Long term dipyridamole therapy of angina pectoris

Report on Therapy Long Term Dipyridamole

Therapy

of

Angina Pectoris* c MICHAEL

T.

NEWHOUSE,

b1.D.t

Montreal,

T

HE benefit of drugs employed in angina pectoris has traditionally been attributed to their ability to cause vasodilatation of the coronary arteries. More recently, however: it has been suggested that their long term use may actually cause the establishment and permanent anastomoses. enlargement of intercoronary Such conclusions are based on postmortem injection studies of the coronary vasculature of pigs following administration of nitrite preparations for long periods’ z and experiments in dogs with surgically induced vascular occlusion following long term administration of dipyridamole (Persantin@).3-5 Furthermore? Fam et al.6 have demonstrated an increase in intercoronar) anastomoses by the retrograde flow technic in normal dogs qivcn long term dipyridamole \,t’hile there seems little doubt that a therapy. permanent increase in collateral channels can be brought about in these animals by such therap).. there is no clear evidence that similar therap) would cause the same beneficial effect in man with diseased coronary \:essels. Basing their conclusions largely on patients’ reports of the incidence of pain and on nitroglycerine conseveral authors have claimed consumption, siderable benefit from such therapy.7-‘o Furthermore, in 11 patients Seuhaus et al.,” using a hypoxic stimulus to evoke electrocardiographic changes, found that most of their patients were improved by quite small doses of dipyridamole administered alternately with placebo over a period of two years. Others, however, have not confirmed this.‘? The discrepancy is probably attributable to the considerable difficulty of

and MAURICE MCGREWR,

11.1)

Canada

assessing a drug which may be presumed to take some months to cause the desired effect in a condition so variable as angina pectoris. The following report is based on the premise that improvement can be assessed more objectively in selected patients by repeatedly observing their ability to perform exercise on a treadmill without the occurrence of pain or electrocardiographic changes. We ha5.e attempted in this way to judge the effects of continuous administration of large doses of dipyridamole given for at least 10 months to a series of such patients. ME.rHOD Thirteen patients (Table I) werr chosen because of a history of typical angina of rffort which had remained more or less unchanged for several months. One patient who only occasionally experienced chest pain was included because three minutes of the standard exercise load invariably produced marked flat S-T segment depression of 3 mm. or more, and we wished to observe the effect of dipyridamole on this electrocardiographic evidence of myocardial ischemia. Half of our patients had electrocardiographic evidence of myocardial ischemia at rest, and typical S-T segment depression developed in all when exercised on a treadmill.*3 Patients \vere studied fox 12 to 24 months and acted as their own controls during the initial 2-6 months during which they were seen on at least five separate occasions. Treadmill Exercise Test: At each visit an exercise test was performed on a treadmill. All the effort tests were performed in the semifasting state at comparable times of the day and at a fairly constant room temperature (25 to 30’ C). Prior to the effort test, patients rested in a chair for at least half an hour, and a control electrocardiogram was recorded. Initially

* From the Joint Cardiorespiratory Services of the Royal Victoria Hospital and the Montreal Children’s Hospital, Montreal, Canada. ‘This study was supported by a grant from the Medical Research Council of Canada (MT-1241 ). t Present address: St. Joseph’s Hospital, [Hamilton, Ontario, Canada. 234

THE

AMERICAN

JOIIRh‘AI.

OF CARDIOLOGY

Dipyridamole

Therapy

of Angina

TABLE

235

Pectoris

I

Results of Treadmill Exercise Tests

Case x0. & Sex

.4ge kyr.,

1 ?vl 2 hi 3M: 4M 5 M 6 M 7F 8M 9F 10 M 11 M 12 hl&

.?‘I 55 02 51 53 57 .ii 00 44 45 h1 Ob

Treatment Months

17 10 12 12 11 13 12 10 11 10 15 14

---Load-Speed (mph)

2.0 2.0 3.0 2.5 3.0 2.0 2.0 2.0 2.25 2.0 1.75 3.0

Slope (deg.)

