ATTEMPTS TO DELAY PROGRESSION IN OCCLUSIVE ATHEROSCLEROSIS* E. N. Terry, L. R. Rouen, R. H. Clauss, M. C. Katz, and Walter Redisch Circulation Research Unit and Departments of Medicine, Surgery. and Radiology New York Medical College New York. New York 10029
Atherosclerotic lesions are said to begin very early in life and to progress at different rates in given individua1s.l Clinical manifestations represent the end result of a complex set of factors that act upon, and probably accelerate, this process. Atherosclerotic lesions in the peripheral vasculature can be diagnosed before symptoms occur. Arresting, or at least slowing down, the progression of such atherosclerotic lesions to the point of avoiding or delaying functional impairment is highly desirable. Because noninvasive techniques will at best demonstrate lesions that compromise the arterial lumen by at least 25%,2 and because angiographic examinations are not applicable to large nonsymptomatic populations due to risk and expense, it has been suggested that any intervention to retard the progression of the process to advanced lesions would have to begin in the latter part of the second decade of the life of an individual, or even earlier.3 METHODS A K D MATERIALS The present study deals with the effect of pyridinol carbamate (PDC) on the progression of atherosclerosis in patients with advanced disease in the lower extremities. Ninety-four patients were involved in the program (TABLEI). This population consisted of 56 males with an average age of 60.9 (+9.4) years and 38 females with an average age of 62.9 ( 4 . 5 ) years; the average age of the total population was 61.7 (k9.0) years. The main criteria for selecting patients were the presence of atherosclerotic occlusive arterial disease in the lower extremities with a degree of severity of complaints to indicate reconstructive arterial surgery. Surgery, however, was not performed on all of the patients, because the extent of atherosclerosis technically precluded such intervention in several patients. All patients were assessed prior to the decision to perform reconstructive surgery. In addition to the standard clinical workup, including angiography, they underwent three specialized examinations: determination of claudication distance, assessment of perfusion, and evaluation of microcirculatory changes. Patients undergoing surgery underwent an additional assessment of the results of surgery, including angiography, prior to their discharge from the hospital. These patients and those with extensive disease not subjected to operation were then randomly placed on a double-blind basis on either 5 0 0 mg of pyridinol carbamate or an identical-looking placebo four times per day. Thereafter, patients were followed at regular 4-week intervals as outpatients in the Research Clinic of New York Medical College. Patients underwent a complete assessment, including angiography, at yearly *Supported by the Japan Arteriosclerosis Research Foundation.
379
380
Annals New York Academy of Sciences
intervals, except when their clinical condition required these procedures at an earlier date. Detailed descriptions of methods used in this study have been previously published.* The results were assessed by the following criteria: Pulses. Disappearances of pulses for a prolonged period of time were considered to represent progression of disease. One-time failure to palpate pulses was not considered to be meaningful. Claudication Distance. This parameter was expressed and recorded in meters, derived from a nomogram based on treadmill velocity, duration of exercise, and elevation of the treadmill. Treadmill walking was continued after subjects indicated onset of pain, until discomfort precluded continued exercise. A decrease of 20% reproduced in consecutive months was considered to represent progression. Perfusion. Progression of disease was defined as a consistent decrease of 20% from baseline of perfusion per 100 ml of tissue per minute at rest and after exercise, or of peak flow, or of time of onset of peak flow, or of duration of response to exercise. Microcirculatory Changes. This parameter was assessed by counting the number of abnormalities at each examination and documenting them photographically. An increase that exceeded 15% in the number of abnormalities visualized at repeat examinations led to a statement of progression in this parameter. TABLE1 N Total population Males Females
94 56 38
61.7 f 9.0 60.0 f 9.4 62.9 8.5
Angiography. Serial angiograms (two films per second per field) were interpreted by the radiologist, who was unaware of the patients’ participation in the study. In addition, angiograms were assessed by two independent observers, one surgeon and one internist, equally unaware of the assignment of patients to placebo or active treatment. A conference of the three readers discussed any lack of agreement, but the radiologist’s interpretation became the final record, accepted over the internist’s and surgeon’s views. Determination of progression or nonprogression was based on observance of encroachment, new lesions, increased severity of preexisting stenosis, or occlusion of segment. The protocol of the study had been approved by the Ethics Committee and the Research Committee of New York Medical College, which also monitored progression of the study at yearly intervals. Informed consent in writing was obtained from patients, in accordance with regulations that govern the use of human subjects in evaluating experimental drugs. An Investigational New Drug Application (no. 7137) on pyridinol carbamate was submitted on July 29, 1970 to the Food and Drug Administ ration. RESULTS The results of this study are reported in two parts. Part I is devoted to the assessment of treatment results with pyridinol carbamateor placebo over a 2-year observation period under tightly controlled double-blind conditions. Part I1 deals with
T e r r y et al. : Occlusive Atherosclerosis
