Drugs 44 (Suppl. I): 123-127, 1992 0012-6667/92/0100-0123/$2.50/0 © Adis International Limited. All rights reserved. DRSUP3341
Can the Coronary Atherosclerotic Process Be Influenced by Calcium Antagonists? G. Kober, I W. Schneider,2 G. CieslinskP and M. Kaltenbach 2 I Clinic Nordrhein, Bad Nauheim, Federal Republic of Germany 2 University Hospital, Frankfurt, Federal Republic of Germany
Summary
Cell culture experiments and various animal models have shown that calcium antagonists can inhibit atheroma development. A number of antiatherosclerotic mechanisms have been proposed and the promising results of these in vitro and animal experiments prompted clinical trials. Retrospective analyses indicated that verapamil might retard disease progression and the development of new stenoses. Prospective clinical studies, however, have revealed no effect by calcium antagonists on preexisting coronary stenoses (~ 20%) and it is suggested that the study duration (2 to 3 years) may have been too short and that advanced stages of atheromatous disease are not influenced by calcium antagonists. Current data suggest that only early stages of coronary atheromatosis may be affected by treatment with calcium antagonists; however, optimum drug, dosage and suitable patients are yet to be defined.
Degenerative as well as proliferative processes are involved in human atherosclerosis. The importance of calcium ions has been identified in many of the metabolic and proliferative processes involved in the initiation and progression of the atherosclerotic process. Among these processes are the following: endothelial damage; hyper-contraction of vascular smooth muscle cells; release of platelet-derived growth factors; cellular lipid metabolism; proliferation and migration of cells; and synthesis of proteins and collagen fibres (Kramsch et al. 1981; Mehta et al. 1983a,b; Metcalfe et al. 1986; Ribeiro et al. 1982; Ross 1981; Ross & Glomset 1976; Schanne et al. 1979; Srinivasan & Sawyer 1970). Because of this, it seemed reasonable to anticipate a beneficial effect of calcium antagonists on the atherosclerotic process.
1. Experiments in Isolated Vessels and Cell Cultures Several calcium antagonists have been studied in cell culture and isolated vessel experiments. Effects noted include protection of cellular membranes, inhibition of proliferation and migration of smooth muscle cells, inhibition of platelet aggregation, and improvement of cellular lipid metabolism with no effect on plasma lipid concentrations (Etingin & Hajjar 1985; Kramsch 1985; Kummerow 1985; Nayler & Szeto 1972; Mehta et al. 1983a,b; Ono & Kimura 1981; Schmitz et al. 1988; Ware et al. 1986; Waters et al. 1989).
2. Animal Experiments Retardation of atheroma development by calcium antagonists has been demonstrated in various animal models (especially in rats and rabbits),
Drugs 44 (Suppi. 1) 1992
124
e.g. atheromas induced by cholesterol-rich food, electrical stimulation of the arterial wall, mechanical vessel trauma, malignant hypertension, or vitamin D3 intoxication. Nifedipine, nicardipine, verapamil, diltiazem and flunarizine are all active in this respect; however, efficacy is dependent on the time of application. Protective effects could only be demonstrated when the drugs were given before or, at the latest, as vessel damage occurred (Blumlein et al. 1984; Fleckenstein et al. 1983; Frey et al. 1980; Ginsburg et al. 1983; Handley et al. 1986; Henry & Bentley 1981; Jackson et al. 1988; Lichtor et al. 1989; Rouleau et al. 1983; Sievers et al 1987; Sugano et al. 1986).
3. Retrospective Analysis in Humans The encouraging results of animal experiments prompted several retrospective analyses in humans, and these have shown a possible beneficial effect of calcium antagonists on human atherosclerosis progression. In our own retrospective study with the calcium antagonist verapamil, 26 patients were treated with the drug (mean dosage of 251 mg/day), while 17 patients in the control group were not given a calcium antagonist. After a mean follow-up period of 13 and 16 months, respectively, a lower rate of progression (23 vs 41 %; not significant), a higher rate of stenosis regression (21 vs 8%; not significant) and a lower incidence of new stenoses development (3.3 vs 10.9%; p < 0.05) were found in the patients receiving verapamil (Kober et al. 1986, 1988).
