Intemutrot~al Journal of Cardiology, 35 (1992) 87-93 6 lY92 Elsevier Science Publishers B.V. All rights reserved
CARD10
x7 0167.5273/91/$05.00
01418
Fish oil supplements for prevention of restenosis after coronary angioplasty U. Kaul, S. Sanghvi, V.K. Bahl, V. Dev and H.S. Wasir The Depurtmmt of Cardiology, The Cardiothoracic Cenfre. All India butitutc uf Medical Sciences. New Delhi. Imliu (Received
5 September
1091: revision
accepted
29 October
Kaul U, Sanghvi S, Bahl VK, Dev V, Wasir HS. Fish oil supplements coronary angioplasty. Int J Cardiol 1992;35:87-93.
1091)
for prevention
of restenosis after
We have evaluated the effect of fish oil supplementation in the prevention of restenosis after percutaneous transluminal coronary angioplasty by a randomised trial conducted in 107 patients. The treatment group (n = 58, 96 significant coronary narrowingsl received 10 capsules of fish oil (1.8 g eicosapentaenoic acid, 1.2 g docosahexaenoic acid) besides aspirin and calcium blockers, beginning 4.3 (SD 2.9) days before coronary angioplasty. The conventional medical treatment group (n = 49, 81 significant coronary narrowings) received only aspirin and calcium blockers. Enrollment required the presence of angina pectoris and successful dilatation of all significant coronary narrowings. All patients were followed-up for at least 6 months. Restenosis was identified by symptoms and exercise testing and confirmed by angiography. The incidence of angiographic restenosis was 32% in the fish oil group and 27% in the conventional treatment group. Biochemical investigations showed a greater decrease in serum triglyceride levels in fish oil group as compared to the conventional treatment group. There was no significant difference in the cholesterol levels over the treatment period. Administration of fish oil in a dose of 3 g per day did not reduce the incidence of early restenosis after coronary angioplasty. Key words: Coronary angioplasty; N-3 fatty acids; Restenosis
Introduction Percutaneous transluminal coronary angioplasty has emerged as a well-accepted, safe and
Correspondence 10: Dr. U. Kaul. Dept. of Cardiology, Cardiothoracic and Neurosciences Centre, All lndia Institute of Medical Sciences, New Delhi-l 10029, India.
effective treatment for selected patients with ischemic heart disease [l-4]. Despite the growth and success of angioplasty, restenosis remains a major problem and has limited its long-term benefits [4-71. A large number of pharmacologic trials have been attempted to reduce the restenosis rate but there has been no significant success [8-121. Fish oil supplements, which are rich in N-3
fatty acids, inhibit inflammatory response and platelet aggregation [13-151 and seem to have a direct antiatherosclerotic effect [16,17]. They have been shown to prevent coronary arterial obstruction after coronary catheter abrasion and to reduce the extent of vein graft intimal thickening [18]. Studies of fish oil supplementation in patients undergoing coronary angioplasty have so far provided conflicting results with three trials showing a beneficial effect [19-211 and two, a lack of benefit [22,23]. In this study we report our results of a randomized unblinded trial to determine the efficacy of fish oil supplementation to prevent restenosis. Methods Study design During the study period (February 1990 to January 1991) 107 patients undergoing coronary angioplasty in our centre were enrolled for the trial. The following category of patients were not included: those who had a history of a bleeding disorder, patients on oral anticoagulants, emergency angioplasty, recent myocardial infarction, coronary angioplasty of a saphenous vein bypass graft, angioplasty for restenosis, and inability to perform a treadmill test. Standard detailed clinical evaluation comprising history, physical examination, electrocardiogram, chest X-ray, biochemical test and lipid profile were done in each patient. Patients were randomly assigned to receive fish oil supplements along with aspirin (150 mg/ day) and a calcium channel blocker or only conventional treatment (aspirin and calcium blocker). The randomization was done by means of computer-generated list of random numbers. Those randomised to receive fish oil supplements were given 10 capsules of Maxepa (supplied by Seven Seas Health Care Limited, Hull, U.K.) which contains 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid. When possible, study medication was given 7 days before coronary angioplasty; however, periods of pretreatment as short as 1 day were permitted if clinical circumstances precluded longer pretreatment.
Angioplasty
procedure
Coronary angioplasty was performed with the standard steerable dilatation catheters via the femoral route. At the beginning of the procedure heparin was given intravenously as 10,000 units bolus with an additional 5,000 units repeated hourly during the procedure upto a maximum of 20,000 units. Subsequently heparin was administered by infusion at 1000 units/hour for 24 hours. Successful angioplasty was defined as an increase in the degree of coronary artery diameter by > 20% with the ultimate result being < 50% lumen diameter and absence of myocardial infarction, death or coronary artery bypass graft surgery during the initial hospitalization. Patients in whom angioplasty was not attempted or was unsuccessful became ineligible for further participation in the protocol. Follow-up Patients were given a 6-week supply of study medication at hospital discharge. Follow-up was done at 2 weeks, 6 weeks, 3 months and 6 months after angioplasty. Compliance was assessed by patient’s report of the number of bottles remaining. Supply of the medication was replenished at 6-week intervals. During the follow-up all the reported symptoms were evaluated in the coronary clinic. Lipid profile was also repeated. Exercise tests were performed within 2 weeks of angioplasty and then repeated at 6 months after angioplasty or earlier if the patients became symptomatic. Stress tests were performed with thallium scintigraphy if clinically indicated. Positive stress test was defined as the presence of 1 mm or more of horizontal or downsloping ST segment depression 80 msec after J point and/or a reversible rhallium defect, not present in the early post-angioplasty study. Symptom-free patients with negative exercise tests were classified as not having restenosis. All patients with angina1 symptoms and/or positive exercise tests were advised to undergo repeat coronary angiography. All exercise tests and cineangiograms were analysed by investigators blinded to treatment group assignment.
