A double-blind, double cross-over trial of

prenylamine in angina pectoris

Travis Winsor, M.D. Kenneth Bleifer, M.D. Seymour Cole, M.D. I. Ralph Goldman, M.D. Harold Karpman, M.D. Robert Oblath, M.D. Samuel Stone, M.D.

Los Angeles, Calif.

P renylamine is used widely for the management of angina pectoris. Sev-

Patients and trial design

eral controlled studies have demonstrated that the drug, given at proper doses, re- duced the frequency of angina1 attacks,1-4 except for one trial in which the observed differences between the results of placebo and prenylamine medication were not con- sidered significant.5

Discrepancies in the findings of con- trolled drug trials in angina pectoris are well known and emphasize the difficulties besetting the clinical evaluation of anti- angina1 agents. The problems arising from the capricious nature of the disease have only recently been pointed out again to- gether with the need for elaborate trial designs to obviate or reduce at least some of the factors that could affect the relevance of the findings.6

The patients were selected from among those visiting the investigators’ offices. The most important criterion for inclusion in the trial was a history of recurrent typical angina1 attacks, characterized by the nature, site, and radiation of pain, which had to be elicitable by exertion and reliev- able by rest with or without nitroglycerin. The diagnosis was to be further supported by electrocardiographic changes suggestive of ischemic heart disease and appearing at rest or after exercise. No restrictions were imposed with regard to age and sex.

To assess the efficacy of prenylamine under even more stringent conditions than those used previously, a double-blind, double cross-over study was carried out in office patients with angina pectoris.

Each patient was to participate in the trial for 36 weeks. The first phase of 12 weeks served primarily to establish the maximal daily dose of prenylamine that the individual patient could well tolerate. Done in a single-blind manner, this part of the study began with a two-week placebo period. During the subsequent six weeks the patient was given active drug (prenylamine lactate, 60 mg. of free base per tablet) at an initial dose of 240 mg.

Received for publication Aug. 31, 1970. Reprint requests to: Travis Winsor, M.D., 4041 Wilshire Hlvd., Los .4ngeles, Calif. 90005.

1’01. 82, No. 1, pp. 43-54 July, 1971 American Heart Journal 43

Table I. Distributiolz of ptrticnts among groups

So. oj patients / I -~___- .-.

Group No. and sex of patieds

I !

Criteria for inclusion Sequence Sequence

A 1 NlA 21~2 NIAIN,~Q

I

II

17 (11 M, 6 F)

27 (20 RI, 7 F)

8

17

9 Complete records with correct intervals

10 Complete records; at least one interval deviating by one or more days from correct number of days; medication uninterrupted

III 6 (5 M, 1 F) 1 5 Incomplete double-blind period, but adjacent A and N sequences avail- able

IV 19 (15 M, 4 F) Terminated trial in single-blind or early in double-blind period, or highly irregular and confusing records

(four tablets). The dose was then raised or lowered within a range of 120 to 300 mg. depending on its tolerability. The dose- titration period was followed by another four weeks of placebo administration to avoid the possibility of a carry-over effect of the active drug into the next phase of the trial.

The second phase lasted 24 weeks and was designed as a double-blind, double cross- over study. Each patient received the ac- tive drug (A) and the placebo (N) in alter- nating sequences of six weeks. The se- quences could be either prenylamine- placebo-prenylamine-placebo (A1N1A2N2) or placebo - prenylamine - placebo - prenyl- amine (N,A1N2AJ. The daily number of prenylamine or placebo tablets was that found in the preceding dose-titration period as the maximal well-tolerated dose. The investigators were unaware of the order of the sequences, nor did they know that the active drug and the placebo were to be crossed-over twice.

the frequency of angina1 attacks and the number of nitroglycerin tablets taken in the appropriate two-week interval. The cards also contained spaces for entering the pertinent comments regarding the severity of the attacks (more severe, less severe, same); the distance the patient could walk (more, less, same); and how he felt (better, worse, same).

The investigator examined blood pres- sure and heart rate during the visit. On a case report form he entered side effects ex- perienced by the patient, any intercurrent diseases, and other items of interest for the trial. Antianginal drugs other than prenyl- amine and nitroglycerin were not used.

