Preventing Sudden Cardiac Death during Marathons with Pre-Race Aspirin

Objectives: Prevention of sudden cardiac death is the number one clinical priority in sports cardiology. While the overall cardiovascular risk of long distance running is acknowledged as low, the frequency of cardiac arrests and sudden death has increased in middle-aged males during marathons since the year 2000. An evidence-based strategy for protecting susceptible runners from these acute cardiac events during races is considered based on identification of the underlying cause. Method: Review of articles in Pub Med on adverse cardiac events during marathons. Findings: Recent epidemiological studies have identified an increasing frequency of cardiac arrest in middle-aged males during marathons since the year 2000 with atherosclerotic heart disease as the main cause of sudden cardiac death. Same-aged asymptomatic middle-aged male physician-runners showed a post-race polymorphonuclear leukocytosis with sequential increases in interleukin-6 and C-reactive protein as a likely consequence of rhabdomyolysis after “hitting the wall”. Increased fibrinogen, von Willebrand factor and D-dimer with in vivo platelet activation indicated a concurrent hemostatic imbalance with pro-coagulant effects. Cardiac troponins I and T and NT-pro-B-type natriuretic peptide were elevated after races as additionally predictive of acute cardiac events in asymptomatic persons. Conclusions: High short-term risk for acute cardiac events in asymptomatic middle-aged male runners is shown by stratification of validated biomarkers, which may render non-obstructive coronary atherosclerotic plaques vulnerable to rupture during marathons. Pre-race aspirin usage is prudent to reduce these events mediated by atherothrombosis based on conclusive evidence for prevention of first acute myocardial infarctions in same-aged healthy male physicians. Prospective studies are needed to determine the efficacy of pre-race low-dose aspirin for curtailing the increasing frequency of race-related cardiac arrest and sudden death in susceptible runners.

