Antithrombotic Therapy for Patients With Both Stable Coronary Artery Disease and Atrial Fibrillation

There is a high prevalence of coronary artery disease (CAD) in patients with atrial fibrillation (AF), ranging from 18-47%, partly due to common risk factors such as older age, hypertension, and diabetes.1,2 However, there are differences in the pathogenesis of thrombosis in AF and CAD.3 The major complications in patients with AF are stroke and systemic embolic events (SEE). The major clinical events associated with CAD are myocardial infarction (MI) and cardiovascular (CV) death.3 Oral anticoagulation (OAC) is required, and more effective, for patients with moderate-to-high risk AF to prevent stroke and SEE, while antiplatelet therapy is the standard management for CAD to reduce the risk of coronary events. In patients presenting with both AF and CAD, the choice of optimal long-term antithrombotic management to prevent both thromboembolic and cardiac events simultaneously is often challenging. The potential benefit of combination therapy carries an increased risk of bleeding, thus creating a therapeutic dilemma for clinicians.

Unfortunately, in patients with concomitant stable CAD and AF, there is limited evidence and no large randomized clinical trials (RCTs) to help guide clinicians. Current guideline recommendations have been mostly based on findings from retrospective studies, observational data, non-randomized trials or logical extrapolations from RCTs in AF or CAD. For patients with stable CAD and AF at low risk of stroke (i.e., CHA2DS2-VASc = 0-1), low-dose aspirin alone or aspirin and clopidogrel should be effective and safe for prevention of coronary events and stroke/SEE. When the stroke risk is higher, RCTs have shown that the balance of efficacy and safety for thromboembolism prevention favors OAC over antiplatelet therapy.4,5,6 Warfarin alone is also effective and reasonably safe for preventing cardiac events in patients after MI.3,7

The 2012 ESC guideline for AF5 recommends that patients with AF and stable coronary or peripheral arterial vascular disease (i.e., no acute events or revascularization for ≥12 months) can be managed with OAC alone as life-long antithrombotic therapy, or a novel OAC (NOAC). In such stable patients, there is no need for concomitant aspirin, which could increase the risk of serious hemorrhage.

In contrast, the 2011 AHA/ACCF guideline for secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease8 recommends treatment with warfarin for patients with atherosclerosis and AF, in addition to low-dose aspirin (75–81 mg daily).

However, these recommendations are based on sparse observational data. In routine clinical practice, some clinicians prefer to prescribe a combination of warfarin plus aspirin in patients with stable CAD and AF. Therefore, it is still controversial whether warfarin (or a NOAC) alone could provide an adequate reduction in coronary events in patients with coexisting stable CAD and AF.

Recently, Lamberts and his colleagues9 investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonists (VKAs) in patients with AF and stable CAD (defined as 12 months from an acute coronary event: MI or percutaneous coronary intervention [PCI]) from a nationwide Danish cohort study. They found that compared to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (HR 1.12 [0.94-1.34]) or VKA plus clopidogrel (HR 1.53 [0.93-2.52]). The risk of thromboembolism was comparable in all regimens including VKA, while the risk of bleeding increased when aspirin (HR 1.50 [1.23-1.82]) or clopidogrel (HR 1.84 [1.11-3.06]) was added to VKA. They suggested that using VKA only in patients with AF and stable CAD is a valid option. However, this is an observational study from nationwide Danish administrative registries data. Even though the adjusted analyses were controlled for gender, age, inclusion year, PCI status, pharmacotherapy, and comorbidity, different intensities of antithrombotic strategies may be given by clinicians for different coronary risk patients, based on patient/physician preference in real-life practice.

In my view, clinicians should assess not only the stroke risk, but also the risk of coronary events and bleeding before making a decision for patients with both CAD and AF. The purpose is to identify both AF patients at high risk for stroke and stable CAD patients at high risk for cardiac events. The 2013 ACC guideline for AF10 recommends a risk-factor-based approach for determining the optimal antithrombotic therapy. The 2011 ESC guideline for AF5 recommends the CHA2DS2-VASc score for stroke risk assessment in most AF patients. Coronary event risk assessment for stable CAD is also essential because the degree of stability is relative, dynamic, and is dependent upon the clinical circumstances. Although there is still no established prognostic model, both ACC and ESC guidelines for stable CAD11,12 recommend risk stratification into high risk (>3% annual death or MI), intermediate risk (1% to 3% annual death or MI), or low risk (<1% annual death or MI), and the use of risk index and score.

In addition, assessment of bleeding risk is recommended when antithrombotic therapy is given. The 2012 ESC guideline5 recommends the use of the simple, yet fairly accurate, HAS-BLED score for OAC therapy in patients with AF. While no bleeding risk score is widely accepted for patients with stable CAD, the ACTION, CRUSADE, or ACUITY/HORIZONS bleeding risk scores derived in patients with ACS may be extended to the population with stable CAD to help guide the clinician.13

For most patients with AF with an indication for VKA who have stable CAD, warfarin alone will provide satisfactory antithrombotic prophylaxis against cerebral and myocardial ischemic events. But for patients with high risk stable CAD, moderate-to-high risk AF, and low risk of bleeding, combination of well-controlled warfarin (target INR 2.0-2.5) plus low-dose aspirin (<100mg/d) may be considered to enhance protection against ischemic cardiac events. A randomized controlled trial evaluating the efficacy of warfarin monotherapy as compared to warfarin plus aspirin in patients with AF and prior (>12 months) coronary stenting is currently ongoing in Japan (see, NCT01962545). This prospective randomized controlled open-label trial will randomize patients to either adjusted dose warfarin alone with target INR of 2.0-3.0 for those <70 years (target INR of 1.6-2.6 for those ≥70 years) or adjusted dose warfarin alone with the same INR target plus aspirin of 81-324 mg/day. The primary endpoint is a composite of all-caused death, MI, and stroke or SEE, and the anticipated mean follow-up duration will be 1.5 years.

With regard to the NOACs, analyses from the RE-LY trial showed that there was a modest increase in MI with dabigatran compared with warfarin (see September 2013 Hot Topic).14 Meanwhile in the ROCKET-AF trial, CV death, MI, or unstable angina rates tended to be lower in patients with rivaroxaban compared with warfarin, and the patients with prior MI assigned to rivaroxaban had a non-significant 14% reduction of ischemic cardiac events compared with warfarin.15 To date, there are too little data regarding the efficacy, safety, and net clinical benefit of the combination of NOAC plus antiplatelet therapy compared to NOAC alone or warfarin alone in patients with both stable CAD and AF. A registry is about to start comparing rivaroxaban with warfarin in patients with AF and prior (>12 months) coronary stenting (see, NCT02024230). Patients with clinically stable AF who underwent coronary artery stenting more than one year ago and are treated or are scheduled to be treated with an oral anticoagulant will be included. The primary outcomes are the composite of adverse events (over three years), including cardiac or stroke death, non-fatal MI, non-fatal stroke, coronary artery revascularization, and SEE.

In conclusion, clinicians should take into account the risk of thromboembolic and coronary events and bleeding risk, and consider the tradeoff between efficacy benefit and bleeding safety of various available antithrombotic treatments when making treatment decisions for patients with both CAD and AF. More randomized controlled trials that evaluate the optimal antithrombotic strategies´╝îespecially with NOACs, are warranted in these complicated patients.


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Keywords: Atrial Fibrillation, Coronary Artery Disease, Coronary Disease, Diabetes Mellitus, Hemorrhage, Myocardial Infarction, Prevalence, Risk Factors, Stroke, Thrombosis

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