Thrombosis in Atrial Fibrillation

AF is associated with a significant risk of stroke and thromboembolism. Patients with nonvalvular AF not taking antithrombotic medications have an annual rate of ischemic stroke or thromboembolism of approximately 5% compared with 0.5% to 1% in age-matched controls without AF. AF-related strokes are cardioembolic, which are more disabling and have a higher early mortality rate than atherothrombotic strokes. Increased thromboembolic risk in patients with AF mainly stems from the activation of the coagulation cascade rather than from platelet activation, and this fact explains why anticoagulants that impact the coagulation cascade are more efficacious than antiplatelet agents in preventing thromboembolic events in patients with AF.

The risk of thromboembolism is similar among patients with paroxysmal, persistent, or permanent AF and is increased by certain risk factors, notably Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack (CHADS ₂ ). Higher CHADS ₂ scores are associated with greater absolute benefit of oral anticoagulation with warfarin. Taking into consideration the presence of vascular disease, intermediate age (65–74), and female gender, the CHA ₂ DS ₂ -VASc score has been shown to be a better predictor of stroke risk, particularly in low-risk patients. Table 1 summarizes the rates of thromboembolism and death in patients not on oral anticoagulation according to the CHA ₂ DS ₂ -VASc score.

Oral anticoagulant therapy is an effective means of stroke prophylaxis in patients with AF ; a meta-analysis showed that warfarin reduced stroke risk by 64% versus placebo and by 39% versus aspirin. Although the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events-A (ACTIVE-A) trial results suggested that aspirin and clopidogrel could be used in patients with AF unsuitable for vitamin K antagonist therapy, ACTIVE-W demonstrated clear superiority of warfarin compared with dual antiplatelet therapy in patients who were suitable.

Thrombogenesis in ACS or After PCI

Localized damage of the coronary artery endothelium is the underlying mechanism triggering thrombosis in ACS and typically stems from an underlying atherosclerotic plaque rupture exposing thrombogenic material in the plaque core to blood, triggering platelet aggregation and fibrin formation. This process results in the formation of a platelet-rich thrombus. Because of the role of platelet aggregation in this process, antiplatelet agents have become part of the primary treatment in ACS. In addition, antithrombin agents are also efficacious in the acute setting of myocardial infarction. Stent thrombosis, however, is largely platelet dependent and is significantly prevented by antiplatelet agents.

PCI results in additional trauma to the vessel wall, initiating local prothrombotic activation. Stent implantation after angioplasty-induced dilation triggers further acute and chronic prothrombotic and proinflammatory reactions toward the stent. Drug-eluting stents inhibit restenosis and delay re-endothelialization; therefore, prothrombotic and proinflammatory activations can continue to occur and can lead to stent thrombosis even after 12 months.

The incidence of stent thrombosis in the published data shows variation ( Table 2 ) but is increased among patients with ACS and is greatest in the first month regardless of the type of stent used. The rate decreases to <0.1% per year after the first year for bare-metal stents and 0.4% to 0.6% after the first year for drug-eluting stents. Early or late stent thrombosis is associated with a mortality rate of 10% to 20% and a myocardial infarction rate of 30% to 70%.

Premature discontinuation of dual antiplatelet therapy is the greatest risk factor for stent thrombosis, producing a 2.5- to 5-fold risk increase if discontinued before 6 months in patients with first-generation drug-eluting stents. The need for dual antiplatelet therapy beyond 6 months is debatable as some studies demonstrate an increased risk for stent thrombosis if dual antiplatelet therapy is discontinued, whereas others do not. In particular, new-generation drug-eluting stents may not require dual antiplatelet therapy beyond 3 to 6 months. Additional known stent thrombosis risk factors include incomplete stent apposition, stent length, left anterior descending artery location, diabetes mellitus, postprocedural Thrombolysis In Myocardial Infarction flow <3, bifurcation stents, renal failure, and low ejection fraction.

Thrombogenesis in ACS or After PCI

Localized damage of the coronary artery endothelium is the underlying mechanism triggering thrombosis in ACS and typically stems from an underlying atherosclerotic plaque rupture exposing thrombogenic material in the plaque core to blood, triggering platelet aggregation and fibrin formation. This process results in the formation of a platelet-rich thrombus. Because of the role of platelet aggregation in this process, antiplatelet agents have become part of the primary treatment in ACS. In addition, antithrombin agents are also efficacious in the acute setting of myocardial infarction. Stent thrombosis, however, is largely platelet dependent and is significantly prevented by antiplatelet agents.