Electrocardiograms (ECG’s) at rest and frequently after exercise were recorded at the beginning of the single-blind period and 8 and 12 weeks later, as well as 6, 12, 18, and 24 weeks following the beginning of the double-blind period.

Results

Office visits of the patients were spaced Forty-four (31 men, 13 women) of the at two-week intervals during the entire 36 69 patients (51 men, 18 women) who had weeks of the trial. At each visit the patients consented to participate in the study were given a supply of prenylamine or finished it and returned complete records. placebo sufficient for two weeks. The un- Seventeen of these records were perfect. used tablets of the preceding two weeks The remaining 27 contained minor devia- had to be returned. In addition to the tions from the prescribed number of days medication the patients also received a in at least one placebo or prenylamine in- card on which they had to record daily terval, but medication was at all times

Volume 82 Number 1 A trial of prenylamine in angina pectoris 45

Table II. Frequency of angina1 attacks, number of nitroglycerin tablets, and average pulse rates in combined prenylamine (Al + A,) and placebo (N1 + Nz) periods. Sequence: NIAINzAP

Group

No. of angixal No. of nitro. Average pulse No. of days attacks tabs. taken rates of treatment

“’ ‘,-+A,) N,+N* /,,+A2 / NI+Nz ),,,-[N,+% / A,+A? 1 NI+Nz

I 1 2 3 4 5 6 7 8 9

-

Subtotal 9 P

3 12 23 27

0 5 23 37

6 11 3 2

13 39 163 210

32 34 - -

266 377 <O.Ol

0 7 15 11

0 5 29 48

5 12 1 2

14 57 181 247

13 29 - - 258 418

0.01

62 64 62 62 69 70 76 76 62 64 43 54 60 80 6.5 67 53 66

- -

552 603 <o.oos

II 10 11 12 13 14 15 16 17 18 19 -

Subtotal 10 P

33 33 1 6

85 264 646 6.59

4 9 50 111 96 110 27 41 44 93

635 608

1,621 1,934 <0.02

12 42

7: 8

262 641 673

8 18 0 18 6 0

24 39 50 94

636 597 - - 1,458 1,751

0.1

87 90 81 74 67 72 62 80 68 78 62 70 68 73

68 2

;: 82

- -

715 770 <0.025

Total 19 1,887 2,311 1,716 2,169 1,267 1,373

P <O.Ol <O.Ol <o.oos

84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84 84

756

-

756

88 84 81 84 82 86 a7 85 84 83 83 88 84 82 84 83 84 83 85 83

- --

842 841

1,598 1,957

uninterrupted. Six other patients returned records that were incomplete with, how- ever, one adjacent prenylamine and placebo sequence present. The remaining 19 pa- tients terminated the study prematurely or submitted unsatisfactory records. De- pending on the quality of the records and the completion of the study the patients were divided into four groups which, in turn, were subdivided in accordance with the two possible sequences, AINIAzNz and N1ArN2A2. Table I shows the number of patients in each group and subgroup, as well as the criteria used for inclusion in the particular group.

Table II presents the number of angina1 attacks and nitroglycerin tablets taken for the combined prenylamine (A, + A,) and placebo periods (N1 + NJ and the number

of days reported by the patients of Groups I and II who started with placebo (se- quence NrArN,A,). Table III lists the same information for those patients who started with prenylamine (sequence A1N1A2N2). Both tables, in addition, show the pulse rates averaged for the prenylamine and placebo periods.

For the statistical analysis the Wilcoxon matched-pair signed-rank test was selected because individuals differ in their responses to drugs not only in their averages but also in the variance. Use of a nonparametric test without the assumption of equally distributed or normally and equally dis- tributed random variables precludes the danger inherent in other tests that a few exceptional responders might dominate the analysis. To allow for the qualitative

I 20 21 22 23 24 2.5 ‘6 27

68 83 84 84 65 68 84 84 73 81 84 84 62 63 84 84 62 77 84 84 63 64 84 84 72 78 84 84 - 84 84

-

Subtotal 8 I’

