fo I ORIGINAL ARTICLE /itamin E in angina pectoris W. Anderson, 3.M, 8.CH., PID. Toronto Tew. rmmary: The claim that the symptoms of angina ctoris can usually be relieved by large doses of amin & has been reinvestigated by means of & idomized double-blind tral, The trial lasted nine weeks 4 consisted of two parts. One part was conducted 2 regular double-blind ‘vial involving 40 patients, fof whom received 3200 IU of vitamin € daily, while ‘equal number received an indistinguishabie placebo. 2 second part of the «tal involved 15 pationts who wer dy taking a regular daily dose of between 400 1 2400 IU of vitamin E. Eight patients were assigned same (oF a larger) dose of vitamin E, while ‘seven eived placebo, Neither part of the trial yielded Ustically convincing evidence that vitamin E is of 40 in the treatment of angina, but a small beneficial et could not be ruled out. Taken in conjunction 4 the positive (but statistically non-significant) sits obtained in the only other double-blind ‘rial of min E ever carried out on angina, and the encouraging ‘ts reported by other investigators in the treatment Intermittent claudication, it fe suggested that further ble-blind tials are justi, umé: La vitamine E dane fangine de poitrine ous avons réévalué fe bien-fondé de Yatfimmation de fortes doses de vitamine E peuvent généralement ager les symptémes de Tangine de poitrine et avons. A effet, utilisé ta méthode & double insu, les des tant pris au hasard. Ces essais ont duré neuf aines et ont été divisés en deux parties, La premiére ©. faite suivant les ragles classiques de la méthode ‘uble insu, portaient sur 40 malades, dont fa 16 recevaient 3200 Ul de vitamine E par jour, nombre égal de malades un piacébo qu’on ne peut ‘guer. La seconde partie portait sur 19 malades vrenaient déja régulérement une dose quotidienne itamine € variant de 40 a 2400 Ul. Huit do ces es ont continué de prendre leur dose habituelle tamine E (voire une dose plus forte), tandlis que ept autres recevaiont un placébo, Ni la premiere 'essais, ni a seconde nvont fourni de preuve dineante, sur te plan statistique, que la vitamine E valeur thérapeutique dans Tangine de poitrine. quit soit impossible possiblité d'un léger effet favorable, Si on compare ces résultats aux résultats positifs (bien que négligeables ‘u point de vue statistique) qui ont été obtenus dans la seule autre étude & double insu de Ia vitamine E ‘sur Vangine qui ait jamais 6té publiée, et si on les approche des résultats encourageants rapportés par d'autres cchercheurs dans lo traitement de ia claudication intermittente, if semble bien que dautres essais du ‘genre seraient justtigs. The tocopherols are a group of substances that are widely distributed in nature and whose main function appears to be that of protecting unsaturated fatty acids (particularly the polyunsaturates) from oxidation, a property demon- strable both in vitro and in vivo. Of the eight known toco pherols, the alpha form is the most powerful in its an oxidant action, and has been designated vitemin E, Deficiency causes illness and death in a wide range of animal species, owing to the formation of highly reactive lipid peroxides that seriously disrupt the metabolism of 4 variety of tissues, including the myocardium, It is ther fore theoretically possible that a deficiency of the ant oxidant tocopherols could lead to myocardial damage in ‘man, and that an adequate intake of vitamin E (currently thought to be of the order of 20 to 30 mg per day) might help to protect the human myocardium. However, most of the controversy that has existed for the past quarter of a century over the place of vitamin E in cardiovascular disease ‘has been concerned not so much with the possible importance of an adequate dietary intake of this vitamin as over its use in large doses as 1 therapeutic agent ‘The first claim that angina pectoris could be relieved by massive doses of vitamin E appeared in a letter to Nature in June 1946, in which Vogelsang and. Shute re ported that they had found that vitamin E in a dose range ‘of 200 to 600 mg per day would dramatically diminish oF abolish anginal pain.’ In the following year Shute, Shute and Vogelsang supported this claim with 84 case histories of angina patients in 90% of whom improvement had curred safler an average of seven weeks on vitamin E therapy. Between 1947 and 1950 a number of negative reports were published," but like the original postive report, most were based on uncontrolled clinical “observations. Only three controlled studies were reported, and only that by Rinzler et uf was double-blind (Table D. Since 1950 there hhave been no published reports of further trials, although some physicians have continued to claim dramatic success CMA JOURNAL/FEBRUARY 16, 1974/VOL. 110401 cane 4 CKin the treatment of angina and other diseases, and have criticized the early negative trials on the grounds of ina- equate design, dosage and duration." These conflicting claims have been widely publicized in the last few years, and the medical profession has been accused of rejecting vitamin E without a fair trial!" Unfortunately, itis notoriously difficult to evaluate anti- angina deugs. Not only is angina almost entirely subjective in nature, but anxiety often plays a major role in the symp- tomatology. It follows that any substance, however inert, will appear to be effective provided it is. prescribed with enough enthusiasm by a physician in whom the patient has confidence. ‘The problem in evaluating the dramatic claims made for vitamin E is therefore not to establish whether the claims are exaggerated (they are almost bound to be), but whether beneath the placebo effect is a small but useful therapeutic effect. ‘None of the early controlled trials involved large enough umbers of subjects to demonstrate convincingly the pres- fence or absence of an effect of small magnitude, However, the results of the double-blind trial by Rinzler were com. patible with a small positive effect (Table 1D), and it was hoped that in the present study it would be possible to recruit large enough numbers to establish whether this ‘was a real effect or a statistical artefact. (Unfortunately, as will be seen, only a modest number of subjects could be recruited) In the opinion of Dr. E. V. Shute, the failure of the Rinzler trial to demonstrate a statistically significant effect of vitamin E was due to the use of an inadequate dose.” Jn the present trial a much higher dose (3200 IU_per day) was therefore proposed, and at this dosage level Drs. E, V. and W. E. Shute believed that a trial of nine weeks' duration would be adequate to demonstrate a large effect, of the order of 80% improvement.” Initially it was hoped that it would be possible to quan- titate the change (f any) in the anginal status of some Patients by means of exercise testing. This did not prove possible, sp that apart from nitroglycerin consumption the assessments in this study were purely qualitative. Contrary. to some widely held opinions, however, this need not invalidate a trial of antiangina therapy. Since the object of treatment is to reduce symptoms and inerease the patient’s ability to lead a normal life, these are the criteria on Which assessment of treatment should be based. The fact that they are subjective criteria should be no obstacle to valid group comparisons, provided that the subjective bias is the same in both groups, Le. that the trial is truly double-blind.” (As normally carried out, exercise testing ‘also has a large subjective component: the patient is taken, through increasing levels of exercise until he or she can do no more, either because of pain or because of inadequate motivation.) Inthe present trial, changes in angina status were therefore judged on the basis of the attending physician's clinical impression, changes in nitroglycerin consumption, and changes in the patient's daily record of severity of pain and amount of activity Method A letter was submitted to this journal” inviting the cooperation of interested physicians, and a similar invita tion was circulated to a number of cardiologists in the Toronto area. Physicians who responded were sent a de tailed description ‘of the proposed trial, together with an explanatory letter and consent form for their patients, Both documents had previously been approved by the University of Toronto committee on human experiments. Patients were informed that half of them would receive 402 CMA JOURNAL/FEBRUARY 16, 1974/VOL. 110 placebo, and that they were free to withdraw from the (rial at any time if they so desired, Physicians were asked to recruit patients whose angina was reasonably stable, who had had no major change in health status (Such as an acute myocardial infarction) ot