Clinical Trial
Total Page：16
File Type：pdf, Size：1020Kb
Postgrad Med J: first published as 10.1136/pgmj.40.464.351 on 1 June 1964. Downloaded from POSTGRAD. MED. J. (1964), 40, 351 Clinical Trial A CONTROLLED TRIAL OF LONG-ACTING GLYCERYL TRINITRATE FOR THE PREVENTION OF ANGINA PECTORIS D. W. EVANS, M.B., B.Sc., M.R.n.P., D.C.H. J. G. DOMENET, M.B., CH.B. Senior Registrar Formerly Research Assistant United Birmingham Hospitals NITROGLYCERIN sublingually remains the drug of During the first fortnight of the trial either Sustac choice for the relief of the acute anginal episode x/io gr. (6.5 mg.) or an inactive tablet of identical and used it has appearance was swallowed by each patient three times (Bunn Chremos, I963). Correctly daily. The first dose was taken on rising and the last no competitor in this field (Evans, 1963) and is the on retiring. During the second fortnight no trial tablets only therapy necessary or desired by the great were taken. During the third fortnight each patient majority of patients with angina of effort. took whichever ofthe trial tablets, active drug or placebo, In the search for an effective long-term pro- he had not received during the first fortnight. Initial phylactic, glyceryl trinitrate swallowed in slow- random allocation to drug or placebo was made by the release tablet form (Sustac) seemed likely to be pharmacist who knew the tablets only as A or B. The successful if absorption of the active principle, clinician was unaware, throughout the whole period of once released from the tablet, proved adequate. the trial and until the final analysis was completed, and which of these tablets any patient was receiving. Huppert Boyd (1955), Jablons, Schilero, The average age of the patients was 56.3 years (range Sicam and Estrellado (I956), and Kutschera and 38 to 70 years). Thirty-nine of them were male Perger (I957) thought this preparation clinically (average age 55.3 years) and i female (average age by copyright. useful, but other reports (Russek, Zohman and 59.6 years). Eighteen patients had electrocardiographic Dorset (I955), Russek, Zohman, Drumm, Weingar- evidence of myocardial infarction and 9 of these were ten and Dorset, (1955); Riseman, Altman and considered to have suffered such episodes within the Koretsky (I958); Parry and Wells (I960); Pilkington preceding 12 months. Only 2 patients were on anti- and Purves (I960)) were not encouraging. In an coagulant therapy (phenindione). None was taking attempt to decide the place of Sustac in the manage- hypotensives. Duration of angina ranged from 2 months ment of those patients with angina for whom to 13 years (average 37.5 months). sublingual nitroglycerin alone seemed inadequate, we undertook a double-blind controlled trial in Results of the selected patients. Thirty-seven 50 patients completed http://pmj.bmj.com/ the trial. Non-completion was due to occurrence of Material and Methods side-effects in 4 cases; 3 patients were excluded During the course of two years, 50 patients with because of inadequate records, 5 others defaulted, coronary artery disease were selected from several and one was admitted to hospital with a myocardial hundred anginal subjects attending a cardiac clinic. infarction during the third week of the trial. Selection for the trial was governed by apparent stability The records were first of the attack-rate, a stated average requirement ofat least 37 completed analysed four glyceryl trinitrate tablets sublingually per day, and with a view to separating those patients in whom a of sufficient to with the rather there was a statistically significant difference at degree intelligence cope on September 23, 2021 by guest. Protected complicated recording system. Each patient was asked the 5% level between either the first or third to record, on cards provided, the number of attacks of fortnight and each of the other two fortnights in angina pectoris experienced during the waking hours respect of: each day, the number of any such attacks while in bed (a) total of trinitrate at night, and the total number of sublingual trinitrate consumption sublingual tablets consumed in each 24-hour period. Patients were tablets, specifically and repeatedly asked not to use sublingual (b) number of attacks of nocturnal angina, trinitrate prophylactically during the six-week period (c) number of attacks whilst up and about. but were urged to suck or chew these tablets as usual at It was evident when the records were first the first onset of recognized anginal pain. All other examined that certain patients had suffered very anti-anginal therapy was suspended during the trial. few attacks of pain during the trial, and that some Weekly totals of 'day' and 'night' attacks, and of had required only a minimal number of nitro- sublingual nitroglycerin tablets taken, were thus obtained glycerin tablets. It was calculated that it would from the completed cards. Information