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Prevention of restenosis by lovastatin after successful coronary angioplasty
Prevention successful
of restenosis by lovastatin coronary angioplasty
after
Prevention of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains a major challenge. To determine whether lovastatin could prevent restenosis, between December 1987 and July 1988, a total of 157 patients undergoing successful PTCA were randomly and prospectively assigned to the lovastatin group or a control group. Seventy-nine patients received lovastatin (20 mg daily if the serum cholesterol level was <300 mg/dl and 40 mg daily if the serum cholesterol level was 2300 mg/dl) in addition to conventional therapy (lovastatin group). Seventy-eight patients received conventional therapy alone (control group). Fifty patients in the lovastatin group and 29 in the control group were evaluated with coronary angiography at an interval of 2 to 10 months (mean 4 months). The restenosis rate was evaluated according to the number of patients showing restenosis, the number of vessels restenosed, and the number of PTCA sites restenosed. Restenosis was defined as the presence of >50% stenosis of the PTCA site. In the lovastatin group 6 of 50 patients (12%) had restenosis compared with 13 of 29 patients (44.4%) in the control group (p < 0.001). When the number of vessels restenosed was considered, only 9 of 72 vessels (12.5%) restenosed in the lovastatln group compared with 13 of 34 vessels (38.2%) in the control group (p < 0.002). Similarly, 10 of 80 (12.5%) PTCA sites restenosed in the lovastatin group compared with 15 of 36 (41.7%) in the control group (p < 0.001). The serum cholesterol level in the lovastatin group decreased from 212 -+ 49 to 175 + 41 mg/dl (p < O.OOl), whereas in the control group it only decreased from 207 t 49 to 196 i 48 mg/dl (p = 0.015). In summary, lovastatin significantly reduces the incidence of restenosis after successful PTCA. Possible mechanisms include a decrease in the serum cholesterol level and a decrease in smooth muscle cell proliferation as a result of inhibition of endothelial DNA synthesis by lovastatin. (AM HEART J 1991;121:1600.)
Rakesh Sahni, MD, Alan R. Maniet, DO, Gerard0 Voci, MD, and Vidya S. Banka, MD. Philadelphia, Pa.
Restenosis after successful coronary angioplasty (PTCA) occurs in 25 % to 40 % of patients and adds considerably to the morbidity and the cost of this treatment strategy. 1-SAttempts to decrease the incidence of restenosis with the use of a large variety of pharmacologic interventions have been unsuccessfu1.6-11 Some studies have suggested that the use of fish oils reduces the incidence of restenosis,12, l3 whereas others have indicated no benefit.14 Restenosis after angioplasty appears to result mainly from intimal smooth muscle cell proliferation.15-l7 Results of experiments after balloon injury of the arterial wall in cholesterol-fed animals have led to the concept that restenosis occurs primarily because of the miFrom the Division of Cardiology, ical College of Pennsylvania. Received
for publication
June
Episcopal
Hospital,
5, 1990; accepted
Affiliate
of the Med-
Nov. 9, 1990.
Reprint requests: Vidya S. Banka, MD, Division of Cardiology, Episcopal Hospital, Front St. and Lehigh Ave., Philadelphia, PA 19125-1098. 4/l/28515
1600
gration and proliferation of smooth muscle cells in response to platelet-derived growth factor released from platelets adherent to the site of deendothelialization.18-2” However, even though both aspirin and calcium channel-blocking agents have been effective in decreasing restenosis in experimental preparations,24-26 they have had a marginal effect if any in humans. Therefore these models may not appropriately mimic the postcoronary angioplasty state in humans.6s 7, g, lo Initial results of a recent preliminary study in a rabbit mode127 indicate that lovastatin, a HMG CoA (3.hydroxy-3 methylglutaryl-coenzyme A) reductase inhibitor, reduces restenosis after balloon angioplasty of iliac arteries in atherosclerotic hypercholesterolemic rabbits. However, the effect of lovastatin in preventing restenosis after angioplasty in human coronary arteries has not been tested. Accordingly this study was undertaken to evaluate the effect of lovastatin on restenosis in human coronary arteries after successful elective coronary angioplasty.
Volume 121 Number 6, Part
1
METHODS Patient population. Between December 2,1987 and July 17, 1988, a total of 206 patients referred for angioplasty were screened for entry into the study. Eligibility criteria included a history of angina pectoris or equivalent, stenosis greater than 70% of the vessel to be dilated, and a successful PTCA result as determined by a reduction in the percentage of narrowing by at least 30% with a final stenotic diameter of less than 50 % . Exclusion criteria included abrupt coronary occlusions necessitating coronary artery bypass grafting, previously administered lovastatin, history of opthalmologic problems or liver function abnormalities, and patients who refused to participate in the study. According to these criteria 194 (94%) had successful PTCA and 37 (19 % ) were eliminated because of exclusion criteria, resulting in 157 total patients eligible for randomization. After successful PTCA the patients were randomly assigned to one of two groups. Seventy-nine patients were assigned to the lovastatin group and 78 to the control group. In addition to conventional therapy (aspirin, 650 mg/day, dipyridamole, 75 mg three times a day, and a calcium channel blocker), patients in the lovastatin group were started on a regimen of 20 mg of lovastation/day if their serum cholesterol level was lower than 300 mg/dl or 40 mg lovastatin/day if their serum cholesterol level was higher than 300 mg/dl. Lovastatin therapy was started on the same day as the angioplasty and continued for 6 months or longer depending on the timing of repeat angiography. All patients were followed clinically for a minimum of 6 months. Follow-up opthalmologic examination, lipid profiles, and liver enzyme levels were again obtained at 2, 4, and 6 months by the attending cardiologist, and data were tabulated by the primary investigator. Since this study was conducted at one laboratory, all attending cardiologists actively participated in data collection. Drug compliance was monitored by the attending cardiologist and recorded. Clinical outcome was also confirmed by a phone interview with the patient by the primary investigator. Follow-up coronary angiograms were obtained between 2 and 10 months after the procedure in the same laboratory. Patients in the control group continued to receive conventional therapy and were followed for a minimum of 6 months in the same manner. Crossover. One patient could not afford lovastatin and crossed over to the control group; one patient who was given lovastatin in the hospital did not continue to take it, and crossed over to the control group. Angioplasty procedure. All angioplasties were performed by one experienced operator (V. S. B.). A conventional “over-the-wire” technique was used in the majority of patients. Other systems were used only when the “overthe-wire” technique failed. By means of a transfemoral approach, arterial and venous sheaths with angioplastyguiding catheters were inserted. Heparin (15,000 units intravenous bolus) and nifedipine (10 mg sublingually three times) were then administered. Heparin boluses were repeated as necessary during the procedure to maintain an
Lovastatin
on post-PTCA
restenosis
1601
activated clotting time longer than 300 seconds. Preliminary angiography of the coronary artery to be dilated was performed in at least two projections, both by tine and digital subtraction techniques, recording the same view for later comparison at follow-up angiography. The dilating catheter system was then inserted and, after administration of intracoronary nitroglycerin (200 pg), the balloon was positioned across the stenosis. After measurement of the pressure gradient, the balloon was inflated as many times as needed to produce an optimal hemodynamic and angiographic result. Successful angioplasty was defined as reduction of diameter stenosis to less than 50 % . Each stenosis was dilated to an optimal diameter by exchanging the dilating catheter to a maximally acceptable balloon size for the caliber of the vessel. The PTCA data and visual determination of results were recorded and later compared to measurements obtained with videodensitometry. At the conclusion of the procedure patients were transferred to a telemetry monitoring unit. A 12-lead ECG was obtained immediately after angioplasty and every 6 hours for 24 hours. Patients continued to receive intravenous heparin and intravenous nitroglycerin for 24 hours. Arterial and venous sheaths were removed the next day. Discharge medications included conventional therapy for the control group and in addition lovastatin for the lovastatin group. Data collection and entry. Clinical information and angioplasty data concerning success or complications were recorded prospectively during hospitalization by the primary investigator on standardized forms. Clinical followup for symptoms of angina, myocardial infarction, coronary bypass surgery and death was carried out at 2, 4, and 6 months by patient visits in cooperation with the attending cardiologist or with the patient by phone. The data were entered into a computerized data base for analysis only after all patients were entered into the study. Angiographic follow-up and exercise thallium scintigraphy were recommended 6 months after successful angioplasty but were performed earlier when clinically indicated. Thus followup angiograms were available at 2 to 10 months with a mean follow-up angiography time of more than 4 months. Coronary angiograms were analyzed by two experienced angiographers independently without knowledge of group randomization. Luminal diameter stenosis was evaluated by videodensitometry with a Vanguard Coronary Analyzer System (Vanguard Instrument Corp, Melville, N.Y.). This system uses a rapid microprocessor technique28 for measuring the cross-sectional area, diameter, and relative percentage of stenosis of coronary atherosclerotic lesions. Video images of 35 mm coronary arteriographic tine frames were analyzed from cinevideodensitometric profile curves recorded from the catheter shaft, normal artery, and stenotic segment. Correlation between observed stenosis at the time of PTCA and videodensitometry differed in only two instances and was resolved by the consensus of a third angiographer. Definitions. Restenosis was defined as a residual stenosis at the time of follow-up angiography of more than 507;
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Sahni
et al.