0 0 10 10 10 2.5 0 2.5 10 10 10 10

ECC Positive ----(%)--. Control Treatment Period Period

100 100 100 80 100 100 50 40 50 80 80 100

100 100 100 100 100 100 40 60 33 80 100 100

Control Mean

3.0 2.6 2.7 1.5 2.8 3.7 4.2 2.3 3.7 0.9 2.0 3.0

* Standard deviation of the difference between the means of “control” period t Sieni6cantlv different from control value (+J
(n)

(5) is, I:; (6) (5) (5) I:; (5) vs. “over

Time to Onset of Pain -(min.) --Treatment PcriodO-8 MO. Over 8 MO. Meall MeZUl @) (n)

2.3 3.0 2.7 2.5 2.4 2.2 3.4 1.7 3.7 2.3 30

(3) (3) (3) (1) (3) (4) (2) (2) (2) (4) (4)

1.5 3.0 2.8 2.2 2.8 5.3 4.2 3.5 6.1 2.7 2.3

(5H

(61 (6) (5) (5) (5H (5)

3.0

(4)

3.0

(5)

SD*

0.142 0.78 0.15 0.095 0.076 2.76 0.68 0.975 10.7 0.59 0.79

8 months.”

.

$

the speed and slope of the treadmill was adjusted to provoke typical angina1 pain within one to three minutes, and the same exercise load was repeated on all subsequent tests. At the onset of pain the exercise was stopped, its duration noted and a left chest lead (V,, Vs or Vs) recorded immediately and at minute intervals thereafter until the electrocardiogram had The time again returned to the control pattern. required for the electrocardiogram to return to control and for chest pain to disappear were also noted. In most patients the pain end-point at which treadmill exercise was stopped was invariably accompanied by flat S-T segment depression of over 1.5 mm. In the others, although electrocardiographic abnormalities were noted on every occasion, pain sometimes occurred before these changes were characteristic. The frequency with which this was observed is recorded in Table I. During the control period all patients Treatment: Treatment conreceived a placebo preparation. sisted of two 25 mg. tablets of dipyridamole three times a day before meals for 10 to 17 months (mean 12.25), and during this period they were seen approximately every two months for evaluation and a treadmill effort test. Throughout the study patients were ambulatory and continued, as much as possible, to engage in their previous normal activity. While they took no other drugs reported to have a prolonged coronary vasodilating effect, they continued to take nitroglycerine when necessary and other routine medications which they required, in the same dosage, during the control and trial periods. We attempted to supplement our objective evaluation of effort tolerance in the laboratory by asking our subjects to keep a record of the number and severity of anginal attacks and, the number of nitroglycerine tablets ingested each day throughout the control and trial periods. VOLUME

Period

16,

AUGUST

1965

RESULTS

Of the original 13 patients, 1 had a myocardial infarct during the control period and was dropped from the group. Another (Case 3) died suddenly of presumed myocardial infarction two weeks after dipyridamole had been discontinued at the end of the trial period. Objective Results: Comparison was made between the duration of exercise necessary to cause pain at each test (Table I). When the patients were studied month by month, there was no obvious trend toward an increased or decreased exercise tolerance. On the assumption that establishment of intercoronary collateral vessels might take up to eight months, the duration of exercise was separately averaged for the “O-8 months” and “over 8 months” treatment periods, and these were compared to the average duration of exercise in the control period. In the “control” and “over 8 months” periods there were sufficient observations to allow statistical evaluation. As judged by Student’s t-test’* there was a significant change in effort tolerance (p < 0.01) from control values in 3 patients. One of these showed deterioration while 2 showed a statistically significant improvement. In no case was the improvement in exercise tolerance great, nor was there any consistent improvement in the electrocardiogram. In the 2 patients in whom improvement was noted, this developed gradually during the first six to eight months of therapy and continued after medication was stopped. Recovery time, judged by the duration of pain after the end of exercise or

Newhouse

236

and

McGregor

TABLE II Average Number of Anginal Attacks and Nitroglycerine Intake per Month in Each Period and Patient’s Subjective Impression

--Angina1 Case No.