usual medications for at least three months, and who ‘could be depended on to take their test capsules regularly Jand keep adequate records (In view of some of the reported side effects of lurge doses of vitamin E" physicians were asked not to recruit patients who were on the brink of congestive failure, or Who had any evidence of rheumatic heart disease) Since the object was to assess the effect of fone variabIe“(vitamin ) while all others remained con- stant, patients remained on their other usual medications throughout the trial Physicians who were already prescribing vitamin E. for their angina patients were invited to enrol these patients in a separate trial in which the effect of discontinuing the vitamin E could be assessed, Dr. W. E. Shute has claimed that such patients have a recurrence of symptoms, often after only a few days without their vitamin E."" Patienis were paired as closely as possibly by sex and age, then assigned a code number from a computer- generated list of paired random numbers that had pre- Viously been used to number the vitamin and placebo bottles. After the code list had been used to number the botties. it was given to a colleague for safe-keeping until after all the records had been returned and initial tabuls- tions carried out. Each patient then received numbered bottle containing enough capsules for the nine-week tial, together with 2 list of instructions and U1 record cards, two for a pre- liminary baseline period and nine for the trial itself. (Sub. sequently, it was necessary to use the first two wecks of the trial as the baseline period since very few of the preliminary two cards were Sent in) Table I-Some of tho major negative reports on the efficacy ‘of vitamin E in angina pectoris ‘Mean duration Mean d No.of patents of vitamin of wlan (oat eatrol) treatment (vesks)_ (me) i alk we 6 a teres tenes) Gane toson ‘Makinson, Ofeesky 7 masta sean 3 1% 18 Donegan eal 774 4 Py Grepnte) (age 90h) Rovin an KIL et 8 Grange 150, ter tat? 1834 & wi ‘where arange of doses was used, a weighed mean has beoncalelted; 1 mg efvitzmn es apooximatyogualtone interna unt {Same patents on ater mesrzians or placebo; singe ind ‘Matched contels; double stad Table Results of the double-blind trial by Rinzler et af in 1950, using approximately 300 mg of vitamin E daily for an average of 16 weeks Pasebo Vitamin inner change Worse Totadouble-blind trial is to have any validity, the placebo be truly indistinguishable from the active preparation, rt of chemical analysis. This may be very difficult to chieve, particularly if (xs in this case) the active prepara ion ean casily be obtained from any drug store and used sa basis of comparison by the inquisitive patient or hysician, The form of vitamin E used in this study was the uecinate, available in eapsules-as a dry powder of creamy olour, with a slightly nutty flavour and siightly. granular exture. This powder proved to be very difficult to imitate, nd after several unsuccessful aitempts to modify the olour and texture of the placebo powder (lactose) to suit, was decided to colour both preparations bright yellow nd to have @ small amount of crystalline sucrose added to ich. This appeared to obscure effectively the colour, taste nd texture of the original material, and this was verified y having 23 colleagues examine the capsules and their ratents, using the commercially available preparation as standard of reference. Fourteen were unable to identity we experimental vitamin capsule, five identified it cor- ely, and four incorrectly picked the placebo capsule, ‘The potency of the vitamin capsules were subsequently ynfirmed by analysis at the laboratories of the health ‘tection branch, Health & Welfare Canada ipsicians’ records When enrolling a patient in the trial the attending phy tn was asked to fill in a basic record sheet that provided. formation on the paticm’s age, sex, duration of angina, To reduce the possibilty of undesirable side_effects ssing unnoticed during the course of the trial, the ysician was asked to record resting pulse and. blood 2ssure each week and to enquire after any change in 2 patient's general health. Between visits patients were vised to temporarily discontinue their capsules “and ntact their physician if any unusual symptoms appeared. At the end of the trial the attending physician was ‘ed to record his overall