XY
Restenosis
Restenosis was defined as loss of 50% of the gain in luminal diameter at angioplasty [24]. Patients with recurrence of stenosis in only one of the two segments of vessel dilated were also classified under restenosis. Each stenosis was visually assessed by the angiographers and was examined in at least two orthogonal planes. Progression of disease was defined as the presence of a new luminal narrowing > 70% in the non-dilated vessel. For patients refusing coronary angiography, restenosis was defined as the presence of a positive exercise test, new since the early postangioplasty study, with or without angina1 symptoms. Patients were not considered to have restenosis on the basis of symptoms alone. Statistical
TABLE
1
Baseline
clinical
Age (years) Male Smoking Unstahle angina Diluted ~xmris LAD CIRC RCA Multivessel No. of lesions dilated/pt.
and angiographic
characteristics.
Fish oil (rz=58)
Conventional treatment 01 = 40)
5h+_ 11 50 (86%) 1x (31%) 31 (36% )
5’)+9 * 41(X4%) 17 (35?)
*
IY (33%) 14 (24%‘) 16 (27%) Y(l6%)
17 (35%) X(16%) 17 (35%;;) 7 (14%)
* * * *
1.38fO.61
* 1s(31%) *
I .?Y * 0.43 *
II = number of patients; LAD = left anterior CIRC = left circumflex; RCA = right coronary patient; * P = not significant.
descending; artery; pt =
analysis
Standard f-test and contingency table analysis were performed for univariate comparison of difference. Multivariate analysis was carried out by linear modelling, assuming normal errors using the standard statistical package GLIM. Results were not termed as significant if the nominal P value was > 0.05. Results
The patients randomised to fish oil group were comparable to those randomised to control group. Fish oil treatment was started 4.3 (SD 2.9) days before angioplasty in the treatment group. The data on selected clinical and angiographic variables is shown in Table 1. The only noteworthy baseline angiographic difference was a higher number of dilatations of circumflex artery in the control group than in the active treatment group. The mean residual coronary artery stenosis after angioplasty was 27% (SD 7%) in the fish oil group and 31% (SD 8%) in the conventional treatment group. The fish oil capsules were found to be palatable and acceptable. Only 2 patients stopped taking the capsules because of gastrointestinal intolerance. Bleeding times were not
measured; however, no patient suffered bleeding complications during follow-up. Follow-up
and clinical
from
results
One patient on fish oil with initially successful angioplasty underwent coronary artery bypass surgery on 16th day due to delayed closure resulting in a ST-T myocardial infarction. All patients had angina pectoris before angioplasty and at follow-up 36 (34%) of the 107 patients had recurrence of chest pain including 6 patients who had NYHA class IV angina pectoris. Restenosis
Restenosis documented by repeat coronary angiography was seen in 19 (33%) of 58 patients on fish oil and 13 (27%) of 49 patients on conventional treatment (Table 2). If we add the 4 patients who refused angiography the overall restenosis rate was 38% for fish oil group and 29%~ for conventional treatment group (difference not significant). Restenosis rates were not influenced significantly by age, sex or previous unstable angina. Among men, the restenosis rate was 36% in the
90 TABLE Restenosis
2 and other
clinical
Angiographic restenosis Clinical restenosis Progression of disease at other site Repeat angioplasty Late CABG AMI Major clinical events (total)
events. Fish oil (n = 5X)
Conventional treatment (n = 49)
19 (33%) 22 (38%)
13 (27%) * 14 (39%) *
4 (7%)
3 (6%) *
16 (28%‘) 2 (3%) 4 (7%)
IO (2O%‘F)* 7 (4%) * 2 (4%) *
25 (43%)
1x (37%) *
/t = number of patients; CABG = coronary artery bypass grafting; AMI = acute myocardial infarction; * P = not significant.
fish oil group compared to 28% in conventional treatment group. The corresponding rates among women were 32% and 18% (not significant). The length of pretreatment with fish oil seemed to have no influence on restenosis (Fig. 1). lb ‘RESTENOSIS 50 Y-mm
Repeat angiography was performed in 38 (36%) patients. Of these, 27 had restenosis, 5 had both restenosis and progression, 2 had progression of disease at other sites without evidence of restenosis and 4 had no significant lesion. Among the 69 patients without follow-up angiograms 4 had recurrence of angina and a newly positive exercise test and were classified as clinical restenosis, 1 had anteroseptal infarction 4 months after angioplasty of right coronary artery and was classified as progression. The remaining 64 were classified as having neither restenosis nor progression. All of them had undergone exercise testing which was negative in 60 (94%) patients, and positive but unchanged from the early post angioplasty exercise test in the remaining 4 patients. In all these 4 patients there was improvement in post-angioplasty stress test as compared to the preangioplasty test. Lipid and lipoprotein
effects
There was a significant fall in triglyceride levels in the fish oil group as compared to the
-.