42 51 30 28 59 84 82 102 77 461 76 461

588 828 588 829 1 4 2 6 0 il 0 3 1 15 0 4 5 13 82 92

773 1,456 860 1,525 < 0 0 1 < 0. 02

-- -

46.5 514 0.01

II 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 -

Subtotal 17 P

12 23 101 135

8 12 7 11

397 425 17 13

259 34.5 19 17

191 216 59 69

0 3 38 46 90 97

8 71 60 90

9 28 13 132

__ __ 1,288 1 ,733

<o. 01

1 4 22 26 20 3.5 12 16

466 482 7 4

47 83

7: 5

126 183 193

0 4 7 7

186 198 0 0

116 139 10 3.5 13 132

1,174 1,489 <O.Ol

-

77 78 6.5 73 57 62 79 75 65 76 5.5 66 62 74 49 65 71 80 70 79 88 90 60 55 62 76 59 61 76 80 81 89

1,076 1,179 <0.005

Total ‘5 2,061 3,189 2,034 3,014 1,541 1,693 I’ <O.Ol <O.Ol <o.oos

672

--

672

83 84 84 83 79 87 85 77 8.5 84 84 85 83 84 80 80 84 83 83 84 80 84 87 93 87 88 80 83 82 86 83 80 81 83

--- 1,417

2,089

--

1,440

2,112

differences in the patient’s records, and thus for even more stringent criteria in the statistical analysis, the results of the two groups of patients and again for the two possible treatment sequences within each group were evaluated separately. The small irregularities in the lengths of the treatment intervals recorded by the pa- tients constituting Group II were corrected by dividing the number of attacks or nitroglycerin tablets by the number of days reported per interval.

As Tables II and II I show, the number of angina1 attacks and nitroglycerin tablets

during the combined prenylamine periods was significantly lower than during the combined placebo periods. The mean per- centage reduction in the daily number of angina1 attacks during the prenylamine periods as compared to that during placebo periods was about 38 per cent, the median percentage reduction about 30.5 per cent.

To find out whether prenylamine was similarly effective in those patients whose deficient record keeping had ruled out a formal statistical analysis, the daily aver- age number of angina1 attacks and nitro- glycerin tablets was calculated for both

A triul of #renykmine in angina pectoris 47

Combined No. of Daily Attacks

50

40

30

20

10

El Prenylamine 0 Placebo

Single-Blind Period Double-Blind Period

1 r ::::.:.::::::: i j

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~

: : : : : : : : : : : : : : : : : : : : : : : : : : : . : . : . : . :+: . : . : . : . : . : : : : : : : : : : : : :y : . . . . . , . , . , . , . , . . . , . , . ,

. . . . . . . . . . ..A. A.. . . . ..A.... : . : . : . : . : . ; . : . ; . .~.;.:.&~~:::: ::~:::::~:~:~:::: . : . : . : . : . : . : . :c . : : : : : : : : . : . : . : . : .:.~.:.~.~.~.:.:. : : : j : : : : : : : : : : : : : : : : : : : : : : : : : : : %g#$:s y: : : : : : : : : : : : : : . : . : . : . : . : . : . : . , . , . , . , . . . , .~.~., : : : : : : : : : : : : : : : : :$sgj:;:$i : : : : : : : : : : : : : : : : : : . : . : . : . : . : . : : : : . , . , . . . , . . . , . , . , . : . : . : . : . : . : . : . : . . : . : . : . : . : . : . .._. : . : . : . : . : . : . : . : . . . . . . ..A.... . . . . : . : . : . : . : . : . : . :

: . : . : . : . : : : : : : : : :

:;:g$$; v. . . . . . . . . . ..c

z:#$>;: .:.:$:: xc.:,: : . : . . . ..A......

A.. . . . : : : : : : : : : : : : : : : : : . : . ; . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : .

I I

F 1

L -

I I I I I I

-

-

-

I I I I I I I I I I I I

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Weeks

Fig. 1. Combined daily number of angina1 attacks in patients of Groups I and II (n = 19) during single-blind and double-blind periods of trial. Double-blind sequence: NlAlNzA*.

types of medication. In the seven patients that could be evaluated because of an adjacent prenylamine and placebo se- quence (Group III) the daily average num- ber of angina1 attacks during prenylamine treatment was 1.7, and during placebo medication for a comparable period, 2.5. The same patients took a daily average of 2.9 nitroglycerin tablets during prenyl- amine treatment and 3.7 tablets during comparable placebo periods. These results agree well with the over-all results obtained for Groups I and II and support their statistical evaluation.