Control

1 2 3 4 5 6 7 8 9 10 11 12

180 209 9 26 25 50 130 135 12 78 100 2

Attacks per MO.-Over O-8 MO. 8 MO. 418 174 18 38 16 57 143 125 43 67 102 2

382 134 18 44 1 33 139 147 20 99 174 2

by the time required for the electrocardiogram to return to its pre-exercise pattern, did not obviously decrease during the months of diThus, as judged by the pyridamole therapy. graded exercise test, this prolonged period of therapy could not be shown to have produced any very great benefits. Subjective Results: By contrast, as judged by subjective criteria (Table II), the results were Five subjects (41.6%) resomewhat different. ported subjective improvement. In only 3 of these, however, was this accompanied by a decrease in the incidence of angina or a decrease in the number of nitroglycerine tablets ingested. One patient stopped taking nitroglycerine altogether, even though the reported number of Although in angina1 attacks increased slightly. 2 other patients nitroglycerine intake became negligible during the trial period, in neither had it ever exceeded one to two tablets per day Two patients during the control period. (16.6%) reported deterioration in their condition, but in only one of these was the patient’s subjective impression matched by a deterioration in his treadmill effort tolerance. Except for mild dyspepsia noted by 2 patients, and readily managed by ingesting the medication with milk, no side effects were noted. DISCUSSION This study demonstrates that the majority of a small group of patients with moderate to severe angina pectoris failed to improve their

-Nitroglycerine Intake-[tablets (0.6 mg.) per mo.] Over O-8 MO. Control 8 MO. 190 209 10 30 25 35 226 138 7 25 159 0

456 174 24 0 10 42 474 125 22 28 163 0

402 134 21 0 2 20 388 147 14 36 207 0

Subjective Evaluation Worse Worse Dead Better Better Better No change No change Better Better No change No chahge

effort tolerance when given dipyridamole in high There was dosage levels for 10 to 17 months. improvement in 2, deterioration in 1 and death in 1 case. These results are consistent with those of Soloff and co-workers,12 who found no objective evidence of improvement using the Master two-step test in 12 angina1 patients given They differ dipyridamole for one to six months. markedly, however, from the 64 to 80 per cent improvement reported by authors whose studies were based chiefly on subjective criteria,7~g~10 as well as the findings of Neuhaus and associates.lL The subjective evaluation of patients with angina pectoris is notoriously difficult because the incidence of angina and level of nitroglycerine intake is, to a great extent, dependent on the patient’s emotional state, the ambient temperature, and other factors impossible to assess Thus, in the present study 40 per or control. cent of the patients claimed subjective improvement, 30 per cent decreased nitroglycerine intake and 25 per cent decreased incidence of angina1 pain ; but only 16 per cent showed, an objective improvement in effort tolerance. However, there may be another explanation for the discrepancy between the results of our study and those of Soloff and co-workers,12 on the one hand, and those which suggest a markedly beneficial effect of dipyridamole therapy on Studies by Vineberg et al.5 suggest the other. that dipyridamole might enhance the effect of ischemia by increasing the size of intercoronary anastomoses in the presence of a single, well THE AMERICAN JOURNALOF CARDIOLOGY

Dipyridamole

Therapy

localized obstruction. In the presence of extensively narrowed coronary vessels such as one usually sees in arteriosclerotic man, it is unlikely that much increase in collateral flow would take place whatever the size of the potential anastoin the presmotic channels ; and furthermore ence of severe chronic ischemia these collateral vessels may already be maximally dilated. It may be significant that the patients studied by Wireckis and Griep’ were taken from a general practice and might have had less severe arteriosclerosis, while the cases reported by Soloff et a1.,12 as well as those in the present study, were patients referred because of the chronicity or It is possible that most severity of their angina. of our patients did not improve because they presented with severe and long-standing angina; our results do not exclude the possibility that this drug might be of value in the management of patients with myocardial ischemia due to well localized narrowing of a coronary artery without severe disease of the remaining vessels. SUMMARY

Twelve patients with long-standing angina pectoris were given dipyridamole (Persantin) for approximately one year. Improvement was assessed by comparing the patients’ treadmill effort tolerance under fairly standard conditions during the control period with that during and after completion of therapy. Although 5 claimed subjective improvement, only 2 patients showed statistically significant improvement of their effort tolerance. One patient died toward the end of the study, and 1 showed statistically significant deterioration. We would conclude from this study that long term dipyridamole therapy is of little benefit to patients with angina pectoris due to severe arteriosclerotic heart disease. ACKNOWLEDGMENT The authors gratefully acknowledge the supply of dipyridamole (Persantin@) from Messrs. Boehringer Ingelheim (Canada) Ltd.

VOLUME 16. AUGUST 1965

of Angina

Pectoris

237

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