4. Prospective Trials in Humans The promising findings in animal experiments and in retrospective analyses in humans have prompted prospective trials in humans to clarify further the potential role of calcium antagonists as inhibitors of coronary atherosclerosis progression. Three prospective double-blind clinical trials were initiated with nifedipine 20mg 4 times daily [International Trial on Antiatherosclerotic Therapy (INTACT); Lichtlen et al. 1990], nicardipine 30mg 3 times daily [Montreal Heart Institute Study
Table I. Prospective studies of calcium antagonists in atherosclerosis
No. of vessels involved (% of patients) 0 1 2 3 History of infarction (% of patients) Angiographic follow-up (years) Angiographic evaluation
INTACTB
MHISb
FIPSC
0 28 29 26 30
15 28 38 19 44
0 6 47 47 70
3
2
1&3
Visual CAAS
Visual CMS
Visual Calibrated
a
International Trial on Antiatherosclerotic Therapy; Uchtlen et al. (1990). b Montreal Heart Institute Trial; Waters et al. (1990). c Frankfurt Isoptin Progression Study; Kober et al. (1989); Schneider et al. (1990, 1992). Abbreviation: CAAS = computer analysis of angiogram.
(MHlS); Waters et al. 1990] and verapamil 120mg 3 times daily [Frankfurt Isoptin Progression Study (FIPS); Kober et al. 1989; Schneider et al. 1990, 1992]. In all 3 studies, similar numbers of patients were randomised to either active drug or placebo with angiographic follow-up periods of between 2 to 3 years (INTACT, 425 patients; MHlS, 335 patients; FIPS, 445 patients). However, the studies differed with regard to the severity of coronary atherosclerosis (table I). INTACT and MHIS enrolled mainly patients with early stages of the disease, whereas FIPS patients were eligible only after bypass surgery (i.e. advanced stages of coronary artery disease). In the INTACT and MHIS studies, 28 and 43% of patients had zero and single vessel disease, respectively, compared with only 6% in the FIPS study. Triple vessel disease, however, was evident in 26% (INTACT), 19% (MHlS) and 47% (FIPS) of patients, and a history of preceding myocardial infarctions was also higher in FIPS patients (INTACT 30%; nicardipine 44%; FIPS 70%). Changes in coronary atherosclerosis were analysed visually and/or by computer analysis, with
Influence of Calcium Antagonists on Atherosclerosis
absolute or relative changes in stenosis diameter (INTACT, > O.4mm or ~ 20%; MHIS, ~ O.4mm or ~ 10%), changes in coronary score (~ 0.345 in FIPS) or the development of new stenoses, new occlusions or changes in bypass vessels being sought. In the INTACT study, no significant difference was found between placebo (n = 175) and nifedipine patients (n = 173) with regard to progression and regression as related to existing stenoses or to the disease in individual patients (table II). However, there was a significant difference in the development of new stenoses (~ 20%). There were 144 new lesions in the placebo group and 103 in the nifedipine group, i.e. 0.82 vs 0.59 new lesions per patient in the respective patient groups (- 28%; p = 0.03). In the MHIS, mean progression and regression of single lesions and of the disease in individual patients were not different between patients on placebo (n = 167) or nicardipine (n = 168; table III). However, there was a significantly lower rate of progression of minor grade stenoses ('" 20% of luminal narrowing) in the nicardipine group compared with the placebo group: 16% of stenoses vs 9% (p < 0.05) and 37% of patients vs 15% (p < 0.05). In the FIPS study, angiographic evaluations were performed 3 years after enrolment in 79 verapamil
125
