BMS versus DES in patients with triple therapy are limited. One observational study of anticoagulated patients undergoing percutaneous coronary intervention (PCI) with either BMS or DES found that the latter was associated with a significantly increased risk of major bleeding (2.3 versus 1.2 percent per 10,000 days of exposure) . A registry study of 929 patients found no difference in the risk of bleeding between DES and BMS at one year .
The ZEUS trial provides some evidence supporting the use of DES in patients at high bleeding risk, including those receiving oral anticoagulation (OAC). In ZEUS, 1606 patients with high bleeding or thrombotic risk were randomly assigned to DES with a zotarolimus-eluting DES (ZES) or BMS implantation . Median DAPT duration was 32 days in both groups, and approximately 13 percent of patients had concomitant OAC. The primary combined end point of death (myocardial infarction [MI] or target vessel revascularization) occurred less often with ZES (17.5 versus 22.1 percent; hazard ratio [HR] 0.76, 95% CI 0.61-0.95). There was no difference in major, minor, or any bleeding complications between both groups.
In an analysis of the 929 patients in the prospective Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) registry, the largest observational study of patients receiving triple therapy, 673 (72.4 percent) patients received BMS and 220 (23.7 percent) at least one DES . At 12-month follow-up, rates and risks of major adverse cardiac and cerebrovascular events and total bleeding events were comparable between the groups (22.0 percent with BMS versus 19.5 percent with DES, p = 0.51) and (19.5 versus 15.0 percent, respectively, p = 0.16). Definite/probable stent thrombosis was more frequent in the BMS group (1.9 versus 0 percent, respectively, p = 0.046).
MANAGEMENT AFTER TRIPLE THERAPY — The optimal antithrombotic regimen for patients who have completed a course of triple oral antithrombotic therapy (triple therapy) has not been well studied.
For patients who have received either drug-eluting stents (DES) or bare-metal stents (BMS), our experts suggest continuing oral anticoagulant (OAC) and one antiplatelet agent (usually clopidogrel) up to one year, as opposed to continuing OAC alone, after the required duration of triple therapy.
After one year, most of our experts continue patients on OAC plus aspirin. This recommendation to continue aspirin after the required period for triple therapy differs from that of the American College of Chest Physicians . (See 'Recommendations of others' below.)
This recommendation to continue aspirin (plus anticoagulation) in patients who have been stented is based on the observation of a continued risk of stent thrombosis after one year and the lack of evidence showing that anticoagulation alone is an effective preventive strategy. (See "Long-term antiplatelet therapy after coronary artery stenting in stable patients", section on 'Duration'.)
For those patients in whom bleeding is problematic, we consider stopping aspirin.
RECOMMENDATIONS OF OTHERS — Guidelines from American College of Cardiology/American Heart Association (2014), the European Society of Cardiology (2014), the American College of Chest Physicians (2012), and the European Heart Rhythm Association address the approach to patients who require long-term anticoagulant therapy for atrial fibrillation (AF) and antiplatelet therapy for intracoronary stenting [15,28,29,33,34]. These guidelines were all published prior to the results of ISAR-TRIPLE; some of the guidelines were published before other studies included in this topic (see 'Duration' above). The reader is referred to these documents for details.
●For patients requiring long-term oral anticoagulation (OAC), either a vitamin K antagonist (VKA) or non-vitamin K antagonist oral anticoagulant (NOAC) may be considered taking patient and clinician preference into account. There are no published head-to-head trials comparing one NOAC with another.
●The duration of dual antiplatelet therapy (DAPT) should be minimized.
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".)
SUMMARY AND RECOMMENDATIONS
●For stented patients who have indications for both dual antiplatelet therapy (DAPT) and oral anticoagulant (OAC), we suggest initial triple oral antithrombotic therapy (triple therapy), as opposed to any other antithrombotic strategy (Grade 2C). (See 'Efficacy' above.)
The available evidence does not allow for firm conclusions regarding the optimal duration of triple therapy. We use one to three months of triple therapy in most patients. After this time, we continue with OAC plus clopidogrel for one year in most patients. This issue is discussed in detail above. (See 'Our approach' above and 'Duration' above.)
●For stented patients taking warfarin to decrease the risk of embolization due to atrial fibrillation (AF) who are started on DAPT, we suggest continuing warfarin as opposed to switching to a non-vitamin K antagonist oral anticoagulant (NOAC) (Grade 2B).
Patients whose international normalized ratio (INR) has been difficult to control, or who are at increased risk of bleeding for reasons other than triple therapy, may reasonably be switched to a NOAC. (See 'Alternatives to warfarin' above.)
●We suggest newer-generation, drug-eluting stents (DES), rather than bare-metal stents (BMS), for most patients, especially those with a low bleeding risk (HAS-BLED score ≤2) (Grade 2B). For patients at highest risk of bleeding where a very short duration of DAPT is desired and the risk for restenosis is low, BMS are reasonable. (See 'Choice of stent' above.)
●The dose of the administered antithrombotic drugs should be minimized. We suggest that aspirin be given at a daily dose of less than or equal to 100 mg and that clopidogrel be given at a daily dose of 75 mg. For patients taking warfarin, reasonable targets are INRs of 2.5 to 3.0 for patients with mechanical valves and 2.0 to 2.5 for patients with other indications. To maintain the INR at the narrower level, laboratory testing of INR should be performed more often than is commonly recommended. (See 'Prevention' above.)
●For stented patients who have reached the end of triple therapy, we suggest continuing low-dose aspirin and OAC indefinitely after triple therapy rather than any other antithrombotic regimen (Grade 2C). (See 'Management after triple therapy' above.)
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