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 CAD^11,12 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 www.clinicaltrials.gov, 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 www.clinicaltrials.gov, 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，especially with NOACs, are warranted in these complicated patients.

References

1. Kralev S, Schneider K, Lang S, et al. Incidence and severity of coronary artery disease in patients with atrial fibrillation undergoing first-time coronary angiography. PLoS One 2011; 6:e24964.
2. Emelia J. Benjamin, Daniel Levy, Sonya M. Vaziri, et al. Independent Risk Factors for Atrial Fibrillation in a Population-Based Cohort. The Framingham Heart Study. JAMA 1994; 271:840-844.
3. Vedovati MC, Becattini C, Agnelli G. Combined oral anticoagulants and antiplatelets: benefits and risks. Intern Emerg Med 2010;5:281-90.
4. Fuster V, Rydén LE, Cannom DS, et al. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. J Am Coll Cardiol 2011;57:e101-98.
5. Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J 2012;33:2719-47.
6. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, Pfeffer M, Hohnloser S, Yusuf S. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006; 367(9526): 1903-12.
7. Anand SS, Yusuf S. Oral anticoagulants in patients with coronary artery disease. J Am Coll Cardiol 2003; 41(4 Suppl S):62S-69S.
8. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF Secondary Prevention and Risk Reduction Therapy for Patients with Coronary and other Atherosclerotic Vascular Disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. J Am Coll Cardiol 2011;58:2432-2446.
9. Lamberts M, Gislason GH.  Lip  GYH, et al. Antiplatelet Therapy for Stable Coronary Artery Disease in Atrial Fibrillation Patients on Oral Anticoagulant: A Nationwide Cohort Study. http://circ.ahajournals.org/content/early/2014/01/27/CIRCULATIONAHA.113.004834.abstract.
10. Anderson JL, Halperin JL, Albert NM, et al. Management of Patients With Atrial Fibrillation (Compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS Recommendations): A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935-1944.
11. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:2564-2603.
12. Task Force Members, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.
13. Amador P, Santos JF, Gonçalves S, et al. Comparison of ischemic and bleeding risk scores in non-ST elevation acute coronary syndromes. Acute Card Care 2011;13:68-75.
14. Hohnloser SH, Oldgren J, Yang S, et al. Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012;125:669-76.
15. Mahaffey KW, Stevens SR, White HD, et al. Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial. Eur Heart J 2014;35:233-41.

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

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