A by pronethalol has been

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The Prophylactic Value of Propranolol in Angina Pectoris*

RALPH RABKIN, M.B., DEREK P. STABLES, M.B., NATHAN W. LEVIN, M.B.

and MOSES M. SUZMAN, M.D.

Johannesburg, South Africa

DRENERGIC beta receptor blockade, induced

A

by pronethalol (Alderlin@),r has been shown to be effective in the prevention of attacks of angina pectoris.2-4 With the introduction of propranolol (Inderal@), an agent with a therapeutic potency tenfold that of pronethalol and virtually free of the untoward side effects attributed to the latter drug,5 clinical trials to test its prophylactic value in patients with angina pectoris have been reported. Srivastava et al6 studied 20 patients receiving 60 mg. of pro- pranolol daily and placebo, each for a two week period and found that significant improvement had occurred in approximately one half of the patients. Hamer et al.’ reported an improve- ment in exercise tolerance following the intra- venous administration of propranolol. Keelan in a double-blind trial compared the effect of propranolol in the dosage of 30 mg. thrice daily and placebo, each given for four weeks in ran- domized order to 19 patients, and concluded that the drug significantly reduced the fre- quency and severity of their angina1 attacks.

Scrutiny of his results showed significant im- provement in approximately one half of the pa- tients. Gillam and Prichard9 in an eight week study of 14 patients receiving 90 to 400 mg. daily of propranolol and placebo, each for two periods of two weeks in randomized order, reported improvement in all patients taking the drug.

Earlier experience in this hospital with pro- nethalol for angina pectoris having shown the effective daily dosage to be 300 mg. in the majority of cases,iO a pilot double-blind trial was instituted in 14 patients with angina pectoris to test the effect of propranolol in the correspond- ing dosage of 30 mg. daily. Fourteen patients received drug and placebo alternately each for a

period of two weeks in random order, but no preference could be demonstrated for either medication at this dosage level. In conse- quence, the drug was again put to the test in a double-blind trial but at a substantially higher dosage and for a longer period.

In addition, a separate trial of propranolol therapy was made in another group of patients with angina pectoris but on a single-blind basis, with the dosage being adjusted and the duration of drug and placebo therapy being varied according to the individual response in each pa- tient. The purpose of this trial was not only to test the prophylactic efficacy of the drug but also to glean information concerning aspects of pro- pranolol therapy that may not become apparent or are likely to escape recognition under the exigencies inherent in a rigidly designed, double- blind trial of relatively short duration where the dosage and the periods of medication are prede- termined and uniform, thus allowing no adjust- ment to individual requirements that would re- veal variations in individual response.

DOUBLE-BLIND TRIAL MATERIAL AND METHODS

Selection of Patients: Twenty patients (9 men, 11 women) attending the outpatient department were selected for admission to the trial on the basis of a history of angina of effort which had been virtually unchanged in severity and frequency over the pre- vious six months and in whom no episodes of acute myocardial infarction had occurred during this time.

One patient (Case 15, Table I) had previously been in cardiac failure. The resting electrocardiogram showed evidence of healed myocardial infarction or ischemic changes in all but 3 cases (Cases 2, 10, 13) but the exercise electrocardiogram revealed the ischemic changes in these 3. In 7 patients, including the 3 with normal resting electrocardiograms, a clear

* From the Department of Medicine, University of Witwatersrand Medical School and the Johannesburg General Hospital, Johannesburg, Republic of South Africa.

370 THE AMERICAN JOURNAL OF CARDIOLOGY

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Propranolol and Prophylaxis of Angina Pectoris

‘1’ABI.E 1

I)ouble-Blind I‘rial. \l:eekly Glyceryl Trinitrate Con- sumption Relative to Medication Sequences

PIT-

Trial W?Ck Week Wrrk Week Total for 4 WCP k 1st 2nd 1st 2nd 1st 2nd 1st 2nd Wreks

