Circulation AF PCI.pdf

113

Atrial fibrillation (AF), the most common cardiac arrhyth-mia, occurs in 1% to 2% of the general population, with a prevalence varying from 0.5% in subjects 40 to 50 years old to 5% to 15% in the elderly who are >80 years old.13 Stroke is the most feared complication of AF, resulting in death or disabling symptoms in a vast proportion of cases.4 In the Framingham study, the age-adjusted incidence of stroke was 5-fold higher in subjects with AF, and the attributable risk raised from 1.5% at 50 to 59 years to 23.5% at 80 to 89 years.5

Chronic oral anticoagulation (OAC) therapy is the main-stay of stroke prevention in patients with AF at high risk for cardioembolic sequelae; 70% to 80% of all patients with AF have an indication for OAC, and coronary artery dis-ease coexists in 20% to 30% of them.6,7 With an estimated prevalence of AF in 1% to 2% of the population, it may be projected that 1 to 2 million patients on OAC in both the United States and Europe are candidates for coronary revas-cularization, often in the form of percutaneous coronary interventions (PCI). Patients undergoing PCI, as well as those who present with an acute coronary syndrome (ACS), also require dual antiplatelet therapy (DAPT), usually aspi-rin in combination with a platelet adenosine diphosphate P2Y

12 receptor antagonist, with the goal of reducing the

risk of ischemic recurrences, including stent thrombosis.8 However, the efficacy and safety of combining OAC with DAPT (triple antithrombotic therapy) in these patients is a topic of debate. In fact, although this combination can poten-tially prevent both thromboembolism and atherothrombotic events, it is also associated with an increased risk of severe bleeding. In a large nationwide registry of 40 812 patients hospitalized with myocardial infarction (MI), the risk of subsequent hospitalizations for bleeding increased with the number of antithrombotic drugs used, being 1.8-fold in patients on vitamin K antagonists (VKAs) and aspirin, 3.5-fold in patients on VKAs and clopidogrel, and 4-fold in patients on triple therapy, with numbers needed to harm of 45.4, 15.2, and 12.5, respectively.9 On this background, treatment with OAC and antiplatelet agents requires careful

consideration of the risks and benefits associated with each drug and their combination.

On one hand, the challenge of balancing the risk of throm-boembolism (ie, stroke) and atherothrombotic events (ie, stent thrombosis) and, on the other, the risk of bleeding demand for a timely review of the literature on using various com-binations of OAC and antiplatelet therapies in patients with coexisting AF and coronary artery disease. This is also under-scored by the recent availability of newer antithrombotic agents, including oral anticoagulants (ie, dabigatran, rivarox-aban, apixaban) and antiplatelets (ie, prasugrel, ticagrelor). This article reviews the evidence supporting antithrombotic agents for AF and ACS/PCI, and describes contemporary antithrombotic regimens and practical recommendations for patients with both conditions, with focus on new data and ongoing development of novel oral anticoagulant (NOAC) and antiplatelet drugs.

Epidemiology of Relevant Clinical ScenariosTriple antithrombotic therapy may be required as the result of several commonly encountered clinical scenarios in daily practice. First, patients with paroxysmal, persistent, long- standing, or permanent AF on OAC may experience an ACS, either nonST-segment elevation ACS (NSTE-ACS) or ST-segment elevation MI, or undergo elective PCI. In a prospec-tive series of 261 consecutive patients with AF undergoing coronary angiography, the overall incidence of coronary artery disease was relatively high at 34%, and revascularization by either PCI or coronary artery bypass grafting was needed in 21%.10 Second, new-onset AF may occur within 7 days dur-ing or after hospitalization in 6% to 8% of patients after an ACS or PCI.1114 In a meta-analysis of 120 566 patients from 10 clinical trials, AF occurred in 8% of patients with a ST-seg-ment elevation MI and in 6.4% of patients with NSTE-ACS.15 Importantly, 7-day mortality was higher in patients with AF (5.1%) than in those without AF (1.6%), with adjusted hazards of 1.65 in ST-segment elevation MI and 2.30 in NSTE-ACS. At present, the underlying mechanisms of AF in myocardial ischemia remain poorly understood.16

(Circ Cardiovasc Interv. 2014;7:113-124.) 2014 American Heart Association, Inc.