38 1
TABLE 2 ~
N
Dropouts and no show Nonrelated medical and surgical Amputation Personal problems Physician’s objection
PDC placebo PDC placebo PDC placebo PDC placebo PDC placebo
3 13 4 5 2 3 1
4 1
I
Age (mean * S D ) 51.67 f 9.02 64.96 A 8.60 61.00 A 11.17 64.40 A 9.61 5 1 . 0 0 ~ 1.41 56.00 A 5.57 64 A 64.75 f 3.1 60 + 56 f -
patients in whom treatment was continued with either pyridinol carbamate or placebo after having completed the preceding 2-year period of drug administration. This part of the study was performed open and covers periods of a mean duration of 18 and 24 months, respectively. Treatment was discontinued in 37 patients for the following reasons (TABLE2). Sixteen patients, three on pyridinol carbamate and 13 on placebo, dropped out relatively early throughout the study. Nine patients, four on pyridinol carbamate and five on placebo, were eliminated from the study throughout its course for medical and surgical reasons unrelated to occlusive arterial disease or any drug effects. In five patients, two on pyridinol carbamate and three on placebo, amputation of a leg became necessary. All of these patients were at an early stage of treatment with either pyridinol carbamate or placebo, respectively, and it was felt that after their surgical procedure, they should be eliminated from the study. Five patients, one on pyridinol carbamate and four on placebo, were discontinued from the study due to personal problems, again unrelated to the aims of the study. In two patients, one on pyridinol carbamate and one on placebo, their personal physicians objected to the patients continuing in the study, despite the fact that the physicians in question had been fully informed of the purpose and procedures involved. Throughout the course of the study, three patients died (TABLE3). Their deaths were not related to drug administration. One, a 69-year-old male, died after completing 2 years on pyridinol carbamate and subsequent to final assessment of his condition. Though he had been found to show no progression of his atherosclerotic condition in the 2-year period, he died of an acute myocardial infarction. A 71-year-old female died of an unrelated condition early in the study. Reports on these deaths were made to the Food and Drug Administration, giving full details. TABLE 3 DEATHS Patient No.
Sex
Death
Status in Study
Cause
7 31 41
male female male
71 69 66
completed 2 years on PDC 3 months on PDC 33 months after adverse reaction to PDC, which had occurred after 2 months on the drua
M.I. hepatitis
Age at
M.I.
Annals New York Academy of Sciences
382
TABLE 4 ADVERSEEFFECTS PDC
Placebo Age
Age
(mean + SD)
Total No.
(mean + SD)
19
67.47
2
70.00 i 1.41
12 males 7 females
65.42 i 6.60 71.00 + 17.67
2 females
70.00 i 1.41
Total No.
i
6.34
One patient died, 33 months after an adverse drug reaction to pyridinol carbamate, of a myocardial infarction. Adverse effects were encountered in 21 patients, 19 of whom were found, after 4). breaking the code, to have been on pyridinol carbamate (TABLE These adverse effects were primarily gastrointestinal problems, untractable diarrhea, nausea, and others. We were able to rechallenge patients with the medication they had been taking, and those on pyridinol carbamate suffered the same effects on readministration of the drug; treatment had to be discontinued. Thirty-eight patients completed the planned course of treatment; they received either pyridinol carbamate or placebo for a 2-year period (TABLE5). In 19 of 22 patients on pyridinol carbamate, progress of atherosclerosis seemed to be arrested, according to the criteria used in this study. Such nonprogression of occlusive atherosclerosis is seen in only one of 16 patients on placebo. Progression of atherosclerosis, on the other hand, can be seen in 15 of 16 patients on placebo and in three patients of 22 on pyridinol carbamate. These differences, subjected to a chi-square test, are significant at a level of p < 0.001. Subsequent to the 2-year evaluation, several patients continued to receive either placebo or pyridinol carbamate for mean periods between 17 and 27 months (TABLE 6). Of 18 patients who received pyridinol carbamate, two showed progression, whereas of 10 patients on placebo, nine progressed. On the other hand, nonprogression of atherosclerosis was seen in 16 of 18 patients on pyridinol carbamate and in only one patient on placebo. It is to be noted, in particular, that three of the 16 patients on pyridinol carbamate who showed nonprogression for a period of 27.33 (lt2.89) months had initially been on placebo for 2 years and progressed during this period. These differences, subjected to a chi-square test, are significant at a level of p < 0.001. TABLE 5 RESULTS OF 2 YEARS OF TREATMENT Drug Progression PDC
Placebo Nonprogression PDC
Placebo
No. of Patients
Age (mean A SD)
3 15
47.67 + 5.03 60.93 + 8.31
19 1
58.47 + 9.43 63 i -
Terry et al. : Occlusive Atherosclerosis
38 3
DISCUSSION
In the present study, we were able to confirm the relentless progression of atherosclerosis as observed by other^.^-^ We could also confirm that evidence of progression of obstructive arterial disease can be assessed only by reexaminations at intervals of about 2 y ~ s . ~At- ~the time of our interim report, based on the findings obtained after one year of administration of either pyridinol carbamate or placebo, we were unable to distinguish between the groups, because we could not objectively determine progression or nonprogression of the c o n d i t i ~ n . ~ * ~ * ~ Any treatment, therefore, aimed at arresting or delaying the progression of atherosclerosis has to be continued for prolonged periods of time. The present study demonstrates the difficulties in maintaining long-term treatment with an experimental drug of a patient population large enough to give statistical significance to the findings. The degree and site of atherosclerosis present initially, in addition to surgical intervention, if any, differ between any two patients, which makes the matching of patients impossible for practical purposes. Selecting patients at a stage in the progress of the disease that requires surgical intervention does, however, permit the comparison of results of treatment in this group. 6 TABLE CONTINUED TREATMENT AFTER 2 YEARS OF EVALUATION