A H B A .4 1~

10 0 0 4 6 8 5 0 0 0 23

3 2 0 0 0 1 0 0 0 2 L

8 3 1 6 4 1 6 4 0 6 17

37 49 29 43 37 61 35 43 41 162 176

B A B A

10 6 6 2 2 8 5 2 4 10 25

3 37024211 4 16

43 62 49 33 21 57 13 30 15 99 211

5 4 C, 4 2 1 1 1 3 10 12

A B A B

9 10 II 12

5 11121111 4 5

8 00372278 4 25

15 4 6 13 1: 4 6 13 17 20 60

1 6 6 4 5 6 5 5 5 3 20 19

B A A B

13 14 15 16

2 1310 2 I3 12 8 7 33

8 24000013 0 IO

R 5 6 6 1 12 11 13 11 30 35

6 36110001 2 10

Total 185 382 678

Average

Per wk. 11.5 59 10.6

A = drug therapy; B = placebo

history of previous acute myocardial infarction could not be elicited. With the exception of 2 patients (Case 3, 170,/115 mm. Hg; Case 2, 190/115), all were normotensive.

Design of Trial: The trial was double-blind and its duration 8 weeks, divided into four two-week periods, during each of which an equal number of patients received at random either drug or placebo according to one of four possible paired sequences, namely.

ABBA, BABA, ABAB, BAAB (Table I).

DoJage of Propranolol: A fixed dosage of 50 mg.

four times daily was employed, to be taken at meal times and at night on retiring. The 10 mg. tablets were dispensed in indistinguishable gelatin capsules, each containing five tablets. This technic of admin- istration was devised to circumvent the difficulty of prevailing upon patients to swallow 20 tablets each day, to obviate the slight difference in taste between drug and placebo, and to minimize errors in dispens- ing and consumption of the drug. 4t each attend-

ance, the patients were required to rct\Irn ally un- used capsules from the previous issue for counting and with each re-icsur were not informed of the chanqr in their medication.

Assrmnent oJ 7’herapeutic &%a( I’: ‘l’he therapeutic response was assessed on the individual consumption of glyceryl trinitratc tablets and the number of at- tacks of angina pectoris. One, week prior to thr commencement of the trial proper. the patients were requested to discard all drugs in their possession utilized for the prevention or relief of their angina1 attacks and were issued an adequate supply of glyc- eryl trinitrate tablets which they were instructed to take for relief of their angina1 attacks but not TOI their prevention.

The patients were issued a special card on which to enter daily the number of angina1 attacks experienced and the number of glyceryl trinitrate tablets used throughout the trial. including the pre-trial period.

At each fortnightly visit the number of glyceryl tri- nitrate tablets consumed was recorded after having been checked by noting the number of unused tablets remaining in the container.

At the end of each two-week period the patients attended a special clinic where each was seen by the same clinician who inquired about the general condi- tion of the patient. recorded the blood pressure and pulse rate. and obtained an electrocardiogram. For the detection of possible drug toxicity, blood was drawn for the determination of hemoglobin concen- tration. total and differential leucocyte count; blood urea. sodium, potassium, chlorides. and CO? com- bining power; liver function tests. which included thymol turbidity and flocculation, colloidal red test, cephalin cholesterol flocculation. Takata Ara reac- tion. zinc sulphate turbidity. van den Bergh reaction, bilirubin (1 min. and total), cholinesterase, mucopro- tein, serum albumin and globulin; and the enzymes, alkaline phosphatase, glutamic oxalacetic trans- aminase. glutamic pyruvic transaminase and lactic dehydrogenase.

RESULTS

Four patients (3 women, 1 man) failed to complete the trial. Two defected, another took medication irregularly, and 1 died of a myo- cardial infarction while on placebo Inedication.

The results in the remaining 16 patients are shown in Table II, which depicts for each patient the number of angina1 attacks as ,judged by the glyceryl trinitrate consumption. The actual number of attacks experienced did not differ materially from the number of glyceryl tri- nitrate tablets conwuned and are therefore omitted. Of the 16 patients completing the trial, 10 experienced considerably fewer angina1 attacks while taking propranolol than they had taking the placebo, and of these, 2 patients were

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372 Rabkin et al.

TABLE ,I

Double-Blind Trial of Propranolol in Xngina Pcctoris

(No.)

1 14 10 16 13 6 11

3

9 8 15 4 12 2 Total

Age 6r Sex

66 M 7 1

64 F 10 0

45 F 2.5 0

68 F 6 1

50 M 4 0

63 M 2 1

51 M 4 0

60 F 2.5 1

53 F 2 1

51 M 5 1

56 F 4 1

64 F 5 0

53 M 7 6

56 M 5 0

57 M 7 3

46 F 2 0

Previous Duration Attacks of of Angina Infarction

(yr.) (no.)

