- Email: [email protected]
Aspirin to Prevent Sudden Cardiac Death in Athletes with High Coronary Artery Calcium Scores
Accepted Manuscript
Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores Arthur J. Siegel M.D. , Timothy D. Noakes M.D. PII: DOI: Reference:
S0002-9343(18)30938-0 https://doi.org/10.1016/j.amjmed.2018.09.015 AJM 14841
To appear in:
The American Journal of Medicine
Please cite this article as: Arthur J. Siegel M.D. , Timothy D. Noakes M.D. , Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores , The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.09.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Clinical Significance
Cardiac arrests due to coronary heart disease have increased in middle-aged males during marathons and triathlons in the U.S. since 2000. Coronary artery calcium scores over 100 Agatston units indicate a 10-year cardiac risk
CR IP T
greater than 7.5% at which threshold aspirin for primary prevention is justified as shown to reduce first heart attacks in same-aged males.
Aspirin use is prudent to reduce exertional cardiac arrest and death in susceptible
AC
CE
PT
ED
M
AN US
athletes after considering the benefit and risks with their physician.
ACCEPTED MANUSCRIPT
Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores Subtitle: Reducing sudden cardiac death in high-risk athletes Arthur J. Siegel, M.D.1,2,3, Timothy D. Noakes, M.D.4
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Division of General Internal Medicine1, Massachusetts General Hospital, Boston MA USA, Department of Internal Medicine2, McLean Hospital, Belmont, MA USA, Harvard Medical School3, Boston, MA, USA, Department of Human Biology4, University of Cape Town, Cape Town, South Africa
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McLean Hospital 115 Mill Street, Belmont, MA 02478-1064 TEL: 617.855.2358 FAX: 617.855.3731 EMAIL: [email protected]
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Word count: 2715 References: 57 Key words: marathons, cardiac arrest, coronary artery calcium scores, aspirin prophylaxis Conflicts of interest: none Disclaimer: both authors had access to all the information presented herein and both contributed to the writing of this manuscript
ACCEPTED MANUSCRIPT
Abstract:
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While proficient cardiac resuscitation has improved survival following cardiac arrest during road races in Japan, this accomplishment does not address coronary artery disease as the underlying cause of an increasing frequency of cardiac arrest in middle-aged males during marathons and ironman triathlons in the United States since the year 2000. Based on the high prevalence of subclinical coronary artery disease by cardiac computed tomography in endurance athletes with low conventional cardiac risk
AN US
factor profiles, we recommend coronary artery calcium scores as a more reliable and independent predictor of incident cardiac events including death as validated among adults aged 30-46 years. Scores over 100 Agatston units indicate a 10-year cardiac risk of 7.5% at which additional measures for primary prevention are recommended including aspirin, as shown conclusively to reduce first myocardial infarctions in same-aged men in a prospective double-blind controlled trial. Targeted screening for
M
subclinical coronary atherosclerosis with coronary artery calcium scores is prudent to guide
appropriately dosed aspirin use to mitigate the increasing frequency of sports-related sudden cardiac
ED
death due to plaque rupture.
PT
While the incremental cardioprotective benefit of increasing sports participation is indisputable, vigorous exercise may also trigger sudden cardiac death (1). A reduction in
CE
fatalities by proficient cardiac resuscitation in road races in Japan warrants timely replication worldwide, as prospective registries in the United States and Europe document a similar high
AC
incidence of cardiac arrest (1 per 65,509 or 1.53 per 100,000) during road races mainly in males with an average age under 50 years (2-4). Their accomplishment does not, however, address coronary artery disease as the root cause of excess of premature cardiovascular morbidity and mortality during marathons and ironman triathlons in the United States since the year 2000 (36).
ACCEPTED MANUSCRIPT
Based on male gender and the marathon as significant risk factors for cardiac arrest in U.S. races since 2000, a single dose of pre-race aspirin has been recommended to mitigate the transient high cardiac risk for participants in marathons and triathlons whose 10-year cardiovascular risk usually falls below the threshold indicating a net benefit for continuous prophylaxis by conventional measures (7-10). An increased incidence of acute cardiovascular
CR IP T
events after discontinuing aspirin for primary prevention is the latest evidence to suppor this recommendation, which corroborates the conclusive (44%) decrease in first acute myocardial infarctions in middle-aged men in the Physicians Health Study, a randomized controlled primary prevention trial (11,12).