Table I. Baseline tion
American
clinical
Clinical characteristics
Male Female Age (yr) Smokers Diabetes mellitus Hypertension Family history of CAD Previous CABG Previous MI Z-Vessel disease f-Vessel disease 1-Vessel disease Serum cholesterol Serum triglycerides Serum HDL Serum LDL
characteristics
of patient
popula-
Lovastatin group (76) (n = 79)
Control group (%) (n = 78)
56 23 64.2 28 18 39 28
(71) (29) f 9.3 (35) (23) (49) (35)
54 (69) 24 (31) 56.3 k 9.4 19 (24) 29 (37) 16 (21)
NS NS p < 0.001 NS NS NS p = 0.035
4 31 13 22 44 212 117 36 141
(5) (39) (16) (28) (56) It 49 +- 78 + 10 * 40
4 (5) 17 (22) 16 (21) 24 (31) 38 (49) 207 f 49 104 * 51 37 k 9 136 k 40
NS p = 0.017 NS NS NS NS NS NS NS
19 (24)
P Value
CAD, Coronary artery disease; CABG, coronary artery bypass graft; myocardial infarction; HDL, high-density lipoprotein; LDL, low-density poprotein. NS, not significant at p < 0.05.
Table
II. Distribution
of coronary
vessels for PTCA
Lovastatin group (n = 120)
Control group (n = 91)
PTCA vessels n = 211
No.
(75)
No.
(%)
LAD Circumflex RCA Graft Branches
43 24 22 3 28
36 20 18 3 23
41 16 22 1 II
45 17 24 1 12
LAD,
Left anterior
descending;
MI, li-
RCA, right
coronary
artery.
of the luminal diameter. This definition has been widely acceptedl-3, 6,8, 11, 12and is clinically useful. Study design and statistical analysis. The study was designed to accept a minimum of 150 patients randomly assigned to treatment with lovastatin and/or conventional therapy, which would provide us with at least 250 vessels to be evaluated, considering that each patient would have approximately 1.5 PTCA vessels. With a 30% to 35% historical restenoses rate with conventional therapy and the independent risk of restenosis for individual PTCA vessels in the same patient, as suggested by results of earlier studies, we believed that the present study should provide a sample size large enough to produce significant differences (p = 0.05) to illustrate a 50% reduction in the restenosis rate at a 95% confidence interval. Data were collected and analyzed with PC!INFO (Retriever Data Systems, Seattle, Wash.) with differences in categoric
June 1991 Heart Journal
variables analyzed by chi-square test and continuous ables by paired or unpaired Student’s t test. RESULTS Clinical characteristics of the patient population.
vari-
The clinical characteristics of the patient population randomly assigned to the lovastatin and control groups are shown in Table I. The patient population was quite similar with respect to sex distribution, presence of three-, two-, and one-vessel disease, and history of smoking, hypertension, diabetes, and previous coronary bypass surgery. The distribution of patients with a positive family history for coronary disease and previous myocardial infarction was, however, higher in the lovastatin group than in the control group. There was no difference in the lipid profiles of the patients in the two groups. However, the patients in the control group were younger than those in the lovastatin group. Table II shows the angiographic distribution of stenotic vessels dilated in the lovastatin and control groups. Although the distribution for left anterior descending and right coronary artery stenoses was similar, a significantly higher number of circumflex arteries and branch vessels (circumflex marginals and diagonals) were dilated in the lovastatin group. Effects on serum cholesterol levels. Administration of lovastatin reduced serum cholesterol levels significantly from 212 * 49 to 175 f 41 mg/dl (p < 0.001) in the treated patients (Fig. 1). In the control group, however, there was only a mild reduction in cholesterol levels from 207 rt 49 to 196 f 48 mg/dl (p = 0.015), probably induced by dietary modifications. Follow-up angiographic results. Follow-up angiography was performed in 50 patients in the lovastatin group and 29 patients in the control group (Table III). There were 72 vessels (1.4 vessels/patient) with 80 stenotic lesions (1.6 lesions/patient) dilated in the lovastatin group. In the control group there were 34 vessels (1.1 vessels/patient) with 36 stenotic lesions (1.2 lesions/patient). Table III also shows the restenosis rates in both groups. In the lovastatin group only 6 of the 50 patients (12%) had restenosis in contrast to 13 of the 29 patients (44.8%) in the control group (p < 0.001). Similarly, vessels (12.5 % ) in the lovastatin
only
9 of the
72
group restenosed compared with 13 of the 34 vessels (38.2%) in the control group (p < 0.002). When restenosis was evaluated in terms of lesions, only 10 of the 80 (12.5% ) stenotic lesions demonstrated restenosis in contrast to 15 of the 36 (41.7%) lesions in the control group (p < 0.001). A flow diagram (Fig. 2) shows the patency and restenosis rates of the vessels included in the lovastatin and control groups.
Number
121 6. Part 1
Lovastatin
Fig.
1.
Follow-up
evaluation
of serum cholesterol
The distribution of patent and restenosed coronary vessels at follow-up angiography shown in Table IV indicates that the restenosis rate in all groups of vessels in the lovastatin group was lower when compared with the vessels in the control group. The morphology of lesions at high risk for restenosis was essentially similar in the lovastatin and control groups (Table V). Quantitative angiographic analysis. Table VI shows the severity of coronary stenosis as measured by videodensitometry before PTCA, immediately after PTCA, and at follow-up in patent and restenosed vessels. There was no significant difference in the percentage of the area of stenosis, percentage of the diameter of stenosis, and mean stenotic diameter before PTCA, immediately after PTCA, and at followup in the lovastatin or control group. The length of the stenotic segment was also similar in the two groups. However, the mean stenotic diameter at restenosed sites at follow-up was significantly higher than the mean stenotic diameter before PTCA in both groups (p < 0.05). Exercise thallium scintigraphy and exercise ECG. To obtain more complete data on restenosis rates in patients in whom coronary angiograms were not available for evaluation of restenosis, results of exercise thallium scintigraphy or exercise ECG were added to the angiographic data. Positive exercise thallium or exercise ECG findings were considered indicative of the presence of restenosis, whereas negative results of exercise thallium tests or exercise ECGs were considered indicative of absence of restenosis. In this manner restenosis could be evaluated in 75 of 79 patients in the lovastatin group and 54 of 78 patients in
Table
levels in lovastatin
Ill.
Restenosis
and control
at follow-up
Louastatin
No. of patients No. of vessels No. of lesions
on post-PTCA
group
Total No.
Restenosis No. (“G)
50 72 80
6 (12) 9 (12.5) 10 (12.5)
restenosis
1603
groups.
angiography Control group Total Rcstenosis No. No. (5;) 29 34 36
13 (44.8) 13 (38.2) 15 (41.7)
p Value p = 0.001 p = 0.002 p < 0.001
the control group. Table VII represents the restenosis rates detected by a combination of angiography and exercise test results. In the lovastatin group 69 of 75 patients (92%) were considered to have no restenosis, and only 6 of 75 (8%) were considered to have restenosis. In contrast, in the control group 39 of 54 patients (72 % ) were considered to have no restenosis and 15 of 54 (28%) were considered to have restenosis. The difference in restenosis rates between the lovastatin group and the control group was highly significant (p = 0.003). One patient in the lovastatin group and two patients in the control group with positive test results did not have restenosis at followup angiography. Follow-up clinical results. The clinical follow-up data are presented in Table VIII. Ninety percent of the patients in the lovastatin group and 88% in the control group remained asymptomatic at follow-up. Although the incidence of recurrence of symptoms, myocardial infarction, and death was similar in the two groups, the incidence of coronary bypass surgery during follow-up was higher in the control group compared with that in the lovastatin group. In the
Sahni et al.
1604
American
TOTAL
June ,991 Heart Journal
PTCA VESSELS 225
Lo”*sT*f
kTROL
132 (59%)
93 (41%) FOLLOW
72 (55%)
PATENT 63 (87.5%) Fig. 2. Flow diagram trol groups.
Table
IV.
follow-up
Distribution angiography Lovastatin
PTCA vessel
LAD Circumflex RCA Branch vessels Graft Total LAD, Left anterior NS, not significant
showing
of patent group
3I
and restenosed
vessels at
fect on the restenosis rate.“.I’ Experimental studies on restenosis carried out in animal models indicate that after balloon angioplasty platelet aggregation starts to occur immediately, is maximal within the first hour, and decreases between 4 and 48 hours.2g-;j’ Platelet fibrin mass releases mitogens that probably lead to smooth muscle cell proliferation. Platelet-derived growth factor is also responsible for smooth muscle cell proliferation. 3’ Smooth muscle cell proliferation is maximal between 48 and 96 hours, and recruitment of cells is largely completed by 3 days.:‘:’ These studies indicate that the primary mechanism initiating restenosis involves platelet aggregation and smooth muscle cell proliferation. The effect of lipid metabolism on the development of restenosis and the role interventions may play in altering lipid metabolism, however, have not been investigated. Lovastatin has been shown to alter smooth muscle cell proliferation in tissue cultures and may reduce atherogenesis by altering lipid metabolism. Our results indicate that there is a marked reduction in the incidence of restenosis in the lovastatin-treated group compared with the control group (Table III; Fig. 2). Only 6 of 50 patients (12 % ) in the lovastatin group showed restenosis compared with 13 of 29 patients (44.8%) in the control group (p < 0.001). Similarly, only 9 of 72 vessels (12.5%) in the lovastatin group restenosed compared with 13 of 34 vessels (38.2 % ) in the control group (p < 0.002). When restenosis was evaluated in terms of lesions, only 10 of 80 (12.5%) stenotic lesions exhibited restenosis in contrast with 15 of 36 (41.7%) lesions in the control group. Table IV demonstrates that the incidence of restenosis in the lovastatin group, although not statis-
3
1(11) 0
3 29
72
9 (12.5r<
descending; RCA, right at p < 0.05.