-__---
45 tm 40 31
35, : 25 30 20 I 15 t 10; 5 0I
_
1 DAY
1~32 Fig.
@@ 2-3
DAYS
w14
I. Effect of length of pretreatment
on restenosis
1-2
4-7 DAYS n-12
in the fish oil group.
TABLE
3
Lipid and lipoprotein
levels in control
and treated patients. Triglycerides
Total cholesterol (mg/dl)
Lipoproteins HDL
LDL
VLDL
?‘I * 37.0 215- +40.2 ** ~
38 * 10.1 37 rf- IO.5 * *
1% f 2x.2 I31 f 30.1 **
37 * 17.x 3.5 * 15.8 **
707 & I IO.5 21.5 i_ 113.x *:I-
Treured purwrlt.~ 218 * 32.6 Baseline 2’4 * 39.x * * 6 Month5
XI+ II.? 37 + 10.5 **
IL5 * x.7 1x+31.7
34 + 16.2 71 + IS.4 *
711 f 115.x Ihl f 95.5 *
Controb Baseline 6 Months
(mg/dl)
**
* P < ().I)1 (as compared 10 baseline levels); * * P = not significant (as compared LDL = low density lipoprotein: VLDL = very low density lipoprotein.
(Table 3). There was no significant change in the total cholesterol, high density and low density lipoprotein levels in both the groups. The very low density lipoprotein levels, however, showed a significant reduction in the treatment group. conventional
treatment
group
Discussion Restenosis after successful coronary angioplasty remains a major problem and limits the long-term benefits of the procedure [4-71. Although the primary success rate of balloon angioplasty has improved [l-4], restenosis rate does not seem to be declining despite the trial of a number of therapeutic agents [8-121. The mechanism of restenosis is possibly multifactorial [7,25]. Balloon angioplasty produces a localized injury to the arterial wall leading to plaque splitting, stretching of the arterial wall, plaque compression and endothelial denudation. This leads to immediate platelet aggregation and thrombus formation, and subsequent neointimal proliferation of smooth muscle cells [26,27]. Recent studies using coronary atherectomy devices have shown a densely cellular component of material removed from restenosis lesions supporting the response to injury hypothesis whereby platelet aggregation leads to production of growth factors and incites smooth muscle cell proliferation [28]. Fish oils, which are rich sources of N-3 fatty acids, are potent inhibitors of platelet function and have been reported to inhibit formation of
11) baseline
(mg/dl)
level); HDL high density
lipoprotein;
atherosclerotic lesions in coronary arteries of experimental animals [16,17]. N-3 fatty acids have also been reported to decrease intimal proliferation in the canine vein graft model [18]. In view of the favourable effects of fish oils by causing changes in plasma lipids and lipoprotein concentration, and by altering prostaglandin and leukotrine metabolism resulting in decreased platelet aggregation, it has been believed that dietary supplementation with N-3 fatty acids could significantly reduce the incidence of restenosis [19]. The literature, however, has conflicting reports on this subject. To our knowledge, 5 studies have examined the effect of fish oil on restenosis rates after coronary angioplasty [ 1%231. Three of these studies [19-211, in contrast to our results, have reported beneficial effects in the groups treated with fish oil. In one of these studies angiography has been taken as the end-point, while the other two studies have undertaken a stepwise evaluation with angiography being done only in patients with a positive stress test, as done in the present study. The length of pretreatment has also been variable in these studies. Dehmer et al. [19] administered fish oils for at least 7 days before the procedure, while the other 2 studies administered it for only 24-72 hours before angioplasty. The effects of fish oil on platelet function are slow in onset, since N-3 fatty acids are gradually incorporated into platelet membranes. Previous studies have demonstrated that 6 g/day of N-3 fatty acids administered for 6 days results in measurable effects on plasma and platelet
92
membrane phospholipids with corresponding inhibition of platelet aggregation [29]. In our study there was no trend towards decreased restenosis with longer pretreatment periods. Reis et al. [23] have also reported similar results. The results of the present study are in agreement with the observations of Grigg et al. [22] and Reis et al. [23]. The type and dose of fish oil used by us was the same as in a previous study [22]. Milner et al. [20] reported a beneficial effect after the use of Promega, which has a higher percentage of N-3 fatty acids than Maxepa (50% vs 30%). Reis et al., however, using Promega and Super EPA in a similar dose reported no benefits [23]. It is noteworthy that at least one study has reported a trend suggesting higher incidence of coronary events in patients on fish oil following angioplasty [23]. This is an alarming finding and suggests that use of fish oils in post-angioplasty patients, pending further results from multicentre studies, should not be encouraged.
