Acta med. scand. Vol. 189, pp. 299-301, 1971

TREATMENT OF ANGINA PECTORIS WITH BETA-RECEPTOR BLOCKING AGENTS

Effects of Long-term lreatment and Treatment with Sustained Release Tablets

Per Bjorntorp

Frorn the First Medical Service, Sohlgreriska Sjukhuser, University of Goteborg, Giitehorg, Sweden

Abstract. Nine patients with angina pectoris had been treated between two and three years with the beta block- ing agent alprenolol when they agreed to withdrawal of treatment and introduction of a double-blind cross-over trial with placebo. All had more attacks on placebo than on alprenolol. Six patients had no attacks on alprenolol, but angina pectoris returned when they were on placebo. The same nine patients, one year later, compared the ordinary tablet of alprenolol (100 mg x 4) and sustained release tablets (200 mg x 2). No significant difference was found in frequency of attacks of angina pectoris or in subjective ranking of these two drugs. It is concluded that ,$-receptor blockade as treatment of angina pectoris cannot be withdrawn even after a long period of treat- ment. Furthermore, the sustained release tablets were ef- fective against angina pectoris, because they showed no difference from alprenolol in ordinary tablet form, and the latter were much more effective than placebo in the same patients.

Treatment of angina pectoris with p-receptor blocking agents has been found effective in sev- eral well-controlled trials (3). The effect is be- lieved to be caused by a decrease in myocardial oxygen consumption due to a decrease in ar- terial blood pressure, heart rate and contractility, and with some of these agents a decrease in cardiac output (3, 4). Myocardial analgesia, due to the local anesthetic effect of the drugs, is probably not responsible (2).

Improvement of angina pectoris allows an in- creased physical activity. Increase of everyday physical activities such as walking etc. might per- haps result in physical training of the patient. Physical training of patients with angina pectoris causes improvement because of a lowering of pulse rate, blood pressure and cardiac output on submaximal work loads (5, 6, 8). Theoretically,

therefore, after long-term treatment, p-receptor blocking agents might be thought to bc unneces- sary, because the effects seen on the patients might be a consequence of physical training made possible by the drug treatment. In order to test this possibility, the effects of a p-receptor block- ing agent (alprenolol, Aptin@, Hhsle, Goteborg, Sweden) were tested after several years of treat- ment in a group of patients with angina pectoris. On the same patients the effect of a sustained release tablet with the same amount of the drug mentioned was tested in order to see whether ad- ministration of the tablets twice a day could re- place administration four times daily (7).

MATERIAL AND METHODS Nine patients took part in both trials. These patients had participated in previous trials (1, 2) and takcn alprenolol for 24 to 38 months in a dose of 100 mg four times daily. They had been controlled in ordinary out-patient routine about every sixth week during this period. Before the present trials they were told that it was possible that the drug was no longer necessary and that, during a period, blind tablets or the drug would be given. In the trial with the sustained release tablets the patients also agreed to testing a tablet which, if effective, had considerable prac- tical advantages.

The patients taking part in the trials all had typical angina pectoris coming on with physical exercise, being relieved immediately after rest or after nitroglycerin. All had suffered a myocardial infarction between 8 and 5 years before the trial. They were all men between the ages of 45 and 73 years. One patient suffered from es- sential hypercholesterolemia (case 2) and two from es- sential hypertension treated with saluretics (cases 6 and 8).

The trial method has been described in detail previously (1, 2). In short, patients were seen weekly or every second week during identical procedures, including taking a history and making a physical examination. Blood samples

Acta med. scand. 189

300 P . Bjorntorp

C A S E 1 2 3 4 5 6 7 8 9

Fig. 1 . Number of attacks of angina pectaris per two weeks in individual patients in a double-blind cross-over trial of alprenolol (100 mg 4 times daily) and placebo. Patients treated with alprenolol 24-38 months before this trial. White columns, placebo; black columns, alprenolol; 100 mg 4 times daily.

were taken on the last visit in each test period and de- terminations were made of bilirubin, alkaline phosphatase, thymol turbidity, GOT, OPT, hemoglobin, white blood cell and blood platelet counts and plasma creatinine.

The first trial was performed during February through April, 1969, and the second during March through April, 1970. The first trial consisted of two 3-week periods during which either alprenolol (100 mg four times daily) or placebo tablets of identical taste and appearance were given, The patients were instructed to swallow the tablets immediately with a glass of water in order to avoid bias because of anesthetic effects of alprenolol on the mucous membranes of the mouth. In order to avoid possible carry-over effects, the two last weeks of the trial periods were evaluated. Drug and placebo were given by double- blind cross-over technique.