RES‘TENOSIS 13 (38%)
patency
group
Total NO. no. of restenosed vessels (rn)
)
PATENT 21 (62%)
angiographic
15 8 7
9
34 (374) 0
follow-up
6 (19) 1 (6) 1 (8)
17 12
-
RESTENOSIS 9 (12.5%)
Control
Total No. no. of restenosed vessels i%)
UP CATH 106
34
p Value
7 (47) 3 (38)
NS NS
2 (29) 1 (33)
NS NS NS
13 (38.2’1)
P = 0.002
coronary
artery.
lovastatin group eight patients had recurrence of symptoms. Two of these patients had had incomplete revascularization because of the presence of additional significant obstructive lesions in the other vessels that were not amenable to PTCA. The remaining six patients had restenosis. In contrast, of the 13 patients with recurrence of symptoms in the control group, all were judged to have complete initial revascularization and had angiographic restenosis at follow-up. DISCUSSION
Restenosis after successful PTCA remains a major challenge. The results of several clinical trials with the use of anticoagulants, calcium antagonists, corticosteroids, or mechanical interventions (i.e., prolonged balloon inflation) have failed to show any ef-
and restenosis
rates in Lovastatin
and con-
Volume 121 Number 6, Part 1
tically significant, was lower in all subgroups of vessels compared with vessels in the control group. These data provide strong evidence that lovastatin is effective in reducing the restenosis rate. Although this study was not double blinded, it is apparent (Table I) that the patients in the lovastatin and control groups had similar characteristics with regard to sex distribution, smoking, hypertension, and diabetes. Only age and history of coronary artery disease differed significantly (i.e., patients in the lovastatin group were older and had a greater tendency for positive family histories of coronary artery disease). It seems reasonable to conclude that these factors should have favored the control group. The baseline lipid profile and the severity of coronary artery disease, as assessed by the number of vessels involved, were also similar in the two groups. The pre- and post-PTCA management with aspirin and Persantine was also similar in the two groups. At the time when this study was initiated, postPTCA management with both aspirin and Persantine was a standard treatment in our laboratory and was used in both the control and lovastatin groups. Intravenous heparin was continued for 24 hours after PTCA in both groups. Although heparin may have independent effects on restenosis, this therapy was again similar in the two groups. A recent study from Emory University showed no effect of heparinization on restenosis rates for 24 hours.34 Lovastatin was administered to patients irrespective of their baseline cholesterol levels, and all patients from December 2,1987 to July 17,1988 were included irrespective of their lipid profiles. At the time of data analysis the serum cholesterol levels were slightly higher in the lovastatin group compared with the control group (Table I, Fig. l), but the difference was not statistically significant. Since restenosis rates are now shown to be related to baseline cholesterol levels and other lipoproteins,35 these data may further strengthen the effectiveness of lovastatin in reducing restenosis rates. The only angiographic difference between the two groups was reflected in a higher number of circumflex arteries and branch vessel stenoses in the lovastatin group. Since the smaller vessels, that is, branch vessels are more prone to restenosis, this factor would count in favor of lovastatin causing a reduction in restenosis. Again all other angiographic criteria of lesions that affect restenosis were similar in the two groups (Table V). In fact the number of tandem lesions, bifurcation lesions, and lesions longer than 1 cm were higher in the lovastatin group than in the control group. Videodensitometric studies for evaluation of the
Lovastatin
on post-PTCA
restenosis
1605
V. Baseline characteristics of coronary stenotic lesions among patients with follow-up angiography
Table
LOUUStUtiTl
Baseline characteristics
.imUP
n = 50 (%,I
Area of stenosis 290 “0 Total occlusion Tandem lesions Bifurcation lesions Lesion length >1 cm Calcified lesions Eccentric lesions Tubular lesions Thrombus NS. not significant
29 3 8 4 22 4 18 21 8
(58) (6) (16) (8) (44) (8) (36) (42)
(W
Control mup
n = 29 f%,) 16 1 2 1 10 2 7 11 3
(55) (3) (7) (3) (34) (7) (24) (38) (10)
p Value NS NS NS NS NS NS NS NS NS
at p < 0.05.
severity of coronary stenosis showed no difference in the pre-PTCA or post-PTCA stenotic diameter or percentage of stenosis in the lovastatin group compared with the control group in patients in whom the vessels remained patent and those in whom restenosis occurred (Table VI). The length of the stenosis was also similar in the two groups (Table VI). It was therefore not possible to explain the reduction in restenosis rate on pre- or post-PTCA angiographic findings. In both groups there was a slight improvement in the stenotic diameter at follow-up angiography compared with immediate post-PTCA results (Table VI). When restenosis occurred the stenotic diameter did not return to the pre-PTCA diameter and remained significantly higher (restenosis greater than 80% in the control group and less than 75% in the lovastatin group) than the mean diameter before PTCA (Table VI). This may explain the lack of symptoms in many patients despite the occurrence of angiographic restenosis. Since the angiographic follow-up was significantly different in the two groups, we attempted to obtain more complete data on restenosis rates by the addition of exercise thallium or exercise ECG results in the two groups. A positive thallium or exercise ECG finding was considered indicative of restenosis and a negative thallium or negative exercise ECG result was considered indicative of the absence of restenosis. This allowed more complete follow-up of 75 of the 79 patients in the lovastatin group and 54 of the 78 patients in the control group. Thus only 8% of the patients in the lovastatin group had restenosis in contrast to 28% in the control group (p = 0.003) (Table VII). These findings substantiate the pure angiographic data for restenosis. Clinical follow-up data indicate that although re-
1606
Sahni et al.
Table
VI. Severity
American
of coronary
stenosis Patent Lovastatin
% Area stenosis Pre-PTCA Post-PTCA Follow-up OUDiameter stenosis Pre-PTCA Post-PTCA Follow-up Mean stenotic diameter (mm) Pre-PTCA Post-PTCA Follow-up Stenosis length (mm) All comparisons
not significant
vessels
group
Restenosed Control
group
Control
group
89 k 6 21 + 9 82 I 8
89 -c 5 25 i 9 81 t 5
a2 t 7 16 + 8 14 + 9
79 f 14 13 It 9 12 i 9
84 k 9 20 i 9 80 t 10
86 + 4 25 i 9 79 k 6
0.5 3.5 3.6 10
t + f *
0.2 0.5 0.5 4
0.7 + 0.8 3.4 + 0.9 3.9 zi 1.6 9*3
0.5 3.4 0.9 10
-t 0.3 +- 0.3 f 0.4 I 4
0.5 3.4 0.9 11
* 0.2 _t 0.4 k 0.2 i 3
at p < 0.05.
group
(n = 75) (%o)
Table
Lovastatin
86 k 10 15 -+ 13 13 1 9
VII. Restenosis as determined by the addition of stress results to angiographic data
No restenosis Restenosis
group
vessels
86 + 7 17 + 10 15 t- 10
Table
Lovastatin
June 1991 Heart Journal
Control group (n = 54) (%)
69 (92) 6W
39 (72) 15 (28)
p Value
p = 0.003
VIII. Clinical follow-up data Follow-up
Relief of symptoms Recurrence of symptoms Myocardial infarction Deaths Cardiac Noncardiac Coronary artery bypass graft
Lovastatin group (n = 79) (%)
Control
group
(n = 78) (%)
71 (90) 8 (10) 2 (3)
69 (88) 9 (12) 1 (1)
1 (1) 2 (3) 0
3 (4) 1 (1) 5 (6)
currence of symptoms, incidence of myocardial infarction, and cardiac death were essentially similar in the two groups, the incidence of coronary bypass surgery was higher in the control group than in the lovastatin group. The explanation for this observation is not clear. It may be entirely related to the recurrence of &noses or incomplete revascularization or to the fact that symptoms were not fully recognized because of the early time period studied. The mechanisms by which lovastatin prevents restenosis may be twofold. Results of preliminary studies in a rabbit model have indicated that lovastatin being a HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor may reduce restenosis
by decreasing serum cholesterol levels and inhibiting cell growth by blocking DNA synthesis.27 Although no direct evidence is available to indicate that lovastatin reduces smooth muscle proliferation in humans, its ability to reduce atherogenesis by favorably altering lipid metabolism has been demonstrated in experimental and epidemiologic studies.36-38 Thus the significant reduction of serum cholesterol levels that occurred in the lovastatin group maybe responsible for the decreased incidence of restenosis. None of the previous studies on restenosis except that of Dehmer et a1.12 has paid attention to inhibition of atherosclerosis, regardless of the underlying mechanism, as a contributing factor in the prevention of restenosis. In their randomized study these investigators showed that a diet supplemented with N-3 fatty acids reduced the incidence of early restenosis to 16% in the treated group versus 35% in the control group. Our results are similar and show a restenosis rate of 12.5 % in the lovastatin group versus 38.2% in the control group. The present study was limited in that complete angiographic follow-up findings were not available in all patients. However, the lovastatin-treated group of 50 patients in whom follow-up angiograms were available represents a large enough cohort of patients with a 12.5% restenosis rate observed. This rate is unquestionably the lowest when compared with that reported in many series. l-* Considering the current acceptable restenosis rate as cited in the literature (serving as a historical control value), which coincided with the higher restenosis rate in our patients comprising the control group, it is logical to conclude that lovastatin has been effective in contributing to this lower restenosis rate. These data are further
“Ol”n-m 121 Number 6, Part 1
Lovastatin
supported by inclusion of exercise test results, which allowed a more complete follow-up and still maintained a highly significant difference in the restenosis rates between the lovastatin and control groups. Another limitation of this study is that double blinding was not possible. However, compliance was confirmed by more severe reduction in serum cholesterol levels in the treated group compared with the control group. No significant side effects were noted in the treated group. Only one patient had an increased alkaline phosphatase level and was withdrawn from the study. Another patient was withdrawn from the study because he could not afford the drug. This study, however, is valuable in that it provides an appreciation of the restenosis rate in all treated and untreated patients undergoing successful coronary angioplasty. Our observations indicate that supplemental therapy with lovastatin started immediately after successful PTCA, irrespective of serum cholesterol levels, reduces the incidence of restenosis. The probable mechanism may be related to inhibition of smooth muscle cell proliferation and/or reduction in atherogenesis by altering the lipid metabolism favorably. Although in this study lovastatin was administered immediately after PTCA, pretreatment with lovastatin may be even more efficacious. We also believe that further trials with lovastatin and other HMG CoA reductase inhibitors are warranted to evaluate these findings. We thank Drs. Bindu K. Kansupada, Ranga manyam Chivukula, Mahmoud Gbusson, Mian Gold, Azam Husain, Mosen Alavi, Hass Shafia, Samuel Ruby, Roger Weiner, and Bodh N. Das following pat.ients for this study. We are grateful Carpenter, Mrs. Margaret O’Connell, and Mrs. for their help in preparation of the manuscript.