Figs. 1 and 2 represent the combined means of the daily number of angina1 at- tacks for each two-week interval of the trial, including the initial single-blind dose-titration part. The two graphs clearly demonstrate that the prenylamine effect is reproducible with each change in medica- tion. A statistical comparison of the periods of the double-blind parts confirmed the

visual demonstration. In all of the six possible combinations of adjacent medica- tion periods in the two sequences of the double-blind part (NrAi, AiN2, N2A2, and ArNr, NiA2, AzN2) prenylamine reduced the number of attacks significantly except for the comparison NrAi. The decrease of nitroglycerin consumption during prenyl- amine administration was similarly repro- ducible with each change in medication.

The qualitative data entered by the pa- tients on their report cards (severity of at- tacks, general well-being, walking distance) were also subjected to a statistical analysis using the sign test (Table IV). For each patient, a total of 144 possible comparisons is possible, because each of the twelve placebo weeks can be compared with each of the twelve prenylamine weeks. Thus, it can be stated for each weekly comparison whether with placebo the severity of the attacks, for example, was the same as, or more, or less than with prenylamine. If

4s ?t:i7zsor ct trl.

Combined No. @ Prenylamine 0 Placebo of Daily Attacks

50

40

30

20

10

Single-Blind Period Double-Blind Period

I II I

r r

- -

-

-

I I I I I I I I I I I I I I I I I I I

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Weeks

Fig. 2. Combined daily number of angina1 attacks in patients of Groups I and II (n = 24) during single-blind and double-blind periods of trial. Double-blind sequence: A~N~AzN~.

the sum of all weekly comparisons un- favorable for prenylamine is smaller than that unfavorable for placebo, the patient is considered a responder and counted in n and n+ in Table IV. In the reverse case, where the sum of all weekly comparisons unfavorable for prenylamine exceeds the sum of those unfavorable for placebo, the patient is counted in n but not in n+. In case of equal sums, the patient is not counted in either n or nf.

The consistency of the data in Table IV is such that they could be summarized across the four groups and then be tested for significance with a simple sign test. Obviously, the difference between prenyl- amine and placebo is highly significant re- garding the severity of attacks, weeks with no attacks, and how the patient felt. With respect to the walking distance, the dif- ference between placebo and prenylamine is not statistically significant.

In 3 multiclinical trial, it is necessary to

check whether one or a few investigators could influence the outcome by studying more patients than the others. Moreover, it had to be evaluated whether the results were affected by other variables such as the dosage, age of patient, history of myo- cardial infarction, and concurrent diseases.

As shown in Table V, none of the vari- ables had an effect sufficient to justify the computation of a statistical test of signifi- cance.

The blood pressure did not differ to any noticeable degree during the various inter- vals of the trial. This observation agrees with earlier findings that therapeutic doses of prenylamine do not significantly affect blood pressure. In contrast, the pulse rate was generally lower when the patients took prenylamine than during placebo periods (see Tables II and III). Fig. 3 shows the mean pulse rates for nine patients of Groups I and II who began the double- blind part with placebo and whose records

-4 triul of prenyhanine in angina pectoris 49

Table IV. Statistical analysis (sign test)* of qualitative v&ablest

Group Sequence

Severity of Weeks with no attacks attacks How pt. felt Walking

-__-_____~ .--___-_-

n n+ n nf n n+ n nf

I A,NlAzNz 7 6 5 5 8 6 7 3 I NANA 9 7 5 5 8 6 5 3

II A,N,AzN2 16 14 8 7 16 12 16 10 II NANA 8 6 4 3 9 5 9 3

- - - - - - -

Total 40 33 22 20 41 29 37 19 14 0.000 0.000 0.006 0.500

*Twelve weeks of placebo and twelve weeks of prenylamine medication allow 144 comparisons for each patient and his answers to one of the three questions below. As judged by the totals of the number of comparisons of weeks, the comparison may be favorable or unfavorable for prenylamine in that patient. Equal totals are a third possibility. If the result is in favor of prenylamine the patient is counted in both n and n+. Should the result be in favor of placebo, the patient is counted in n only. In case of equal totals the patient is not counted in either n or n+.

tThe questions asked were the following: Were angina1 attacks: more severe, same as usual. less severe? I” general, I felt: better. same. worse. I walked: more. same. less.