AN US
Based on the increased prevalence of subclinical coronary artery disease demonstrated in
masters endurance athletes with low conventional risk factor profiles, coronary artery calcium scores are recommended over conventional calculators as an independent predictor of cardiac events to guide use of additional measures for primary prevention (13-16). The inverse correlation of coronary artery plaque volume with short-term cardiac event-free survival and
M
documentation of coronary atherosclerosis as the cause of race-related sudden cardiac deaths even in the most experienced runners attest to the morbidity and mortality associated with
ED
what has been called by some "hearts of stone” of undetermined significance (17-23).
PT
An explanation for increased coronary atherosclerosis in experienced endurance athletes compared to matched control persons is that inflammation during repetitive bouts of exertional
CE
rhabdomyolysis promotes calcification through recurrent injury to vascular endothelium (2426). Repetitive episodes of acute inflammation due to exertional rhabdomyolysis may accelerate atherogenesis similar to the mechanism for this finding in the clinical setting of
AC
cocaine dependency and radiation-induced coronary artery disease (27,28). This explanation revisits a speculation in the first medical study on in the Boston Marathon runners in 1899 of an adverse effect of “violent and prolonged muscular exercise upon the heart” (29). We now know that male runners in the Boston Marathon, who are asymptomatic except for skeletal muscle soreness, demonstrate post-race biomarkers similar to those seen in patients with acute coronary syndromes, including markers of inflammation (interlukin-6, C reactive protein), a
ACCEPTED MANUSCRIPT
hemostatic imbalance with procoagulant effects including in vivo platelet activation and release of cardiac enzymes (cardiac troponins, NT-pro B-natriuretic peptide) consistent with transient myocardial strain and ventricular dysfunction as documented by echocardiography (30-33). The high prevalence of subclinical coronary artery disease detected by cardiac computed
CR IP T
tomography in experienced middle-aged male runners makes coronary artery calcium scores "the right test at the right time” to stratify cardiac risk as a guide to aspirin use (34,35).
Associated in a graded fashion with incident coronary heart disease and death in adults aged 32 to 46, coronary artery calcium scores greater than 100 Agatston units identify a 10-year
cardiovascular risk above the 7.5% threshold, justifying additional measures for primary
AN US
prevention including aspirin prophylaxis as evidenced–based to be cardioprotective in the same-aged men (36-38). Such targeted use to reduce the high risk for acute cardiac events due to rupture
of transiently unstable atherosclerotic plaques during strenuous sports is distinct from recent evidence showing no clear benefit in persons at average risk (39).
M
One’s coronary artery calcium score is the test result every athlete should know to discuss aspirin use with their primary care physician (40,41). In contrast to zero or minimal findings
ED
(42), scores greater than 100 indicate a net benefit from aspirin use, also providing the athlete with the advantage of having on board the only medication with a class 1A recommendation for
PT
prehospital administration in the event of an acute coronary syndrome. Dosed according to body weight, aspirin use may mitigate an athlete’s concern about becoming a statistic on the
CE
up-slope of the U-shaped curve showing incremental cardiovascular risk with exercise intensity, perhaps like having one's cake (if chocolate) and eating it, too (43-48).
AC
A predominance of current clinical evidence in our view suggests that aspirin use guided by coronary artery calcium scores can decrease cardiovascular morbidity and mortality in middleaged male endurance athletes as demonstrated in women at high risk for preterm preeclampsia with low-dose aspirin (49). Such use is similar to aspirin for reducing exertional sudden cardiac death due to coronary heart disease in U.S. firefighters in a case-controlled study with findings similar to acute cardiac event registries in runners (50,51).
ACCEPTED MANUSCRIPT
The efficacy of aspirin for reducing excess premature cardiac morbidity and mortality in athletes can be assessed prospectively once usage gains traction based on wider endorsement from the marathon medical community (52). The future of endurance events for recreational athletes may rest upon finding a solution to the increasing frequency acute cardiac events due to coronary heart disease. Safe, inexpensive and readily available worldwide, aspirin use is
CR IP T
congruent with validated clinical paradigms including the proof of concept that modulation of atherogenesis with anti-inflammatory agents is associated with reduced cardiovascular event rates (53,54). It would be serendipitous if a remedy known to Hippocrates shortly after
Pheidippides’ triumph were to reduce recurrences of his tragic demise in the modern era below the frequency of one in every 50,000 participants (Figure 1) (55,56). Risk stratification by
AN US
coronary artery calcium scores to guide aspirin use represents the best opportunity in our view to mitigate the increasing frequency of exertional cardiac arrest and sudden death due to
M
rupture of coronary artery plaques in middle-aged male athletes (57).