The second trial was identical to the first except that two sorts of tablets had to be given in each period. These tablets were either a combination of alprenolol (100 mg) and placebo simulating the sustained release tablets or sustained release tablets of alprenolol (Aptin Duretterm, 200 mg) and placebo simulating alprenolol tablets. Al- prenolol or its placebo was taken four times daily (7 am. , noon, 5 and 10 pm.) and the sustained release tablets or their placebos at 7 a.m. and 5 p.m.

The alprenolol tablets had a disintegration time of 5 min according to the British Pharmacopoeia. The sus- tained release tablets released approximately 50% of the dose during the first hour and the rest continuously for 5 hours (7).

IiESULTS Fig. 1 shows the results of the trial comparing alprenolol and placebo after a long period of

Acra rned. scand. 189

alprenolol treatment. All patients had more angina pectoris attacks on placebo than on the drug. Six out of nine patients were free from angina pec- toris on treatment, but had chest pain in the placebo period. All patients considered the al- prenolol period better.

In cases 5 and 6 the treatment period was re- peated, and in cases 7 and 9 the placebo period, in order to evaluate the reproducibility of the test. The reproducibility was found to be quali- tatively acceptable because cases 5 and 6 had no attacks in either of the alprenolol periods, while cases 7 and 9 had attacks of angina pectoris in placebo periods. The numerical agreement be- tween the two placebo periods of the latter pa- tients was, however, rather poor.

Fig. 2 shows the results of the comparison be- tween alprenolol in ordinary tablet form and in sustained release tablets. Three patients had more attacks on alprenolol in ordinary tablets (cases 1, 5 and 7), while four patients had more attacks on the sustained release tablets (cases 2 , 3, 8 and 9). Two patients had a similar number of attacks on both treatments (cases 4 and 6). There is no statistical difference between the effect of these two preparations.

Both trials thus included a period with alpre- nolol, 100 mg x 4 in the same patients. Ap- proximately one year elapsed between the trials. The results, seen in Figs. 1 and 2 for individual patients, allow a comparison between alprcnolol treatment in the same patients with approximately

lei

Fig. 2. Number of attacks of angina pectoris per two weeks in individual patients in a double-blind cross-over trial of alprenolol in ordinary tablet form (100 mg 4 times daily) and in sustained release tablets (200 mg 2 times daily). Same patients as in Fig. 1. Trial performed one year after that in Fig. 1. White columns, sustained release tablets; black columns, ordinary tablets.

Angina pectoris and ,+receptor blocking agents 301

one-year interval. It is then seen that there is a considerable variation in number of attacks be- tween the two times of testing.

Blood pressure showed no significant changes in the first or second trial.

In case 3 GOT was found to be 42 during treatment with sustained release tablets. He also admitted increased alcohol consumption during this period. Otherwise no pathological blood tests developcd.

Case 3 reported a slight headache when taking sustained release tablets, and case 2 had a long period of chest pains giving rise to suspicion of myocardial infarction during the treatment with ordinary tablets in the second trial. During the placebo periods various minor complaints were reported such as anxiety (case I ) , sleeplessness (casc 7) and gastritis (case 6). Otherwise no ob- servations possibly suspicious of side-effects were seen.

DISCUSSION

The results of the present investigation show that treatment of angina pectoris with beta-receptor blocking agents during a long period does not prevent recurrence of the symptom when the drug is withdrawn. Whether or not an improve- ment of angina pectoris would have occurred in these patients when they were without the drug. as compared with their original status before 0-receptor blockade was introduced as treatment, is difficult to judge. The patients tested had all previously been tested with placebo after a run-in period ( 1 , 2 ) , and the total number of attacks during this initial placebo period was 120 during

two weeks, while it was now 109. This difference is not statistically significant. No detailed con- clusions from this result seem warranted, par- ticularly because the spontaneous development of the angina pectoris of these patients is not known. It can thus not be stated whether an increase in physical activity, which treated patients undoub- tedly experience, had any effect or not in these patients in terms of physical training. Physical training improves angina pectoris both subjectively and objectively (5, 6, 8). It may be concluded, however, that /&receptor blockade has an effect on angina pectoris after several years of treat- ment.

The ordinary tablet and a sustained release tablet of alprenolol showed no differences in ef- fect, evaluated as angina pectoris attack fre- quency. Since placebo was found milch less ef- fective than alprenolol in the same patients, it seems possible to conclude that the sustained release tablet is effective and, in two doses a day, gives the same protection from angina pectoris as ordinary tablets four times a day.

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4. Forsberg, S.-A. & Johnsson, G.: Acta pharmacol.

5 . Frick, M. H. & Katila, M.: Circulation 37: 192, 1968. 6. Hansson, J . S., Tabakin, B. S., Levy, A. M. & Nedde,

7. Johnsson, G., Sjogren, J. & SolveU, L.: To be published. 8. Varnauskas, E., Bergman, H., Houk, P. & Bjorntorp,

Clin. pharmacol. Ther. 10: 765, 1969.

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W.: Circulation 38: 783, 1968.

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