The association between the size, severity, and location of an MI and risk of developing stroke remains controversial [5]–[14]; nonetheless, practice guidelines recommend anticoagulation in certain settings [15]. For instance, left ventricular (LV) thrombus formation after an MI poses an increased risk of cardioembolism, which is reduced by anticoagulation [7], [14], [16]–[25]. Anterior-wall location of a MI has historically been considered a surrogate marker for potential focal dyskinesia leading to LV aneurysm or thrombus complication, which some estimate occurs in approximately one-third of individuals within the first 2 weeks following an anterior MI [26]. Myocardial infarction treatment patterns and subsequent post-MI complications have evolved dramatically in the past 20 years, particularly with regard to effectiveness and expediency in medication use, revascularization, ventricular imaging, and hospital discharge. As a result, practice patterns vary on whether or not anterior MI alone warrants anticoagulation in an era of early revascularization and coronary artery stent therapy that may reduce LV dysfunction or LV thrombus formation.

The utility of anticoagulation for the prevention of stroke after anterior MI is unclear. Anticoagulation might prevent the development of LV thrombus, which once detected is considered an established risk factor for embolic stroke [7], [14], [16]–[25]. However, previous estimates of anterior MI as an independent risk factor for LV thrombus or stroke have been inconsistent [5]–[14], [16]–[25], and information on their propensity for development after current standard interventions (e.g. antiplatelet and fibrinolytic therapy) for acute MI is limited [14]. Some studies have suggested that LV dysfunction is a stronger predictor of LV thrombus formation [16], [17], [21], [22] and the development of stroke [4]. Hence, the 2005 American College of Cardiology/American Heart Association practice guidelines [15] recommend those with STEMI complicated by LV dysfunction and extensive regional wall-motion abnormalities or LV mural thrombus noted on an imaging study receive a minimum of 3 months of warfarin for secondary prevention of stroke. There have only been a few small, non-blinded, randomized trials and observational studies of warfarin for established LV thrombus after MI for secondary prevention of systemic emboli, and these have demonstrated inconsistent results [36]–[39]. All were conducted before fibrinolytic and antiplatelet therapy had become routine. Our data suggests that overall, anterior MI patients do not have a higher risk of stroke, or death, as compared to other types of MI patients.

No prospective randomized controlled trial using warfarin has been conducted to study its efficacy after anterior STEMI in preventing left ventricular thrombus for prevention of stroke. The Fragmin in Acute Myocardial Infarction trial [40] prospectively demonstrated that administration of subcutaneous dalteparin (150 IU/kg body weight every 12 hours) for the duration of hospital stay after anterior MI reduced the risk of LV thrombus formation by 37 percent. But this trial was underpowered to demonstrate a significant effect on stroke and only followed patient outcomes for 11 days. Administration of subcutaneous heparin after thrombolysis for a STEMI [12], or alone in anterior STEMI [41], also did not demonstrate an effect on stroke. In a retrospective analysis [42], warfarin use in patients with heterogeneous causes of chronic left ventricular dysfunction demonstrated improved survival and risk of hospitalization for heart failure, but had no effect on stroke.

Meta-analyses of randomized controlled studies of moderate intensity warfarin with aspirin therapy after acute coronary syndrome (ACS) have demonstrated a relative risk reduction of stroke of approximately 40–46%, representing an absolute risk reduction between 0.5–1.28 percent [43], [44]. These studies were conducted before routine use of coronary artery stenting and, as warfarin is not considered adequate for preserving stent patency compared to thienopyridine agents [45], [46], [47], its use has lost ground to competing antiplatelet and antithrombin regimens. Warfarin use after a MI has not become the standard of practice within North America also due to concerns regarding its cost-effectiveness [48] and potential bleeding complications [49]. Stroke outcomes after MI may still change as practice patterns incorporate new guidelines based on studies that demonstrated benefit in combined cardiovascular endpoints with the use of various antithrombin agents [50], [51], [52] and newer antiplatelet agents [53], [54] throughout the index hospitalization after acute MI.

Patients who developed stroke after MI were older, had previous hypertension, heart failure, diabetes, prior stroke, and LV dysfunction complicating their index MI (Table 6), in keeping with well established risk factors for stroke following MI. These observations reinforce that secondary prevention efforts should focus on identifying and treating these risk factors for stroke, prior to hospital discharge as opposed to routine pre-emptive anticoagulation of all anterior MI patients. For instance, ACE inhibitor [55], [56], [57], [58] and beta-blocker [59], [60], [61], [62] therapy after acute MI complicated by congestive heart failure or LV dysfunction has demonstrated a 15–20% relative risk reduction in mortality and cardiovascular morbidity within stable patients. Whether a specific class of antihypertensive therapy offers additional protection against stroke post-MI, particularly in prevention of atrial fibrillation, has yet to be determined [63].

A major strength of our study was the longitudinal analysis of medication use and consideration of relative indications for appropriate anticoagulation after index hospitalization, such as atrial dysrhythmia. We also considered relative contraindications to, and complications from, anticoagulation therapy, such as major bleeding that required hospitalization. Our research has some limitations that merit emphasis. Our study was a population-based cohort analysis, and as such has inherent limitations and survival bias associated with its retrospective nature and lack of randomization. As well, the elderly cohort of anterior MI patients who survived to hospital discharge may not represent the general post-MI population. Because we used administrative data to measure stroke outcomes, we were limited in the amount of clinical information regarding the nature of each outcome. For instance, left ventricular ejection fraction data was only available for approximately half of the entire EFFECT cohort. We cannot ascertain data on the development of conditions that did not require hospitalization, such as out-of-hospital atrial fibrillation, stroke or hemorrhage, which may have occurred over the 4 year period, and as such our study may be underpowered due to the limited number of stroke hospitalizations. Ischemic stroke etiologies vary, and may be from causes other than cardioembolism, such as large artery atherosclerosis or small-vessel lacunar disease. In addition, we cannot ascertain the appropriateness of warfarin therapy, intensity of anticoagulation, or compliance in individual patients. For instance, our observation that a significant proportion of warfarin users who developed stroke were concomitantly discharged on an antiarrhythmic agent or digoxin, may suggest that many of these patients developed atrial dysrhythmia, a well-known immediate post-MI complication, and may be appropriately anticoagulated. Finally, we cannot exclude a short-term benefit from anticoagulation during the acute hospitalization phase post-MI as the number, and information on the timing, of stroke prior to discharge is limited.

Table S1