Clinical Significance:
The frequency of cardiac arrest due to coronary heart disease has increased in middle-
ED
PT
aged males during marathons and triathlons in the U.S. since 2000. Coronary artery calcium scores over 100 Agatston units indicate a 10-year risk greater
CE
than 7.5%, which justifies aspirin use for primary prevention as evidence-based to reduce first heart attacks in same-aged males. Aspirin use is prudent to prevent exertional cardiac arrest in susceptible athletes after
AC
considering this benefit and risks with their physician.
References:
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1. Albert CM, Mittleman MA, Chae CU, Lee I-M, Hennekens CH, Manson JE. Triggering of sudden death from cardiac causes by vigorous exercise. N Engl J Med. 2000; 343: 13551366. 2. Kinoshi T, Tanaka S, Sagisaka R, et.al. Mobile Automated External Defibrillator Response
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System during Road Races. N Engl J Med. 2018; 379(5):488-489. 3. Kim JH, Malhotra R, Chiampas G, et al. Race-Associated Cardiac Arrest Event Registry (RACER) Study Group. Cardiac arrest during long-distance running races. N Engl J Med. 2012; 366(2):130-140.
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4. Gerardin B, Collet JP, Mustafic H, et al. Registry on acute cardiovascular events during endurance running races: The prospective RACE Paris registry. Eur Heart J. 2015;8:472480.
5. Karam N, Petchmajou L, Dumas F, et al. Comprehensive assessment of coronary artery Circulation 2018.
May 02, pii:
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disease and sports-related sudden cardiac arrest.
CIRCULATIONAHA.118.034664. doi: 10.1161/CIRCULATIONAHA.118.034664.
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6. Harris KM, Creswell LL, Haas TS, Thomas T, Tung M, Isaacson BS, et al. Death and cardiac arrest in U.S. triathlon participants, 1980 to 2016: a case series. Ann Int Med.
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2017;167(8):529-535.
7. Siegel AJ. Pre-race aspirin to protect susceptible runners from cardiac arrest during
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marathons: is opportunity knocking? Open Heart 2015. July 2; 2(1): e000102. Doi.
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10.1136/openhrt-2014-000102. 8. Siegel AJ, Noakes TD. Can prerace aspirin prevent sudden cardiac death during marathons? Br J Sports Med. 2017;51(22):1579-1581.
9. Siegel AJ. Death and cardiac arrest in US triathlon participants. Ann Int Med. 2018;168; 752–753.
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10. Bibbins-Domingo K for United States Preventative Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force recommendation statement. Ann Int Med. 2016;164:83 6-845. 11. Sundstrom J, Hedberg J, Thursessen M, Aarskog P, Johannesen KM, Oldgren J. Low-dose
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aspirin discontinuation and risk of cardiovascular events. Circulation. 2017;136:1183– 1192.
12. Steering Committee of the Physicians’ Health Study Research Group. Final report on the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med. 1989; 321(3):
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129-135.
13. Roberts WO, Schwartz RS, Garberich RF, et.al. Fifty men, 3510 marathons, cardiac risk factors and coronary artery calcium scores. Med Sci Sports Exerc. 2017; 49(12):23692373.
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14. Merghani A, Maestrini V, Rosmini S, et AL. Prevalence of subclinical coronary artery disease in Masters endurance athletes with low atherosclerotic risk profiles. Circulation
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2017;136(2):126–137.
15. Aengevaeren VL, Mostard A, Braber TL, et al. Relationship between lifelong exercise
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volume and coronary atherosclerosis in athletes. Circulation 2017;136(2):138–148.
16. Curfman GD. Prediction of cardiovascular risk to guide primary prevention. JAMA Intern
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Med. 2018; 178(9): 1240–1241. 17. Schwartz RS, Merkel Kraus S, Schwartz JG, et al. Increased Coronary artery plaque volume among male marathon runners. Missouri Medicine 2014;111:89-94.
18. Mohlenkamp S, Lehmann N, Breuckmann F, et al. Running: The risk of coronary events: Prevalence and prognostic relevance of coronary atherosclerosis in marathon runners. Eur Heart J. 2008; 29(15): 1903-1910.