Drug
No. of Patients
Age
(mean
SD)
Duration (months)
Progression
PDC Placebo Nonprogression PDC Ex-placebo Placebo
2 9
50.00 rt 4.24 61.78 rt 8.51
17.00 =t16.97 26.44 rt 2.92
13 3 1
58.69 f 7.52 53.33 rt 4.04 57
18.31 f 7.93 27.33 rt 2.89 24
Because 19 of 22 patients treated with pyridinol carbamate over a 2-year period did not show progression, whereas 15 of 16 patients treated with placebo did progress, based on the criteria used in this study, we do consider this nonprogression to be treatment related. This assumption is reinforced by the fact that during continued treatment, after the initial 2-year period, 16 of 18 patients treated with pyridinol carbamate did not progress. It may be of particular significance that three patients who previously, during the 2-year double-blind period of the study, had been treated with placebo, when switched to pyridinol carbamate, did not show progression of atherosclerosis during the subsequent 27 months. They had progressed during their placebo period. A causal relationship between our findings and the treatment regimen cannot be proven at this moment. Hypothetically, one may consider that Shimamoto and colleagues, on whose pharmacologic studies in the rabbit l o our decision to administer pyridinol carbamate had been based, have observed in subsequent studies” that the drug apparently protects the integrity of the endothelial layer. Vascular endothelical In injury is followed by smooth muscle cell proliferation and intimal thi~kening.’~.’~ vivoI3 and in vitro14 studies have suggested that the intact endothelium protects the arterial wall smooth muscle cells, currently thought to play a fundamental role in the development of atherosclerosis. l 3 The effects of pyridinol carbamate, if substantiated
384
Annals New
York Academy of Sciences
in larger studies, could be considered to be related to such an “endothelium-protective” pattern. With regard to platelet function, thought to be involved in the progression of atherosclerosis,15we were unable to obtain reproducible results in platelet aggregation and adhesion studies.16The results did not follow any recognizable pattern, even within the same patient. This finding is in contrast to those of earlier studies by 0 t h e ~ s . IThe ~ capacity of an agent to inhibit platelet function in vitro is not necessarily indicative of its effects in vivo, as shown by the failure of acetylsalicylic acid to correct platelet consumption in patients with intravascular prosthetic devices or arterial However, pyridinol carbarnate, in a dose of 200 mg/kg, also failed to prevent platelet consumption in baboons with an arteriovenous silastic cannula, a very sensitive model to test the efficacy of antiplatelet agents.I8 This finding would tend to confirm our results. Under the experimental conditions of our study, we did not observe any undesirable effects other than those centered on the gastrointestinal tract. A particularly unpleasant type of diarrhea with frequent loose movements occurred in patients and disappeared with discontinuation of drug administration. This diarrhea reoccurred in those who, after initial discontinuation of drug administration, were rechallenged with the drug. This adverse effect proved to be dose independent and of delayed onset; it required readministration of the drug for about 6 days. No common features among those who experienced the side effects could be found that would explain their becoming victims of it. It has been suggested that an investigation into the mode of action of the effect may be worthwhile. Another long-term study with pyridinol carbarnate has been performed,2o and, though criteria differ considerably, a beneficial effect has apparently been observed. Arrest of progression of atherosclerosis, a highly desirable goal of medical treatment, apparently has become feasible, as seen in the results of this study. Further investigations therefore are essential. Only long-term large-scale studies, tightly controlled, and employing criteria given to objective analysis will make the final judgment possible. Such future studies should perhaps deal with populations with a lesser degree of severity of occlusive atherosclerotic arterial disease. Different approaches would have to be found to screen such populations and monitor progress of their disease. Provided that some technical problems are overcome, ultrasonic arteriography may replace, at least for such purposes, contrast arteriography to establish the presence of intimal irregularities due to atherosclerosis.21.Z2 Such future work seems to be a must, because even those who express the most favorable prognosis for progression in the atherosclerotic lower limb conclude that the average life expectancy in such individuals is 10 years less than that for the general population of that age.23Atherosclerosis thus, regardless of clinical manifestations, represents a problem of such magnitude that it is worth a great deal of attention. REFERENCES MCGILL,H. C., JR., J. C. GEER& J. P. STRONG, 1963. The natural history of human atherosclerosis. I n Atherosclerosis and Its Origin. M. Sandler & G. H. Bourne, Eds. Chap. 2. Academic Press, Inc., New York, N.Y. 2. CARTER, S. A. 1972b. Response of ankle systolic pressure to leg exercise in mild or questionable arterial disease. N . Engl. J. Med. 287:578-582. 3. MCGILL,H. C., JR. 1974. The lesion. In Atherosclerosis 111. G. Schettler & A. Weizel, Eds.: 27. Springer-Verlag. New York, Heidelberg, Berlin. 4. REDISCH, W., E. N. TERRY, L. ROUEN& R. H. CLAUSS.1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease. I n 1.