Resting ECG

Infarct LBBB Normal Infarct Normal S-T dep.

S-T dep.

S-T dep.

S-T dep.

LBBB Infarct S-T dep.

LBBB Infarct Infarct Normal

Wilcoxon matched-pairs signed-ranks test T = f 130; p 5 0.000076.

---Glyceryl Trinitrate- ---

Drug

4 20 10 8 99 4 10 30 162 20 2 382

Consumption (No. Tablets)

Placebo Improvement

231 10 25 10 33 16 )

Significant, 10 cases 60

25 17 211, 51

12 Not significant, 176 i 35 6 cases

19 i 1

678 16

LBBB = left bundle branch block; dep. = depression.

completely relieved ; 6 patients reported no significant preference for either medication.

The average reduction in the total number of attacks on propranolol was 44 per cent. By using the Wilcoxon matched-pairs signed-ranks test to evaluate the significance of the difference in glyceryl trinitrate consumption during drug and placebo medication, a value of T = +130 was found for which the probability of being equaled or exceeded is 0.000076. The thera- peutic response was unrelated to the duration or severity of the angina or to the age or sex of the patients.

Fewer attacks occurring during the whole or the early part of a placebo period following pro- pranolol than before its use would suggest a carry-over effect of the drug. This was noted to have occurred in 4 cases (Cases 9, 13, 14, 16), as shown in Table I, which gives the number of glyceryl trinitrate tablets used by each patient in the pre-trial week and in each week throughout the trial according to the 4 medication se- quences. It will be noted that the average weekly consumption per patient in the pre-trial and placebo weeks correspond closely.

In comparison with the number of angina1 attacks recorded during the pre-trial period alone or combined with the first placebo period, the improvement which occurred under the

drug continued through both placebo periods in Case 9, for both weeks of the second placebo period in Case 16 and for the first week in Cases 13 and 14. On a weekly basis, the ratios of the number of attacks recorded in the placebo periods before and after propranolol in these 4 patients were 4.0,4.1,4.7 and 10.0, respectively.

These observations would suggest that in some patients a carry-over effect of propranolol may occur after its administration is discontinued.

Since patients may fail to respond simply be- cause of inadequate dosage, an attempt was made to check this possibility in 4 of the 6 cases not responding to 200 mg. daily dose of pro- pranolol, but no improvement followed dosage increments up to 400 mg. daily.

The pulse rate slowed to less than 70 per cent of the baseline reading in 6 patients during both drug periods, but 2 of these patients did not experience a reduction in the frequency of angina1 attacks. No patient exhibited a signifi- cant fall in blood pressure.

SIDE EFFECTS

One patient complained of dizziness, insomnia and depression severe enough to warrant a reduction in the dosage of propranolol to 100 mg. daily, which not only relieved her symptoms but also was still effective in controlling her

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Propranolol and Prophylaxis of Angina Pw(oris .i73 a ngi na Two other patients experienced mild

dizziness, and a fourth complained of constipa- tion and increased frequency in rnicturition during only one of their two periods on the drug.

One patient complained of dizziness and another developed insomnia while taking the placebo.

Serial laboratory tests revealed no deleterious changes in the hepatic, renal and hemopoeitic systems or in electrolytes during the trial.

SINGLE BLIND TRIAL

As the object of this trial was to inquire into the broader aspects of propranolol therapy, the dosage and duration of medication were individ- ualized. Consideration was given to individual variability in effective dosage and to the factors which might influence it. In addition, observa- tions were made on the long term effects of the prolonged use of propranolol as regard changes in tolerance in either direction, the duration of action of the drug after its discontinuation and its influence on symptoms relative to other sys- tems, particularly those dependent on neuro- vegitative reactivity. For the detection of possible toxicity with prolonged administration, comprehensive laboratory investigations were made.

MArERIAL AND METHODS

Selection of Patients: Patients were selected for study whose history of angina was of long duration and its degree of severity well known and in whom resl’onse to other forms of prophylactic medication had previously been tested. In none had there been episodes of cardiac failure or of recent myocardial infarction, and with one exception (Case 5, Table III). cardiac size was normal on x-ray examination.