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19. Mohlenkamp S, Leineweber k, Lehmann N, et al. Coronary atherosclerosis burden, but not transient troponin elevation, predicts long-term outcome in recreational marathon runners. Basic Res Cardiol. 2014 Jan; 109(1): 391-95.
of stone”. Circuilation 2017;136(2):149-151.
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20. Baggish AL, Levine BD. Coronary artery calcification among endurance athletes: ”hearts
21. Rao P, Hutter AM, Baggish AL. The limits of cardiac performance: can too much exercise
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damage the heart? Am J Med. 2018;000: 1-6 E-PUB ahead of print
22. Tunstall Pedoe DS. Marathon cardiac deaths: The London experience. Sports Med.
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2007; 37 (4-5): 448–450.
23. Noakes TD, Opie LH, Rose AG, Kleynhaus PH, Schepers NJ, Dowdeswell R. Autopsy-
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proved coronary atherosclerosis in marathon runners. N Engl J Med. 1979;301:86-89.
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24. Adams V. CrossTalk proposal: Acute exercise elicits damage to the endothelial layer of systemic blood vessels in healthy individuals. J Physiol. 2018; 596 (4): 537-539.
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25. Siegel AJ. Does habitual high intensity exercise provoke coronary atherosclerosis due to repetitive inflammatory injury to the vascular endothelium? J Physiol. 2018; 596 (4):
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537-539. Crosstalk supporting information; tjp12765-sup-0001-Comments.docx https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP274750 , access August 20, 2018.
26. Nakahara T, Strauss HW. From inflammation to calcification in atherosclerosis. Eur J Nucl Med Mol Imaging. 2017;44: 858-860.
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27. Siegel AJ, Mendelson JH, Sholar MB, et al. Effect of cocaine usage on C-reactive protein, vonWillebrand factor and fibrinogen. Am J Cardiol. 2002;89:27-29.
28. Borges N, Kapadia SR. Radiation-induced CAD: incidence and management outcomes. Expert analysis. J Amer Coll Cardiol. May 25, 2018.
heart. Philadelphia Med J. 1899;1233-1239.
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29. Williams H, Arnold H. The effects of violent and prolonged muscular exercise upon the
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30. Siegel AJ, Silverman LM, Lopez RE. Creatine kinase elevations in marathon runners: relationship to training and competition. Yale J Biol Med. 1980;53(4):275-9. 31. Siegel AJ, Stec JJ, Lipinska I, Van Cott EM, Lewandrowski KB, Ridker PM, Tofler GH. Effect of marathon running on inflammatory and hemostatic markers. Am J Cardiol. 2001;88:35-37.
32. Kratz A, Wood MJ, Siegel AJ, Hiers JR, VanCott EM. Effects of marathon running on platelet
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activation markers. direct evidence for in vivo platelet activation. Am J Clin Pathol.
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2006;125:296-300.
33. Neilan TG, Januzzi JL, Lee-Lewandrowski E, et al. Myocardial injury and ventricular dysfunction related to training adequacy among non-competitive participants in the Boston Marathon.
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Circulation. 2006;114(22):2325-33.
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34. Tsiflikas I, Thomas C, Fallmann C, et al. Prevalence of the subclinical coronary artery disease in middle-aged, male marathon runners detected by cardiac CT. Rofo. 2015;
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320(3): 242-244. 35. Wilkins JT, Lloyd-Jones DM. USPSTF Recommendations for assessment of cardiovascular risk with nontraditional risk factors: Finding the right test for the right patients. JAMA 2018;320(3):242-244. 36. Greenland P, Blaha MJ, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Amer Coll Cardiol. 2018;72(4);434-447.
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37. Carr JJ, Jacobs DR Jr, Terry JG, et al. Association of coronary artery calcium in adults aged 32 to 46 with incident coronary heart disease and death. JAMA Cardiol. 2017;2(4): 391399. 38. Budoff MJ, Young R, Burke G, et al. Ten-year association of coronary artery calcium with
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atherosclerotic cardiovascular disease (ASCVD) events: The multi-ethnic study of atherosclerosis (MESA). Eur Heart J. 2018;39(25):2401-2408.
39. Gaziano JM, Brotons C, Coppolecchia R, et al. Use of aspirin to reduce risk of initial
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vascular events in patients at moderate risk cardiovascular disease (ARRIVE); a randomized,double-blind, placebo-controlled trial. Lancet. 2018; Aug 24. pii: S 0140– 6736 (18) 31924–X.