Terry et al.: Occlusive Atherosclerosis
5. 6. 7. 8.
9. 10.
11.
12. 13. 14.
15. 16. 17. 18. 19. 20.
21. 22. 23.
385
Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 287-294. Excerpta Medica. Amsterdam, The Netherlands. KUTHAN,F., A. BURKHALTER, R. BAITSCH,H. LUDIN& L. K. WIDMER. 1971. Development of occlusive arterial disease in lower limbs. Arch. Surg. 103: 545-547. WARREN. J. A. P. MARSTON & J. S. T. COX.1964. Femoromuliteal ar, R.., R. L. GOMEZ. teriosclerosis obliterans: arteriographic patterns and rates of progression. Surgery 55: 135- 143. STRANDNESS, D. E., JR. 1969. Peripheral Arterial Disease: A Physiologic Approach: 124. Little, Brown and Company. Boston, Mass. TERRY, E. N., W. REDISCH,L. ROUEN& R. H. CLAUSS.1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease (discussion). In Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 295,296. Excerpta Medica. Amsterdam, The Netherlands. CLAUSS,R. H. 1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease (discussion). In Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 297-300. Excerpta Medica. Amsterdam, The Netherlands. SHIMAMOTO, T. & T. SUNGA. 1973. The contraction and blebbing of endothelial cells accompanied by acute infiltration of plasma substances into the vessel wall and their prevention. In Atherogenesis 11. T. Shimamoto & F. Numano, Us.: 3-31. Excerpta Medica. Amsterdam, The Netherlands. SHIMAMOTO, T. & F. NUMANO. 1974. Beta-lipoprotein entry into the arterial wall and its Drevention. In Atherosclerosis 111. G. Schettler & A. Weizel, Eds.: 89-92. Springer. kerlag. New York, Heidelberg, Berlin. STEMERMAN, M. B. & R. ROSS. 1972. Experimental arteriosclerosis: I. Fibrous plaque formation in primates, an electron microscopic study. J. Exp. Med. 136: 769-789. Ross, R. & J. A. GLOMSET.1973. Arteriosclerosis and the arterial smooth muscle cell. Science 180: 1332-1339. Ross, R., J. A. GLOMSET, B. KARIYA & L. HARKER.1974. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc. Nat. Acad. Sci. USA71: 1207-1210. DUGUID,J. B. 1948. Thrombosis as a factor in the pathogenesis of aortic atherosclerosis. J. Pathol. Bacteriol. 60:57-61. REDISCH,W., R. H. CLAUSS,L. R. ROUEN,M. C. KATZ & E. N. TERRY.1975. Progression of occlusive atherosclerosis: long-term administration of pyridinol carbamate. Arch. Surg. 110: 258-261. DIDISHEIM, P., R. E. STURM & C. A. OWEN,JR. 1971. Experiments on thrombosis and its prevention. Thromb. Diath. Haemorrhag. Suppl. 46: 177. HARKER, L. A. & S. J. SLICHTER. 1972. Platelet and fibrinogen consumption in man. N. Engl. J. Med. 287: 999-1005. HARKER, L. A. 1975. Personal communication. ATSUMI,T., Y.HONDA& M. MATSUDA. 1974. Follow-up study on patients suffering from arteriosclerosis obliterans under pyridinolcarbamate treatment and other treatment. J. Jap. Coll. Angio. In press. Cited by T. Shimamoto: In Atheroslcerosis 111. G. Schettler & A. Weizel, Eds.: 68-82. Springer-Verlag. New York, Heidelberg, Berlin. D. S . SUMNER & D. E. STRANDNESS, JR. 1971. UltraHOKANSON, D. E., D. J. MOZERSKY, sonic arteriography. A new approach to arterial visualization. Biomet. Eng. 6: 420. MOZERSKY, D. J., D. E. HOKANSON, D. S. SUMNER & D. E. STRANDNESS, JR. 1972. Ultrasonic visualization of the arterial lumen. Surgery 72: 253-259. BOYD,A. M. 1962. The natural course of arteriosclerosis of the lower extremities. proc. Med. 55: 591-593. Roy. SOC. I
I
Atherosclerotic lesions are said to begin very early in life and to progress at different rates in given individua1s.l Clinical manifestations represent the end result of a complex set of factors that act upon, and probably accelerate, this process. Atherosclerotic lesions in the peripheral vasculature can be diagnosed before symptoms occur. Arresting, or at least slowing down, the progression of such atherosclerotic lesions to the point of avoiding or delaying functional impairment is highly desirable. Because noninvasive techniques will at best demonstrate lesions that compromise the arterial lumen by at least 25%,2 and because angiographic examinations are not applicable to large nonsymptomatic populations due to risk and expense, it has been suggested that any intervention to retard the progression of the process to advanced lesions would have to begin in the latter part of the second decade of the life of an individual, or even earlier.3 METHODS A K D MATERIALS The present study deals with the effect of pyridinol carbamate (PDC) on the progression of atherosclerosis in patients with advanced disease in the lower extremities. Ninety-four patients were involved in the program (TABLEI). This population consisted of 56 males with an average age of 60.9 (+9.4) years and 38 females with an average age of 62.9 ( 4 . 