Stroke Following Myocardial Infarction
ABSTRACT & COMMENTARY
Synopsis: There is a substantial risk of stroke in the five years following MI that is greatest in older patients and those with reduced left ventricular ejection fractions.
Source: Loh E, et al. N Engl J Med 1997;336:251-257.
Stroke is an infrequent complication of myocardial infarction (MI), but the relation of stroke risk to left ventricular function following MI is unknown. Thus, Loh et al evaluated data from the Survival and Ventricular Enlargement (SAVE) trial to assess this issue. SAVE was a prospective study of more than 2000 acute MI patients with left ventricular ejection fractions (EF) less than 0.40 but without clinical signs of congestive heart failure, who were randomly assigned to placebo or captopril therapy. Since randomization was done 3-16 days post MI, some patients had revascularization before study entry. Other than captopril, drugs were given at the discretion of the treating physicians: aspirin 59%, other antiplatelet agents 14%, and oral anticoagulants 28%. No data were available on the intensity of anticoagulant therapy. Follow-up averaged 42 months. The average EF was 0.31, and 10% had atrial fibrillation during hospitalization for the index MI.Stroke occurred in 0.5% of the patients between the acute MI and randomization; post randomization, 4% had stroke for a cumulative rate of 8% per five years or 1.5% per patient-year. One-half of the patients had CT or MRI which showed that almost all of the strokes were ischemic in etiology.
Multivariate analysis showed that advanced age was the most powerful predictor of stroke (relative risk, 7.8; P < 0.001) followed by low EF (RR, 4.7 for each 0.05 decrease in EF; P = 0.03). Anticoagulants and aspirin use reduced the risk of stroke (RR, 0.19 and 0.44; both P < 0.001). After adjusting for these characteristics, no other factors were significant including diabetes, history of hyper-retention, and atrial fibrillation complicating the acute MI.
To further analyze the effect of EF, patients with EF less than 0.28 had a relative risk of stroke of 1.86 compared to those with an EF greater than 35% (P < 0.01). The location of the MI and captopril use had no effect on stroke rate. There was a trend toward lower stroke risk in the 34% of patients who were treated with thrombolytic agents (RR, 0.62; P = 0.06).
The authors conclude that there is a substantial risk of stroke in the five years following MI that is greatest in older patients and those with reduced EF. Anticoagulation and aspirin use each decreased this stroke risk.
COMMENT BY MICHAEL H. CRAWFORD, MD
Studies from the 1970s of anticoagulation therapy post MI showed variable results, with some studies showing stroke reduction and others showing no effect. However, these studies antedated thrombolytic therapy and the widespread use of aspirin in patients following MI. Two control trials of warfarin in post-MI patients (WARIS and ASPECT) showed reduced stroke rates with anticoagulant therapy, but neither had data on EF.Retrospective analysis of the SAVE data suggests that after advanced age, EF has a profound effect on the risk of stroke, with a 0.05 decrease in EF correlating to an 18% increase in stroke risk. The authors suggest that decreased EF represents larger MI size and increased left ventricular size. Other studies have shown a relationship between stroke risk and left ventricular size. Interestingly, the SAVE trial showed decreased LV size and increased EF on captopril therapy yet captopril therapy did not affect the stroke rate in this retrospective analysis.
Warfarin and aspirin decreased the risk of stroke, with warfarin showing the greater benefit (81% vs 56%) over the five-year follow-up. The use of thrombolytic therapy showed a trend toward reduced stroke rates, especially in the early hospital phase, which is consistent with other studies. However, echo studies have shown left ventricular thrombus formation despite thrombolysis followed by intravenous heparin, suggesting that stagnant blood can clot despite anticoagulant therapy.
One limitation to this study is that the level of anticoagulation was unknown. Also, the study was not designed to test the relative efficacy of warfarin vs. aspirin vs. both. In addition, later atrial fibrillation was not known, yet early atrial fibrillation did increase the stroke risk. Finally, the study was not a randomized control trial of therapy.
Since SAVE only enrolled patients with EF less than 0.40, we cannot extrapolate the results to patients with an EF greater than 0.40 although other trials suggest there may be a benefit across the spectrum of left ventricular function. The risk of anticoagulation seemed minimal since only 4% of the stroke patients had hemorrhagic stroke by CT or MRI.
Unfortunately, not all patients had the etiology assessed by these methods. The AHCPR guidelines on heart failure treatment state that anticoagulants are not routinely recommended, but they do recommend them for patients with pulmonary embolus, atrial fibrillation, or mobile left ventricular thrombi observed on echocardiography. The American College of Cardiology/American Heart Association MI guidelines also don’t recommend oral anticoagulation for all post-MI patients, but suggest that in those with a dilated left ventricle and marked wall motion abnormalities it should be strongly considered. The SAVE analysis suggests that all patients with an EF less than 0.40 should be considered for anticoagulant therapy, more strongly if the EF is less than 0.28.
The duration of anticoagulant therapy appears to be indefinite following MI, since the incidence of stroke steadily increased over five years of the study. These results do not support three months of therapy and then discontinuing warfarin as has been suggested in other papers evaluating left ventricular thrombi by echo. This is not good news for patients and doctors who don’t like warfarin therapy. Fortunately, aspirin seems to provide some benefit and may afford a reasonable alternative to oral anticoagulation therapy, especially in those with EFs of 30% or greater.
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