5
6
7
8
9
10
II
Study limitations Complete angiographic follow-up is always desirable in studies addressing the problem of restenosis to detect symptom-free restenosis. This is a limitation in our study but complete angiographic follow-up could only increase this rate. Of the reported studies on this subject, angiography has not been the end-point in three studies [20,21,23]. References
12
13
14
15
1 Kent KM, Bentivoglio
LG, Block PC et al. Long-term efficacy of percutaneous transluminal coronary angioplasty (PTCA); report from the registry of the National Heart, Lung, and Blood Institute PTCA Registry. Am J Cardiol 1984;53:27C-32C. 2 Gruentzig AR, King SB, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty, the early Zurich experience. N Engl J Med 1987;316:1127-1132. 3 Detre K, Holubkov R, Kelsey S et al. Percutaneous transluminal coronary angioplasty in 1985-1986 and 1977-1981. N Engl J Med 1988.318:265-270. 4 Ernst SM. Vander Feltz TA. Bal ET et al. Long-term
16
I7
18
19
angiographic follow-up, cardiac events and survival in patients undergoing percutaneous transluminal coronary angioplasty. Br Heart J 1987;57:220-225. Holmes DR, Vlietstra RE, Smith HC et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53 tsupp0:77C-81C. Levine S. Ewels CJ. Rosing DR, Kent KM. Coronary angioplasty: clinical and angiographic follow-up. Am J Cardiol 1985;55:673-676. McBride W, Lange RA, Hillis LD. Restenosis after successful angioplasty. pathophysiology and prevention. N Engl J Med 1988;318:1734-1737. Thornton MA, Gruentzig AR, Hollman J, King SB 111. Douglas JS. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984,69:721-727. Whitworth HR. Roubin GS, Hollman J et al. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1986;8: I27 I- 1276. Pepine CJ, Hirshfeld JW. Macdonald RG et al. A controlled trial of corticosteroids to prevent restenosis following coronary angioplasty (abstract). Circulation 198878 (suppl II) 291. Schwartz L. Bourassa MG, Lesperand J et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988;318,1714-1719. Ellis SG, Roubin GS, Wlilentz Jr, Douglas JS. King SB. Effect of 18 to 24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. Am Heart J 1989,117:777-782. Goodnight SH Jr, Harris WS, Connon WE. The effects of dietary omega-3 fatty acids on platelet composition and function in man a prospective, controlled trial. Blood 1981;58:880-885. Von Schacky C, Fisher S. Weber PC. Long-term effects of dietary omega-3 fatty acids upon plasma and cellular lipids, platelet function. and eicosanoid formation in man. J Clin Invest 1985;76:1626-1631. Thorngren M, Gustafson A. Effects of 11 week increases in dietary eicosapentaenoic acid on bleeding time, lipids and platelet aggregation. Lancet: 1981;2:1190-1193. Bo-qing Z, Smith DC, Sievers RE, Isenberg WM. Parmley WW. Inhibition of atherosclerosis by fish oil in cholesterol fed rabbits. J Am Coll Cardiol 1988;12:1073-1078, Weiner BH. Ockene IS, Levine PH et al. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model. N Engl J Med 1986,315:841-846. Landymore RW. Kinley CE, Cooper JH, Mac Aulay M, Sheridan B, Cameron C. Cod-liver oil in the prevention of intimal hyperplasia in autogenous vein grafts used for arterial bypass. J Thorac Cardiovasc Surg 1985:89:351-357. Dehmer GJ. Popma JJ, Van den Berg EK et al. Reduction in the rate of early restenosis after coronary angioplasty by
Y3
20
21
22
23
24
a diet supplemented with n-3 fatty acids. N Engl J Med 1988;319:733-740. Mimer MR. Gallino RA. Leffingwell A et al. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1989;64:294-299. Slack JD, Pinkerton CA, Van Tassel J et al. Can oral fish oil supplement minimize restenosis after percutaneous transluminal coronary angioplasty (abstract)? J Am Coil Cardiol 1987;9:64 A. Grigg LE. Kay TWH. Valentine PA et al. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coll Cardiol 1989:13:665-672. Reis G. Sipperly ME, McCabe CH et al. Randomised trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989;2:177- 181. Kaul U. Rao YV. Dev V, Manchanda SC, Sharma S. Rajani M. Restenosis after successful coronary angioplasty in single vessel disease. Ind Heart J 1991;43:11-15.
25 Fanelli 26
27
28
29
C. and,Aronoff
R. Restenosis
following
coronary
angioplasty. Am Heart J 1990;357-368. Steele PM, Chesebra JH. Stanson AW et al. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circulation Res 1985;57:105-112. Austin GE. Raltliff NB. Hallman J. Tabei S, Phillips DF. Interval proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal angioplasty. J Am Coil Cardiol 1985;6:369-373. Johnson DE, Robertson G, Simpson JB. Coronary atherectomy: light microscopic and immunohistochemical study of excised tissues (abstract). Circulation 198X:78:1182. Von Schacky C. Weber PC. Metabolism and effects on platelet function of the purified eicosapentaenoic and docosahexaenoic acid in humans. J Clin Invest 19X5:76: 244662450.