A. Rao, SubrahA. Jan, Jonathan Suketu Nanavati, for recruiting and to Mrs. Esther Brenda Pressley
REFERENCES
1. Leimgruber PP, Roubin GS, Hollman J, Cotsonis GA, Meier B, Douglas JS, King SB, Gruentzig AR. Restenosis after successful coronary angioplasty in patients with single vessel disease. Circulation 1986;73:710-17. 2. Levine S, Ewels CJ, Rosing DR, Kent KM. Coronary angioplasty: clinical and angiographic follow up. Am J Cardiol 1985;55:673-6. 3. Holmes DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF; Detre KM. Van Raden MJ. Mock MB. Restenosis after nercutaneous transluminal coronary angioplasty (PTCA): a report from PTCA registry of the National Heart, Lung and Blood Institute. Am J Cardiol 1984;53:77C-81C. 4. Mata LA, Bosch X, David PR, Rapold HJ, Corcos T, Bourassa MG. Clinical and angiographic assessment 6 months after double vessel percutaneous coronary angioplasty. J Am Co11 Cardiol 1985;6:1239-44. 5. Jang GC, Block PC, Cowley MJ, Gruentzig AR, Dorros G, Holmes DR, Kent KM, Leatherman LL, Myler RK, Sjolander SME, Stertzer SH, Vetrovec GW, Willis WH, Williams DO.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
21. 22.
23.
on post-PTCA
restenosis
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Relative costs of coronary angioplasty and bypass surgery in a one-vessel disease model. Am J Cardiol 1984:53:52C-5C. White CW, Knudson M, Schmidt D, Chisholm M, Vandormael M, Morton B, Roy L, Khaja F, Reitman M, and the Triclopidine Study Group. Neither triclopidine nor aspirin-dipyridamole prevents restenosis post PTCA: results from a randomized placebo-controlled multicenter trial. Circulation 1987;76 (suppl):IV-213. Whiteworth HB, Roubin GS, Hollman J, Meier B, Leimgruber PP, Douglas JS, King SB, Gruentzig AR. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronarv anaioulastv. J Am Co11 Cardiol 1986:8:1271-6. Thornton MA, GruentzigAR, Hollman J, King SB; Douglas JS. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984;69:721-7. Schwartz L, Bourassa MG, Lesperance J, Aldridge H, David PR. Henderson M. Hudon G. Kazim F. Failure of antinlatelet agents to reduce restenosis after PTCA in a double blind placebo controlled trial. J Am Co11 Cardiol 1988;11:236A. Corcos T, David PR, Guiteras Val P, Renkin J, Dangoisse V, Rapold HG, Bourassa MG. Failure of diltiazem to prevent restenosis after percutaneous transluminal coronary angioplasty. AM HEART J 1985;109:926. Knudson ML, Duff HJ, Flintoff VF, Roth DL, Hansen JL. Does short term prostacyclin administration lower the risk of restenosis after PTCA? A prospective randomized trial [Abstract]. Circulation 1986;74:11-282. Dehmer GJ, Popma JJ, Van Den Berg EK, Eichhorn EJ, Prewitt JB, Campbell WB, Jennings L, Willerson JT, Schmitz JM. Reduction in the rate of early restenosis after coronary angioplasty hv a diet supplemented with N-3 fattv acids. N - _ Engl J Med <988;319:73%40. Milner MR. Gallino RA. Leffinewell A. Pichard AD. Robinson SB, Rosenberg J, Little’T, Lindsey Jr’J. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1989;64:294-9. Reis GJ, Sipperly ME, McCabe CH, Sacks FM, Boucher TM, Silverman DJ, Bairn DS, Grossman W, Pasternack RC. Randomized trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989;7:177-81. Essed CE, Van Den Brand M, Becker AE. Transluminal coronary angioplasty and early restenosis-fibrocellular occlusion after wall laceration. Br Heart J 1983;49:393-6. Austin GE, Ratliff NB, Hollman J, Tabei S, Phillips DF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Co11 Cardiol 1985;6:36975. Waller BF, Gorfinkel HJ, Rogers FJ, Kent KM, Roberts WC. Early and late morphological changes in major epicardial coronary arteries after percutaneous transluminal coronary anaioulastv. Am J Cardiol 1984:53:42C7C. - _ Friedman RJ, Sternerman M; Wenz B, Moore S, Gauldie J, Gent M, Tie11 ML, Spaet H. The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle cell proliferation and re-endothelialization. J Clin Invest 1977;66:1191-201. Schwartz SM, Reidy MR, Clowes A. Kinetics of atherosclerosis: a stem cell model. Ann NY Acad Sci 1985;454:292-304. Ross R, Glomset J, Kariya B, Harker L. A platelet dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Nat1 Acad Sci USA 1974;71:1207-10. Kohler N, Lipton A. Platelets as a source of fibroblast growth promoting activity. Exp Cell Res 1974;87:297-301. Ross R, Bowen-Pope D, Raines EW. Platelets, macrophages, endothelium and growth factors: their effects upon cells and their possible roles in atherogenesis. Ann NY Acad Sci 1985;454:254-60. Moore A, Freidman RJ, Singal LDLP, Gauldie J, Blajchman
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24.
25.
26.
27.
28.
29.
30.
Sahni et al.
MA. Inhibition of injury induced thromboatherosclerotic lesions by anti-platelet serum in rabbit. Thromb Haemost 1975;35:70. Kramsch DM, Aspen AJ, Rozler LJ. Atherosclerosis: prevention by agents not affecting abnormal levels of blood lipids. Science 1981;213:1511-2. Faxon DP, Sanborn TA, Haudenschild CC, Ryan TJ. Effect of antiplatelet therapy on restenosis after experimental angioulastv. Am J Cardiol 1984:53:72C-6C. Nakia J, Hideki I, Oyama T, Wen-Chang C, Muroto S. Calcium dependency of aortic smooth muscle cell migration induced by 12 L-hydroxy-5,8,10,14-eicostatetraenoic acid. Atherosclerosis 1983;46:309. Gellman J, Ezekowitz MD. Lovastatin A: HMG CoA reductase inhibitor reduces restenosis following balloon angioplasty in an atherosclerotic hvoercholesterolemic rabbit. Clin Res 1989;37:261A. ”_ Silver KH, Buczek JA, Esser PD, Nichols AB. Quantitative analysis of coronary arteriograms by microprocessor cinevideodensitometry. Cathet Cardiovasc Diagn 1987;13:291-300. Wilentz JR, Sanborn TA, Haudenschild CC, Valeri CR, Ryan TJ, Faxon DP. Platelet accumulation in experimental angioplasty: time course and relation to vascular injury. Circulation 1987;75:636-42. Groves HM, Kinlough-Rathbone RL, Richardson M, Moore S, Mustard JF. Platelet interaction with damaged rabbit aorta. Lab Invest 1979;40:194-200.