assessment of the patient's sith daring the trial, and particularly whether the patients, sina had improved oF worsened, dle l—Characteristies of vitamin and placebo groups the regular and discontinua Tabs 1am) = ale may 1K Female 7 7 Mean SMG) 63462 993 Range ae Se Moen Ses tion of angina (ears): trem 606 5261) a4 Range 13 sie mu yearn ansumgtion™ On ue) cdo 92a ange a a {presure (um Hay: Ypstoc, Mean "13803 1353) aa a3 Rone 1-180 110 190 adw150 13150 Yastole, Mean 9108) —g¢87) 8 a Range 6-110 60--f00 0-89 90 2sin parentheses include the fou patients who were posible non reactors, ‘eth, ase on first ino weeks. " (reer Patient's records ‘A set_of weekly record cards was supplied to each Patient. These were ordinary thin white cards measuring 4X6 inches. One side was marked off into seven columns, hheaded Sunday through Saturday, and eight horizontal rows, The first two rows were for recording on each day the umber of “vitamin” capsules taken and the number of nitroglycerin tablets used. The next three rows were headed “Anginal pain” and the patient was asked to put a cheek mark in one of the rows marked “worse than usual”, “same 2s usual”, or “better than usual”. The last three rows were headed “Activity”, and the patient was asked to put a check mark against “able to do less than usual", “able to do same as usual”, or “able to do more than usual” ‘At the top of each card was a space for the patient’s name, the attending physician's name, the date, and a brief set of instructions, including the suggestion that the back of the card be used to record unusual symptoms or other comments, To assist in the analysis of the pain and activity records, 4 weekly net score was calculated for each patient, assign. ing @ value of —I to each day on which pain was “worse than usual", 0 for each day “same as usual", and +1 for each day “better than usual". Similarly, the information ‘on activity was coded as —1 (less), 0 (same), or + (more than usual). ‘The weekly score for either pain or activity could thus range between a high of +7 and a low of —7. Subjects ‘The 19 collaborating physicians (9 family physicians and 10 cardiologists) were able to enrol a total of 68 patients, 48 for the “regular” trial and 20 for the “discontinuation” ial, Regular trial Of the 48 patients initially enrolled in the regular trial, seven patients (V3, P4) were later withdrawn for the fol. lowing reasons: One patient (P) was admitted to hospital for coronary artery surgery, one (P) suffered a myocardial infarction in the first week, one (V) suffered a stroke in the third week, and two (1V, IP) lost interest and failed to take their capsules or keep records, The other two Patients were withdrawn from the trial after a few days Because of suspected side effects. One (V) complained of diarrhea; one (P) complained of severe heartburn, (These {two patients are included in the later discussion of side effects.) In addition, one patient stopped taking his cap: Sules after only five weeks because of an. influenza-like illness. His physician considered that this illness was. in fectious in nature and was unrelated to the capsules he was taking. ‘There thus remained 40 patients, 33 of whom completed thine full weeks of records. In five cases GV, 2P) only eight weeks of records could be used becatise one record card was incomplete or missing, in one (V) only seven Weeks of records were available, and one other patient (Y) withdrew from the study afier seven weeks. because of persistent diarrhea, Ten patients had at some time tried vitamin E on their own initiative. In six the dosage used had been relatively small or the petiod of ingestion relatively short, but in the other four the dosage and duration had been great enough to raise the possibility that these patients had already demonstrated themselves to be “non. In ‘most of the subsequent analysis their results hi been expressed separately from those of the other 36 patients Some of the basic characteristics of the patients involved in the regular trial are summarized in Table Ill. As might be expected, in view of the pairing procedure used, the CMA JOURNAL/FEBRUARY 16, 1974/VOL. 110 403‘age and sex distribution were reasonably similar in the ‘two groups, but the average nitroglycerin. consumption in the vitamin group was considerably higher than in. the placebo group. The first recorded blood