#p is the probability of obtaining n+ or m”re s”ccesse~ of n independent trials of an exwriment having two possible outcomes. each having a probability of one half.

Table V. Efect of several variables on trial results”

1. Age of patients (yr.) 40 or less 41-50 51-60 61-70 71 and over No. of patients 2w 9(9) 803) 12(12) 12(12) No. of responders? 2(l) 7(6) 8(7) lO(10) 12(12)

2. Investigator$ 36) 2 5 6 7 No. of patients 2G9 7;) 4 (4) 9(9) 15(15) No. of responders 3(2) 2Gv 3(3) 7(7) 2(Z) 9 (9) 13(11)

3. No. of prenylamine or placebo tablets per day 2

No. of patients 10) 24;4) 4

14(14) 4(i) No. of responders l(1) 21(19) 13(12) 4(4)

4. Previous myocardial infarction Yes No No. of patients 25 (26) 18(17) No. of responders 23 (22) 16(14)

5. No. of concomitant diseases No. of patients 18;s) 12i2) &I 3;f3)

5 20)

No. of responders 16(14) 12(11) 7(7) Z(2) 20)

Total 43 (43) 39(36)

Total 43 (43) 39(36)

Tofal 43 (43) 39(36)

Total 43 (43) 39(36)

Total 43 (43) 39(36)

*Figures without parentheses are based on number of angina1 attacks per day; figures in parentheses are bawd on number of nitro- glycerin tablets taken per day.

tExcluded from the number of patients are those who had the same number of anginal attacks in the prenylamine. and placebo periods. Responders are those patients whose number of attacks (or nitroglycerin tablets) per day was less in prenylamine than in placebo periods.

$Seven of the eight authors were the investigators responsible for the performance of the trial.

contained a complete series of measure- ments. For patients starting with prenyl- amine, ten complete series were available and their means are shown in Fig. 4.

The resting and exercise ECG’s were evaluated after the trial by one of the investigators without his knowledge at which period of the study they had been

Q Prenylamine

0 Placebo

Beats/minute

80

N2 A2 NI + N2 AI+&

P-Values N, -A, =O.Ol N,-A,=>o.o5 (N,+NJ - (A,+A,) = CO.005

recorded. Subsequent assignment of the electrocardiographic records to the ap- propriate medication period did not reveal any distinct effect of prenylamine.

Dropouts and side effects

Twenty-one patients did not complete the trial for a variety of reasons. Among these were three deaths. One patient died of cardiac arrest during the single-blind period in the initial two weeks of placebo administration; a second patient died of myocardial infarction during the same period while he was taking prenylamine. The third patient died suddenly of myo- cardial infarction during the placebo period of the double-blind part of the trial.

Of the remaining 18 patients, nine terminated the study in the single-blind part and nine in the double-blind part. The reasons for discontinuation and the

periods at which this occurred are listed in Table VI.

In accordance with the clinical literature on prenylamine, sedation was by far the most common side effect during the trial. It was reported, under a variety of de- scriptive terms, by 92 per cent of the patients when they took the active drug, as compared to 67 per cent for the placebo periods. At various times, but most often during the dose-titration part, 36 per cent of the patients experienced the opposite effect, nervousness or an allied symptom. The corresponding figure for the placebo periods was 14 per cent. A high incidence of gastrointestinal reactions was reported for both the prenylamine and placebo pe- riods. Thus, episodes of nausea with or without vomiting occurred in 35 per cent of the patients while taking the active drug, but also in 22 per cent during placebo

A trial of prenylzmine in nn& pectoris 5 1

q Prenylamine 0 Placebo

Beats/minute

80

70

60

50

40

30

20

10

0

AI NI

.~~~:_:_~~~~~:.~~~~~~~~~~:.:.:.:

: . : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : . : . : . : : : : : : : : : : : . : : : . : .