CARD10
x7 0167.5273/91/$05.00
01418
Fish oil supplements for prevention of restenosis after coronary angioplasty U. Kaul, S. Sanghvi, V.K. Bahl, V. Dev and H.S. Wasir The Depurtmmt of Cardiology, The Cardiothoracic Cenfre. All India butitutc uf Medical Sciences. New Delhi. Imliu (Received
5 September
1091: revision
accepted
29 October
Kaul U, Sanghvi S, Bahl VK, Dev V, Wasir HS. Fish oil supplements coronary angioplasty. Int J Cardiol 1992;35:87-93.
1091)
for prevention
of restenosis after
We have evaluated the effect of fish oil supplementation in the prevention of restenosis after percutaneous transluminal coronary angioplasty by a randomised trial conducted in 107 patients. The treatment group (n = 58, 96 significant coronary narrowingsl received 10 capsules of fish oil (1.8 g eicosapentaenoic acid, 1.2 g docosahexaenoic acid) besides aspirin and calcium blockers, beginning 4.3 (SD 2.9) days before coronary angioplasty. The conventional medical treatment group (n = 49, 81 significant coronary narrowings) received only aspirin and calcium blockers. Enrollment required the presence of angina pectoris and successful dilatation of all significant coronary narrowings. All patients were followed-up for at least 6 months. Restenosis was identified by symptoms and exercise testing and confirmed by angiography. The incidence of angiographic restenosis was 32% in the fish oil group and 27% in the conventional treatment group. Biochemical investigations showed a greater decrease in serum triglyceride levels in fish oil group as compared to the conventional treatment group. There was no significant difference in the cholesterol levels over the treatment period. Administration of fish oil in a dose of 3 g per day did not reduce the incidence of early restenosis after coronary angioplasty. Key words: Coronary angioplasty; N-3 fatty acids; Restenosis
Introduction Percutaneous transluminal coronary angioplasty has emerged as a well-accepted, safe and
Correspondence 10: Dr. U. Kaul. Dept. of Cardiology, Cardiothoracic and Neurosciences Centre, All lndia Institute of Medical Sciences, New Delhi-l 10029, India.
effective treatment for selected patients with ischemic heart disease [l-4]. Despite the growth and success of angioplasty, restenosis remains a major problem and has limited its long-term benefits [4-71. A large number of pharmacologic trials have been attempted to reduce the restenosis rate but there has been no significant success [8-121. Fish oil supplements, which are rich in N-3
fatty acids, inhibit inflammatory response and platelet aggregation [13-151 and seem to have a direct antiatherosclerotic effect [16,17]. They have been shown to prevent coronary arterial obstruction after coronary catheter abrasion and to reduce the extent of vein graft intimal thickening [18]. Studies of fish oil supplementation in patients undergoing coronary angioplasty have so far provided conflicting results with three trials showing a beneficial effect [19-211 and two, a lack of benefit [22,23]. In this study we report our results of a randomized unblinded trial to determine the efficacy of fish oil supplementation to prevent restenosis. Methods Study design During the study period (February 1990 to January 1991) 107 patients undergoing coronary angioplasty in our centre were enrolled for the trial. The following category of patients were not included: those who had a history of a bleeding disorder, patients on oral anticoagulants, emergency angioplasty, recent myocardial infarction, coronary angioplasty of a saphenous vein bypass graft, angioplasty for restenosis, and inability to perform a treadmill test. Standard detailed clinical evaluation comprising history, physical examination, electrocardiogram, chest X-ray, biochemical test and lipid profile were done in each patient. Patients were randomly assigned to receive fish oil supplements along with aspirin (150 mg/ day) and a calcium channel blocker or only conventional treatment (aspirin and calcium blocker). The randomization was done by means of computer-generated list of random numbers. Those randomised to receive fish oil supplements were given 10 capsules of Maxepa (supplied by Seven Seas Health Care Limited, Hull, U.K.) which contains 1.8 g of eicosapentaenoic acid and 1.2 g of docosahexaenoic acid. When possible, study medication was given 7 days before coronary angioplasty; however, periods of pretreatment as short as 1 day were permitted if clinical circumstances precluded longer pretreatment.
Angioplasty
procedure
Coronary angioplasty was performed with the standard steerable dilatation catheters via the femoral route. At the beginning of the procedure heparin was given intravenously as 10,000 units bolus with an additional 5,000 units repeated hourly during the procedure upto a maximum of 20,000 units. Subsequently heparin was administered by infusion at 1000 units/hour for 24 hours. Successful angioplasty was defined as an increase in the degree of coronary artery diameter by > 20% with the ultimate result being < 50% lumen diameter and absence of myocardial infarction, death or coronary artery bypass graft surgery during the initial hospitalization. Patients in whom angioplasty was not attempted or was unsuccessful became ineligible for further participation in the protocol. Follow-up Patients were given a 6-week supply of study medication at hospital discharge. Follow-up was done at 2 weeks, 6 weeks, 3 months and 6 months after angioplasty. Compliance was assessed by patient’s report of the number of bottles remaining. Supply of the medication was replenished at 6-week intervals. During the follow-up all the reported symptoms were evaluated in the coronary clinic. Lipid profile was also repeated. Exercise tests were performed within 2 weeks of angioplasty and then repeated at 6 months after angioplasty or earlier if the patients became symptomatic. Stress tests were performed with thallium scintigraphy if clinically indicated. Positive stress test was defined as the presence of 1 mm or more of horizontal or downsloping ST segment depression 80 msec after J point and/or a reversible rhallium defect, not present in the early post-angioplasty study. Symptom-free patients with negative exercise tests were classified as not having restenosis. All patients with angina1 symptoms and/or positive exercise tests were advised to undergo repeat coronary angiography. All exercise tests and cineangiograms were analysed by investigators blinded to treatment group assignment.
