2. Magnesium was administered late in ISIS-4. The ISIS-4 protocol required that acute phase treatments for MI, including lytic therapy, were administered prior to randomization and initiation of study drug therapy (i.e. magnesium). By design, therefore, magnesium could not be administered in the "early" lytic phase (e.g. first hour). Although the time from onset of symptoms to randomization was recorded in ISIS-4, time from randomization to actual administration of magnesium was NOT recorded. The median time to randomization from the onset of chest pain for all patients was 8 hours; in the subset of patients who did not receive thrombolytic therapy (30 percent of trial patients) the median time to randomization from onset of chest pain was QUITE prolonged at 12 hours.. No further details of the distribution of time to randomization have been reported by the ISIS-4 investigators. In an effort to answer these concerns, they conducted a retrospective survey of a 1,000 randomly selected patients. This revealed that among those receiving thrombolytics only about 50 percent received magnesium within the two hours following the start of thrombolytic therapy. LIMIT-2 randomized patients a median of 3 hours from the onset of chest pain, and in Schechter's study 19 of nonthrombolytic treated patients, the average time from chest pain to initiation of treatment was about seven hours in both the treatment and placebo groups (a full five hours earlier than in the non thrombolized group in ISIS-4) Attempts at subgroup analyses in ISIS-4 also suffer from a critical lack of precise information on the actual time of administration of magnesium. Thus although no apparent benefit of magnesium was seen in the 23,000 patients randomized within six hours of the onset of chest pain, or among the 17,000 who did not receive thrombolytic therapy (including 9,000 randomized within 12 hours), since most of these patients received magnesium several hours after randomization, one cannot be confident that reperfusion (pharmacologically induced or spontaneous) took place in the presence of a raised serum magnesium level in any subgroup. Experimental attempts aimed at ameliorating cellular calcium overload have shown that calcium antagonists must be administered before reperfusion or during a critical window of only a few minutes following reperfusion in order to minimize contractile dysfunction. Calcium flux inhibitors, such as magnesium, administered too late after reperfusion appear to be ineffective.