_kwrsment of Therapeutic Response: Close contact was maintained with the patients both through personal interviews and by telephone when they were questioned closely about each episode of angina they had experienced, its duration and severity, as well as the circumstances of its occttrrence and the response to glyceryl trinitrate. They \rere also interrogated concerning any change in their general sense of well- being and symptoms relative to other systems, par- ticularly those which might be accounted for on a psychogenic or emotional basis. At each visit. the frequency of which varied according to circumstance, the patient underwent a clinical examination with special reference to the detection of signs of incipient cardiac failure. Exercise electrocardiograms were obtained before treatment was started and serially thereafter, depending on the individual response.

In this way not only could an accurate assessment be made of changes in the frequency and severity of their angina1 attacks throughout the trial, but an

“01 UMI’ 18, SEPTEMBER 1966

opportumty \Y;~s att’orded to note the eilrctq 01‘ the drug in other respects, both salrttary and untoward.

On the basis of the response observed in each Patient and depending on the severity of the angina prcvail- ing at the time. adjustments in dosage were made and decisions taken as to the expediency of changing the medication from drug to placebo or the reverse.

With two exceptions (5 mg. in Case 15; 30 mg. in Case 19, ‘l‘ablr III). the initial dosage of propranolol was 10 mg. four times daily taken before meals and at night on retiring. In patients reporting complete relief. the initial dosage was not changed, whereas in those with partial or no improvement, it was increased at intervals of three to seven days by increments of 5 to 10 mg. per dose until maximal benefit had been obtained. As a rule, when the optimal maintenance dose had been established and continued for periods of one to three weeks, placebo therapy was qubsti- tuted until unequivocal evidence of recrudcscc.ncc ot the angina was reported, whereupon the drug \vau re- instituted and the effect again noted. If. however, the recurrence of angina was inordinately severe, the drug was resumed forthwith (Case 7. ‘Table III). In some patients (Cases 3. 4. 11, 18 and 10. ‘l‘able III)

propranolol therapy was continued for several months before changing to placebo medication in order to study specifically the consequences of the long term use of the drug, both during its administration and after its discontinuation.

RESULTS

Excluding 4 patients who defaulted, 21) have been followed for periods ranging front 1 to 18 months, 15 for longer than three months and 0 for over six months. The periods of placebo medication \,aried from one day to eight weeks.

Sixteen patients improved and 4 failed to iill- prove (Table IV).

Complications During Thrrai,):: Within the first month of propranolol therapy, 2 patients (Cases 1 and 10) had nonfatal rny,ocardial infarctions. After recovery, 1 of these (Case 10) continued to take the drug and experienced relief of her angina, but three months later a second infarction developed; since then the drug has again continued to afford definite relief. In another patient with postinfarction cardiornegaly (Case 5) aciitc left \zentriculai failure promptly developed when the dosage was increased from 40 to 120 mg.

There were two deaths, both occurring iii pa- tients whose angina had been relieved. One occurred suddenly in the third week of treatiiient and was presiuned to be of cardiac origin (Chase 15). In the other patient (Case ll), who had been on pronethalol therapy for 21 Iiionths followed by propranolol for five months, death

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374 Rabkin et al.

TABLE m

Single-Blind Trial of Propranolol in Angina Pectoris

Case

Optimal

Dailv Medication Age PC Dosage Se-

(No.) Sex (mg.) quence*

1 47

M

2 68

M

3 60

F

4 59

M

5 50

M

6 74

F

7 72

M

8 52

M

9 50

M

10 43

F

11 69

F

12 65

M

P A P A B A B A P .4 B A B A P A B A

P A A A P .4 B A P A B A P A .4 B A P A B A P A B A P A B P A B

Duration (wk.)

3

52 2 12

1 day 20

36 10 24 4 3

24 2 6

3 1 2 days

2 6 5

16”’

1 day 10

4 18 4 18

20’

5 2

‘28 2 6

28 1

. 4 3

Time Before Recur- rence of Severity Angina of Angina? (days)

3 3 3 1 2 0 3 0 3 o-1 2 o-1

3

3 o-1 2 0

4 3 3 3 2 1 1 1 4 1 4 0 4 3 1 3 1 2 1 2

3 1 3 o-1 4 2 2 3 o-1 1

14 1

ii 23

il

1

1

ii

;7

Remarks

.\cute myocardial infarction. Drug discontinued after 3 wk.