. . . . . . . . . . . . . . . . . ( . . . . . . . . . . . : . : . : . : . : . : . . . . ..i

: : : : : . : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : ~ ~ ~ ~ , ~ . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . :

:j:i:i:i:i:j.~:j.I:j:~:~:~:~:~:~:~~~:~:~:~:~:~

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. : . : . : . : . : . : . : . : . : . : . ~ . ~ . ~ . ~ . ~ . ~ . 2 . . : : : : _ . _

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. : : : : : : : : : : : : : : : : : : : , : , : : : : : : : : : : : : : : : : : : : : : : : . : , : , _ . _ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . , . , .j:j:j:j:i:i:i:j:j:j:i:i:i:i:i:!:!:!:!:::’:’:::::~:

: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : . : . : . : . : . : . . . . . . . . . . . . . . _ . _ . . . . . . . . . . . . . . . . . . . . . . . . . : . : . , . , . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . . . . . . . . . . . . . . . . . . . . . . . . . : , . . . . . : . . : : : . : . > > : . : . : . ) : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . : . . . . . , . , . . . . . . . . . . . . _ . . . . . . . . . . . . . . . . . . . . . . . . . . : . : . : . : . : . . . : . : . : . : . : . : . : . : . . . : . : . : . : . : . : . : . : . : . : . . . . . . . . . . . . I . . . . . . , . . . . . . . . . . , . , . . . . . . . . . . . . . . : . > : . : . : . : . : . : . : . . . : . . . . . : . : . : . : . : . j : . : . j : . : . . .

: : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : :

. . . . . . . . . . . . . . . . l . . . . . . . . . , . , . , . , . , , . , . , . . . .

: : : : : : : : : : : : : : : : : : ; : ; : ; : , : ; : ~ : , : : : : : : : : ’ : : : : : : : : : : : . . . . . . . . . . . . . . . . . . . , . . . , . , . , . . . . . . . . . . . ~ ~ ~ : . : . : . , . : . : . . . : . : . : . : . : . : . : . : . : . : . : . : . : . : . > : . : . : . : . : . : : : , : . : . y . : . : . : . : . : . : : : : :

. , . , . , . , . . . ( . . . ( . , . . , . , . . . . : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : , : : : , : : , : : : : : :

. . . . . . . . . . . . . . . . . . . . . . . . . , . , . , . . , . . . . :

. . . Y.>. . . . . . . . . . . . . . . , . , . , . , . , . . . .

A2 N2 AI+& NI + N2

P-Values A,-N,= co.01 A,-N,=<0.025 (A,+&)-(N,+N,)=<0.005

Fig. 4. Pulse rates for patients (n = 10) during treatment with prenylamine (A) and placebo (N). Sequence:

administration. Among a host of other side effects, more or less evenly distributed be- tween prenylamine and placebo periods, one case of urticarial dermatitis is most likely attributable to the active drug be- cause similar skin reactions have been reported in the literature.

Discussion

The combination of a single-blind part of 12 weeks with a double-blind, double cross-over part of 24 weeks represents a very sensitive trial design for the evaluation of an antianginal drug. In addition to al- lowing the effectiveness of the agent to be assessed over an extended period of time, this design also lends itself well to investi- gating the reproducibility of the anti- angina1 action.

The close agreement between the num- ber of angina1 attacks at the beginning and

at the end of the placebo sequences of the single-blind period of the trial demon- strates that the angina was stable and thus the main criterion for selecting patients fulfilled. The similarity in the antianginal effect of prenyIamine during the single- blind and the double-blind periods of the trial strongly supports the evidence for the reproducibility of that effect in a trial lasting as long as nine months.

Both in the single-blind and the double- blind periods prenylamine reduced the number of angina1 attacks by an average of about 30 per cent. This figure agrees well with the results of previous controlled studies with prenylamine.1-4 An examina- tion of Tables II and III reveals, however, that for the therapeutic success in an indi- vidual patient the 30 per cent figure has little meaning. There are patients whose response is excellent and reproducible,

.41wr. flow t .T. ILIlY, 1971

Tuble VI. Reasons for rii.scontinlLc~tiola cf tviul

Reason for disconti~~uatioa Single-blind part Double-blind part -.._--___~ ~~

I’renylamine Placebo Prenylamine Plucebo

Death (myocardial infarction, 2 ; cardiac arrest, 1)

Hospitalization (senile dementia, 1; probable myocardial infarction, 1; orthopedic problem, 1)

Wanted coronary artery surgery Acute pulmonary edema Progressive heart failure Skin rash Nausea (and vomiting) ‘Tiredness Unknown