PCI results in additional trauma to the vessel wall, initiating local prothrombotic activation. Stent implantation after angioplasty-induced dilation triggers further acute and chronic prothrombotic and proinflammatory reactions toward the stent. Drug-eluting stents inhibit restenosis and delay re-endothelialization; therefore, prothrombotic and proinflammatory activations can continue to occur and can lead to stent thrombosis even after 12 months.

The incidence of stent thrombosis in the published data shows variation ( Table 2 ) but is increased among patients with ACS and is greatest in the first month regardless of the type of stent used. The rate decreases to <0.1% per year after the first year for bare-metal stents and 0.4% to 0.6% after the first year for drug-eluting stents. Early or late stent thrombosis is associated with a mortality rate of 10% to 20% and a myocardial infarction rate of 30% to 70%.

Premature discontinuation of dual antiplatelet therapy is the greatest risk factor for stent thrombosis, producing a 2.5- to 5-fold risk increase if discontinued before 6 months in patients with first-generation drug-eluting stents. The need for dual antiplatelet therapy beyond 6 months is debatable as some studies demonstrate an increased risk for stent thrombosis if dual antiplatelet therapy is discontinued, whereas others do not. In particular, new-generation drug-eluting stents may not require dual antiplatelet therapy beyond 3 to 6 months. Additional known stent thrombosis risk factors include incomplete stent apposition, stent length, left anterior descending artery location, diabetes mellitus, postprocedural Thrombolysis In Myocardial Infarction flow <3, bifurcation stents, renal failure, and low ejection fraction.

Guidelines and Recommendations

Current American College of Cardiology/American Heart Association guidelines use the risk factors included in the CHADS ₂ risk schema to assess thromboembolic risk and recommend anticoagulation with a vitamin K antagonist for patients with >1 moderate risk factor. For patients who have just 1 of the CHADS ₂ -validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable. European Society of Cardiology guidelines recommend use of the CHA ₂ DS ₂ -VASc risk schema and that an oral anticoagulant (vitamin K antagonist, direct thrombin inhibitor, or direct factor Xa inhibitor) should be used for patients with a CHA ₂ DS ₂ -VASc score of ≥2 and should be considered for patients with a score of 1, unless the patient is a female aged <65 years (i.e., has lone AF).

Current American College of Cardiology/American Heart Association guidelines recommend dual antiplatelet therapy for patients with non–ST elevation myocardial infarction (NSTEMI) or unstable angina for up to 12 months and recommend dual antiplatelet therapy for patients with ST elevation myocardial infarction (STEMI) receiving PCI for up to 1 year for bare-metal stents and at least 1 year with drug-eluting stents. Current European Society of Cardiology guidelines also recommend dual antiplatelet therapy for patients with ACS for a duration of 12 months. For patients with NSTEMI undergoing PCI (i.e., patients without STEMI) who require long-term anticoagulation for AF, the European Society of Cardiology guidelines do not necessarily recommend the use of triple therapy; if such therapy is chosen, however, they urge careful monitoring of the international normalized ratio (INR), with target values in the range of 2.0 to 2.5 and recommend that triple therapy is limited in duration depending on the clinical setting. American College of Cardiology/American Heart Association guidelines also do not specifically recommend the use of dual antiplatelet therapy in combination with warfarin for patients with NSTEMI undergoing PCI but state that for patients who have an indication for anticoagulation, the addition of warfarin may be reasonable.

A European Society of Cardiology consensus document recommends triple therapy for at least 1 month after the implantation of a bare-metal stent and longer with a drug-eluting stent (at least 3 months for a “-limus” stent [sirolimus, everolimus, and zotarolimus] and at least 6 months for a paclitaxel-eluting stent). It is recommended that drug-eluting stents be avoided or strictly limited to clinical and/or anatomic cases such as long lesions, small vessels, or patients with diabetes, in whom an increased benefit compared with a bare-metal stent is expected. In all cases, warfarin should be dose adjusted and monitored closely to keep the INR from 2.0 to 2.5.