Marked improvement

Marked improvement. Acute myo- cardial infarction on 28th day of sec- ond placebo trial

Marked improvement with relief of vas- cular headaches which relapsed on placebo

Cardiomegaly. Acute left ventricular failure on high dosage

Mild angina. No preference demon- strated. Hypoglycemic coma de- veloped ; cause undetermined

Status anginosus. Marked improve- ment. Placebo relapse violent.

Strange dreams

Marked improvement. Dose requirc- ment decreased

Moderate improvement. ECG deterio- ration on placebo

.Acute infarctions 4th week and 4th month on drug, but angina relieved

Marked improvement.

ertional ventricular placebo

Marked improvement.

Fatal postex- fibrillation on

Multiple ex- trasystoles; angina disappeared on drug (Fig. 5)

* P = pre-trial; A = drug; B = placebo.

t 0 = nil; 1 = mild; 2 = moderate; 3 = severe; 4 = very severe.

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--

Cast :Ige &

(No.) Sex

13

14

15

16

17

18

19

20

74 M

83 M

73 F 59 M

79 M

54 F

63 F

60 M

Propranolol and Prophylaxis of Angina Pectoris 375

TABLE III (conhzued:

-

Time Before

Optimal Kecur-

Daily Medication rcnce of

Dosage Se- Duration Severitv Angina

quence* (wk.) of Angina1 (days) Remarks

2

.2

16

40

2 P

B A P A B A P A P A B P A B A P A B A B A P A B A P A B A

3 7

12 ” 1 31

. 3

28’

2

16’ ” 1 3

5 2 40 3 1

32 6 3

2 1 4

2 l-2 l-2 3 o-1

3 o-1

3 o-1

3 1 2 3 1 3 1 4 1 3 1 2 0 3 o-1 1 o-1 3 0 3 0

Mild angina. Effect of drug uncertain

Marked improvement

Marked improvement of angina but died suddenly after 3 wk.

Marked improvement

Moderate improvement

Marked improvement. Dose require- ment decreased

Marked improvement. Multiple ex- trasystoles with angina cleared on drug and returned on placebo (Fig. 1, 3, 4)

Marked immediate improvement after 23 years continual angina (Fig. 4)

occurred one week after placebo medication was started and in circumstances which are note- worthy. Immediately after a short period of mild exercise performed for a routine serial electrocardiogram, ventricular fibrillation super- vened ; but with external cardiac massage, normal rhythm was restored and consciousness regained within a few minutes, the patient ap- pearing none the worse. The electrocardio- gram revealed only S-T segment depression which gradually diminished in subsequent serial tracings, but some two hours later the heart rate began to increase and the S-T segments to deepen, culminating in the sudden return of ventricular fibrillation which, however, failed to respond to cardiac massage or to direct shock.

Effect on Angina: Of the remaining 15 pa- tients, 13 showed unequivocal improvement in

VOLUME 18. SEPTEMBER 1966

the frequency and severity of their angina1 attacks while taking propranolol in optimal dosage (Table IV), whereas in 2 patients (Cases 6 and 13) a preference for either medication could not be demonstrated, and in both the angina was of mild degree.

TABLE IV

Single-Blind Trial of Propranolol in 20 Patients with Angina Pectoris

Uncomplicated 13 2

Cardiac failure (Left ventricular) I

Acute myocardial infarction

Discontinued drug 1

Continued with relief of angina I

Deaths 2

Total IO 4

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376

Rabkin et al.

REST LEAD V2 EFFORT

FIG. 1. (Case 19, Table III). fin~qincl pcctoris ruith nrulttfJv ~,xtrusysto/r,J. l\ prolonged carry-over rffect is indicated by ventricular extrasystoles and their prompt elimination within hours of resuming propranolol. Compare with Fignw 3 and note also elimination of S-T segment depression in the excrcisr electrocardiogram.

As a rule, the response was prompt and the rate of action of the drug was such that it could be shown objectively to have exerted its full effect within a matter of hours, as judged by slowing of the heart rate or by disappearance of postexertional extrasystoles (Case 19, Fig. 1).

The optimal daily dose of propranolol in dif- ferent patients ranged between 40 and 200 mg., and in the same patient it did not necessarily remain constant but tended rather to decrease

TABLE v

Single-Blind Trial. Duration of Effect of Propranolol After Its Discontinuation (Carry-Over) in 14 Trials in 11

Patients

Ca.Se (no.)

Period of Therapy

(wk.)

