When a new agent is introduced into therapeutics it is important to obtain reliable comparison with existing drugs. Examination of the published reports on guanethidine, methyldopa, and bethanidine provides only an approximate estimate of their comparative merits. Most reports indicate that about 70% of patients achieve reasonable control of their blood pressure with each drug. However, the conditions of the trials varied in many respects, such as levels of blood pressure accepted as good and fair control, the severity of the hypertension in the patients treated, and the clinic routine. In addition, it is difficult to obtain a clear idea of the acceptability of these drugs by patients and of the incidence of side-effects. It was with these factors in mind that, following our initial studies with bethanidine (Johnston, Prichard, andRosenheim, 1962, 1964), we designed a formal trial to compare bethanidine with the established drugs guanethidine and methyldopa.Patients.-Details of the 30 patient-volunteers completing the trial are summarized in Table I; four of the original 34 patients were withdrawn (see below). The patients were selected solely by the criteria that it was thought necessary to treat them with potent hypotensive drugs and that they were able to attend regularly. All except one patient were on potent drugs before the trial-14 on bethanidine, 11 on guanethidine, and 4 on methyldopa.
Method Summary of TrialA within-patient comparison was designed in which each patient received bethanidine, guanethidine, and methyldopa. These drugs were prepared in identical capsules and were given in random order, the randomization being stratified according to the treatment the patient was receiving before the trial.Patients were seen at two-weekly intervals during the trial (except for the intrusion of their holidays) under After careful consideration it was not thought desirable for physician A to be " blind." Safe and reasonably rapid adjustment of the dose was essential in order to avoid exposing the patients to unnecessary risk, and as the duration of action of the drugs varies different dose schedules have to be followed. The final decision on instructions to adjust the dose had to be tempered with the knowledge of any side-effects being experienced, most notably symptoms of postural hypotension. In addition, the drugs have several characteristic side-effects which would have permitted physician A in many instances to know which drug was being used.Previous to the " period of assessment " (see below) on each of the three drugs there was a " run-in period." The run-in period was to enable the dose of each drug to be adjusted to obtain the optimal therapeutic effect. The run-in before the first drugs also served to familiarize the patients with clinic procedure, to ensure that they understood the " weekly symptom record sheet" (see below) which they kept, and, lastly, it went some way to ensure that the greater part of the hypotensive effect of increased interest by the physician became stabilized before the tr...