Treatment Outcomes in Patients Receiving Dual Antiplatelet Therapy Plus Oral Anticoagulants

Although there has only been 1 randomized controlled trial investigating the benefits and risks of triple therapy in patients with AF undergoing PCI, the combination of oral anticoagulants with dual antiplatelet therapy has been reported to result in an increased risk of major bleeding in other retrospective studies. Major bleeding alone was associated with a three to sevenfold greater mortality risk among patients with ACS compared with patients without bleeding. In published studies ( Table 3 ), the frequency and severity of bleeding events vary significantly, which may be in part caused by the many definitions of bleeding.

Much of the available data on the risk of bleeding with triple therapy comes from retrospective and observational studies. Several of these studies have primary end points of major bleeding and demonstrate increased risk of major bleeding with the use of triple therapy in ACS and post-PCI patients requiring warfarin. In a few of these studies, a large percentage of bleeding events occur in the setting of a supratherapeutic INR, in patients with baseline anemia, or involve triple therapy durations of ≥6 months. When the duration of triple therapy was limited to 30 days in patients with ACS receiving PCI, bleeding developed in 11% of patients, although bleeding was minor in most episodes. In a meta-analysis of studies of patients with AF undergoing coronary stenting by Paikin et al, the 1-month risk of major bleeding on triple therapy was estimated to be 2.2%. This risk increased to 12% at 1 year, demonstrating that bleeding increases with a longer duration of triple therapy.

Not all studies, however, have shown an increase in bleeding risk with triple therapy, and some have examined other important end points such as ischemic or adverse cardiac events. In a study of patients with AF who were receiving stents, Ruiz-Nodar et al found that among the patients who were prescribed oral anticoagulants at discharge, there was a nonsignificant increase in major bleeding but also a significantly better major adverse cardiac event–free prognosis and less all-cause mortality. A study using the CHA ₂ DS ₂ -VASc schema and the newly recommended Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drug/alcohol concomitantly (HAS-BLED) schema to assess bleeding risk offers a valuable “net clinical benefit” assessment of using oral anticoagulation in patients with AF who are undergoing coronary stenting. Even in those with high bleeding risk (HAS-BLED score ≥3), oral anticoagulation therapy was associated with a lower mortality rate and fewer major adverse cardiac events at 1-year follow-up, with higher rates of major bleeding. Predictors of major bleeding were chronic renal failure and the use of drug-eluting stents.

As mentioned previously, the only prospective, randomized, controlled trial evaluating triple therapy has been the recently published WOEST trial, which was a multicenter study of patients receiving oral anticoagulants and undergoing PCI. Patients receiving clopidogrel alone (double therapy) were compared with those receiving clopidogrel plus aspirin (triple therapy). The primary outcome was any bleeding episode within 1 year of PCI. In this study, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events, suggesting that the addition of aspirin provides no additional benefit in this setting while increasing the risk of bleeding. The study was not powered to detect differences in stent thrombosis occurrence. Of note, the study featured higher-than-expected bleeding rates in both arms of the study probably owing to the use of drug-eluting stents and femoral access in most cases and proton pump inhibitor use in only a minority of cases.

As suggested by the WOEST trial, treatment of these patients with an oral anticoagulant and single antiplatelet therapy may represent a viable and possibly safer option with less risk of bleeding. Until the findings of this study are supported by additional trials, it remains unclear whether this oral anticoagulant plus clopidogrel regimen represents the most favorable option. It is also not known if this regimen provides the same benefits and risks when applied to a world population or if the novel oral anticoagulant agents can be used in this regimen.

Currently, there are at least 3 ongoing trials (Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation [ISAR-TRIPLE], Anticoagulation in Stent Intervention [MUSICA-2], and A Study Exploring Two Strategies of Rivaroxaban and One of Oral Vitamin K Antagonist in Patients With Atrial Fibrillation Who Undergo Percutaneous Coronary Intervention [PIONEER AF-PCI]) evaluating different strategies of antiplatelet agents and oral anticoagulants in patients with AF and stenting. These trials should help to clarify the best drug regimen and duration of therapy to minimize bleeding risk and ischemic events. Other trials may be necessary to clarify if there is a net benefit of triple therapy in patients with AF with recent ACS who do not receive stenting.