XY
Restenosis
Restenosis was defined as loss of 50% of the gain in luminal diameter at angioplasty [24]. Patients with recurrence of stenosis in only one of the two segments of vessel dilated were also classified under restenosis. Each stenosis was visually assessed by the angiographers and was examined in at least two orthogonal planes. Progression of disease was defined as the presence of a new luminal narrowing > 70% in the non-dilated vessel. For patients refusing coronary angiography, restenosis was defined as the presence of a positive exercise test, new since the early postangioplasty study, with or without angina1 symptoms. Patients were not considered to have restenosis on the basis of symptoms alone. Statistical
TABLE
1
Baseline
clinical
Age (years) Male Smoking Unstahle angina Diluted ~xmris LAD CIRC RCA Multivessel No. of lesions dilated/pt.
and angiographic
characteristics.
Fish oil (rz=58)
Conventional treatment 01 = 40)
5h+_ 11 50 (86%) 1x (31%) 31 (36% )
5’)+9 * 41(X4%) 17 (35?)
*
IY (33%) 14 (24%‘) 16 (27%) Y(l6%)
17 (35%) X(16%) 17 (35%;;) 7 (14%)
* * * *
1.38fO.61
* 1s(31%) *
I .?Y * 0.43 *
II = number of patients; LAD = left anterior CIRC = left circumflex; RCA = right coronary patient; * P = not significant.
descending; artery; pt =
analysis
Standard f-test and contingency table analysis were performed for univariate comparison of difference. Multivariate analysis was carried out by linear modelling, assuming normal errors using the standard statistical package GLIM. Results were not termed as significant if the nominal P value was > 0.05. Results
The patients randomised to fish oil group were comparable to those randomised to control group. Fish oil treatment was started 4.3 (SD 2.9) days before angioplasty in the treatment group. The data on selected clinical and angiographic variables is shown in Table 1. The only noteworthy baseline angiographic difference was a higher number of dilatations of circumflex artery in the control group than in the active treatment group. The mean residual coronary artery stenosis after angioplasty was 27% (SD 7%) in the fish oil group and 31% (SD 8%) in the conventional treatment group. The fish oil capsules were found to be palatable and acceptable. Only 2 patients stopped taking the capsules because of gastrointestinal intolerance. Bleeding times were not
measured; however, no patient suffered bleeding complications during follow-up. Follow-up
and clinical
from
results
One patient on fish oil with initially successful angioplasty underwent coronary artery bypass surgery on 16th day due to delayed closure resulting in a ST-T myocardial infarction. All patients had angina pectoris before angioplasty and at follow-up 36 (34%) of the 107 patients had recurrence of chest pain including 6 patients who had NYHA class IV angina pectoris. Restenosis
Restenosis documented by repeat coronary angiography was seen in 19 (33%) of 58 patients on fish oil and 13 (27%) of 49 patients on conventional treatment (Table 2). If we add the 4 patients who refused angiography the overall restenosis rate was 38% for fish oil group and 29%~ for conventional treatment group (difference not significant). Restenosis rates were not influenced significantly by age, sex or previous unstable angina. Among men, the restenosis rate was 36% in the
90 TABLE Restenosis
2 and other
clinical
Angiographic restenosis Clinical restenosis Progression of disease at other site Repeat angioplasty Late CABG AMI Major clinical events (total)
events. Fish oil (n = 5X)
Conventional treatment (n = 49)
19 (33%) 22 (38%)
13 (27%) * 14 (39%) *
4 (7%)
3 (6%) *
16 (28%‘) 2 (3%) 4 (7%)
IO (2O%‘F)* 7 (4%) * 2 (4%) *
25 (43%)
1x (37%) *
/t = number of patients; CABG = coronary artery bypass grafting; AMI = acute myocardial infarction; * P = not significant.
fish oil group compared to 28% in conventional treatment group. The corresponding rates among women were 32% and 18% (not significant). The length of pretreatment with fish oil seemed to have no influence on restenosis (Fig. 1). lb ‘RESTENOSIS 50 Y-mm
Repeat angiography was performed in 38 (36%) patients. Of these, 27 had restenosis, 5 had both restenosis and progression, 2 had progression of disease at other sites without evidence of restenosis and 4 had no significant lesion. Among the 69 patients without follow-up angiograms 4 had recurrence of angina and a newly positive exercise test and were classified as clinical restenosis, 1 had anteroseptal infarction 4 months after angioplasty of right coronary artery and was classified as progression. The remaining 64 were classified as having neither restenosis nor progression. All of them had undergone exercise testing which was negative in 60 (94%) patients, and positive but unchanged from the early post angioplasty exercise test in the remaining 4 patients. In all these 4 patients there was improvement in post-angioplasty stress test as compared to the preangioplasty test. Lipid and lipoprotein
effects
There was a significant fall in triglyceride levels in the fish oil group as compared to the
-.