and 80 placebo patients. Coronary atherosclerosis was analysed in native nonbypassed vessels, and in bypass grafts. No significant differences were found between groups with regard to coronary score, progression and regression of pre-existing stenoses, development of new stenoses or new occlusions in both the native vessels and in bypass grafts. In addition, there were no differences in progression or regression of stenoses of low or high grade between treatment groups. In 71 patients in the INTACT study, minor side effects identical to those encountered in patients treated with dihydropyridine-type calcium antagonists were seen (55 nifedipine patients compared with 16 placebo patients), and included dizziness, headache, ankle oedema, tachycardia, hypotension, angina pectoris and flushing. In the MHIS, no data on side effects were published. In the FIPS, a total of 532 minor side effects, most with no influence on the continuation of the study, were reported (254 placebo and 278 verapamil reports). Among these, only constipation was encountered more frequently in the verapamil group (52 vs 30 patients). Critical clinical events occurred in the INTACT study more often in the nifedipine group (cardiac events, 52 vs 14; cardiac death, 8 vs 2; noncardiac death, 4 vs 0). In the MHIS, cardiac death was dis-
Table II. Summary of INTACT (International Trial on Antiatherosclerotic Therapy) results (Lichtlen 1990) Placebo (n
= 175)
Nifedipine (n
= 173)
Significance
number (%)
number (%)
Progression (patients) Regression (patients) Progression only (patients) Regression only (patients) No change (patients)
42 25 39 22 111
48 (28) 17 (10) 43 (25) 12 (7) 113 (65)
NS NS NS NS NS
Progression (leSions) Regression (leSions) Progression to occlusion New lesions (~ 20%) New lesions (per patient) Patients with new lesions
62/657 (9) 27/657 (4) 14/657 (2) 144 0.82 85 (49)
70/598 (12) 18/598 (3) 11/598 (2) 103 0.59 (-28) 70 (40)
NS NS
Abbreviation: NS
(24) (14) (22) (13) (63)
= no significant difference.
P
= 0.03
Drugs 44 (Suppi. 1) 1992
126
Table III. Summary of Montreal Heart Institute Trial (Waters et al. 1990)
Coronary events Reangiography Progression (patients) Regression (patients) Progression (lesions) Regression (lesions) Stenoses
Can the Coronary Atherosclerotic Process Be Influenced by Calcium Antagonists? G. Kober, I W. Schneider,2 G. CieslinskP and M. Kaltenbach 2 I Clinic Nordrhein, Bad Nauheim, Federal Republic of Germany 2 University Hospital, Frankfurt, Federal Republic of Germany
Summary
Cell culture experiments and various animal models have shown that calcium antagonists can inhibit atheroma development. A number of antiatherosclerotic mechanisms have been proposed and the promising results of these in vitro and animal experiments prompted clinical trials. Retrospective analyses indicated that verapamil might retard disease progression and the development of new stenoses. Prospective clinical studies, however, have revealed no effect by calcium antagonists on preexisting coronary stenoses (~ 20%) and it is suggested that the study duration (2 to 3 years) may have been too short and that advanced stages of atheromatous disease are not influenced by calcium antagonists. Current data suggest that only early stages of coronary atheromatosis may be affected by treatment with calcium antagonists; however, optimum drug, dosage and suitable patients are yet to be defined.
Degenerative as well as proliferative processes are involved in human atherosclerosis. The importance of calcium ions has been identified in many of the metabolic and proliferative processes involved in the initiation and progression of the atherosclerotic process. Among these processes are the following: endothelial damage; hyper-contraction of vascular smooth muscle cells; release of platelet-derived growth factors; cellular lipid metabolism; proliferation and migration of cells; and synthesis of proteins and collagen fibres (Kramsch et al. 1981; Mehta et al. 1983a,b; Metcalfe et al. 1986; Ribeiro et al. 1982; Ross 1981; Ross & Glomset 1976; Schanne et al. 1979; Srinivasan & Sawyer 1970). Because of this, it seemed reasonable to anticipate a beneficial effect of calcium antagonists on the atherosclerotic process.