Circ Cardiovasc Interv is available at http://circinterventions.ahajournals.org DOI: 10.1161/CIRCINTERVENTIONS.113.001150

Received December 9, 2013; accepted January 2, 2014.From the Cardio-thoraco-vascular Department, Ferrarotto Hospital, University of Catania, Catania, Italy (D.C.); and Department of Medicine, Division

of Cardiology, University of Florida College of Medicine-Jacksonville, FL (D.C., D.J.A).Correspondence to Dominick J. Angiolillo, MD, PhD, University of Florida College of Medicine-Jacksonville, 655 W 8th St, Jacksonville, FL 32209.

E-mail [email protected]

Management of Antiplatelet and Anticoagulant Therapy in Patients With Atrial Fibrillation in the

Setting of Acute Coronary Syndromes or Percutaneous Coronary Interventions

Davide Capodanno, MD, PhD; Dominick J. Angiolillo, MD, PhD

Advances in Interventional Cardiology

by guest on June 27, 2015http://circinterventions.ahajournals.org/Downloaded from
mailto:[email protected]://circinterventions.ahajournals.org/

114 Circ Cardiovasc Interv February 2014

Stroke/Embolic Risk in Patients With AF on Anticoagulation With VKAs or NOACsIn patients with AF, adjusted-dose warfarin and antiplate-let agents reduce the risk for stroke by 65% and by 20%, respectively.17 However, oral antiplatelet agents do not perform as well as OAC with warfarin in this context. The Atrial fibril-lation Clopidogrel Trial with Irbesartan for prevention of Vas-cular Events (ACTIVE-W) trial performed in patients with AF plus 1 risk factor for stroke was stopped prematurely because of a clear evidence of superiority of OAC compared with DAPT with aspirin and clopidogrel, particularly in those already receiving OAC at study entry, with no increase in bleeding complications.18 In a meta-analysis of 6 contemporary random-ized clinical trials published between 2002 and 2012, focus-ing on patients with AF on warfarin therapy, the stroke rates were found to be higher in elderly, female, subjects who were VKAs nave or those with previous stroke or transient isch-emic attack, renal impairment, previous aspirin use, or high CHADS

2 (cardiac failure, hypertension, age, diabetes mellitus,

stroke [doubled]) score.19 However, even in the highest risk subgroup (previous stroke), the annualized risk of stroke with warfarin therapy was relatively low (2.5% per year). These results have corroborated the role of OAC with warfarin as the mainstay of cardioembolic prevention in patients with AF. In contrast, despite its undeniable benefits, warfarin is affected by a number of known limitations, including bleeding complica-tions, dietary or drug interactions, and need for international normalized ratio (INR) monitoring and dose adjustment. These limitations may contribute to explain why only approximately half of patients who would benefit from OAC actually receive warfarin.20 Patients deemed unsuitable for warfarin therapy may benefit from DAPT with aspirin and clopidogrel, which in the ACTIVE-A trial was shown to reduce the risk of major vascular events and stroke, compared with aspirin alone, at the price of an increased risk of major bleeding.21

NOACs, which act by directly and selectively inhibiting key coagulation factors such as thrombin (ie, dabigatran) or fac-tor Xa (ie, rivaroxaban and apixaban), have recently entered the market and clinical practice guidelines for the management of patients with nonvalvular AF.22 NOACs hold several favor-able characteristics, including good availability, rapid onset of action, minimal drug/food interaction, no need for coagulation monitoring or dose adjustment, established efficacy and low risk of bleeding.23 In meta-analyses of warfarin-controlled tri-als, NOACs have been shown to reduce mortality significantly by 11% to 12%, the combination of stroke and systemic embo-lism by 18% to 23%, and intracranial hemorrhage by 21% to 54%.2154 The annualized absolute risks of stroke or systemic embolism in these pooled analyses have been estimated at 2.4% to 2.8% with NOACs and 3.1% to 3.5% with warfarin.24,25

Ischemic Risk in Patients With ACS and/or Undergoing PCI on Antiplatelet Therapy With Aspirin and P2Y12 Receptor InhibitorsDAPT with aspirin and a P2Y

12 receptor inhibitor is the cor-

nerstone of pharmacological ischemic prevention after an ACS or PCI.2629 Clopidogrel, the most studied P2Y