5 ) years; the average age of the total population was 61.7 (k9.0) years. The main criteria for selecting patients were the presence of atherosclerotic occlusive arterial disease in the lower extremities with a degree of severity of complaints to indicate reconstructive arterial surgery. Surgery, however, was not performed on all of the patients, because the extent of atherosclerosis technically precluded such intervention in several patients. All patients were assessed prior to the decision to perform reconstructive surgery. In addition to the standard clinical workup, including angiography, they underwent three specialized examinations: determination of claudication distance, assessment of perfusion, and evaluation of microcirculatory changes. Patients undergoing surgery underwent an additional assessment of the results of surgery, including angiography, prior to their discharge from the hospital. These patients and those with extensive disease not subjected to operation were then randomly placed on a double-blind basis on either 5 0 0 mg of pyridinol carbamate or an identical-looking placebo four times per day. Thereafter, patients were followed at regular 4-week intervals as outpatients in the Research Clinic of New York Medical College. Patients underwent a complete assessment, including angiography, at yearly *Supported by the Japan Arteriosclerosis Research Foundation.
379
380
Annals New York Academy of Sciences
intervals, except when their clinical condition required these procedures at an earlier date. Detailed descriptions of methods used in this study have been previously published.* The results were assessed by the following criteria: Pulses. Disappearances of pulses for a prolonged period of time were considered to represent progression of disease. One-time failure to palpate pulses was not considered to be meaningful. Claudication Distance. This parameter was expressed and recorded in meters, derived from a nomogram based on treadmill velocity, duration of exercise, and elevation of the treadmill. Treadmill walking was continued after subjects indicated onset of pain, until discomfort precluded continued exercise. A decrease of 20% reproduced in consecutive months was considered to represent progression. Perfusion. Progression of disease was defined as a consistent decrease of 20% from baseline of perfusion per 100 ml of tissue per minute at rest and after exercise, or of peak flow, or of time of onset of peak flow, or of duration of response to exercise. Microcirculatory Changes. This parameter was assessed by counting the number of abnormalities at each examination and documenting them photographically. An increase that exceeded 15% in the number of abnormalities visualized at repeat examinations led to a statement of progression in this parameter. TABLE1 N Total population Males Females
94 56 38
61.7 f 9.0 60.0 f 9.4 62.9 8.5
Angiography. Serial angiograms (two films per second per field) were interpreted by the radiologist, who was unaware of the patients’ participation in the study. In addition, angiograms were assessed by two independent observers, one surgeon and one internist, equally unaware of the assignment of patients to placebo or active treatment. A conference of the three readers discussed any lack of agreement, but the radiologist’s interpretation became the final record, accepted over the internist’s and surgeon’s views. Determination of progression or nonprogression was based on observance of encroachment, new lesions, increased severity of preexisting stenosis, or occlusion of segment. The protocol of the study had been approved by the Ethics Committee and the Research Committee of New York Medical College, which also monitored progression of the study at yearly intervals. Informed consent in writing was obtained from patients, in accordance with regulations that govern the use of human subjects in evaluating experimental drugs. An Investigational New Drug Application (no. 7137) on pyridinol carbamate was submitted on July 29, 1970 to the Food and Drug Administ ration. RESULTS The results of this study are reported in two parts. Part I is devoted to the assessment of treatment results with pyridinol carbamateor placebo over a 2-year observation period under tightly controlled double-blind conditions. Part I1 deals with
T e r r y et al. : Occlusive Atherosclerosis
38 1
TABLE 2 ~
N
Dropouts and no show Nonrelated medical and surgical Amputation Personal problems Physician’s objection
PDC placebo PDC placebo PDC placebo PDC placebo PDC placebo
3 13 4 5 2 3 1
4 1
I
Age (mean * S D ) 51.67 f 9.02 64.96 A 8.60 61.00 A 11.17 64.40 A 9.61 5 1 . 0 0 ~ 1.41 56.00 A 5.57 64 A 64.75 f 3.1 60 + 56 f -
patients in whom treatment was continued with either pyridinol carbamate or placebo after having completed the preceding 2-year period of drug administration. This part of the study was performed open and covers periods of a mean duration of 18 and 24 months, respectively. Treatment was discontinued in 37 patients for the following reasons (TABLE2). Sixteen patients, three on pyridinol carbamate and 13 on placebo, dropped out relatively early throughout the study. Nine patients, four on pyridinol carbamate and five on placebo, were eliminated from the study throughout its course for medical and surgical reasons unrelated to occlusive arterial disease or any drug effects. In five patients, two on pyridinol carbamate and three on placebo, amputation of a leg became necessary. All of these patients were at an early stage of treatment with either pyridinol carbamate or placebo, respectively, and it was felt that after their surgical procedure, they should be eliminated from the study. Five patients, one on pyridinol carbamate and four on placebo, were discontinued from the