Carry- over

Duration (days)

2 52

:

14

18 40 16

3 36

19 32 :

61 30

3 24 23

4 24 :

11

8 22

9 20 s- ;;

17 16 0

7 16 0

2 12 0 . .

18 5 0

12 4 + ;;

20 2 0 .

+ = present; 0 = absent.

in the course of time (Cases 8 and 18). The duration of angina prior to the institution of propranolol treatment did not appear to in- fluence the response. A patient who had been plagued by angina1 attacks virtually every day for 23 years enjoyed his first completely pain- free day when he started taking propranolol (Case 20, Fig. 2).

The effects, immediate and remote, of dis- continuing propranolol and instituting placebo medication varied in different patients. Table v shows that, of 14 placebo trials in 11 patients in whom the drug was effective, there was a prompt relapse of angina in 6 instances, whereas in the remaining 8 the recrudescence was de- layed for periods ranging from 11 to 61 days.

With few exceptions, this delay, which might possibly be construed as a carry-over effect of the drug, appeared to be related to the duration of therapy rather than to its intensity, since it occurred most frequently following the more prolonged periods of therapy.

Effect on Arrhythmias and Electrocardiogram:

Multiple ventricular extrasystoles which in- variably accompanied bouts of effort angina in 2 patients (Cases 12 and 19) were promptly elimi- nated by propranolol therapy (Fig. 1, 3, 4 and 5), the arrhythmia in Case 12 having previously been shown to be refractory to Isoptin@. Ob- jective evidence of a carry-over effect after dis-

continuation of the drug was provided by the considerable delay noted in the return of the postexertional extrasystolic arrhythmia which,

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Propranolol and Prophylaxis of Anqi:irla Pectoris

EFFORT ECG

FIG. 2. (Case 20, Table III.) This patient with a long history of angina (since November 1942) with S-T segment depression after exercise obtained complrte and prompt relkf with propranolol therapy and some lessening of S-T segment depression.

Ir4 BEFORE TREATMENT .L,. ,. ,*e,-, . . ..-.. II

FIG. 3. (Case 19, Table III.) Angina pectorir (since January 1964). Ventric- ular extrasystoles and S-T segment depression induced by exercise were elim- inated and the heart rate decreased during propranolol therapy (started Dec. 14, 1964).

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378 Kabkin et al.

{NDERAL 4’3 MGS Q.I.D. INOERAL 30 MGS Q.I.D.

4 MAY 1965 8 SEPT 1965 PLACEBO 7’ _1,

FIG. 4. (Case 19, Table III.) Exercise electrocardiograms show elimination of S-T segment depression and ventricular cxtrasystoles during propranolol therapy, increase in heart rate on reducing the dosage, and the return of occasional extrasystoles during placebo.

incidentally, antedated the recurrence of angina1 pain (Case 19, Fig. 1 and 4).

Concurrent with the relief of angina and the increase in effort tolerance during propranolol therapy, electrocardiographic changes indicated a lessening of coronary ischemia as judged by diminishing prominence or eventual elimination of effort-induced S-T segment depression (Case 19, Fig. 1, 3 and 4).

Effect on Associated Symptoms: In some in- stances, concomitant symptoms were allayed during propranolol therapy but recurred during placebo medication. Noteworthy, in Case 4, long standing vascular headaches were promptly relieved by propranolol only to return during placebo medication; this observation suggests either their ischemic nature or their dependence on beta adrenergic pathways. Several patients

reported an improvement in their general sense of well-being with a lessening of emotional ten- sion and apprehension and in consequence found themselves able to face day to day prob- lems with greater equanimity and composure.

Side Effects: No untoward side effects attrib- utable to the drug were reported. For the detection of drug toxicity, a number of labora- tory tests were made on 8 patients who had been maintained on therapy for periods longer than 16 weeks, the mean duration for all being 32 weeks. These tests, all of which proved to be normal, included hemoglobin estimation, total and differential leucocyte count, erythrocyte sedimentation rate, blood urea, uric acid, serum glutamic oxalocetic and pyruvic transaminases, lactic dehydrogenase and leucine amino- peptidase.

DAILY~:

8 DAYS

FIG. 5. (Case 12, Table III.) Efort angina with extrasystoles. Exercise elec- trocardiograms show marked slowing of the heart rate and elimination of ven- tricular extrasystoles during propranolol therapy after ineffectiveness of tsoptin.