was also sought be in regard to any intercurrent illness, changes in activity impossible to demonstrate any significant or exposure to cold and wind, and any side-effects benefit from any treatment given unless a thought to be due to the trial tablets. An additional patient had suffered four or more attacks of angina question concerned the amount of breathlessness on or had required four or more sublingual trinitrate exertion, where present. tablets in at least one of the three fortnightly Postgrad Med J: first published as 10.1136/pgmj.40.464.351 on 1 June 1964. Downloaded from 352 POSTGRADUATE MEDICAL JOURNAL June I964 periods. All patients with fewer attacks, or lower TABLE I requirements for sublingual nitroglycerin, than this were therefore excluded from the relevant Significant (p<o.05) reduction in Sublingual Frequency Frequency sub-groups. trinitrate of nocturnal of diurnal consump- attacks attacks Total consumption of sublingual trinitrate tablets tion In addition to the 13 patients who failed to complete the trial, 2 were excluded having re- Sustac 8 6 6 quired less than 4 sublingual trinitrate tablets per Placebo 6 I 5 fortnight throughout the trial. No. of patients There remained therefore 35 patients, 18 of studied 35 I3 35 whom were tablet A the first Difference be- given during fortnight. tween Sustac X2 = 5.2786 In 6 instances tablet A proved statistically superior, and placebo Not Not whilst tablet B was significantly better in 8 cases. signi. 0.02<p<0.0o5 signi. Table showing the difference in therapeutic effect of Number attacks nocturnal Sustac and placebo on total sublingual trinitrate of of angina consumption, frequency of nocturnal anginal attacks, In addition to the 13 patients who failed to and complete the trial, 23 were excluded having ex- frequency of diurnal anginal attacks. perienced less than 4 attacks of nocturnal pain per TABLE 2 fortnight throughout the trial, and one patient did not a record for the Number of keep middle fortnight. No trial patients There remained therefore 13 patients, 6 of whom were given tablet A during the first fortnight. Sustac Placebo tablets reporting Statistical analysis showed that in one instance symptoms tablet A prove;i superior whilst tablet B was better Headache 13 5 3 I7 in 6 instances. Abdominal complaints 3 4 7 Number of attacks ofanginalpain whilst up and about Giddiness 2 I 3 In addition to the 13 patients who failed to Others 3 2 5 complete the trial, 2 were excluded having ex- Table the incidence by copyright. perienced less than 4 attacks of diurnal pain per showing of side-effects. fortnight throughout the trial. There remained therefore 35 patients available Sustac, and in 5 patients whilst on placebo, was the for analysis in this group. 18 patients were given most frequent side-effect. This table is based on tablet A first. In 5 instances tablet A proved the 37 patients who completed the trial and the significantly better, whilst in 6 cases tablet B was 4 patients who defaulted because of side-effects. superior. Discussion Effect of various factors on therapeutic response In so far as angina pectoris is a symptom, it is The results were analysed in order to ascertain apparent that it cannot be objectively evaluatedhttp://pmj.bmj.com/ whether certain factors were associated with (Oram and Sowton, I96I). It is a pity, therefore, differing therapeutic response. It was found that that some authors have recently claimed objectivity no difference could be detected when sex, age, in their assessment of glyceryl trinitrate, and other duration of history of angina, or evidence of a so-called coronary dilators, for the relief of ischaemic previous myocardial infarct were taken into consi- cardiac pain. Most of the early trials of Sustac deration. were similarly pseudo-objective or inadequately No meaningful information could be derived controlled subjective assessments. A more recent from answers to the patients' ancillary questions trial (Meciani and Brina, 1962) comes within the on September 23, 2021 by guest. Protected which had been included in the record charts. latter category. At this stage the hitherto secret key to the iden- We decided that the value of Sustac, or any tity of the trial tablets was revealed and it was other long-acting angina prophylactic, could be found that tablet B was the active (Sustac) tablet. demonstrated only by its ability to reduce the Table i summarizes the results obtained in each frequency of patients' anginal attacks. This widely- group. shared point of view has recently required reitera- It is seen that Sustac was effective in reducing tion (Brit. med. J., I963). We therefore selected the frequency of nocturnal angina in 6 out of 13 for trial a number of patients who, from their own cases and that in this respect it was statistically statements, appeared to need a sufficiently large superior to placebo (X2=5.2786, o.o2<p<o.o5).