pressure readings ako tended to be somewhat higher in the vitamin group. In the majority of patients the diagnosis of angina ‘was purely clinical, based on a history of exercise-induced cchest pain promptiy relieved by nitroglycerin or rest. In ‘most cases there was also evidence of a closely related disorder such as myocardial infarction, cerebrovascular ischemia, or peripheral vascular disease. Eight patieats (AV, 4P) had had coronary angiograms done, all of which showed severe narrowing of the coronary arteries. Two patients (both on placebo) had undergone surgical treat- ‘ment for their angina; one had had a Vineberg procedure in 1970, the other a bypass operation ently in 1972. Thirty-one patients (I6V, 15P) had at some time suf- fered a recognized myocardial infarction, In 25 cases (13V, 12P) the angina had appeared following the infarction, while in the other six eases it had developed some time before the first recognized infarction. Two patients (LV, 1P) had previously experienced transient ischemic attacks, and another (P) had previously suffered a mild stroke, Three patients (all in the vitamin group) suffered. from peripheral vascular disease. Seven patients (GV, 4P) were being treated for hypertension, three (2V, 1P) were mildly diabetic, two (IV, IP) had chronic obstructive lung disease, and there was one case (V) of hyperuricemia. In addition to nitroglycerin, patients were receiving the following drugs: propranolol (SV, 12P), long-acting nitrates (IV, 8P), diuretic or antihypertensive drugs (5V, 6P), digitalis compounds (6V, 2P) and diazepam (2V, 4P) Eight patients were cigarette smokers (4V, 4P), two smoked cigars (IV, IP), to smoked a pipe (IV, 1P), and 28 were nonsmokers (14V, 14P). Twenty-three patients (OV, 14P) were under the care of @ family physician; 17 (IIV, 6P) were under the care of a cardiologist Discontinuation trial Initial enrolment was 20 patients, but four were with- drawn by their attending physician because of unreliability (mainly failure to keep records), and one decided not to take part in the trial because of persistent dizziness and nausea that developed a few days before she was due 10 begin taking the test capsules Of the 15 patients that remained, eight continued to receive a dose of vitamin E that was as large or larger ‘Table 1V—Final assessment by attending physicians ‘of change in angina symptoms in patients in vitamin and placebo groups by the end of the regular trial Vita nach improved 1 Improved 4 Sigil improved 0 Hoven 1415) Sigil a 7) Figures parentheses inde the four pallens who were paibienon-eadors, Table V—Final assessment by attending physicians ‘of change in angina symptoms in patients in vitamin and placebo groups by the end of the discontinuation trial than theit regular dose, while the seven patients on placebo had their daily dose reduced to nil from 400 (2 patients), 800 (1). 1200 (3), oF 2400 (1) TU. ‘The basic characteristics of the patients in the discon- tinuation tial are also summarized in Table Ik. Results Regular trial ‘According tothe final assessment by attending physicians, the. majority of patients in each group experienced no change in their angina, while the temainder experienced shanges that ranged from "mach improved” slighty worse". There was no striking difference betven the (Ho roups, although the dstnbution was slightly more favour. able to the wlanin group (Table 1V), Inclusion ofthe four posible non-teacions improved the record. of the placebo group, but had no effect on the vitamin. gr0Up, | thus virtually ‘liminating the difference between the two soups Nitrogen consumption was higher inthe vitamin roup from the start, and the ean weekly intake rose fom Is.rin the frst weck to 23° in the last week (Fig. 1). In the placebo patients the corresponding ‘figures. were 10:9 and 6.4. Interpretation of these changes was made dificult by the fact that they were due largely to one or two patients in each group who hada large inital Intake and Showed great vatation (Fg. 2) One patient in the vitamin. group (esponsible for the Bigh postive value in Fige 2) had an 30 NITROGLYCERIN *1F pain score i) in 2 3 4 8 6 + tice 4 i weeks rs (repped oot) = 5 FIG. Weekly menos of sitcoglyeesin consumption, pain Tota 406 CMA JOURNAL/FEBRUARY 16, 1974/VOL. 110 and activity scores, in the regular tial (excluding the four ‘possible non-reactors)