2018;26(3):111-112.
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40. Sengkerij P, Hemels MEW. What the elite athlete does not want to know. Neth Heart J.
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41. Brody JE. One more heart test to consider: a calcium scan. Personal health/New York
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Times/April 2, 2018. https://nyti.ms/2Gsk3w3. (accessed 14 May, 2018).
42. Joshi PH, Blaha MJ, Budoff MJ, et al. The 10-year prognostic value of zero and minimal
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CAC. J Amer Coll Cardiol.2017;10 (8):957-958. 43. Rothwell PM, Cook NR, Gaziano JM, et al. Effect of aspirin on risks of vascular events and
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cancer according to bodyweight and dose: Lancet 2018: analysis of individual patient data from randomized trials. Lancet 2018;392(10145):387-399
44. Merghani A, Malhotra A, Sharma S. The U-shaped relationship between exercise and cardiac morbidity. Trends Cardiovasc Med. 2016; 26(3):232-240.
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45. Schnohr P, O’Keefe JH, Marott JL Lange P, Jensen GB. Dose of jogging and long-term mortality: The Copenhagen city heart study. J Am Coll Cardiol. 2015;65(5):411-419. 46. Ducharme J. Why you probably shouldn’t worry about exercising yourself to death. TIME Health. Oct 19, 2017. http://time.com/4987426/too-much-exercise/ (accessed 14
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November, 2017).
47. Mittleman MA, Maclure M, Tofler GH, et al. Triggering of acute myocardial infarction by heavy physical exertion—protection against triggering by regular exertion. N Engl J Med.
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1993; 329: 1677–168
48. Ren Y, Liu Y, Sun X-Z, et al. Chocolate consumption and risk of cardiovascular diseases: meta–analysis of prospective studies. Heart E PUB ahead of print: Aug 6,2018: doi: 10/11/1936/heartjnl 2018—313131
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49. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med. 2017;377(7):613-622.
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50. Smith DL, Hailer JM, Korre M, et al. Pathoanatomic findings associated with duty-related cardiac death in US firefighters: a case-controlled study. J Am Heart Assoc. 2018; 7:
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e0096446.
51. Kales SN, Smith DL. Firefighting and the heart: implications for prevention. Circulation
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2017;135:1296-1299.
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52. Siegel AJ. IMMDA Advisory, 2015: pre-race aspirin to prevent heart attack and/or cardiac
arrest
during
long-distance
running.
Available
at
http://immda.org/wpcontent/uploads/2015/Spring-2015-Pre-race ASA.pdf (accessed 14 July, 2016).
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53. Siegel AJ. Fatal water intoxication and cardiac arrest in runners during marathons: prevention and treatment based on validated clinical paradigms. Am J Med. 2015 Oct;128(10):1070-1075. 54. Ridker PM, Libby P, MacFadyen JG, et al. Modulation of the interleukin–6 signaling
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pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (Cantos). European Heart Journal 2018; ehy310, published 26 August 2018 doi.org/10.1093/eurheartj/rhy310
55. Siegel AJ. Pheidippides Redux: reducing the acute cardiac risk during marathon running.
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Am J Med. 2012;125:630-635.
56. Waite O, Smith A, Madge L, Spring H, Noret N. Sudden cardiac death in marathons: a systematic review. Phys Sportsmed. 12016;44:79-84.
57. Noakes T. Time to quit that marathon running? Not quite yet! Basic Res Cardiol. 2014;
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109: 395-396.
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ACCEPTED MANUSCRIPT
Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores Arthur J. Siegel M.D. , Timothy D. Noakes M.D. PII: DOI: Reference:
S0002-9343(18)30938-0 https://doi.org/10.1016/j.amjmed.2018.09.015 AJM 14841
To appear in:
The American Journal of Medicine
Please cite this article as: Arthur J. Siegel M.D. , Timothy D. Noakes M.D. , Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores , The American Journal of Medicine (2018), doi: https://doi.org/10.1016/j.amjmed.2018.09.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Clinical Significance
Cardiac arrests due to coronary heart disease have increased in middle-aged males during marathons and triathlons in the U.S. since 2000. Coronary artery calcium scores over 100 Agatston units indicate a 10-year cardiac risk
CR IP T
greater than 7.5% at which threshold aspirin for primary prevention is justified as shown to reduce first heart attacks in same-aged males.
