Episodes of myocardial ischemia may presage the onset of acute coronary events and may trigger malignant ventricular arrhythmias. Studies of b-blocking agents (44, 173,174), calcium channel blocking agents (175,176), and their combination (173,176) have shown that both agents alone or in combination can reduce the total number of ischemic episodes in a 24-h period, and that b-blocking drugs are particularly effective at attenuating the well-documented morning increase in ischemia (44,173,174). The effect of b-blockers may be mediated by the reduction of heart rate, as heart rate increases precede most episodes of ambulatory ischemia (111,173,174). Long-acting calcium channel blocking agents may not have the same effect on the circadian variation of ischemic episodes (44,175). Calcium channel blocking agents such as nifedipine appear to prevent ischemic episodes that are unrelated to heart rate increases, suggesting that their effect may be mediated by increasing myocardial oxygen supply rather than by decreasing myocardial oxygen demand (174). One randomized crossover study comparing atenolol, amlodipine, and placebo found that atenolol was more effective at suppressing episodes of ambulatory ischemia, whereas amlodipine was more effective at suppressing exercise-induced ischemia (177).
b-Blocking agents have been shown to blunt the heart rate and blood pressure increases that occur in association with mental stress and with handgrip (178), but do not appear to affect indices of hemostatic function (178,179). This further supports the role of b-blockade as primarily a modifier of the hemodynamic factors thought to play a role in the triggering of acute coronary events.
The link between ischemia suppression and cardiac prognosis is supported by at least two randomized studies. The Atenolol Silent Ischemia Study randomized 306 patients to atenolol or placebo (162). The group treated with the b-blocker had significantly fewer episodes of ischemia on ambulatory monitoring, and after 1 yr of follow-up had significantly fewer cardiac events (relative risk 0.44 [95% confidence interval 0.26-0.75]). The Total Ischemic Burden Bisoprolol Study followed 520 patients for 1 yr, with a similar result: patients randomly assigned to the b-blocking agent bisoprolol had significantly fewer cardiac events (163).
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