1 1 1

1* 2 2

1

1.1 1$ 1 2 1 2 1

1 2

*Patient died of congestive heart failure about one month after discontinuation. tDeterioration noted earlier in last placebo period of single-blind part. tPatient died about one month after discontinuation of acute myocardial infarction. Skin rash had also appeared during placebo mrd-

ication.

whereas others respond only moderately well or not at all. The response does not seem to depend on the severity of the angina, nor is it related to the dose of prenylamine (see Table V). Furthermore,

The reduction of the number of angina1 attacks and nitroglycerin consumption is

patients with a previous myocardial in-

only a part, although the most important one, of the over-all therapeutic efficacy of

farction responded as well as those without

prenylamine. Of interest is also the effect of the drug on the severity of the attacks, and

a history of such an event.

on general condition of the patient. The statistical analysis (Table IV) demonstrates a significant decrease in the severity of the attacks, which further supports the effec- tiveness of prenylamine. Expectedly, the number of weeks with no attacks was significantly greater for prenylamine than for placebo. The significant improvement of the general condition of the patients, as indicated by the answers to how they felt, again supports the positive results.

Physical activity, respresented by the distance the patient walked, did not differ significantly during placebo and prenyl- amine periods. This would imply that prenylamine did not improve the patient’s

capability for physical activity. However, more important for the validity of the trial is the conclusion that physical activity was not reduced because of the obvious sedative

The mode of action by which prenyl-

effect of prenylamine. The reduced number

amine reduces the frequency and severity of angina1 attacks has thus far eluded a satisfactory explanation.

of attacks can thus not be attributed to general inactivity of the patients because of sedation.

A reduction of the cardiac rate, which is desirable in angina pectoris, occurred in 37 of 43 patients during the trial. Mean reduction was about 9 per cent, but in individual patients cardiac rate decreased by as much as 2.5 per cent. A relationship between the degree of prenylamine-induced bradycardia and the decrease in the num- ber of angina1 attacks was not apparent. Patients whose angina was not improved by prenylamine showed as little or as much reduction of their pulse rates as those who responded excellently to the drug. It must, however, be considered that measuring the pulse rates in office patients once at two- week intervals is insufficiently exact to find out whether the frequency of attacks is quantitatively related to cardiac rate.

A trid of prenylamine in angina pectoris 53

A negative inotropic effect and a reduc- tion of the effect of isoproterenol on myo- cardial contractility and cardiac rate has been observed only in animal experiments with high doses of prenylamine.7-gs11 In the absence of corresponding findings in man given prenylamine at therapeutic doses, it is unlikely that the antianginal effect of prenylamine is due to decreased myocardial contractility and oxygen consumption.

In isolated preparations and following its intravenous administration in man and dogs, prenylamine increases coronary blood flow, probably by a direct action on the vascular muscle,10,11J4-16 but this effect is assumed to be negligible on oral adminis- tration.

As judged by the rather extensive litera- ture, the most interesting property of prenylamine is its catecholamine-depleting effect.12J3J7~18 No direct evidence for this effect is thus far available for man. Several investigations, however, obtained indirect evidence by showing that the daily oral administration of 180 mg. of prenylamine for five days produced a significant decrease of the effect of intravenously infused tyramine on blood pressure and cardiac rate.r9-21 This decrease implies a prenyl- amine-induced catecholamine depletion since the tyramine effect is due to the re- lease of norepinephrine and thus depends on the catecholamine amount available in the storage granules.

Additional findings are available which suggest a general attenuating effect of prenylamine on the adrenergic system. In patients undergoing emotional stress or exercise the administration of prenylamine at therapeutic doses caused a decrease of vanillylmandelic acid and catecholamine excretion.zzJ3 At the same time, the rise in blood pressure and cardiac rate following exercise was significantly less than in nor- mal controls.24

It is, therefore, conceivable that prenyl- amine diminishes the release of the adre- nergic transmitter in emotion- or exercise- induced activation of the sympathetic nervous system. Among the various hypo- thetical explanations for the mechanism of the antianginal effect of prenylamine, its attenuation of the adrenergic action on the heart seems at present the most likely one.

Furthermore, it agrees well with the sig- nificant reduction of the cardiac rate ob- served during the trial.