Aspirin use is prudent to reduce exertional cardiac arrest and death in susceptible
AC
CE
PT
ED
M
AN US
athletes after considering the benefit and risks with their physician.
ACCEPTED MANUSCRIPT
Aspirin use to prevent exertional cardiac arrest in athletes with high coronary artery calcium scores Subtitle: Reducing sudden cardiac death in high-risk athletes Arthur J. Siegel, M.D.1,2,3, Timothy D. Noakes, M.D.4
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Division of General Internal Medicine1, Massachusetts General Hospital, Boston MA USA, Department of Internal Medicine2, McLean Hospital, Belmont, MA USA, Harvard Medical School3, Boston, MA, USA, Department of Human Biology4, University of Cape Town, Cape Town, South Africa
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McLean Hospital 115 Mill Street, Belmont, MA 02478-1064 TEL: 617.855.2358 FAX: 617.855.3731 EMAIL: [email protected]
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Word count: 2715 References: 57 Key words: marathons, cardiac arrest, coronary artery calcium scores, aspirin prophylaxis Conflicts of interest: none Disclaimer: both authors had access to all the information presented herein and both contributed to the writing of this manuscript
ACCEPTED MANUSCRIPT
Abstract:
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While proficient cardiac resuscitation has improved survival following cardiac arrest during road races in Japan, this accomplishment does not address coronary artery disease as the underlying cause of an increasing frequency of cardiac arrest in middle-aged males during marathons and ironman triathlons in the United States since the year 2000. Based on the high prevalence of subclinical coronary artery disease by cardiac computed tomography in endurance athletes with low conventional cardiac risk
AN US
factor profiles, we recommend coronary artery calcium scores as a more reliable and independent predictor of incident cardiac events including death as validated among adults aged 30-46 years. Scores over 100 Agatston units indicate a 10-year cardiac risk of 7.5% at which additional measures for primary prevention are recommended including aspirin, as shown conclusively to reduce first myocardial infarctions in same-aged men in a prospective double-blind controlled trial. Targeted screening for
M
subclinical coronary atherosclerosis with coronary artery calcium scores is prudent to guide
appropriately dosed aspirin use to mitigate the increasing frequency of sports-related sudden cardiac
ED
death due to plaque rupture.
PT
While the incremental cardioprotective benefit of increasing sports participation is indisputable, vigorous exercise may also trigger sudden cardiac death (1). A reduction in
CE
fatalities by proficient cardiac resuscitation in road races in Japan warrants timely replication worldwide, as prospective registries in the United States and Europe document a similar high
AC
incidence of cardiac arrest (1 per 65,509 or 1.53 per 100,000) during road races mainly in males with an average age under 50 years (2-4). Their accomplishment does not, however, address coronary artery disease as the root cause of excess of premature cardiovascular morbidity and mortality during marathons and ironman triathlons in the United States since the year 2000 (36).
ACCEPTED MANUSCRIPT
Based on male gender and the marathon as significant risk factors for cardiac arrest in U.S. races since 2000, a single dose of pre-race aspirin has been recommended to mitigate the transient high cardiac risk for participants in marathons and triathlons whose 10-year cardiovascular risk usually falls below the threshold indicating a net benefit for continuous prophylaxis by conventional measures (7-10). An increased incidence of acute cardiovascular
CR IP T
events after discontinuing aspirin for primary prevention is the latest evidence to suppor this recommendation, which corroborates the conclusive (44%) decrease in first acute myocardial infarctions in middle-aged men in the Physicians Health Study, a randomized controlled primary prevention trial (11,12).
AN US
Based on the increased prevalence of subclinical coronary artery disease demonstrated in
masters endurance athletes with low conventional risk factor profiles, coronary artery calcium scores are recommended over conventional calculators as an independent predictor of cardiac events to guide use of additional measures for primary prevention (13-16). The inverse correlation of coronary artery plaque volume with short-term cardiac event-free survival and
M
documentation of coronary atherosclerosis as the cause of race-related sudden cardiac deaths even in the most experienced runners attest to the morbidity and mortality associated with
ED
what has been called by some "hearts of stone” of undetermined significance (17-23).