12 recep-

tor inhibitor, was shown to reduce by 20% the incidence of cardiovascular death, nonfatal MI, or stroke in aspirin-treated

patients with ACS from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial.30 Despite a 38% relative increase of major bleeding at 1 year with clopidogrel in the entire cohort, the benefit of clopidogrel treatment out-weighed the risk of bleeding. This benefit was irrespective of patient management (invasive or noninvasive) as well as revas-cularization strategy (PCI or coronary artery bypass grafting). In the Clopidogrel for the Reduction of Events During Obser-vation (CREDO) trial, long-term (1-year) clopidogrel therapy was shown to reduce the risk of adverse ischemic events selec-tively in patients undergoing PCI.31 However, numerous phar-macodynamic investigations have consistently demonstrated that individual responsiveness to clopidogrel is not uniform in all patients and is subject to interindividual and intraindividual variability.32 In parallel, a growing degree of evidence under-scores that recurrence of atherothrombotic complications, including stent thrombosis, may be attributed to poor response to clopidogrel.32 Novel platelet P2Y

12 inhibitors approved by

regulatory authorities in both the United States and Europe (prasugrel, ticagrelor) have generally been shown to improve clinical outcomes in patients with ACS when compared with clopidogrel, particularly those undergoing PCI.33

In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38) trial, during a median follow-up of 15 months, prasugrel reduced the combined risk of cardiovascular mortality, MI, or stroke by 19% in patients with ACS and scheduled PCI (9.9% versus 12.1%; P

Capodanno and Angiolillo Triple Antithrombotic Therapy in ACS/PCI 115

documented in large retrospective series.3942 Importantly, this combination seems to increase the hazard of bleeding regard-less of whether a good control of percentage of time in the therapeutic range of warfarin is achieved.43 Two different meta- analyses have reached similar conclusions in showing that triple antithrombotic therapy is associated with a 2-fold increased risk of major bleeding compared with nontriple antithrombotic regimens.44,45 The most frequent site of seri-ous bleed in patients on triple antithrombotic therapy is the gastrointestinal tract.46 Importantly, bleeding may impact on mortality with multiple suggested mechanisms, including pre-mature discontinuation of antithrombotic therapies, immuno-suppression, and platelet activation by blood transfusion and hemodynamic compromise.47

In contrast to the striking evidence on the safety hazard with triple therapy, data on efficacy are mixed, likely as the reflection of differences in combinations and doses of anti-thrombotic drugs, study design, follow-up durations, bleeding definitions, and indications for therapy in mostly retrospec-tive and observational series.48,49 Accordingly, the 2 above- mentioned meta-analyses yielded conflicting results, with Zhao et al45 reporting fewer major adverse cardiovascular events and mortality with triple therapy compared with DAPT, and Gao et al44 reporting similar outcomes between patients on triple therapy and those on alternative regimens. Both meta-analyses, however, demonstrated a similar benefit of triple therapy in reducing stroke.44,45

Although there are no adequate clinical data on which to base firm recommendations, both United States and European expert consensus documents suggest that triple therapy should be used depending on the balance of ischemic and bleeding risk, favoring a combination of low-dose aspirin (plus a gas-tric acid suppressing agent, preferably a proton pump inhibi-tor), clopidogrel as the P2Y

12 inhibitor of choice, and OAC

with warfarin, targeting an INR between 2.0 and 2.5.48,49 The safety of this approach, particularly regarding the importance of keeping a low-intensity anticoagulation, has been demon-strated in a small series.50

Novel treatment strategies aimed at reducing the risk of bleeding by varying the combination of antithrombotic agents administered are a matter of ongoing interest. Dropping aspirin is one of them. Recently, the results of the open-label, mul-ticenter What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting (WOEST) trial have been published, in which 573 patients on oral anticoagulants (69% for AF) and undergoing PCI were randomized to clopidogrel alone (double therapy) or clopidogrel plus aspirin (triple therapy).51 The trial showed a large reduction in the primary end-point of overall TIMI bleed-ing at 12 months in patients receiving double therapy com-pared with those receiving triple therapy (hazard ratio, 0.36; 95% confidence interval [CI], 0.260.50; P


concomitant clopidogrel use.6264 The only phase III AF trial that allowed concomitant use of clopidogrel was the one of dabigatran, although given the limited number of patients any inference on the efficacy and safety of combination with DAPT, at present, remains speculative.60,65