1. Experiments in Isolated Vessels and Cell Cultures Several calcium antagonists have been studied in cell culture and isolated vessel experiments. Effects noted include protection of cellular membranes, inhibition of proliferation and migration of smooth muscle cells, inhibition of platelet aggregation, and improvement of cellular lipid metabolism with no effect on plasma lipid concentrations (Etingin & Hajjar 1985; Kramsch 1985; Kummerow 1985; Nayler & Szeto 1972; Mehta et al. 1983a,b; Ono & Kimura 1981; Schmitz et al. 1988; Ware et al. 1986; Waters et al. 1989).
2. Animal Experiments Retardation of atheroma development by calcium antagonists has been demonstrated in various animal models (especially in rats and rabbits),
Drugs 44 (Suppi. 1) 1992
124
e.g. atheromas induced by cholesterol-rich food, electrical stimulation of the arterial wall, mechanical vessel trauma, malignant hypertension, or vitamin D3 intoxication. Nifedipine, nicardipine, verapamil, diltiazem and flunarizine are all active in this respect; however, efficacy is dependent on the time of application. Protective effects could only be demonstrated when the drugs were given before or, at the latest, as vessel damage occurred (Blumlein et al. 1984; Fleckenstein et al. 1983; Frey et al. 1980; Ginsburg et al. 1983; Handley et al. 1986; Henry & Bentley 1981; Jackson et al. 1988; Lichtor et al. 1989; Rouleau et al. 1983; Sievers et al 1987; Sugano et al. 1986).
3. Retrospective Analysis in Humans The encouraging results of animal experiments prompted several retrospective analyses in humans, and these have shown a possible beneficial effect of calcium antagonists on human atherosclerosis progression. In our own retrospective study with the calcium antagonist verapamil, 26 patients were treated with the drug (mean dosage of 251 mg/day), while 17 patients in the control group were not given a calcium antagonist. After a mean follow-up period of 13 and 16 months, respectively, a lower rate of progression (23 vs 41 %; not significant), a higher rate of stenosis regression (21 vs 8%; not significant) and a lower incidence of new stenoses development (3.3 vs 10.9%; p < 0.05) were found in the patients receiving verapamil (Kober et al. 1986, 1988).
4. Prospective Trials in Humans The promising findings in animal experiments and in retrospective analyses in humans have prompted prospective trials in humans to clarify further the potential role of calcium antagonists as inhibitors of coronary atherosclerosis progression. Three prospective double-blind clinical trials were initiated with nifedipine 20mg 4 times daily [International Trial on Antiatherosclerotic Therapy (INTACT); Lichtlen et al. 1990], nicardipine 30mg 3 times daily [Montreal Heart Institute Study
Table I. Prospective studies of calcium antagonists in atherosclerosis
No. of vessels involved (% of patients) 0 1 2 3 History of infarction (% of patients) Angiographic follow-up (years) Angiographic evaluation
INTACTB
MHISb
FIPSC
0 28 29 26 30
15 28 38 19 44
0 6 47 47 70
3
2
1&3
Visual CAAS
Visual CMS
Visual Calibrated
a
International Trial on Antiatherosclerotic Therapy; Uchtlen et al. (1990). b Montreal Heart Institute Trial; Waters et al. (1990). c Frankfurt Isoptin Progression Study; Kober et al. (1989); Schneider et al. (1990, 1992). Abbreviation: CAAS = computer analysis of angiogram.