American
June 1991 Heart Journal
31. Steele PM, Chesebro JM, Stanson AW, Holmes Jr DR, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiologic response to injury in a pig model. Circ Res 1985;57:105-12. 32. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500. 33. Clowes AW, Schwartz SM. Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ Res 1985;56:139-45. 34. Ellis SG, Roubin GS, Wilentz J, Douglas JS, King SB. Effect of 18 to 24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. A~I HEART J 1989;117:777-82. 35. Bergelson BA, Jacobs AK, Small DM, Tercyak AM, Cupples A, Garber GR, Erario M, Ruocco NA, Ryan TJ, Faxon DP. Lipoproteins predict restenosis after PTCA. Circulation 1989;80:11-65. 36. Frishman WH, Rapier RC. Lovastatin: an HMG CoA reductase inhibitor for lowering cholesterol. Med Clin North Am 1989;73:437-48. 37. Schnerider D. Lovastatin: a new cholesterol lowering agent. Clin Pharmacol 1988;7:21-36. 38. Frick MH, Elo 0, Haapa K. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237-45.
of restenosis by lovastatin coronary angioplasty
after
Prevention of restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains a major challenge. To determine whether lovastatin could prevent restenosis, between December 1987 and July 1988, a total of 157 patients undergoing successful PTCA were randomly and prospectively assigned to the lovastatin group or a control group. Seventy-nine patients received lovastatin (20 mg daily if the serum cholesterol level was <300 mg/dl and 40 mg daily if the serum cholesterol level was 2300 mg/dl) in addition to conventional therapy (lovastatin group). Seventy-eight patients received conventional therapy alone (control group). Fifty patients in the lovastatin group and 29 in the control group were evaluated with coronary angiography at an interval of 2 to 10 months (mean 4 months). The restenosis rate was evaluated according to the number of patients showing restenosis, the number of vessels restenosed, and the number of PTCA sites restenosed. Restenosis was defined as the presence of >50% stenosis of the PTCA site. In the lovastatin group 6 of 50 patients (12%) had restenosis compared with 13 of 29 patients (44.4%) in the control group (p < 0.001). When the number of vessels restenosed was considered, only 9 of 72 vessels (12.5%) restenosed in the lovastatln group compared with 13 of 34 vessels (38.2%) in the control group (p < 0.002). Similarly, 10 of 80 (12.5%) PTCA sites restenosed in the lovastatin group compared with 15 of 36 (41.7%) in the control group (p < 0.001). The serum cholesterol level in the lovastatin group decreased from 212 -+ 49 to 175 + 41 mg/dl (p < O.OOl), whereas in the control group it only decreased from 207 t 49 to 196 i 48 mg/dl (p = 0.015). In summary, lovastatin significantly reduces the incidence of restenosis after successful PTCA. Possible mechanisms include a decrease in the serum cholesterol level and a decrease in smooth muscle cell proliferation as a result of inhibition of endothelial DNA synthesis by lovastatin. (AM HEART J 1991;121:1600.)
Rakesh Sahni, MD, Alan R. Maniet, DO, Gerard0 Voci, MD, and Vidya S. Banka, MD. Philadelphia, Pa.
Restenosis after successful coronary angioplasty (PTCA) occurs in 25 % to 40 % of patients and adds considerably to the morbidity and the cost of this treatment strategy. 1-SAttempts to decrease the incidence of restenosis with the use of a large variety of pharmacologic interventions have been unsuccessfu1.6-11 Some studies have suggested that the use of fish oils reduces the incidence of restenosis,12, l3 whereas others have indicated no benefit.14 Restenosis after angioplasty appears to result mainly from intimal smooth muscle cell proliferation.15-l7 Results of experiments after balloon injury of the arterial wall in cholesterol-fed animals have led to the concept that restenosis occurs primarily because of the miFrom the Division of Cardiology, ical College of Pennsylvania. Received
for publication
June
Episcopal
Hospital,
5, 1990; accepted
Affiliate
of the Med-
Nov. 9, 1990.
Reprint requests: Vidya S. Banka, MD, Division of Cardiology, Episcopal Hospital, Front St. and Lehigh Ave., Philadelphia, PA 19125-1098. 4/l/28515
1600
gration and proliferation of smooth muscle cells in response to platelet-derived growth factor released from platelets adherent to the site of deendothelialization.18-2” However, even though both aspirin and calcium channel-blocking agents have been effective in decreasing restenosis in experimental preparations,24-26 they have had a marginal effect if any in humans. Therefore these models may not appropriately mimic the postcoronary angioplasty state in humans.6s 7, g, lo Initial results of a recent preliminary study in a rabbit mode127 indicate that lovastatin, a HMG CoA (3.hydroxy-3 methylglutaryl-coenzyme A) reductase inhibitor, reduces restenosis after balloon angioplasty of iliac arteries in atherosclerotic hypercholesterolemic rabbits. However, the effect of lovastatin in preventing restenosis after angioplasty in human coronary arteries has not been tested. Accordingly this study was undertaken to evaluate the effect of lovastatin on restenosis in human coronary arteries after successful elective coronary angioplasty.
Volume 121 Number 6, Part
1
METHODS Patient population. Between December 2,1987 and July 17, 1988, a total of 206 patients referred for angioplasty were screened for entry into the study. Eligibility criteria included a history of angina pectoris or equivalent, stenosis greater than 70% of the vessel to be dilated, and a successful PTCA result as determined by a reduction in the percentage of narrowing by at least 30% with a final stenotic diameter of less than 50 % . Exclusion criteria included abrupt coronary occlusions necessitating coronary artery bypass grafting, previously administered lovastatin, history of opthalmologic problems or liver function abnormalities, and patients who refused to participate in the study. According to these criteria 194 (94%) had successful PTCA and 37 (19 % ) were eliminated because of exclusion criteria, resulting in 157 total patients eligible for randomization. After successful PTCA the patients were randomly assigned to one of two groups. Seventy-nine patients were assigned to the lovastatin group and 78 to the control group. In addition to conventional therapy (aspirin, 650 mg/day, dipyridamole, 75 mg three times a day, and a calcium channel blocker), patients in the lovastatin group were started on a regimen of 20 mg of lovastation/day if their serum cholesterol level was lower than 300 mg/dl or 40 mg lovastatin/day if their serum cholesterol level was higher than 300 mg/dl. Lovastatin therapy was started on the same day as the angioplasty and continued for 6 months or longer depending on the timing of repeat angiography. All patients were followed clinically for a minimum of 6 months. Follow-up opthalmologic examination, lipid profiles, and liver enzyme levels were again obtained at 2, 4, and 6 months by the attending cardiologist, and data were tabulated by the primary investigator. Since this study was conducted at one laboratory, all attending cardiologists actively participated in data collection. Drug compliance was monitored by the attending cardiologist and recorded. Clinical outcome was also confirmed by a phone interview with the patient by the primary investigator. Follow-up coronary angiograms were obtained between 2 and 10 months after the procedure in the same laboratory. Patients in the control group continued to receive conventional therapy and were followed for a minimum of 6 months in the same manner. Crossover. One patient could not afford lovastatin and crossed over to the control group; one patient who was given lovastatin in the hospital did not continue to take it, and crossed over to the control group. Angioplasty procedure. All angioplasties were performed by one experienced operator (V. S. B.). A conventional “over-the-wire” technique was used in the majority of patients. Other systems were used only when the “overthe-wire” technique failed. By means of a transfemoral approach, arterial and venous sheaths with angioplastyguiding catheters were inserted. Heparin (15,000 units intravenous bolus) and nifedipine (10 mg sublingually three times) were then administered. Heparin boluses were repeated as necessary during the procedure to maintain an
Lovastatin
on post-PTCA
restenosis
1601
activated clotting time longer than 300 seconds. Preliminary angiography of the coronary artery to be dilated was performed in at least two projections, both by tine and digital subtraction techniques, recording the same view for later comparison at follow-up angiography. The dilating catheter system was then inserted and, after administration of intracoronary nitroglycerin (200 pg), the balloon was positioned across the stenosis. After measurement of the pressure gradient, the balloon was inflated as many times as needed to produce an optimal hemodynamic and angiographic result. Successful angioplasty was defined as reduction of diameter stenosis to less than 50 % . Each stenosis was dilated to an optimal diameter by exchanging the dilating catheter to a maximally acceptable balloon size for the caliber of the vessel. The PTCA data and visual determination of results were recorded and later compared to measurements obtained with videodensitometry. At the conclusion of the procedure patients were transferred to a telemetry monitoring unit. A 12-lead ECG was obtained immediately after angioplasty and every 6 hours for 24 hours. Patients continued to receive intravenous heparin and intravenous nitroglycerin for 24 hours. Arterial and venous sheaths were removed the next day. Discharge medications included conventional therapy for the control group and in addition lovastatin for the lovastatin group. Data collection and entry. Clinical information and angioplasty data concerning success or complications were recorded prospectively during hospitalization by the primary investigator on standardized forms. Clinical followup for symptoms of angina, myocardial infarction, coronary bypass surgery and death was carried out at 2, 4, and 6 months by patient visits in cooperation with the attending cardiologist or with the patient by phone. The data were entered into a computerized data base for analysis only after all patients were entered into the study. Angiographic follow-up and exercise thallium scintigraphy were recommended 6 months after successful angioplasty but were performed earlier when clinically indicated. Thus followup angiograms were available at 2 to 10 months with a mean follow-up angiography time of more than 4 months. Coronary angiograms were analyzed by two experienced angiographers independently without knowledge of group randomization. Luminal diameter stenosis was evaluated by videodensitometry with a Vanguard Coronary Analyzer System (Vanguard Instrument Corp, Melville, N.Y.). This system uses a rapid microprocessor technique28 for measuring the cross-sectional area, diameter, and relative percentage of stenosis of coronary atherosclerotic lesions. Video images of 35 mm coronary arteriographic tine frames were analyzed from cinevideodensitometric profile curves recorded from the catheter shaft, normal artery, and stenotic segment. Correlation between observed stenosis at the time of PTCA and videodensitometry differed in only two instances and was resolved by the consensus of a third angiographer. Definitions. Restenosis was defined as a residual stenosis at the time of follow-up angiography of more than 507;
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Sahni
et al.
Table I. Baseline tion
American
clinical
Clinical characteristics
Male Female Age (yr) Smokers Diabetes mellitus Hypertension Family history of CAD Previous CABG Previous MI Z-Vessel disease f-Vessel disease 1-Vessel disease Serum cholesterol Serum triglycerides Serum HDL Serum LDL
characteristics
of patient
popula-
Lovastatin group (76) (n = 79)
Control group (%) (n = 78)
56 23 64.2 28 18 39 28
(71) (29) f 9.3 (35) (23) (49) (35)
54 (69) 24 (31) 56.3 k 9.4 19 (24) 29 (37) 16 (21)
NS NS p < 0.001 NS NS NS p = 0.035
4 31 13 22 44 212 117 36 141
(5) (39) (16) (28) (56) It 49 +- 78 + 10 * 40
4 (5) 17 (22) 16 (21) 24 (31) 38 (49) 207 f 49 104 * 51 37 k 9 136 k 40
NS p = 0.017 NS NS NS NS NS NS NS
19 (24)
P Value
CAD, Coronary artery disease; CABG, coronary artery bypass graft; myocardial infarction; HDL, high-density lipoprotein; LDL, low-density poprotein. NS, not significant at p < 0.05.