In the phase 2 Prevention of Embolic and Thrombotic Events in Patients with Persistent AF (PETRO) study, 502 patients with AF at high risk for thromboembolic events based on qualifying inclusion criteria were assigned to a total of 10 treatment groups to identify a safe dose of dabigatran etexilate for subsequent clinical development.59 Adding to a comparator arm of patients receiving INR-adjusted warfarin alone, 3 doses of dabigatran etexilate (50-, 150-, and 300-mg bid) were investigated in a 33 factorial modality with no aspirin or aspirin 81- or 325-mg once daily. With such design characteristics, the PETRO study provides meaning-ful early insights on the safety of combining aspirin and dabigatran. Major bleeding episodes (n=4) within 12 weeks occurred only in patients treated with dabigatran 300-mg bid plus aspirin (6.3% versus 0% in patients treated with dabi-gatran 300-mg bid alone; P


be personalized. Unfortunately, the hazard for ischemic and bleeding events frequently coexists in the same patient, because these complications share multiple risk factors. In such cases, one should carefully weigh the risk and benefit of each drug choice, taking into account the preference of the patient. In addition, the length of triple therapy should be sized in propor-tion to the bleeding risk, the clinical scenario, and tight control of INR values should be achieved in any case.

The CHADS2 risk score is advocated by the European

guidelines as a rapid, bedside means of assessing the risk of stroke.66 Patients with CHADS

2 2 should be prescribed

OAC indefinitely, unless contraindicated, because of higher adjusted risk of stroke per year compared with those with CHADS

2 scores of 0 or 1, for whom DAPT is preferable.67

However, these latter continue to experience a certain degree of stroke risk, which underscores the need for more precise assessment of stroke risk factors in this population. An updated scheme expressed as CHA

2DS

2-VASc (conges-

tive heart failure, hypertension, age 75 [doubled], diabe-tes mellitus, stroke [doubled], vascular disease, age 6574, and sex category [female]) has been proposed to fulfill this aim by incorporating additional stroke risk factors that influ-ence whether or not to use OAC into the simpler CHADS

2

scheme.66 With such approach, OAC should be prescribed only in patients with CHA

2DS

2-VASc 2, whereas those with

a score of 1 should be prescribed either OAC (preferred) or aspirin, and those with a score of 0 should be prescribed no antithrombotic therapy for AF (preferred) or aspirin alone.

Similarly, risk stratification tools are available to estimate the individual risk of bleeding.68 The European guidelines for-mally endorse the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly [>65], drugs/alcohol concomitantly) as a simple method to assess bleeding risk in patients with AF, with scores 3 indicating high risk. The HAS-BLED score has been found to predict bleeding significantly also in patients on triple anti-thrombotic therapy, with a relatively good discrimination (c statistic, 0.67).69 In a study of 590 patients with AF and CHA

2DS

2-VASc 1 undergoing PCI, 71% had a HAS-BLED

3.70 In these patients, OAC was found to reduce the risk of death at 12 month independently, whereas the use of DES, with subsequent need for prolonged DAPT, independently predicted the risk of major bleeding. Interestingly, similar results have been demonstrated in octagenarian patients with AF undergoing PCI (mean HAS-BLED, 3.05).71 Overall, these findings underscore that the benefit of using VKAs on top of DAPT to reduce ischemic events may overshadow the bleed-ing risk even in patients with HAS-BLED 3. This is also in line with registry data showing that patients with AF undergo-ing PCI have a CHADS

2 score 2 in 70% of cases, so that

OAC treatment should not be withdrawn even when combined anticoagulant and antiplatelet treatment is warranted.72

Procedural Considerations for Minimizing the Risk of Bleeding With Triple Antithrombotic TherapyA series of procedural aspects need to be taken into consider-ation when dealing with a patient in need of triple antithrom-botic therapy. Given the complexity and risk associated with management of these patients, it is first important to define

whether there is an indication to be on triple antiplatelet ther-apy. In fact, there are subgroups of patients with AF with a low annual risk of thromboembolic events (ie, CHA

2DS

2-VASc 0

or 1) that do not require OAC. Also, the reduction in stroke with well-controlled warfarin therapy versus DAPT in patients at lower risk of stroke is likely outweighed by the increased risk of bleeding.18 It is also important to note that compliance with treatment is pivotal for demonstrating efficacy with OAC and to minimize bleeding complications. In fact, patients with a time in the therapeutic range


where the safety gain is paralleled by the superior efficacy of DES in reducing the need for repeat revascularization.8183

