The problem of differentiating a true drug effect from spontaneous changes in the frequency of ventric­ular ectopy has received increasing attention in the last ten years. It is now recognized that varia­bility changes with time, namely, that PVC variability increases when ambulatory monitor recordings are separated by longer intervals of time. In the present study, the average length of time from the first baseline Holter recordings to the last Holter recording obtained during each treatment was 8.0 days for the 8-h and 19.4 days for the 12-h dosage regimen.

Anastasiou-Nana et al and Schmidt et al studied the reductions in total PVCs required to exceed the 95 percent confidence limits of spontaneous variability in patients with chronic ventricular arrhythmias. Anas- tasiou-Nana et al found that for elapsed times of one, two and three weeks between baseline and treatment observations, reductions in PVCs would have to be at least 85, 86 and 93 percent, respectively. Schmidt et al determined that for periods ranging up to six days, the minimum reduction in PVC frequency should be 63 percent, and for intervals of 7 to 89 days it should be 79 percent. The baseline characteristics of these investigators’ study populations were comparable to those of our patients in terms of PVC frequency (>30/h), the proportion of patients with CAD (approx­imately 50 percent) and the presence of some patients with no detectable organic heart disease. On the other hand, LV function was considerably more depressed in patients of Schmidt et al. However, Pratt et al, using multiple linear regression for analysis of varia­bility of ventricular arrhythmias in patients with poor (LVEF<40 percent) vs preserved (LVEF>40 percent) LV function, found no significant difference in varia­bility between them. They did observe a significantly higher PVC variability in patients with CAD than in patients without CAD. It, therefore, appears legiti­mate to gauge our results by the efficacy criteria that Anastasiou-Nana et al and Schmidt et al derived from their studies. Given the elapsed times between baseline and treatment Holter recordings in our study, the median PVC reductions we obtained are within the range of the standards established by these inves­tigators.

In our patients, levels of PVC suppression were being steadily maintained during each hour of the 24- h period regardless of whether mexiletine was admin­istered every 8 or every 12 h. Thus, extension of the dosage interval to 12 h is unlikely to alter either the degree or the hour-by-hour consistency of arrhythmia suppression in the majority of patients responding to oral mexiletine given three times a day.

Our results were obtained with doses within the range that is thought to be required to maintain therapeutic plasma levels of mexiletine. Mexiletine plasma levels reportedly have a “therapeutic window” with a lower threshold of 0.4 ug/ml. An upper limit of 2.0 ug/ml usually is imposed by CNS side effects. In our patients, the mean peak and trough levels of mexiletine were within the therapeutic range on both dosing schedules. Our data confirm that a minimum trough concentration of 0.4 ug/ml is in fact generally needed to obtain suppression of ventricular ectopy.

Despite the higher mean individual doses and higher average peak plasma levels on the 12-h regimen the incidence rate of adverse experiences was unchanged as compared with the 8-h dosage.

Our study has demonstrated that patients with ventricular arrhythmias who respond to 300 to 900 mg of mexiletine daily at an 8-h dose interval can also be effectively maintained on a 12-h dosage schedule. The longer interval between doses should improve compliance, especially since it does not seem to be associated with a higher incidence of untoward drug effects.