Table
II. Distribution
of coronary
vessels for PTCA
Lovastatin group (n = 120)
Control group (n = 91)
PTCA vessels n = 211
No.
(75)
No.
(%)
LAD Circumflex RCA Graft Branches
43 24 22 3 28
36 20 18 3 23
41 16 22 1 II
45 17 24 1 12
LAD,
Left anterior
descending;
MI, li-
RCA, right
coronary
artery.
of the luminal diameter. This definition has been widely acceptedl-3, 6,8, 11, 12and is clinically useful. Study design and statistical analysis. The study was designed to accept a minimum of 150 patients randomly assigned to treatment with lovastatin and/or conventional therapy, which would provide us with at least 250 vessels to be evaluated, considering that each patient would have approximately 1.5 PTCA vessels. With a 30% to 35% historical restenoses rate with conventional therapy and the independent risk of restenosis for individual PTCA vessels in the same patient, as suggested by results of earlier studies, we believed that the present study should provide a sample size large enough to produce significant differences (p = 0.05) to illustrate a 50% reduction in the restenosis rate at a 95% confidence interval. Data were collected and analyzed with PC!INFO (Retriever Data Systems, Seattle, Wash.) with differences in categoric
June 1991 Heart Journal
variables analyzed by chi-square test and continuous ables by paired or unpaired Student’s t test. RESULTS Clinical characteristics of the patient population.
vari-
The clinical characteristics of the patient population randomly assigned to the lovastatin and control groups are shown in Table I. The patient population was quite similar with respect to sex distribution, presence of three-, two-, and one-vessel disease, and history of smoking, hypertension, diabetes, and previous coronary bypass surgery. The distribution of patients with a positive family history for coronary disease and previous myocardial infarction was, however, higher in the lovastatin group than in the control group. There was no difference in the lipid profiles of the patients in the two groups. However, the patients in the control group were younger than those in the lovastatin group. Table II shows the angiographic distribution of stenotic vessels dilated in the lovastatin and control groups. Although the distribution for left anterior descending and right coronary artery stenoses was similar, a significantly higher number of circumflex arteries and branch vessels (circumflex marginals and diagonals) were dilated in the lovastatin group. Effects on serum cholesterol levels. Administration of lovastatin reduced serum cholesterol levels significantly from 212 * 49 to 175 f 41 mg/dl (p < 0.001) in the treated patients (Fig. 1). In the control group, however, there was only a mild reduction in cholesterol levels from 207 rt 49 to 196 f 48 mg/dl (p = 0.015), probably induced by dietary modifications. Follow-up angiographic results. Follow-up angiography was performed in 50 patients in the lovastatin group and 29 patients in the control group (Table III). There were 72 vessels (1.4 vessels/patient) with 80 stenotic lesions (1.6 lesions/patient) dilated in the lovastatin group. In the control group there were 34 vessels (1.1 vessels/patient) with 36 stenotic lesions (1.2 lesions/patient). Table III also shows the restenosis rates in both groups. In the lovastatin group only 6 of the 50 patients (12%) had restenosis in contrast to 13 of the 29 patients (44.8%) in the control group (p < 0.001). Similarly, vessels (12.5 % ) in the lovastatin
only
9 of the
72
group restenosed compared with 13 of the 34 vessels (38.2%) in the control group (p < 0.002). When restenosis was evaluated in terms of lesions, only 10 of the 80 (12.5% ) stenotic lesions demonstrated restenosis in contrast to 15 of the 36 (41.7%) lesions in the control group (p < 0.001). A flow diagram (Fig. 2) shows the patency and restenosis rates of the vessels included in the lovastatin and control groups.
Number
121 6. Part 1
Lovastatin
Fig.
1.
Follow-up
evaluation
of serum cholesterol
The distribution of patent and restenosed coronary vessels at follow-up angiography shown in Table IV indicates that the restenosis rate in all groups of vessels in the lovastatin group was lower when compared with the vessels in the control group. The morphology of lesions at high risk for restenosis was essentially similar in the lovastatin and control groups (Table V). Quantitative angiographic analysis. Table VI shows the severity of coronary stenosis as measured by videodensitometry before PTCA, immediately after PTCA, and at follow-up in patent and restenosed vessels. There was no significant difference in the percentage of the area of stenosis, percentage of the diameter of stenosis, and mean stenotic diameter before PTCA, immediately after PTCA, and at followup in the lovastatin or control group. The length of the stenotic segment was also similar in the two groups. However, the mean stenotic diameter at restenosed sites at follow-up was significantly higher than the mean stenotic diameter before PTCA in both groups (p < 0.05). Exercise thallium scintigraphy and exercise ECG. To obtain more complete data on restenosis rates in patients in whom coronary angiograms were not available for evaluation of restenosis, results of exercise thallium scintigraphy or exercise ECG were added to the angiographic data. Positive exercise thallium or exercise ECG findings were considered indicative of the presence of restenosis, whereas negative results of exercise thallium tests or exercise ECGs were considered indicative of absence of restenosis. In this manner restenosis could be evaluated in 75 of 79 patients in the lovastatin group and 54 of 78 patients in
Table
levels in lovastatin
Ill.
Restenosis
and control
at follow-up
Louastatin
No. of patients No. of vessels No. of lesions
on post-PTCA
group
Total No.
Restenosis No. (“G)
50 72 80
6 (12) 9 (12.5) 10 (12.5)
restenosis
1603
groups.
angiography Control group Total Rcstenosis No. No. (5;) 29 34 36
13 (44.8) 13 (38.2) 15 (41.7)
p Value p = 0.001 p = 0.002 p < 0.001
the control group. Table VII represents the restenosis rates detected by a combination of angiography and exercise test results. In the lovastatin group 69 of 75 patients (92%) were considered to have no restenosis, and only 6 of 75 (8%) were considered to have restenosis. In contrast, in the control group 39 of 54 patients (72 % ) were considered to have no restenosis and 15 of 54 (28%) were considered to have restenosis. The difference in restenosis rates between the lovastatin group and the control group was highly significant (p = 0.003). One patient in the lovastatin group and two patients in the control group with positive test results did not have restenosis at followup angiography. Follow-up clinical results. The clinical follow-up data are presented in Table VIII. Ninety percent of the patients in the lovastatin group and 88% in the control group remained asymptomatic at follow-up. Although the incidence of recurrence of symptoms, myocardial infarction, and death was similar in the two groups, the incidence of coronary bypass surgery during follow-up was higher in the control group compared with that in the lovastatin group. In the
Sahni et al.
1604
American
TOTAL
June ,991 Heart Journal
PTCA VESSELS 225
Lo”*sT*f
kTROL
132 (59%)
93 (41%) FOLLOW
72 (55%)
PATENT 63 (87.5%) Fig. 2. Flow diagram trol groups.
Table
IV.
follow-up
Distribution angiography Lovastatin
PTCA vessel
LAD Circumflex RCA Branch vessels Graft Total LAD, Left anterior NS, not significant
showing
of patent group
3I
and restenosed
vessels at
fect on the restenosis rate.“.I’ Experimental studies on restenosis carried out in animal models indicate that after balloon angioplasty platelet aggregation starts to occur immediately, is maximal within the first hour, and decreases between 4 and 48 hours.2g-;j’ Platelet fibrin mass releases mitogens that probably lead to smooth muscle cell proliferation. Platelet-derived growth factor is also responsible for smooth muscle cell proliferation. 3’ Smooth muscle cell proliferation is maximal between 48 and 96 hours, and recruitment of cells is largely completed by 3 days.:‘:’ These studies indicate that the primary mechanism initiating restenosis involves platelet aggregation and smooth muscle cell proliferation. The effect of lipid metabolism on the development of restenosis and the role interventions may play in altering lipid metabolism, however, have not been investigated. Lovastatin has been shown to alter smooth muscle cell proliferation in tissue cultures and may reduce atherogenesis by altering lipid metabolism. Our results indicate that there is a marked reduction in the incidence of restenosis in the lovastatin-treated group compared with the control group (Table III; Fig. 2). Only 6 of 50 patients (12 % ) in the lovastatin group showed restenosis compared with 13 of 29 patients (44.8%) in the control group (p < 0.001). Similarly, only 9 of 72 vessels (12.5%) in the lovastatin group restenosed compared with 13 of 34 vessels (38.2 % ) in the control group (p < 0.002). When restenosis was evaluated in terms of lesions, only 10 of 80 (12.5%) stenotic lesions exhibited restenosis in contrast with 15 of 36 (41.7%) lesions in the control group. Table IV demonstrates that the incidence of restenosis in the lovastatin group, although not statis-
3
1(11) 0
3 29
72
9 (12.5r<
descending; RCA, right at p < 0.05.