On this background, the benefit of a DES over a BMS should be balanced against the increased risk of bleeding with a prolonged triple therapy. The optimal duration of DAPT after DES implantation is still a controversial issue, with large ongoing trials (clinicaltrials.gov identifiers NCT00977938 and NCT00661206) aimed at shedding more light on this topic.84 As noted above, second-generation devices, including stents eluting everolimus or zotarolimus, might offer ideal fea-tures such as less thrombogenicity and no need for long-term DAPT.78,79 The Xience and Promus everolimus-eluting stents have recently gained European CE Mark approval for use with DAPT for 3 months, and the Resolute Integrity zotarolimus- eluting stent for 1 month.85,86 These data have been supported by studies and presentations at major cardiovascular con-gresses demonstrating that discontinuation of DAPT after either 1, 3, or 6 months duration was not associated with a sig-nificant increase in stent thrombosis with these newer stents among low-risk all-comers populations.8791 This is also in line with a recent large registry supporting the relative safety of DES versus BMS should DAPT discontinuation be required early (ie, between 6 weeks and 6 months).92

Overall, the net clinical benefit of treatment with BMS and OAC in conjunction with either mono (clopidogrel) or dual (aspirin plus clopidogrel) antiplatelet therapy remains to be determined when compared with treatment using a second- generation DES (specifically Xience/Promus and/or Resolute Integrity) in conjunction with an abbreviated (13 months) duration of DAPT, but could clearly weigh in favor of the newer generation DES in conjunction with an abbreviated DAPT reg-imen. Bioresorbable coronary scaffolds may have the potential for reducing late thrombotic events in patients undergoing PCI, but the scaffold persists 1 to 2 years, and large-scale studies are needed to characterize the safety of this new technology.93

Intraprocedural AnticoagulationManagement of anticoagulant therapy during PCI is mostly empirical in patients on OAC because of lack of a solid evi-dence base. In the multicenter Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) registry, uninterrupted anticoagulation was shown to be similar to conventional bridging therapy with heparin, after adjustment for propensity score, in terms of both major adverse cardiac and cerebrovas-cular events (1.16; 95% CI, 0.443.05; P=0.76) and bleeding complications (1.38; 95% CI, 0.772.48; P=0.28).94 However, whether continuation of OAC is a safe option in the peri-PCI period remains unproven without confirmation from a dedi-cated randomized clinical trial.

Current US guidelines consider enoxaparin a reasonable option in patients either treated with upstream subcutaneous enoxaparin in the context of an NSTE-ACS (to whom addi-tional dose of 0.3 mg/kg IV should be administered at the time of PCI to patients who have received


undergoing PCI with stenting provides recommendations based on the individual risk for stent thrombosis (ie, low, high, any) and the risk of bleeding (ie, low, high).49 Patients at low risk of both stent thrombosis and bleeding should receive triple therapy for 1 month after placement of a BMS and for 6 months after placement of a DES, followed by OAC plus 1 antiplatelet agent (ie, aspirin or clopidogrel) up to 12 months, with OAC only continued thereafter. In contrast, patients at high risk of stent thrombosis and low risk of bleeding should receive triple therapy for 6 months after a BMS, and for 12 months after a DES. After 12 months, continuation of a single antiplatelet agent in addition to OAC should be considered in patients at high risk for stent thrombosis. Finally, regard-less of the risk of stent thrombosis, patients at high bleeding risk should receive a BMS and maintain triple therapy for 1 month, followed by OAC plus 1 antiplatelet agent up to 12 months and OAC indefinitely thereafter.

The parallel European expert consensus document pro-vides recommendations following a different approach that take into consideration bleeding on one hand, and clini-cal presentation on the other.48 In elective PCI patients who receive BMS and are at low or intermediate risk of bleeding (HAS-BLED 2.0.