PT
An explanation for increased coronary atherosclerosis in experienced endurance athletes compared to matched control persons is that inflammation during repetitive bouts of exertional
CE
rhabdomyolysis promotes calcification through recurrent injury to vascular endothelium (2426). Repetitive episodes of acute inflammation due to exertional rhabdomyolysis may accelerate atherogenesis similar to the mechanism for this finding in the clinical setting of
AC
cocaine dependency and radiation-induced coronary artery disease (27,28). This explanation revisits a speculation in the first medical study on in the Boston Marathon runners in 1899 of an adverse effect of “violent and prolonged muscular exercise upon the heart” (29). We now know that male runners in the Boston Marathon, who are asymptomatic except for skeletal muscle soreness, demonstrate post-race biomarkers similar to those seen in patients with acute coronary syndromes, including markers of inflammation (interlukin-6, C reactive protein), a
ACCEPTED MANUSCRIPT
hemostatic imbalance with procoagulant effects including in vivo platelet activation and release of cardiac enzymes (cardiac troponins, NT-pro B-natriuretic peptide) consistent with transient myocardial strain and ventricular dysfunction as documented by echocardiography (30-33). The high prevalence of subclinical coronary artery disease detected by cardiac computed
CR IP T
tomography in experienced middle-aged male runners makes coronary artery calcium scores "the right test at the right time” to stratify cardiac risk as a guide to aspirin use (34,35).
Associated in a graded fashion with incident coronary heart disease and death in adults aged 32 to 46, coronary artery calcium scores greater than 100 Agatston units identify a 10-year
cardiovascular risk above the 7.5% threshold, justifying additional measures for primary
AN US
prevention including aspirin prophylaxis as evidenced–based to be cardioprotective in the same-aged men (36-38). Such targeted use to reduce the high risk for acute cardiac events due to rupture
of transiently unstable atherosclerotic plaques during strenuous sports is distinct from recent evidence showing no clear benefit in persons at average risk (39).
M
One’s coronary artery calcium score is the test result every athlete should know to discuss aspirin use with their primary care physician (40,41). In contrast to zero or minimal findings
ED
(42), scores greater than 100 indicate a net benefit from aspirin use, also providing the athlete with the advantage of having on board the only medication with a class 1A recommendation for
PT
prehospital administration in the event of an acute coronary syndrome. Dosed according to body weight, aspirin use may mitigate an athlete’s concern about becoming a statistic on the
CE
up-slope of the U-shaped curve showing incremental cardiovascular risk with exercise intensity, perhaps like having one's cake (if chocolate) and eating it, too (43-48).
AC
A predominance of current clinical evidence in our view suggests that aspirin use guided by coronary artery calcium scores can decrease cardiovascular morbidity and mortality in middleaged male endurance athletes as demonstrated in women at high risk for preterm preeclampsia with low-dose aspirin (49). Such use is similar to aspirin for reducing exertional sudden cardiac death due to coronary heart disease in U.S. firefighters in a case-controlled study with findings similar to acute cardiac event registries in runners (50,51).
ACCEPTED MANUSCRIPT
The efficacy of aspirin for reducing excess premature cardiac morbidity and mortality in athletes can be assessed prospectively once usage gains traction based on wider endorsement from the marathon medical community (52). The future of endurance events for recreational athletes may rest upon finding a solution to the increasing frequency acute cardiac events due to coronary heart disease. Safe, inexpensive and readily available worldwide, aspirin use is
CR IP T
congruent with validated clinical paradigms including the proof of concept that modulation of atherogenesis with anti-inflammatory agents is associated with reduced cardiovascular event rates (53,54). It would be serendipitous if a remedy known to Hippocrates shortly after
Pheidippides’ triumph were to reduce recurrences of his tragic demise in the modern era below the frequency of one in every 50,000 participants (Figure 1) (55,56). Risk stratification by
AN US
coronary artery calcium scores to guide aspirin use represents the best opportunity in our view to mitigate the increasing frequency of exertional cardiac arrest and sudden death due to
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rupture of coronary artery plaques in middle-aged male athletes (57).
Clinical Significance:
The frequency of cardiac arrest due to coronary heart disease has increased in middle-
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aged males during marathons and triathlons in the U.S. since 2000. Coronary artery calcium scores over 100 Agatston units indicate a 10-year risk greater
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than 7.5%, which justifies aspirin use for primary prevention as evidence-based to reduce first heart attacks in same-aged males. Aspirin use is prudent to prevent exertional cardiac arrest in susceptible athletes after
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considering this benefit and risks with their physician.
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