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Propranolol and Prophylaxis of’ A2ngina Pectoris 37’)

TllC aforementioned trials indicate that adrellcrgic beta receptor blockade with pro- pranolol effectively prevented angina1 attacks in the majority of the patients suffering from angina pectoris who were tested. The present double- blind trial convincingly showed a preference for the drug, but because a fixed dosage was used, it is possible that the results represent less than the lnaxirnal benefit obtainable.

Of the 4 patients in the double blind trial who showed evidence of a carry-over effect of the drug into the placebo period, 3 had been treated in tht: sequence placebo-drug-drug-placebo (BAAB), which would suggest that the longer period of drug therapy was a factor in prolong- ing its effect (Table I). The findings in the single-blind trial lend support to this possibility (Table v). Combining both trials provides the pertinent data of 28 placebo trials in 22 patients, and from this it can be seen (Fig. 6) that the mean duration of therapy was six weeks in the 15 trials showing no prolongation of drug-in- duced improvement, whereas in the 13 instances showing a carry-over effect the mean period of treatment was considerably longer, 19 weeks.

The duration of therapy is thus a likely factor deternlining the occurrence of a carry-over effect after discontinuation of the drug, but in- dividual susceptibility to adrenergic beta receptor blockade remains a possibility. That the effects of beta receptor blockade may persist after propranolol, clespite the drug’s relatively short half-life, would suggest that, under certain circumstances and through mechanisms as yet undetermined, the restoration of reactivity at receptor sites may be protracted.

A curry-over effect has previously been noted in a double-blind trial of pronethalol in angina pectoris,10 and the implications of the prolonged effect of adrenergic beta-receptor blockade in anesthesia have been stressed.” On the other hand, this effect was not observed by Gillam and Prichardg in their double-blind trial of 14 pa- tients. all of whom had received propranolol in a relatively high dosage for three months or longer in the immediate pre-trial period.

The mechanism of action of ~ro~ranolol in angina is most likely the suppression of unneeded and in- appropriate cardiac overactivity induced by exertion and emotion, mediated through sym- pathetic excitation to which the ischemic myo- cardium is unduly sensitive. On the grounds that the effect of the beta receptor blockade on the heart is to reduce its work load without

VOLUME 18, SEPTEMBER 1966

50

40 DURATION OF

30 PROPRANOLOL

20 THERAPY

10 (WEEKS)

5 L MEAN DURATION

t

F

_ _- .

CARRY-OVER EFFECl PLACEBO TRIALS 28 IN 22 PATIENTS ABSENT

15

.

. . .

. . . .

6 WKS 19 WKSI 21 DAY!

PRESENT 13

IURATION (DAYS)

16 61 30

11 23 35

FIG. 6. Effect of discontinuation of propranolol in rela- tion to duration of therapy is shown. Note the tendency to a longer carry-over effect after prolonged propranolol therapy.

compromising its efficiency, it is reasonable to assume that the benefit the ischemic heart de- rives from its prolonged use is not confined merely to the prevention of angina1 pain. It is suggested, therefore, that advantage be taken of this mechanism of action of propranolol in the prophylactic treatment also of patients who have coronary artery disease without angina pectoris.

It is possible that the reduction of the response to stress might well improve the long term prog- nosis of those patients as well.

This treatment is likely to be effecti\-e only in hearts which are functionally relatively sound and is hazardous in the presence of cardiac failure, overt or impending, and in heart block, because of the blockade of the sympathetic drive.

The smallest effective dose should be used, and there would seem to be no advantage in slowing the heart unduly. In fact, where this does occur: the concomitant use of atropine may warrant consideration to obviate excessive un- opposed vagal influence.

Patients should be instructed not to take ad- vantage of their freedom from angina1 pain to indulge in exercise more strenuous than they had previously been capable of performing.

Only further studies will establish whether or not cardiac standstill may be a potential hazard to the ischemic heart in the face of undue pain- free exertion. Meanwhile, propranolol may be regarded as a safe and most effective agent for the prevention of attacks of angina pectoris.

(11)

SUMMARY

In a double-blind trial of propranolol over an 8 week period in 16 patients with angina pectoris, drug and placebo were each given at random for 2 two-week periods to equal numbers of patients according to one of four possible paired sequences.