(MHlS); Waters et al. 1990] and verapamil 120mg 3 times daily [Frankfurt Isoptin Progression Study (FIPS); Kober et al. 1989; Schneider et al. 1990, 1992]. In all 3 studies, similar numbers of patients were randomised to either active drug or placebo with angiographic follow-up periods of between 2 to 3 years (INTACT, 425 patients; MHlS, 335 patients; FIPS, 445 patients). However, the studies differed with regard to the severity of coronary atherosclerosis (table I). INTACT and MHIS enrolled mainly patients with early stages of the disease, whereas FIPS patients were eligible only after bypass surgery (i.e. advanced stages of coronary artery disease). In the INTACT and MHIS studies, 28 and 43% of patients had zero and single vessel disease, respectively, compared with only 6% in the FIPS study. Triple vessel disease, however, was evident in 26% (INTACT), 19% (MHlS) and 47% (FIPS) of patients, and a history of preceding myocardial infarctions was also higher in FIPS patients (INTACT 30%; nicardipine 44%; FIPS 70%). Changes in coronary atherosclerosis were analysed visually and/or by computer analysis, with
Influence of Calcium Antagonists on Atherosclerosis
absolute or relative changes in stenosis diameter (INTACT, > O.4mm or ~ 20%; MHIS, ~ O.4mm or ~ 10%), changes in coronary score (~ 0.345 in FIPS) or the development of new stenoses, new occlusions or changes in bypass vessels being sought. In the INTACT study, no significant difference was found between placebo (n = 175) and nifedipine patients (n = 173) with regard to progression and regression as related to existing stenoses or to the disease in individual patients (table II). However, there was a significant difference in the development of new stenoses (~ 20%). There were 144 new lesions in the placebo group and 103 in the nifedipine group, i.e. 0.82 vs 0.59 new lesions per patient in the respective patient groups (- 28%; p = 0.03). In the MHIS, mean progression and regression of single lesions and of the disease in individual patients were not different between patients on placebo (n = 167) or nicardipine (n = 168; table III). However, there was a significantly lower rate of progression of minor grade stenoses ('" 20% of luminal narrowing) in the nicardipine group compared with the placebo group: 16% of stenoses vs 9% (p < 0.05) and 37% of patients vs 15% (p < 0.05). In the FIPS study, angiographic evaluations were performed 3 years after enrolment in 79 verapamil
125
and 80 placebo patients. Coronary atherosclerosis was analysed in native nonbypassed vessels, and in bypass grafts. No significant differences were found between groups with regard to coronary score, progression and regression of pre-existing stenoses, development of new stenoses or new occlusions in both the native vessels and in bypass grafts. In addition, there were no differences in progression or regression of stenoses of low or high grade between treatment groups. In 71 patients in the INTACT study, minor side effects identical to those encountered in patients treated with dihydropyridine-type calcium antagonists were seen (55 nifedipine patients compared with 16 placebo patients), and included dizziness, headache, ankle oedema, tachycardia, hypotension, angina pectoris and flushing. In the MHIS, no data on side effects were published. In the FIPS, a total of 532 minor side effects, most with no influence on the continuation of the study, were reported (254 placebo and 278 verapamil reports). Among these, only constipation was encountered more frequently in the verapamil group (52 vs 30 patients). Critical clinical events occurred in the INTACT study more often in the nifedipine group (cardiac events, 52 vs 14; cardiac death, 8 vs 2; noncardiac death, 4 vs 0). In the MHIS, cardiac death was dis-
Table II. Summary of INTACT (International Trial on Antiatherosclerotic Therapy) results (Lichtlen 1990) Placebo (n
= 175)
Nifedipine (n
= 173)
Significance
number (%)
number (%)
Progression (patients) Regression (patients) Progression only (patients) Regression only (patients) No change (patients)
42 25 39 22 111
48 (28) 17 (10) 43 (25) 12 (7) 113 (65)
NS NS NS NS NS
Progression (leSions) Regression (leSions) Progression to occlusion New lesions (~ 20%) New lesions (per patient) Patients with new lesions
62/657 (9) 27/657 (4) 14/657 (2) 144 0.82 85 (49)
70/598 (12) 18/598 (3) 11/598 (2) 103 0.59 (-28) 70 (40)
NS NS
Abbreviation: NS
(24) (14) (22) (13) (63)
= no significant difference.
P
= 0.03
Drugs 44 (Suppi. 1) 1992
126
Table III. Summary of Montreal Heart Institute Trial (Waters et al. 1990)
Coronary events Reangiography Progression (patients) Regression (patients) Progression (lesions) Regression (lesions) Stenoses