Summary

The effectiveness of prenylamine in re- ducing the frequency and severity of angina1 attacks was evaluated in office pa- tients selected by seven investigators. The trial lasted 36 weeks. The initial 12 weeks were done in a single-blind manner and six of these weeks were used to establish the maximal well-tolerated dose of prenyl- amine for each patient. Placebo was given both before and after the dose-titration period. During the next 24 weeks, the trial was carried out as a double-blind, double cross-over study. The patient had to enter the daily number of angina1 attacks and nitroglycerin tablets taken into a report card. He was also requested to fill in the answers about the severity of the attacks, how he felt, and the distance he was able to walk.

Of the 69 patients who started the trial 48 completed it. Four of the complete records could not be used.

The most common side effects during the trial were, in order of their frequency, seda- tion, gastrointestinal intolerance, and ner- vousness. However, all of these symptoms also occurred during the placebo medica- tion. Three patients died during the trial, two others about one month after they had discontinued it. No relationship be- tween the cause of death and prenylamine is apparent. One case of urticarial derma- titis is most likely attributable to the drug.

The statistical analysis by the Wilcoxon matched-pair signed-rank test showed that the number of angina1 attacks and nitro- glycerin consumption were significantly less during prenylamine than during pla- cebo sequences. The reproducibility of the effect of prenylamine in the double cross- over design was excellent.

Qualitative information regarding the severity of the angina1 attacks and how the patients felt showed that the patients clearly benefited during prenylamine ad- ministration.

The statistical analysis of most of the results of the trial was carried out by Stanford Research Insti- tute, Menlo Park, Calif.

I’renylamine lactate (Sepontill@) iv.,5 Wl~l)lietl by Hoechst Pharmaceutical Cornl~~t~~>., Cillc,ilru.lti, Ohio.

K E F E Ii E N C E S

1. Cm-doe, N.: Prenylamine lactate (“Synadrin”) in patients with angina pectoris, Brit. J. Clin. Pratt. 22:299, 1968.

2. Donat, Ii., and Schlosser, G. A.: Problems in the treatment of angina pectoris, Med. Klin. 61:351, 1966.

3. Kappert, A.: Double-blind trial with high doses of Segontin in angina pectoris, Z. Therap. 3:82, 1965.

1. Stoker, J. B.: Effect of prenylamine ill angina pectoris, Brit. J. Clin. Pratt. 22:384, 1968.

5. Bjgrum, N., Christensen, M., and Kathsach, I’.: ~1 double-blind study with prenylamine (Segon- tin) in angina pectoris, Ugeskr. Laeg. 129:47, 1967.

6. Panels on cardiovascular drugs: Statement on criteria for evaluation of long-acting coronary vasodilators in treatment of angina pectoris. Drug eflicacy study. Final report to the Com- missioner of Food and Drugs from the Division of Medical Sciences, National Research Coun- cil, National Academy of Sciences, \Vashington, D. C., 1969, p. 161.

7. Fleckenstein, A., Diiring, II. J., and Kamnler- meier, H.: Influence of prenylamine on the utilization of high energy phosphates in cardiac muscle, in Biochemical aspects of prenylamine, Proc. Symp. Capri, Italy, Oct. 23-24, 1967, Biochim. Appl. (Parma) 14, Suppl. 1:323, 1968.

8. Obiauwu, H.: Actions of prenylamine (Segontin) on the cardiovascular system, Acta Pharmacol. (Kobenhavn) 25:127, 1967.

9. Schmidt, H. D., and Schmier, J.: The relation between cardiodepressive and adrenolytic effect in some beta-receptor blocking agents in the heart-lung preparation of the dog, Klin. \I’schr. 45:698, 1967.

10. Biihm, C., Schlepper, Al., and IVitzleb, E.: A new coronary vasodilating substance. Experi- mental and clinical investigations, Deutsch. Med. \Vschr. 85:1405, 1960.

11. l.indner, E.: Phenyl-propyl-diphenyl-propyl- amin, a new substance with coronary vaso- dilator effect. Communication 1. Effect on cir- culation, Arzneimittelforschung 10:569, 1960.

12. Schoene, H.-H., and Lindner, E.: The effects of N-(3’-phenylpropyl-(2’))-l,l-diphenylpropyl- (3)-amine on serotonin and norepinephrine

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