-__---
45 tm 40 31
35, : 25 30 20 I 15 t 10; 5 0I
_
1 DAY
1~32 Fig.
@@ 2-3
DAYS
w14
I. Effect of length of pretreatment
on restenosis
1-2
4-7 DAYS n-12
in the fish oil group.
TABLE
3
Lipid and lipoprotein
levels in control
and treated patients. Triglycerides
Total cholesterol (mg/dl)
Lipoproteins HDL
LDL
VLDL
?‘I * 37.0 215- +40.2 ** ~
38 * 10.1 37 rf- IO.5 * *
1% f 2x.2 I31 f 30.1 **
37 * 17.x 3.5 * 15.8 **
707 & I IO.5 21.5 i_ 113.x *:I-
Treured purwrlt.~ 218 * 32.6 Baseline 2’4 * 39.x * * 6 Month5
XI+ II.? 37 + 10.5 **
IL5 * x.7 1x+31.7
34 + 16.2 71 + IS.4 *
711 f 115.x Ihl f 95.5 *
Controb Baseline 6 Months
(mg/dl)
**
* P < ().I)1 (as compared 10 baseline levels); * * P = not significant (as compared LDL = low density lipoprotein: VLDL = very low density lipoprotein.
(Table 3). There was no significant change in the total cholesterol, high density and low density lipoprotein levels in both the groups. The very low density lipoprotein levels, however, showed a significant reduction in the treatment group. conventional
treatment
group
Discussion Restenosis after successful coronary angioplasty remains a major problem and limits the long-term benefits of the procedure [4-71. Although the primary success rate of balloon angioplasty has improved [l-4], restenosis rate does not seem to be declining despite the trial of a number of therapeutic agents [8-121. The mechanism of restenosis is possibly multifactorial [7,25]. Balloon angioplasty produces a localized injury to the arterial wall leading to plaque splitting, stretching of the arterial wall, plaque compression and endothelial denudation. This leads to immediate platelet aggregation and thrombus formation, and subsequent neointimal proliferation of smooth muscle cells [26,27]. Recent studies using coronary atherectomy devices have shown a densely cellular component of material removed from restenosis lesions supporting the response to injury hypothesis whereby platelet aggregation leads to production of growth factors and incites smooth muscle cell proliferation [28]. Fish oils, which are rich sources of N-3 fatty acids, are potent inhibitors of platelet function and have been reported to inhibit formation of
11) baseline
(mg/dl)
level); HDL high density
lipoprotein;
atherosclerotic lesions in coronary arteries of experimental animals [16,17]. N-3 fatty acids have also been reported to decrease intimal proliferation in the canine vein graft model [18]. In view of the favourable effects of fish oils by causing changes in plasma lipids and lipoprotein concentration, and by altering prostaglandin and leukotrine metabolism resulting in decreased platelet aggregation, it has been believed that dietary supplementation with N-3 fatty acids could significantly reduce the incidence of restenosis [19]. The literature, however, has conflicting reports on this subject. To our knowledge, 5 studies have examined the effect of fish oil on restenosis rates after coronary angioplasty [ 1%231. Three of these studies [19-211, in contrast to our results, have reported beneficial effects in the groups treated with fish oil. In one of these studies angiography has been taken as the end-point, while the other two studies have undertaken a stepwise evaluation with angiography being done only in patients with a positive stress test, as done in the present study. The length of pretreatment has also been variable in these studies. Dehmer et al. [19] administered fish oils for at least 7 days before the procedure, while the other 2 studies administered it for only 24-72 hours before angioplasty. The effects of fish oil on platelet function are slow in onset, since N-3 fatty acids are gradually incorporated into platelet membranes. Previous studies have demonstrated that 6 g/day of N-3 fatty acids administered for 6 days results in measurable effects on plasma and platelet
92
membrane phospholipids with corresponding inhibition of platelet aggregation [29]. In our study there was no trend towards decreased restenosis with longer pretreatment periods. Reis et al. [23] have also reported similar results. The results of the present study are in agreement with the observations of Grigg et al. [22] and Reis et al. [23]. The type and dose of fish oil used by us was the same as in a previous study [22]. Milner et al. [20] reported a beneficial effect after the use of Promega, which has a higher percentage of N-3 fatty acids than Maxepa (50% vs 30%). Reis et al., however, using Promega and Super EPA in a similar dose reported no benefits [23]. It is noteworthy that at least one study has reported a trend suggesting higher incidence of coronary events in patients on fish oil following angioplasty [23]. This is an alarming finding and suggests that use of fish oils in post-angioplasty patients, pending further results from multicentre studies, should not be encouraged.