study due to personal problems, again unrelated to the aims of the study. In two patients, one on pyridinol carbamate and one on placebo, their personal physicians objected to the patients continuing in the study, despite the fact that the physicians in question had been fully informed of the purpose and procedures involved. Throughout the course of the study, three patients died (TABLE3). Their deaths were not related to drug administration. One, a 69-year-old male, died after completing 2 years on pyridinol carbamate and subsequent to final assessment of his condition. Though he had been found to show no progression of his atherosclerotic condition in the 2-year period, he died of an acute myocardial infarction. A 71-year-old female died of an unrelated condition early in the study. Reports on these deaths were made to the Food and Drug Administration, giving full details. TABLE 3 DEATHS Patient No.
Sex
Death
Status in Study
Cause
7 31 41
male female male
71 69 66
completed 2 years on PDC 3 months on PDC 33 months after adverse reaction to PDC, which had occurred after 2 months on the drua
M.I. hepatitis
Age at
M.I.
Annals New York Academy of Sciences
382
TABLE 4 ADVERSEEFFECTS PDC
Placebo Age
Age
(mean + SD)
Total No.
(mean + SD)
19
67.47
2
70.00 i 1.41
12 males 7 females
65.42 i 6.60 71.00 + 17.67
2 females
70.00 i 1.41
Total No.
i
6.34
One patient died, 33 months after an adverse drug reaction to pyridinol carbamate, of a myocardial infarction. Adverse effects were encountered in 21 patients, 19 of whom were found, after 4). breaking the code, to have been on pyridinol carbamate (TABLE These adverse effects were primarily gastrointestinal problems, untractable diarrhea, nausea, and others. We were able to rechallenge patients with the medication they had been taking, and those on pyridinol carbamate suffered the same effects on readministration of the drug; treatment had to be discontinued. Thirty-eight patients completed the planned course of treatment; they received either pyridinol carbamate or placebo for a 2-year period (TABLE5). In 19 of 22 patients on pyridinol carbamate, progress of atherosclerosis seemed to be arrested, according to the criteria used in this study. Such nonprogression of occlusive atherosclerosis is seen in only one of 16 patients on placebo. Progression of atherosclerosis, on the other hand, can be seen in 15 of 16 patients on placebo and in three patients of 22 on pyridinol carbamate. These differences, subjected to a chi-square test, are significant at a level of p < 0.001. Subsequent to the 2-year evaluation, several patients continued to receive either placebo or pyridinol carbamate for mean periods between 17 and 27 months (TABLE 6). Of 18 patients who received pyridinol carbamate, two showed progression, whereas of 10 patients on placebo, nine progressed. On the other hand, nonprogression of atherosclerosis was seen in 16 of 18 patients on pyridinol carbamate and in only one patient on placebo. It is to be noted, in particular, that three of the 16 patients on pyridinol carbamate who showed nonprogression for a period of 27.33 (lt2.89) months had initially been on placebo for 2 years and progressed during this period. These differences, subjected to a chi-square test, are significant at a level of p < 0.001. TABLE 5 RESULTS OF 2 YEARS OF TREATMENT Drug Progression PDC
Placebo Nonprogression PDC
Placebo
No. of Patients
Age (mean A SD)
3 15
47.67 + 5.03 60.93 + 8.31
19 1
58.47 + 9.43 63 i -
Terry et al. : Occlusive Atherosclerosis
38 3
DISCUSSION
In the present study, we were able to confirm the relentless progression of atherosclerosis as observed by other^.^-^ We could also confirm that evidence of progression of obstructive arterial disease can be assessed only by reexaminations at intervals of about 2 y ~ s . ~At- ~the time of our interim report, based on the findings obtained after one year of administration of either pyridinol carbamate or placebo, we were unable to distinguish between the groups, because we could not objectively determine progression or nonprogression of the c o n d i t i ~ n . ~ * ~ * ~ Any treatment, therefore, aimed at arresting or delaying the progression of atherosclerosis has to be continued for prolonged periods of time. The present study demonstrates the difficulties in maintaining long-term treatment with an experimental drug of a patient population large enough to give statistical significance to the findings. The degree and site of atherosclerosis present initially, in addition to surgical intervention, if any, differ between any two patients, which makes the matching of patients impossible for practical purposes. Selecting patients at a stage in the progress of the disease that requires surgical intervention does, however, permit the comparison of results of treatment in this group. 6 TABLE CONTINUED TREATMENT AFTER 2 YEARS OF EVALUATION
Drug
No. of Patients
Age
(mean
SD)
Duration (months)
Progression
PDC Placebo Nonprogression PDC Ex-placebo Placebo
2 9
50.00 rt 4.24 61.78 rt 8.51
17.00 =t16.97 26.44 rt 2.92
13 3 1
58.69 f 7.52 53.33 rt 4.04 57
18.31 f 7.93 27.33 rt 2.89 24