Sudden cardiac death is the most tragic event during sports and reducing such events is the number one priority in preventive cardiology [1].While the cardiovascular risk of long distance running is acknowledged as low, the marathon has come to be regarded by many as the gold standard for achieving ideal heart health in spite of the disturbing legacy of Pheidippides in 490 B.C. (Figure 1) [2].Epidemiological studies generated by concern over the persistent occurrence of race-related fatalities now provide robust evidence upon which to evaluate these acute cardiac risks.
A 10-year prospective registry of long distance road races in the United States beginning in the year 2000 showed the overall incidence of cardiac arrest and sudden death to be 1 in 184,000 and 1 in 259,000 runners, respectively, which was interpreted by the authors as lower than expected and thereby good news for runners [3] [4].Male gender and the full marathon compared to half-marathon were significant risk factors among 59 cardiac arrests in runners with an average age of 42 years, which events also increased 2.3-fold in middle-aged males since the year 2005.While the overall rate of cardiac arrest was 1 in 57,000 runners since 1980 in United States marathons by retrospective reporting from race medical directors, such events increased in males over age 29 from 1 in 29,000 to 1 in 22,000 since the year 2000 [5] [6].
Atherosclerotic heart disease was the main cause of marathon-related sudden cardiac death in middle-aged males in two retrospective studies including the report of acute myocardial infarction in 17 of 18 cases in those over 45 years of age [7].The increasing frequency of such race-related acute cardiac events in runners whose metrics for cardiovascular risk fall below the threshold for primary aspirin prophylaxis by current subspecialty guidelines is unexpected, especially given a concurrent decline in cardiac mortality rates in the general population [8].
An explanation for these counter-intuitive findings may emerge from observations on asymptomatic middleaged male physician-runners who provided pre-and post-race blood samples at sequential Boston marathons beginning in the 1980s as attendees at pre-race scientific symposia of the American Medical Athletic Association Elevated post-race creatine kinase as an index of rhabdomyolysis after "hitting the wall" was accompanied by a polymorphonuclear leukocytosis with sequential increases in interleukin(IL)-6 and C-reactive protein [9]- [11].Elevations in these inflammatory biomarkers, which predict acute cardiac events in healthy persons, were accompanied by increased fibrinogen, von Willebrand factor and D-dimer with in vivo platelet activation, indicating a concurrent hemostatic imbalance with pro-coagulant effects [12] [13].Cardiac biomarkers including cardiac troponins I and T and NT-pro-B-type natriuretic peptide were transiently increased after races in these same asymptomatic runners [14]- [16].
Asymptomatic middle-aged male physician-runners morph from low to high short-term risk for acute cardiac events during races as shown by the profile of biomarkers similar to those which occur in patients with acute coronary syndromes [17].Inflammatory mediators such as IL-6 have been directly implicated in promoting rupture of previously silent non-obstructive coronary plaques and leakage of cardiac biomarkers to be predictive of thrombotic events in primary prevention studies [18]- [21].The report of acute myocardial infarction due to coronary thrombosis with plaque rupture in 3 runners immediately after the 2011 Boston marathon is the "smoking gun" regarding the pathophysiological relevance of elevated biomarker findings in asymptomatic runners [22].The increasing cardiac morbidity and mortality associated with marathon running in middle-aged males is due mainly to type 1 myocardial infarction similar to the cause of exertional sudden deaths in same-aged participants in other sports and first responders such as on-duty firemen and police officers [23]- [27].
Similar to the systemic effects of rhabdomyolysis after "hitting the wall" during marathons, inflammation related to severe infections such as community-acquired bacteremia and scrub typhus confer an increased shortterm risk for acute cardiac events [28] [29].Aspirin usage has been demonstrated to be cardio-protective in conditions such as sepsis and preeclampsia, leading to proposed usage for mitigating high short-term risk in runners as in patients with severe infections [30]- [35].A single pre-race low-dose aspirin would confer antithrombotic protection during and for the 24 hours after a race even if taken at the starting line so long as it is not enteric coated [36].Pre-race usage provides runners with the only medication receiving a grade 1A recommendation for pre-hospital treatment of an acute coronary syndrome while minimizing the opportunity for complications such as gastrointestinal bleeding with continuous usage [37].
Responsibility rightly falls upon the marathon medicine community to disclose the transiently increased risk for cardiac arrest in middle-aged males during marathons analogous to the United States Food and Drug Administration's urgent advisory on excess sudden cardiac death based on one case per 1.2 million prescriptions for short-course azithromycin [38] [39].Pre-race aspirin usage was first recommended for males over age 40 only after approval by their physicians at the 2014 Rio de Janeiro marathon, following an advisory from the International Marathon Medical Directors Association (IMMDA) [40] [41].Cardiac arrests nevertheless occurred in male runners at the finish line in the last two Rio marathons including coronary stent placements for severe coronary artery disease after successful resuscitation from cardiac arrest in 2015 (personal communication, Paulo Afonso Lourega de Menezes, M.D., medical director) (Figure 2).
Pre-race aspirin usage rightly qualifies as prudent to offset the high, if transient, cardiac risk during marathons based on conclusive evidence for its prevention of first myocardial infarctions in healthy same-aged male non-running physicians in a randomized controlled primary prevention trial [42].Aspirin has additionally been reported as efficacious for short-term cardio-protection in other clinical conditions which confer inflammatory stress.Pre-race aspirin may be viewed as concordant with current guidelines of the American Heart Association (AHA) and the European Society of Cardiology, which endorse such usage for primary prevention in high-risk subgroups based on appropriate risk stratification [43] [44].Middle-aged males who fall below the risk threshold for continuous aspirin prophylaxis at baseline by current subspecialty guidelines qualify for limited treatment during marathons by risk stratification of validated biomarkers.
Middle-aged males may transition from beneficial effects on the myocardium during recreational marathon training into high short-term risk for acute coronary events during races [45].In contrast to mainly non-preventable causes of sudden cardiac death in younger athletes [46] [47], substantial evidence reviewed above supports the case for aspirin as protective against race-related fatalities in susceptible males.Hard data to establish efficacy might emerge from ongoing epidemiological studies following wider acceptance of pre-race aspirin usage as reaffirmed by IMMDA on behalf of marathon medical directors on four continents in response to ongoing cases [48].
A worst-case scenario would be a continued increase in the rate of cardiac arrest related to ever growing participation among middle-aged males many of whom may run marathons under the misapprehension that this activity intrinsically promotes optimal cardiovascular health.Prospective studies using the registry model would determine the impact of wider acceptance of pre-race aspirin recommended to susceptible participants.A statistically significant decrease in events over time would solidify the standing of such usage without needing a randomized controlled clinical trial specifically in susceptible runners.Demonstration of a greater than 30% reduction in cardiac morbidity and mortality with low-dose aspirin in preeclampsia by a systematic literature review demonstrates the potential for applying new clinical findings to current standards of care [31].
Measurement of coronary artery calcium density may be useful for assessing the utility of pre-race aspirin especially for more experienced runners among whom such scores are paradoxically higher compared to matched non-running controls and inversely related to short-term event-free survival [49]- [52].Disclosure of his personal diagnosis of coronary heart disease by Dave McGillivray, race director of the Boston marathon since 1988, appropriately conveyed the message that even accomplished marathoners are subject to the development of symptomatic coronary atherosclerosis [53].With 1322 runners at the most common age of 46 years among the 35,384 entrants in the 2014 Boston marathon and 50% of all runners over the age of 40, disclosure of these cardiovascular concerns warrants inclusion in "cardiac wellness" for runners in official website of the Boston Athletic Association [54] [55].
Reducing excess race-related cardiac morbidity and mortality in susceptible middle-aged males is an ambitious but realistic goal based on the success of the marathon medical community in curtailing fatalities due to exercise-associated hyponatremic encephalopathy since the year 2000 mainly in young females through a robust consensus process [56]- [58].The health of marathon runners and perhaps the future of the sport may depend on it [59] [60].

Figure 1 .
Figure 1.Pheidippides' sudden cardiac death in the Atheneum in 490 B.C. after declaring victory over the invading Persian army on the Plains of Marathon (by anonymous).Unforseeing one!Yes, he fought on Marathon day: So, when Persia was dust, all cried "To Akropolis!Run, Pheidippides, one race more.Till in Athens he broke, 'Rejoice, we conquer!'" Joy in his blood bursting his heart, he died-the bliss!"Pheidippides" by Robert Browning, 1879.

Figure 2 .
Figure 2. Paulo Afonso Lourega de Menezes, M.D., medical director of the Rio de Janiero marathon, with his team at the finish line medical tent.Male runners in cardiac arrest were successfully resuscitated at the finish line of the 2014 and 2015 in spite of their recommendation that males over age 40 take pre-race aspirin only after approval by their personal physicians.