At a uniform daily dosage of 200 mg. given in four divided doses, the individual glyceryl tri- nitrate consumption, which served as the cri- terion of therapeutic response, was significantly lower with propranolol therapy in 10 patients, whereas 6 reported no preference for either medication.

In a separate single-blind trial in 20 patients in which the dosage of propranolol was adjusted and the duration of drug and placebo medica- tion varied according to each individual re- sponse, significant improvement in the angina was observed with propranolol therapy in 16 patients.

After discontinuation of propranolol therapy in a number of cases in both trials, a carry-over effect was noted which appeared to be related to the duration of therapy.

5.

6.

7.

8.

9.

10.

DORNIIORST, A. C. and KOBINSON, B. F. (Xnical pharmacology of a beta-adrenergic-blocking agent (Nethalide). La,~vt, 2: 314, 1962.

ALLEYNE, G. A. 0. et al. Effect of pronethalol in angina pectoris. Brit. M. J., 2 : 1226, 1963.

APTHORP, G. H., CHAMBERLAIN, D. A. and HAY- WARD, G. W. The effects of sympathectomy on the electrocardiogram and effort tolerance in angina pectoris. Brit. Heart J., 26: 218, 1964.

BLACK, J. W., CROWTHER, A. F., SHANKS, K. G., SMITH, L. H. and DORNHORST, 4. C. ;\ new adrenergic beta-receptor antagonist. LanceI, 1 : 1080,1964.

SRIVASTAVA, S. C., DEWAR, H. ,4. and NEWELL, D. J.

Double-blind trial of propranolol (Inderal) in angina of effort. Brit. M. J., 2: 724, 1964.

HAMER, J., GRANDJEAN, T., MELENDEZ, L. and SOWTON, G. E. Effect of propanolol (Inderal) in angina pectoris. Brit. M. J., 2: 720, 1964.

KEELAN, P. A double-blind trial of propranolol (Inderal) in angina pectoris. Brit. M. J., 1 : 897, 1965.

GILLAM, P. M. S. and PRICHARD, B. N. C. The use of propranolol in angina pectoris. Brit. M. J., 2:

337, 1965.

SUZMAN, M. M., SCHNEIR, F., GENTIN, B. and RUTO- WITZ, I. Preliminary observations of the use of pronethalol in angina pectoris and intermittent claudication. Unpublished data, presented at the 43rd Congress of the South African Medical As- sociation, Johannesburg, 1963.

REFERENCES 11.

1. BLACK, J. W. and STEPHENSON, J. S. Pharmacology of a new adrenergic beta-receptor blocking com- pound (Nethalide). Lancel, 2 : 311, 1962.

VETTEN, K. B. and KUNDIG, J. Clinical observations on some pharmacological properties of pronethalol.

A beta-receptor blocker, with special reference to anesthesia. M. Pm. (Johannesburg), 11: 417,

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n- .

mscussion

380 Rabkin et al.

PAPERS BY GRANT ET AL., GILLAM AND PRICHARD AND RABKIN ET AL.

DR. A. A. KATTUS: We have not done con- trolled therapeutic trials, but we have been struck by the remarkable therapeutic effects of propranolol in patients with nocturnal angina.

Those people who are repeatedly wakened at night with severe angina1 attacks have been uni- formly and almost completely relieved. We are hoping to be able to investigate this with overnight monitoring.

of blood pressure, it is possible that the chronic hypotensive effect of propranolol may be one of the reasons for benefit in angina. I wonder if Dr. Gillarn has any information on the blood pressures of the patients who responded well in his study.

DR. S. A. STEPHEN: In our laboratory we have shown that 30 mg. of propranolol will block exercise tachycardia for several hours.

What we are concerned about is why the very much larger doses are necessary for the treat- ment of angina, and it seems clear to us there must be some other mechanism involved in the reduction of angina apart from beta blockade.

Since it is known that some patients with angina get attacks when they have marked elevations

DR. P. M. S. GILLAM: We measured only the blood pressure with a sphygmomanorneter and found no great fall in the exercise blood pressure in our angina1 patients. With the exception of one or two, they were normoten- sive.

DR. E. SOWTON: I would like to ask Dr.

Gillam two things. First of all, most of us suggest to patients that they take their trinitrin prophylactically, and it seems unrealistic to me to count the number of tablets left, if this was in fact the way that they were taking their tablets.

Secondly, I would like to know how he fitted his

THE AMERICAN .JOURNAL OF CARDIOLOGY

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