Opinion

EDITORIAL

Atrial Fibrillation Begets Myocardial Infarction Jonathan W. Dukes, MD; Gregory M. Marcus, MD, MAS

For decades, stroke has been the principally recognized and most clinically relevant sequelae of atrial fibrillation (AF).1 However, a recent analysis demonstrated that AF may also lead to worsening renal function, a particularly important observation given that chronic kidney disease has been primarily considered a risk factor for the development of AF.2 While coronary artery disease and myocardial infarction (MI) have been demonstrated to increase AF risk,1 Soliman et al,3 in this issue of JAMA Internal Medicine, show that AF itself may also lead to an increased risk of incident MI. These data therefore add to the growing recognition of important bidirectional relationships between AF and other cardiovascular comorbidities. Just as “AF begets AF,”4 we are learning it may also lead to kidney disease, heart failure, and now MI. As we consider these new findings and their implications, we must first carefully examine the strengths and limitations of this recent study as well as the mechanisms through which these observed associations might occur. Soliman et al3 analyzed data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study,5 a large biracial population-based cohort study designed to investigate regional and racial disparities in stroke mortality. After observing the subset of 23 928 participants without baseline coronary artery disease for almost 7 years, the auRelated article page 107 thors found that 6.8% of participants with prevalent AF had a nearly 2-fold greater risk of incident MI.3 Several strengths of this analysis suggest that the association is likely “true.” Specifically, this was a large population-based sample that was very carefully characterized. The primary outcome for this study, MI, was appropriately rigorously adjudicated. Finally, the primary results persisted after several thorough multivariable analyses that leveraged the wealth of data collected as part of the parent study (including measurements taken during home visits as well as laboratory analyses) to adjust for potential confounding. However, several limitations should be recognized. Although baseline aspirin and warfarin use was included in the multivariable adjustment, there was no assessment of longitudinal anticoagulant use or effectiveness (such as via serial international normalized ratios). However, it would appear unlikely that those without AF were more often taking therapeutic warfarin, and therefore absence of these data may have actually resulted in an underestimation of the prevalent AF–incident MI relationship. Ascertainment of AF relied on either participant self-report of a prior physician diagnosis or the baseline electrocardiogram findings. While participant selfreport might be most prone to inaccuracies, sensitivity analyses that excluded those patients revealed no meaningful jamainternalmedicine.com

changes in their findings. Regardless, as it is now wellrecognized that AF can be asymptomatic and even clinically occult,6 it remains possible that underascertainment of AF was responsible for their observations. For example, perhaps those less likely to report palpitations (and therefore less likely to receive medical attention for AF) would also be less likely to experience chest pain (and therefore less likely to receive an MI diagnosis). On the whole, the results would appear to be valid, prompting the question how might AF lead to MI? The authors suggest that inflammation may be integral to the bidirectional relationship between AF and MI. Indeed, elevated C-reactive protein (CRP) levels have been shown to presage both MI7 and AF.8 More recently, our research group and others have shown that atrial arrhythmias may also enhance inflammation,9-11 with some evidence that inflammatory markers are sequestered in the heart during AF.11 It is therefore plausible to suggest that AF-mediated inflammation may lead to plaque rupture in susceptible patients. However, of interest, adjustment for CRP did not significantly attenuate the relationship between AF and incident MI in the current study, suggesting that alternative mechanisms need to be considered. Just as stroke is attributed to the cerebral embolization of thrombus from the left atrial appendage, these data may reflect the fact that coronary artery embolism from the same source is more common than conventionally thought. Consistent with this, interaction analyses by Soliman et al3 revealed that both African American and female subgroups exhibited an increased MI risk, mirroring the increased risk for stroke in African Americans and women that has been well established in previous studies.1 Indeed, in an autopsy study of patients with MI cited by the authors, nearly a quarter of all MIs attributed to coronary emboli occurred in patients with known AF12—again, given commonly clinically unrecognized AF, this is likely to be an underestimate. If indeed the increased risk of MI in AF was due primarily to thromboemboli arising from the left atrial appendage, one would expect anticoagulation, a proven strategy to mitigate thromboembolic stroke, to also prove especially useful. We therefore explored this possibility by performing a metaanalysis of all the randomized controlled trials that compared systemic anticoagulation with antiplatelet agents or placebo where incident MI was reported. All available primary and secondary stroke prevention randomized clinical trials (RCTs) meeting these criteria and with follow-up of greater than 6 months were identified using the PubMed and the Cochrane RCT databases.13-23 Using a fixed effects model, we found that warfarin reduced the risk of MI by 25%, with an overall relative risk (RR) of 0.75 (95% CI, 0.57-0.99) (Figure). Additional analyses restricted to the antiplatelet comparator trials alone JAMA Internal Medicine January 2014 Volume 174, Number 1