RES‘TENOSIS 13 (38%)
patency
group
Total NO. no. of restenosed vessels (rn)
)
PATENT 21 (62%)
angiographic
15 8 7
9
34 (374) 0
follow-up
6 (19) 1 (6) 1 (8)
17 12
-
RESTENOSIS 9 (12.5%)
Control
Total No. no. of restenosed vessels i%)
UP CATH 106
34
p Value
7 (47) 3 (38)
NS NS
2 (29) 1 (33)
NS NS NS
13 (38.2’1)
P = 0.002
coronary
artery.
lovastatin group eight patients had recurrence of symptoms. Two of these patients had had incomplete revascularization because of the presence of additional significant obstructive lesions in the other vessels that were not amenable to PTCA. The remaining six patients had restenosis. In contrast, of the 13 patients with recurrence of symptoms in the control group, all were judged to have complete initial revascularization and had angiographic restenosis at follow-up. DISCUSSION
Restenosis after successful PTCA remains a major challenge. The results of several clinical trials with the use of anticoagulants, calcium antagonists, corticosteroids, or mechanical interventions (i.e., prolonged balloon inflation) have failed to show any ef-
and restenosis
rates in Lovastatin
and con-
Volume 121 Number 6, Part 1
tically significant, was lower in all subgroups of vessels compared with vessels in the control group. These data provide strong evidence that lovastatin is effective in reducing the restenosis rate. Although this study was not double blinded, it is apparent (Table I) that the patients in the lovastatin and control groups had similar characteristics with regard to sex distribution, smoking, hypertension, and diabetes. Only age and history of coronary artery disease differed significantly (i.e., patients in the lovastatin group were older and had a greater tendency for positive family histories of coronary artery disease). It seems reasonable to conclude that these factors should have favored the control group. The baseline lipid profile and the severity of coronary artery disease, as assessed by the number of vessels involved, were also similar in the two groups. The pre- and post-PTCA management with aspirin and Persantine was also similar in the two groups. At the time when this study was initiated, postPTCA management with both aspirin and Persantine was a standard treatment in our laboratory and was used in both the control and lovastatin groups. Intravenous heparin was continued for 24 hours after PTCA in both groups. Although heparin may have independent effects on restenosis, this therapy was again similar in the two groups. A recent study from Emory University showed no effect of heparinization on restenosis rates for 24 hours.34 Lovastatin was administered to patients irrespective of their baseline cholesterol levels, and all patients from December 2,1987 to July 17,1988 were included irrespective of their lipid profiles. At the time of data analysis the serum cholesterol levels were slightly higher in the lovastatin group compared with the control group (Table I, Fig. l), but the difference was not statistically significant. Since restenosis rates are now shown to be related to baseline cholesterol levels and other lipoproteins,35 these data may further strengthen the effectiveness of lovastatin in reducing restenosis rates. The only angiographic difference between the two groups was reflected in a higher number of circumflex arteries and branch vessel stenoses in the lovastatin group. Since the smaller vessels, that is, branch vessels are more prone to restenosis, this factor would count in favor of lovastatin causing a reduction in restenosis. Again all other angiographic criteria of lesions that affect restenosis were similar in the two groups (Table V). In fact the number of tandem lesions, bifurcation lesions, and lesions longer than 1 cm were higher in the lovastatin group than in the control group. Videodensitometric studies for evaluation of the
Lovastatin
on post-PTCA
restenosis
1605
V. Baseline characteristics of coronary stenotic lesions among patients with follow-up angiography
Table
LOUUStUtiTl
Baseline characteristics
.imUP
n = 50 (%,I
Area of stenosis 290 “0 Total occlusion Tandem lesions Bifurcation lesions Lesion length >1 cm Calcified lesions Eccentric lesions Tubular lesions Thrombus NS. not significant
29 3 8 4 22 4 18 21 8
(58) (6) (16) (8) (44) (8) (36) (42)
(W
Control mup
n = 29 f%,) 16 1 2 1 10 2 7 11 3
(55) (3) (7) (3) (34) (7) (24) (38) (10)
p Value NS NS NS NS NS NS NS NS NS
at p < 0.05.
severity of coronary stenosis showed no difference in the pre-PTCA or post-PTCA stenotic diameter or percentage of stenosis in the lovastatin group compared with the control group in patients in whom the vessels remained patent and those in whom restenosis occurred (Table VI). The length of the stenosis was also similar in the two groups (Table VI). It was therefore not possible to explain the reduction in restenosis rate on pre- or post-PTCA angiographic findings. In both groups there was a slight improvement in the stenotic diameter at follow-up angiography compared with immediate post-PTCA results (Table VI). When restenosis occurred the stenotic diameter did not return to the pre-PTCA diameter and remained significantly higher (restenosis greater than 80% in the control group and less than 75% in the lovastatin group) than the mean diameter before PTCA (Table VI). This may explain the lack of symptoms in many patients despite the occurrence of angiographic restenosis. Since the angiographic follow-up was significantly different in the two groups, we attempted to obtain more complete data on restenosis rates by the addition of exercise thallium or exercise ECG results in the two groups. A positive thallium or exercise ECG finding was considered indicative of restenosis and a negative thallium or negative exercise ECG result was considered indicative of the absence of restenosis. This allowed more complete follow-up of 75 of the 79 patients in the lovastatin group and 54 of the 78 patients in the control group. Thus only 8% of the patients in the lovastatin group had restenosis in contrast to 28% in the control group (p = 0.003) (Table VII). These findings substantiate the pure angiographic data for restenosis. Clinical follow-up data indicate that although re-
1606
Sahni et al.
Table
VI. Severity
American
of coronary
stenosis Patent Lovastatin
% Area stenosis Pre-PTCA Post-PTCA Follow-up OUDiameter stenosis Pre-PTCA Post-PTCA Follow-up Mean stenotic diameter (mm) Pre-PTCA Post-PTCA Follow-up Stenosis length (mm) All comparisons
not significant
vessels
group
Restenosed Control
group
Control
group
89 k 6 21 + 9 82 I 8
89 -c 5 25 i 9 81 t 5
a2 t 7 16 + 8 14 + 9
79 f 14 13 It 9 12 i 9
84 k 9 20 i 9 80 t 10
86 + 4 25 i 9 79 k 6
0.5 3.5 3.6 10
t + f *
0.2 0.5 0.5 4
0.7 + 0.8 3.4 + 0.9 3.9 zi 1.6 9*3
0.5 3.4 0.9 10
-t 0.3 +- 0.3 f 0.4 I 4
0.5 3.4 0.9 11
* 0.2 _t 0.4 k 0.2 i 3
at p < 0.05.
group
(n = 75) (%o)
Table
Lovastatin
86 k 10 15 -+ 13 13 1 9
VII. Restenosis as determined by the addition of stress results to angiographic data
No restenosis Restenosis
group
vessels
86 + 7 17 + 10 15 t- 10
Table
Lovastatin
June 1991 Heart Journal
Control group (n = 54) (%)
69 (92) 6W
39 (72) 15 (28)
p Value
p = 0.003
VIII. Clinical follow-up data Follow-up
Relief of symptoms Recurrence of symptoms Myocardial infarction Deaths Cardiac Noncardiac Coronary artery bypass graft
Lovastatin group (n = 79) (%)
Control
group
(n = 78) (%)
71 (90) 8 (10) 2 (3)
69 (88) 9 (12) 1 (1)
1 (1) 2 (3) 0
3 (4) 1 (1) 5 (6)
currence of symptoms, incidence of myocardial infarction, and cardiac death were essentially similar in the two groups, the incidence of coronary bypass surgery was higher in the control group than in the lovastatin group. The explanation for this observation is not clear. It may be entirely related to the recurrence of &noses or incomplete revascularization or to the fact that symptoms were not fully recognized because of the early time period studied. The mechanisms by which lovastatin prevents restenosis may be twofold. Results of preliminary studies in a rabbit model have indicated that lovastatin being a HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitor may reduce restenosis
by decreasing serum cholesterol levels and inhibiting cell growth by blocking DNA synthesis.27 Although no direct evidence is available to indicate that lovastatin reduces smooth muscle proliferation in humans, its ability to reduce atherogenesis by favorably altering lipid metabolism has been demonstrated in experimental and epidemiologic studies.36-38 Thus the significant reduction of serum cholesterol levels that occurred in the lovastatin group maybe responsible for the decreased incidence of restenosis. None of the previous studies on restenosis except that of Dehmer et a1.12 has paid attention to inhibition of atherosclerosis, regardless of the underlying mechanism, as a contributing factor in the prevention of restenosis. In their randomized study these investigators showed that a diet supplemented with N-3 fatty acids reduced the incidence of early restenosis to 16% in the treated group versus 35% in the control group. Our results are similar and show a restenosis rate of 12.5 % in the lovastatin group versus 38.2% in the control group. The present study was limited in that complete angiographic follow-up findings were not available in all patients. However, the lovastatin-treated group of 50 patients in whom follow-up angiograms were available represents a large enough cohort of patients with a 12.5% restenosis rate observed. This rate is unquestionably the lowest when compared with that reported in many series. l-* Considering the current acceptable restenosis rate as cited in the literature (serving as a historical control value), which coincided with the higher restenosis rate in our patients comprising the control group, it is logical to conclude that lovastatin has been effective in contributing to this lower restenosis rate. These data are further
“Ol”n-m 121 Number 6, Part 1
Lovastatin
supported by inclusion of exercise test results, which allowed a more complete follow-up and still maintained a highly significant difference in the restenosis rates between the lovastatin and control groups. Another limitation of this study is that double blinding was not possible. However, compliance was confirmed by more severe reduction in serum cholesterol levels in the treated group compared with the control group. No significant side effects were noted in the treated group. Only one patient had an increased alkaline phosphatase level and was withdrawn from the study. Another patient was withdrawn from the study because he could not afford the drug. This study, however, is valuable in that it provides an appreciation of the restenosis rate in all treated and untreated patients undergoing successful coronary angioplasty. Our observations indicate that supplemental therapy with lovastatin started immediately after successful PTCA, irrespective of serum cholesterol levels, reduces the incidence of restenosis. The probable mechanism may be related to inhibition of smooth muscle cell proliferation and/or reduction in atherogenesis by altering the lipid metabolism favorably. Although in this study lovastatin was administered immediately after PTCA, pretreatment with lovastatin may be even more efficacious. We also believe that further trials with lovastatin and other HMG CoA reductase inhibitors are warranted to evaluate these findings. We thank Drs. Bindu K. Kansupada, Ranga manyam Chivukula, Mahmoud Gbusson, Mian Gold, Azam Husain, Mosen Alavi, Hass Shafia, Samuel Ruby, Roger Weiner, and Bodh N. Das following pat.ients for this study. We are grateful Carpenter, Mrs. Margaret O’Connell, and Mrs. for their help in preparation of the manuscript.