Use of Proton Pump InhibitorsAccording to an expert consensus document and the Ameri-can College of Cardiology/the American Heart Association PCI guidelines, use of proton pump inhibitors should be encouraged in patients on DAPT therapy to reduce the risk of gastrointestinal bleeding, particularly in case of concurrent use of OAC.29,106 However, pharmacokinetic and pharmaco-dynamic studies suggest that concomitant use of clopidogrel and omeprazole reduces the antiplatelet effects of clopidogrel, possibly through competitive metabolic effects of cytochrome CYP2C19 or reduced biological action of clopidogrel related to genetic polymorphisms, leading to a box warning from drug regulating agencies in the United States and Europe.107 Although retrospective studies and post hoc analysis have suggested a potential for an increased risk of ischemic events attributable to this drugdrug interaction,108 this has not proven to translate into meaningful differences at the clinical level in a randomized clinical trial.109 It should be noted that the inter-action of clopidogrel with proton pump inhibitors is not class specific because it applies to only those drugs (ie, omeprazole and esomeprazole) interfering with the CYP2C19.110,111 There-fore, in line with PCI guidelines, non-CYP2C19 interfering proton pump inhibitors (ie, pantoprazole, dexlansoprazole) should be preferred.29

Managing Bleeding ComplicationsIn case of bleeding or in asymptomatic patients with exces-sively high INR values, strategies aimed at reversing the effect of oral antithrombotic drugs may be necessary. Antagonizing the effect of warfarin requires suspending the drug and eventu-ally administering a dose of vitamin K (phytonadione) or blood derivatives, including fresh frozen plasma or prothrombin complex concentrates. There are currently no specific antidotes to neutralize the effect of NOACs, although several different drugs and compounds are under investigation as potential reversing agents.101 Clopidogrel, prasugrel, and ticagrelor have no antidotes. When an antidote is not available and bleeding continues despite the usual hemostatic techniques, platelet transfusion has the potential to reverse bleeding by restoring normal hemostasis, even if platelet count is normal, at the price of a slightly increased risk of platelet activation and aggrega-tion.112,113 If deemed necessary in patients treated with novel P2Y

12 inhibitors, platelets should be administered 6 hours

after administration of the loading dose of prasugrel or 4 hours after the administration of the maintenance dose, to avoid interference by the circulating active metabolite of the drug.114 No data exist on the hemostatic benefit of platelet transfusion in patients treated with ticagrelor.

http://circinterventions.ahajournals.org/


Future DirectionsTwo randomized clinical trials are currently testing different antithrombotic combinations for patients on OAC who require stent implantation. The Triple Therapy in Patients on Oral Anticoagulation After Drug Eluting Stent Implantation (ISAR-TRIPLE, clinicaltrials.gov id NCT00776633) trial will address the hypothesis that reducing the length of clopidogrel therapy from 6 months to 6 weeks after implantation of DES is associ-ated with a reduced net composite of death, MI, definite stent thrombosis, stroke, or major bleeding at 9 months on top of treatment with aspirin and an oral anticoagulant. The Antico-agulation in Stent Intervention (MUSICA-2, clinicaltrials.gov id NCT01141153) trial is investigating the safety and efficacy of a triple antithrombotic regimen of acenocoumarol, low-dose (100 mg/d) aspirin, and clopidogrel versus high-dose (300 mg/d) aspirin and clopidogrel in patients with AF and low-to-moderate risk of stroke (CHADS

2 2) referred to PCI.

After an ACS, patients remain at risk for recurrent athero-thrombotic events despite the use of DAPT.34,37 This risk may be partly related to excess thrombin generation, supporting the rationale for use of an anticoagulant on top of DAPT at long-term after an ACS. This strategy was shown to be of potential use with warfarin (but challenges related with drug administration and bleeding concerns have limited its use for this indication) and ximelagatran (but the drug is no longer on the market because of reported hepatotoxicity).115,116 The advent of NOACs has renewed the interest toward the long-term use of oral anticoagulants in ACS. However, dabigatran and dar-exaban were associated with a dose-dependent increased risk of bleeding in their respective phase II trials,117,118 and apixa-ban increased the number of major bleeding events without a significant reduction in the rate of ischemic events in a phase III trial.119 Another phase III trial of low-dose rivaroxaban (2.5-mg bid) on top of aspirin and clopidogrel in patients with ACS showed a significant reduction in mortality at the price of a 4-fold increase in intracranial hemorrhage.120 Importantly, the 2.5-mg bid dose of rivaroxaban used in the trial was about one quarter of that tested in AF. Therefore, whether this regi-men would be sufficiently safe and protective in AF versus warfarin or the combination of a higher dose of rivaroxaban plus a P2Y