Because 19 of 22 patients treated with pyridinol carbamate over a 2-year period did not show progression, whereas 15 of 16 patients treated with placebo did progress, based on the criteria used in this study, we do consider this nonprogression to be treatment related. This assumption is reinforced by the fact that during continued treatment, after the initial 2-year period, 16 of 18 patients treated with pyridinol carbamate did not progress. It may be of particular significance that three patients who previously, during the 2-year double-blind period of the study, had been treated with placebo, when switched to pyridinol carbamate, did not show progression of atherosclerosis during the subsequent 27 months. They had progressed during their placebo period. A causal relationship between our findings and the treatment regimen cannot be proven at this moment. Hypothetically, one may consider that Shimamoto and colleagues, on whose pharmacologic studies in the rabbit l o our decision to administer pyridinol carbamate had been based, have observed in subsequent studies” that the drug apparently protects the integrity of the endothelial layer. Vascular endothelical In injury is followed by smooth muscle cell proliferation and intimal thi~kening.’~.’~ vivoI3 and in vitro14 studies have suggested that the intact endothelium protects the arterial wall smooth muscle cells, currently thought to play a fundamental role in the development of atherosclerosis. l 3 The effects of pyridinol carbamate, if substantiated
384
Annals New
York Academy of Sciences
in larger studies, could be considered to be related to such an “endothelium-protective” pattern. With regard to platelet function, thought to be involved in the progression of atherosclerosis,15we were unable to obtain reproducible results in platelet aggregation and adhesion studies.16The results did not follow any recognizable pattern, even within the same patient. This finding is in contrast to those of earlier studies by 0 t h e ~ s . IThe ~ capacity of an agent to inhibit platelet function in vitro is not necessarily indicative of its effects in vivo, as shown by the failure of acetylsalicylic acid to correct platelet consumption in patients with intravascular prosthetic devices or arterial However, pyridinol carbarnate, in a dose of 200 mg/kg, also failed to prevent platelet consumption in baboons with an arteriovenous silastic cannula, a very sensitive model to test the efficacy of antiplatelet agents.I8 This finding would tend to confirm our results. Under the experimental conditions of our study, we did not observe any undesirable effects other than those centered on the gastrointestinal tract. A particularly unpleasant type of diarrhea with frequent loose movements occurred in patients and disappeared with discontinuation of drug administration. This diarrhea reoccurred in those who, after initial discontinuation of drug administration, were rechallenged with the drug. This adverse effect proved to be dose independent and of delayed onset; it required readministration of the drug for about 6 days. No common features among those who experienced the side effects could be found that would explain their becoming victims of it. It has been suggested that an investigation into the mode of action of the effect may be worthwhile. Another long-term study with pyridinol carbarnate has been performed,2o and, though criteria differ considerably, a beneficial effect has apparently been observed. Arrest of progression of atherosclerosis, a highly desirable goal of medical treatment, apparently has become feasible, as seen in the results of this study. Further investigations therefore are essential. Only long-term large-scale studies, tightly controlled, and employing criteria given to objective analysis will make the final judgment possible. Such future studies should perhaps deal with populations with a lesser degree of severity of occlusive atherosclerotic arterial disease. Different approaches would have to be found to screen such populations and monitor progress of their disease. Provided that some technical problems are overcome, ultrasonic arteriography may replace, at least for such purposes, contrast arteriography to establish the presence of intimal irregularities due to atherosclerosis.21.Z2 Such future work seems to be a must, because even those who express the most favorable prognosis for progression in the atherosclerotic lower limb conclude that the average life expectancy in such individuals is 10 years less than that for the general population of that age.23Atherosclerosis thus, regardless of clinical manifestations, represents a problem of such magnitude that it is worth a great deal of attention. REFERENCES MCGILL,H. C., JR., J. C. GEER& J. P. STRONG, 1963. The natural history of human atherosclerosis. I n Atherosclerosis and Its Origin. M. Sandler & G. H. Bourne, Eds. Chap. 2. Academic Press, Inc., New York, N.Y. 2. CARTER, S. A. 1972b. Response of ankle systolic pressure to leg exercise in mild or questionable arterial disease. N . Engl. J. Med. 287:578-582. 3. MCGILL,H. C., JR. 1974. The lesion. In Atherosclerosis 111. G. Schettler & A. Weizel, Eds.: 27. Springer-Verlag. New York, Heidelberg, Berlin. 4. REDISCH, W., E. N. TERRY, L. ROUEN& R. H. CLAUSS.1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease. I n 1.