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/21/2015

5

Opinion Editorial

Figure. Meta-analysis of Anticoagulation Studies Comparing Anticoagulation With Antiplatelet Therapy or Placebo in Atrial Fibrillation Source

RR (95% CI)

Weight, %

Anticoagulation vs Placebo SPAF,13 1991

1.00 (0.14-7.07)

1.66

SPINAF,14 1993

0.25 (0.03-2.26)

3.30

EAFT,15 1993

0.38 (0.07-1.94)

4.27

Subtotal (I 2 = 0.0%, P = .62) Anticoagulation vs Antiplatelet SPAF II,16 1994

0.45 (0.16-1.28)

9.24

0.78 (0.40-1.51)

15.98

SIFA,17 1997

1.02 (0.14-7.19)

1.65

AFASAK II,18 1998

0.99 (0.25-3.91)

3.34

PATAF,19 1999

0.72 (0.12-4.23)

2.41

NASPEAF,20 2004

0.34 (0.01-8.25)

1.24

ACTIVE-W,21 2006 BAFTA,22 2007

0.63 (0.38-1.06) 0.99 (0.49-2.01)

30.17 12.54

AVERROES,23 2011

0.85 (0.50-1.47)

23.41

Subtotal (I 2 = 0.0%, P = .98)

0.78 (0.59-1.04)

90.76

Overall (I 2 = 0.0%, P = .97)

0.75 (0.57-0.99)

100.00 0.01

0.1

1.0

10

RR (95% CI)

(RR, 0.78 [95% CI, 0.59-1.04]) and the placebo comparator trials alone (RR, 0.45 [95% CI, 0.16-1.28]) showed similar trends without statistical significance. Since aspirin, or antiplatelet agents in general, are believed to be particularly effective for preventing spontaneous (type 1) MI (from atherosclerotic plaque rupture leading to thrombus via platelet activation),24 evidence in favor of the superiority of warfarin (generally believed to be most effective for stasis-related thrombus formation)25 likely supports the contention that atrial-sourced thromboemboli are important in AF-associated MI. Although the findings of the study provided by Soliman et al3 are informative, they do not suggest a change in our AF treatment strategies. The addition of aspirin to systemic anticoagulation regimens in AF results in increased bleeding without any clear benefit.26 In addition, as the increased MI rate was observed only among those with a CHADS2 score27 of ARTICLE INFORMATION Author Affiliations: Division of Cardiology, Section of Electrophysiology, University of California, San Francisco. Corresponding Author: Gregory M. Marcus, MD, MAS, Division of Cardiology, Section of Electrophysiology, University of California, San Francisco, 505 Parnassus Ave, M-1180B, PO Box 0124, San Francisco, CA 94143-0124 (marcusg @medicine.ucsf.edu). Published Online: November 4, 2013. doi:10.1001/jamainternmed.2013.11392. Conflict of Interest Disclosures: None reported. REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6-e245. 2. Bansal N, Fan D, Hsu CY, Ordonez JD, Marcus GM, Go AS. Incident atrial fibrillation and risk of 6

Results are presented as relative risk (RR) of myocardial infarction of warfarin vs placebo or warfarin vs antiplatelet therapy with 95% CI. An RR less than 1 favors anticoagulation use, while an RR greater than 1 favors placebo or antiplatelet therapy. The results for trials using placebo as a comparator alone and antiplatelet agents (including aspirin) as a comparator alone are shown by pale-shaded diamonds. The dark-shaded diamond shows the overall result for the meta-analysis of all studies.

greater than 1,3 these findings would not necessarily warrant anticoagulation in a new population of patients with AF. Instead, the change in management may be most applicable to patients with MI. For example, we now know that a large proportion of strokes are due to subclinical AF.1 Perhaps the same is true for MI? Future studies can teach us if more aggressive or long-term arrhythmia monitoring is useful after MI and, in turn, if standard anticoagulation for AF is sufficient to address the heightened MI risk among selected populations. Soliman and colleagues are to be commended for producing this thought-provoking research that broadens our understanding of AF. In short, AF begets many problems. There is clearly a complex bidirectional relationship between AF and multiple conditions. Our regular clinical practice must extend beyond the common question “why does this patient have AF?” to “could this current problem have occurred due to AF?”