12 inhibitor only is unknown and will be assessed

in a 2100-patient prospective trial (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], clinicaltrials.gov identifier NCT01830543). In this trial, patients with nonvalvular AF undergoing PCI with no history of previous transient ischemic attack or stroke will be random-ized to 1 of 3 treatment arms: (1) triple antithrombotic therapy with aspirin (75100 mg/d), clopidogrel (75 mg/d), and VKAs (INR, 2.03.0); at the discretion of the treating physician, patients will drop clopidogrel at 1, 6, or 12 months, which will be defined at time of randomization; (2) triple antithrombotic therapy with aspirin (75100 mg/d), clopidogrel (75 mg/d), and rivaroxaban (2.5-mg bid); at the discretion of the treating physician, patients will drop clopidogrel at 1, 6, or 12 months, which will be defined at time of randomization; (3) dual anti-thrombotic therapy with rivaroxaban 15-mg/d (or 10-mg for subjects with moderate renal impairment) and clopidogrel (75

mg/d). In a small subgroup of patients, the novel P2Y12

recep-tor antagonists, prasugrel (10 mg/d), or ticagrelor (90 mg bid), will be allowed to be used in lieu of clopidogrel. The primary end-point will be the 12-month composite of TIMI major bleeding, TIMI minor bleeding, and bleeding requiring medi-cal attention. The secondary end-point will be the composite of cardiovascular death, MI, stroke, and stent thrombosis. Most recently, a trial of dabigatran 150-mg or 110-mg twice-daily plus single antiplatelet therapy versus triple therapy with war-farin and DAPT (Randomized Evaluation of Dual Therapy with Dabigatran versus Triple Therapy Strategy with Warfarin in Patients with nonvalvular atrial fibrillation that have undergone PCI with Stenting [RE-DUAL PCI]) has been announced.121

ConclusionsTriple therapy with OAC, aspirin, and clopidogrel is recom-mended for patients with AF with ACS and/or PCI, but evi-dence mainly stems from observational series, mostly from single centers. For this reason, European and US guidelines assign a C level of evidence to this recommendation, and emphasize the need for balancing the thrombotic and the bleeding risks at the individual level. Incorporation of NOACs, prasugrel, and ticagrelor into a triple therapy scheme is chal-lenging in a field where data are limited. Further investigation of less-is-more approaches (ie, WOEST-like trials) is crucial to confirm the effectiveness of adding 2 and not 1 antiplatelet agent on top of OAC.

DisclosuresDr Capodanno received payment as an individual for consulting fee or honorarium from Eli-Lilly, Daiichi Sankyo, AstraZeneca, and The Medicines Company. Dr Angiolillo received payment as an in-dividual for the following: (1) Consulting fee or honorarium from Bristol Myers Squibb, Sanofi-Aventis, Eli-Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Merck, Evolva, Abbott Vascular and PLx Pharma; (2) Participation in review activities from Johnson & Johnson, St Jude, and Sunovion. Institutional payments for grants from Bristol Myers Squibb, Sanofi-Aventis, GlaxoSmithKline, Otsuka, Eli-Lilly, Daiichi Sankyo, The Medicines Company, AstraZeneca, Evolva, Gilead; and has other financial relationships with Esther and King Biomedical Research Grant.

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http://www.abbott.us/news-media/press-releases/abbotts-xience-prime-and-xience-v-drug-eluting-stents-receive-indication-in-europe-for-minimum-th.htmhttp://www.abbott.us/news-media/press-releases/abbotts-xience-prime-and-xience-v-drug-eluting-stents-receive-indication-in-europe-for-minimum-th.htmhttp://www.abbott.us/news-media/press-releases/abbotts-xience-prime-and-xience-v-drug-eluting-stents-receive-indication-in-europe-for-minimum-th.htmhttp://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1361899837211 & lang=en_UShttp://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1361899837211 & lang=en_UShttp://wwwp.medtronic.com/Newsroom/NewsReleaseDetails.do?itemId=1361899837211 & lang=en_UShttp://circinterventions.ahajournals.org/


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KEY WORDS: anticoagulants atrial fibrillation stents

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Davide Capodanno and Dominick J. AngiolilloInterventions

Fibrillation in the Setting of Acute Coronary Syndromes or Percutaneous Coronary Management of Antiplatelet and Anticoagulant Therapy in Patients With Atrial

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