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Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 287-294. Excerpta Medica. Amsterdam, The Netherlands. KUTHAN,F., A. BURKHALTER, R. BAITSCH,H. LUDIN& L. K. WIDMER. 1971. Development of occlusive arterial disease in lower limbs. Arch. Surg. 103: 545-547. WARREN. J. A. P. MARSTON & J. S. T. COX.1964. Femoromuliteal ar, R.., R. L. GOMEZ. teriosclerosis obliterans: arteriographic patterns and rates of progression. Surgery 55: 135- 143. STRANDNESS, D. E., JR. 1969. Peripheral Arterial Disease: A Physiologic Approach: 124. Little, Brown and Company. Boston, Mass. TERRY, E. N., W. REDISCH,L. ROUEN& R. H. CLAUSS.1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease (discussion). In Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 295,296. Excerpta Medica. Amsterdam, The Netherlands. CLAUSS,R. H. 1973. A study of the efficacy and safety of pyridinolcarbamate in patients with demonstrable occlusive arterial disease (discussion). In Atherogenesis 11. T. Shimamoto & F. Numano, Eds.: 297-300. Excerpta Medica. Amsterdam, The Netherlands. SHIMAMOTO, T. & T. SUNGA. 1973. The contraction and blebbing of endothelial cells accompanied by acute infiltration of plasma substances into the vessel wall and their prevention. In Atherogenesis 11. T. Shimamoto & F. Numano, Us.: 3-31. Excerpta Medica. Amsterdam, The Netherlands. SHIMAMOTO, T. & F. NUMANO. 1974. Beta-lipoprotein entry into the arterial wall and its Drevention. In Atherosclerosis 111. G. Schettler & A. Weizel, Eds.: 89-92. Springer. kerlag. New York, Heidelberg, Berlin. STEMERMAN, M. B. & R. ROSS. 1972. Experimental arteriosclerosis: I. Fibrous plaque formation in primates, an electron microscopic study. J. Exp. Med. 136: 769-789. Ross, R. & J. A. GLOMSET.1973. Arteriosclerosis and the arterial smooth muscle cell. Science 180: 1332-1339. Ross, R., J. A. GLOMSET, B. KARIYA & L. HARKER.1974. A platelet-dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc. Nat. Acad. Sci. USA71: 1207-1210. DUGUID,J. B. 1948. Thrombosis as a factor in the pathogenesis of aortic atherosclerosis. J. Pathol. Bacteriol. 60:57-61. REDISCH,W., R. H. CLAUSS,L. R. ROUEN,M. C. KATZ & E. N. TERRY.1975. Progression of occlusive atherosclerosis: long-term administration of pyridinol carbamate. Arch. Surg. 110: 258-261. DIDISHEIM, P., R. E. STURM & C. A. OWEN,JR. 1971. Experiments on thrombosis and its prevention. Thromb. Diath. Haemorrhag. Suppl. 46: 177. HARKER, L. A. & S. J. SLICHTER. 1972. Platelet and fibrinogen consumption in man. N. Engl. J. Med. 287: 999-1005. HARKER, L. A. 1975. Personal communication. ATSUMI,T., Y.HONDA& M. MATSUDA. 1974. Follow-up study on patients suffering from arteriosclerosis obliterans under pyridinolcarbamate treatment and other treatment. J. Jap. Coll. Angio. In press. Cited by T. Shimamoto: In Atheroslcerosis 111. G. Schettler & A. Weizel, Eds.: 68-82. Springer-Verlag. New York, Heidelberg, Berlin. D. S . SUMNER & D. E. STRANDNESS, JR. 1971. UltraHOKANSON, D. E., D. J. MOZERSKY, sonic arteriography. A new approach to arterial visualization. Biomet. Eng. 6: 420. MOZERSKY, D. J., D. E. HOKANSON, D. S. SUMNER & D. E. STRANDNESS, JR. 1972. Ultrasonic visualization of the arterial lumen. Surgery 72: 253-259. BOYD,A. M. 1962. The natural course of arteriosclerosis of the lower extremities. proc. Med. 55: 591-593. Roy. SOC. I
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