end-stage renal disease in adults with chronic kidney disease. Circulation. 2013;127(5):569-574. 3. Soliman EZ, Safford MM, Muntner P, et al. Atrial fibrillation and the risk of myocardial infarction [published online November 4, 2013]. JAMA Intern Med. doi:10.1001/jamainternmed.2013.11912. 4. Wijffels MC, Kirchhof CJ, Dorland R, Allessie MA. Atrial fibrillation begets atrial fibrillation: a study in awake chronically instrumented goats. Circulation. 1995;92(7):1954-1968. 5. Howard VJ, Cushman M, Pulley L, et al. The reasons for geographic and racial differences in stroke study: objectives and design. Neuroepidemiology. 2005;25(3):135-143. 6. Healey JS, Connolly SJ, Gold MR, et al; ASSERT Investigators. Subclinical atrial fibrillation and the risk of stroke. N Engl J Med. 2012;366(2):120-129. 7. Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-874. 8. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation. 2003;108(24):3006-3010.

9. Marcus GM, Smith LM, Glidden DV, et al. Markers of inflammation before and after curative ablation of atrial flutter. Heart Rhythm. 2008;5(2):215-221. 10. Kallergis EM, Manios EG, Kanoupakis EM, et al. The role of the post-cardioversion time course of hs-CRP levels in clarifying the relationship between inflammation and persistence of atrial fibrillation. Heart. 2008;94(2):200-204. 11. Marcus GM, Smith LM, Ordovas K, et al. Intracardiac and extracardiac markers of inflammation during atrial fibrillation. Heart Rhythm. 2010;7(2):149-154. 12. Prizel KR, Hutchins GM, Bulkley BH. Coronary artery embolism and myocardial infarction. Ann Intern Med. 1978;88(2):155-161. 13. Stroke Prevention in Atrial Fibrillation Study: final results. Circulation. 1991;84(2):527-539. 14. Ezekowitz MD, Bridgers SL, James KE, et al; Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. Warfarin in the

JAMA Internal Medicine January 2014 Volume 174, Number 1

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/21/2015

jamainternalmedicine.com

Editorial Opinion

prevention of stroke associated with nonrheumatic atrial fibrillation. N Engl J Med. 1992;327(20):14061412. 15. EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993;342(8882):1255-1262. 16. Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet. 1994;343(8899):687-691. 17. Morocutti C, Amabile G, Fattapposta F, et al; SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. Stroke. 1997;28(5):1015-1021. 18. Gulløv AL, Koefoed BG, Petersen P, et al. Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Arch Intern Med. 1998;158(14):1513-1521. 19. Hellemons BS, Langenberg M, Lodder J, et al. Primary prevention of arterial thromboembolism in

jamainternalmedicine.com

non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ. 1999;319(7215):958-964. 20. Pérez-Gómez F, Alegría E, Berjón J, et al; NASPEAF Investigators. Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. J Am Coll Cardiol. 2004;44(8):1557-1566. 21. Connolly S, Pogue J, Hart R, et al; ACTIVE Writing Group of the ACTIVE Investigators. 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):19031912. 22. Mant J, Hobbs FDR, Fletcher K, et al; BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA):

a randomised controlled trial. Lancet. 2007;370(9586):493-503. 23. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-817. 24. Patrono C. Aspirin as an antiplatelet drug. N Engl J Med. 1994;330(18):1287-1294. 25. Lip GY, Lowe GD, Rumley A, Dunn FG. Increased markers of thrombogenesis in chronic atrial fibrillation: effects of warfarin treatment. Br Heart J. 1995;73(6):527-533. 26. Lane DA, Raichand S, Moore D, Connock M, Fry-Smith A, Fitzmaurice DA; Steering Committee. Combined anticoagulation and antiplatelet therapy for high-risk patients with atrial fibrillation: a systematic review. Health Technol Assess. 2013;17(30):1-188. 27. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-2870.

JAMA Internal Medicine January 2014 Volume 174, Number 1

Copyright 2014 American Medical Association. All rights reserved.

Downloaded From: http://archinte.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/21/2015

7

Atrial fibrillation begets myocardial infarction.

Atrial fibrillation begets myocardial infarction. - PDF Download Free
198KB Sizes 0 Downloads 0 Views