A. Rao, SubrahA. Jan, Jonathan Suketu Nanavati, for recruiting and to Mrs. Esther Brenda Pressley
REFERENCES
1. Leimgruber PP, Roubin GS, Hollman J, Cotsonis GA, Meier B, Douglas JS, King SB, Gruentzig AR. Restenosis after successful coronary angioplasty in patients with single vessel disease. Circulation 1986;73:710-17. 2. Levine S, Ewels CJ, Rosing DR, Kent KM. Coronary angioplasty: clinical and angiographic follow up. Am J Cardiol 1985;55:673-6. 3. Holmes DR, Vlietstra RE, Smith HC, Vetrovec GW, Kent KM, Cowley MJ, Faxon DP, Gruentzig AR, Kelsey SF; Detre KM. Van Raden MJ. Mock MB. Restenosis after nercutaneous transluminal coronary angioplasty (PTCA): a report from PTCA registry of the National Heart, Lung and Blood Institute. Am J Cardiol 1984;53:77C-81C. 4. Mata LA, Bosch X, David PR, Rapold HJ, Corcos T, Bourassa MG. Clinical and angiographic assessment 6 months after double vessel percutaneous coronary angioplasty. J Am Co11 Cardiol 1985;6:1239-44. 5. Jang GC, Block PC, Cowley MJ, Gruentzig AR, Dorros G, Holmes DR, Kent KM, Leatherman LL, Myler RK, Sjolander SME, Stertzer SH, Vetrovec GW, Willis WH, Williams DO.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
21. 22.
23.
on post-PTCA
restenosis
1607
Relative costs of coronary angioplasty and bypass surgery in a one-vessel disease model. Am J Cardiol 1984:53:52C-5C. White CW, Knudson M, Schmidt D, Chisholm M, Vandormael M, Morton B, Roy L, Khaja F, Reitman M, and the Triclopidine Study Group. Neither triclopidine nor aspirin-dipyridamole prevents restenosis post PTCA: results from a randomized placebo-controlled multicenter trial. Circulation 1987;76 (suppl):IV-213. Whiteworth HB, Roubin GS, Hollman J, Meier B, Leimgruber PP, Douglas JS, King SB, Gruentzig AR. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronarv anaioulastv. J Am Co11 Cardiol 1986:8:1271-6. Thornton MA, GruentzigAR, Hollman J, King SB; Douglas JS. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984;69:721-7. Schwartz L, Bourassa MG, Lesperance J, Aldridge H, David PR. Henderson M. Hudon G. Kazim F. Failure of antinlatelet agents to reduce restenosis after PTCA in a double blind placebo controlled trial. J Am Co11 Cardiol 1988;11:236A. Corcos T, David PR, Guiteras Val P, Renkin J, Dangoisse V, Rapold HG, Bourassa MG. Failure of diltiazem to prevent restenosis after percutaneous transluminal coronary angioplasty. AM HEART J 1985;109:926. Knudson ML, Duff HJ, Flintoff VF, Roth DL, Hansen JL. Does short term prostacyclin administration lower the risk of restenosis after PTCA? A prospective randomized trial [Abstract]. Circulation 1986;74:11-282. Dehmer GJ, Popma JJ, Van Den Berg EK, Eichhorn EJ, Prewitt JB, Campbell WB, Jennings L, Willerson JT, Schmitz JM. Reduction in the rate of early restenosis after coronary angioplasty hv a diet supplemented with N-3 fattv acids. N - _ Engl J Med <988;319:73%40. Milner MR. Gallino RA. Leffinewell A. Pichard AD. Robinson SB, Rosenberg J, Little’T, Lindsey Jr’J. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1989;64:294-9. Reis GJ, Sipperly ME, McCabe CH, Sacks FM, Boucher TM, Silverman DJ, Bairn DS, Grossman W, Pasternack RC. Randomized trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989;7:177-81. Essed CE, Van Den Brand M, Becker AE. Transluminal coronary angioplasty and early restenosis-fibrocellular occlusion after wall laceration. Br Heart J 1983;49:393-6. Austin GE, Ratliff NB, Hollman J, Tabei S, Phillips DF. Intimal proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal coronary angioplasty. J Am Co11 Cardiol 1985;6:36975. Waller BF, Gorfinkel HJ, Rogers FJ, Kent KM, Roberts WC. Early and late morphological changes in major epicardial coronary arteries after percutaneous transluminal coronary anaioulastv. Am J Cardiol 1984:53:42C7C. - _ Friedman RJ, Sternerman M; Wenz B, Moore S, Gauldie J, Gent M, Tie11 ML, Spaet H. The effect of thrombocytopenia on experimental arteriosclerotic lesion formation in rabbits. Smooth muscle cell proliferation and re-endothelialization. J Clin Invest 1977;66:1191-201. Schwartz SM, Reidy MR, Clowes A. Kinetics of atherosclerosis: a stem cell model. Ann NY Acad Sci 1985;454:292-304. Ross R, Glomset J, Kariya B, Harker L. A platelet dependent serum factor that stimulates the proliferation of arterial smooth muscle cells in vitro. Proc Nat1 Acad Sci USA 1974;71:1207-10. Kohler N, Lipton A. Platelets as a source of fibroblast growth promoting activity. Exp Cell Res 1974;87:297-301. Ross R, Bowen-Pope D, Raines EW. Platelets, macrophages, endothelium and growth factors: their effects upon cells and their possible roles in atherogenesis. Ann NY Acad Sci 1985;454:254-60. Moore A, Freidman RJ, Singal LDLP, Gauldie J, Blajchman
1608
24.
25.
26.
27.
28.
29.
30.
Sahni et al.
MA. Inhibition of injury induced thromboatherosclerotic lesions by anti-platelet serum in rabbit. Thromb Haemost 1975;35:70. Kramsch DM, Aspen AJ, Rozler LJ. Atherosclerosis: prevention by agents not affecting abnormal levels of blood lipids. Science 1981;213:1511-2. Faxon DP, Sanborn TA, Haudenschild CC, Ryan TJ. Effect of antiplatelet therapy on restenosis after experimental angioulastv. Am J Cardiol 1984:53:72C-6C. Nakia J, Hideki I, Oyama T, Wen-Chang C, Muroto S. Calcium dependency of aortic smooth muscle cell migration induced by 12 L-hydroxy-5,8,10,14-eicostatetraenoic acid. Atherosclerosis 1983;46:309. Gellman J, Ezekowitz MD. Lovastatin A: HMG CoA reductase inhibitor reduces restenosis following balloon angioplasty in an atherosclerotic hvoercholesterolemic rabbit. Clin Res 1989;37:261A. ”_ Silver KH, Buczek JA, Esser PD, Nichols AB. Quantitative analysis of coronary arteriograms by microprocessor cinevideodensitometry. Cathet Cardiovasc Diagn 1987;13:291-300. Wilentz JR, Sanborn TA, Haudenschild CC, Valeri CR, Ryan TJ, Faxon DP. Platelet accumulation in experimental angioplasty: time course and relation to vascular injury. Circulation 1987;75:636-42. Groves HM, Kinlough-Rathbone RL, Richardson M, Moore S, Mustard JF. Platelet interaction with damaged rabbit aorta. Lab Invest 1979;40:194-200.
American
June 1991 Heart Journal
31. Steele PM, Chesebro JM, Stanson AW, Holmes Jr DR, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiologic response to injury in a pig model. Circ Res 1985;57:105-12. 32. Ross R. The pathogenesis of atherosclerosis-an update. N Engl J Med 1986;314:488-500. 33. Clowes AW, Schwartz SM. Significance of quiescent smooth muscle migration in the injured rat carotid artery. Circ Res 1985;56:139-45. 34. Ellis SG, Roubin GS, Wilentz J, Douglas JS, King SB. Effect of 18 to 24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. A~I HEART J 1989;117:777-82. 35. Bergelson BA, Jacobs AK, Small DM, Tercyak AM, Cupples A, Garber GR, Erario M, Ruocco NA, Ryan TJ, Faxon DP. Lipoproteins predict restenosis after PTCA. Circulation 1989;80:11-65. 36. Frishman WH, Rapier RC. Lovastatin: an HMG CoA reductase inhibitor for lowering cholesterol. Med Clin North Am 1989;73:437-48. 37. Schnerider D. Lovastatin: a new cholesterol lowering agent. Clin Pharmacol 1988;7:21-36. 38. Frick MH, Elo 0, Haapa K. Helsinki Heart Study: primary prevention trial with gemfibrozil in middle-aged men with dyslipidemia. N Engl J Med 1987;317:1237-45.