5
6
7
8
9
10
II
Study limitations Complete angiographic follow-up is always desirable in studies addressing the problem of restenosis to detect symptom-free restenosis. This is a limitation in our study but complete angiographic follow-up could only increase this rate. Of the reported studies on this subject, angiography has not been the end-point in three studies [20,21,23]. References
12
13
14
15
1 Kent KM, Bentivoglio
LG, Block PC et al. Long-term efficacy of percutaneous transluminal coronary angioplasty (PTCA); report from the registry of the National Heart, Lung, and Blood Institute PTCA Registry. Am J Cardiol 1984;53:27C-32C. 2 Gruentzig AR, King SB, Schlumpf M, Siegenthaler W. Long-term follow-up after percutaneous transluminal coronary angioplasty, the early Zurich experience. N Engl J Med 1987;316:1127-1132. 3 Detre K, Holubkov R, Kelsey S et al. Percutaneous transluminal coronary angioplasty in 1985-1986 and 1977-1981. N Engl J Med 1988.318:265-270. 4 Ernst SM. Vander Feltz TA. Bal ET et al. Long-term
16
I7
18
19
angiographic follow-up, cardiac events and survival in patients undergoing percutaneous transluminal coronary angioplasty. Br Heart J 1987;57:220-225. Holmes DR, Vlietstra RE, Smith HC et al. Restenosis after percutaneous transluminal coronary angioplasty (PTCA): a report from PTCA registry of the National Heart, Lung, and Blood Institute. Am J Cardiol 1984;53 tsupp0:77C-81C. Levine S. Ewels CJ. Rosing DR, Kent KM. Coronary angioplasty: clinical and angiographic follow-up. Am J Cardiol 1985;55:673-676. McBride W, Lange RA, Hillis LD. Restenosis after successful angioplasty. pathophysiology and prevention. N Engl J Med 1988;318:1734-1737. Thornton MA, Gruentzig AR, Hollman J, King SB 111. Douglas JS. Coumadin and aspirin in prevention of recurrence after transluminal coronary angioplasty: a randomized study. Circulation 1984,69:721-727. Whitworth HR. Roubin GS, Hollman J et al. Effect of nifedipine on recurrent stenosis after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1986;8: I27 I- 1276. Pepine CJ, Hirshfeld JW. Macdonald RG et al. A controlled trial of corticosteroids to prevent restenosis following coronary angioplasty (abstract). Circulation 198878 (suppl II) 291. Schwartz L. Bourassa MG, Lesperand J et al. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988;318,1714-1719. Ellis SG, Roubin GS, Wlilentz Jr, Douglas JS. King SB. Effect of 18 to 24 hour heparin administration for prevention of restenosis after uncomplicated coronary angioplasty. Am Heart J 1989,117:777-782. Goodnight SH Jr, Harris WS, Connon WE. The effects of dietary omega-3 fatty acids on platelet composition and function in man a prospective, controlled trial. Blood 1981;58:880-885. Von Schacky C, Fisher S. Weber PC. Long-term effects of dietary omega-3 fatty acids upon plasma and cellular lipids, platelet function. and eicosanoid formation in man. J Clin Invest 1985;76:1626-1631. Thorngren M, Gustafson A. Effects of 11 week increases in dietary eicosapentaenoic acid on bleeding time, lipids and platelet aggregation. Lancet: 1981;2:1190-1193. Bo-qing Z, Smith DC, Sievers RE, Isenberg WM. Parmley WW. Inhibition of atherosclerosis by fish oil in cholesterol fed rabbits. J Am Coll Cardiol 1988;12:1073-1078, Weiner BH. Ockene IS, Levine PH et al. Inhibition of atherosclerosis by cod-liver oil in a hyperlipidemic swine model. N Engl J Med 1986,315:841-846. Landymore RW. Kinley CE, Cooper JH, Mac Aulay M, Sheridan B, Cameron C. Cod-liver oil in the prevention of intimal hyperplasia in autogenous vein grafts used for arterial bypass. J Thorac Cardiovasc Surg 1985:89:351-357. Dehmer GJ. Popma JJ, Van den Berg EK et al. Reduction in the rate of early restenosis after coronary angioplasty by
Y3
20
21
22
23
24
a diet supplemented with n-3 fatty acids. N Engl J Med 1988;319:733-740. Mimer MR. Gallino RA. Leffingwell A et al. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1989;64:294-299. Slack JD, Pinkerton CA, Van Tassel J et al. Can oral fish oil supplement minimize restenosis after percutaneous transluminal coronary angioplasty (abstract)? J Am Coil Cardiol 1987;9:64 A. Grigg LE. Kay TWH. Valentine PA et al. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaenoic acid on the incidence of coronary artery restenosis after angioplasty. J Am Coll Cardiol 1989:13:665-672. Reis G. Sipperly ME, McCabe CH et al. Randomised trial of fish oil for prevention of restenosis after coronary angioplasty. Lancet 1989;2:177- 181. Kaul U. Rao YV. Dev V, Manchanda SC, Sharma S. Rajani M. Restenosis after successful coronary angioplasty in single vessel disease. Ind Heart J 1991;43:11-15.
25 Fanelli 26
27
28
29
C. and,Aronoff
R. Restenosis
following
coronary
angioplasty. Am Heart J 1990;357-368. Steele PM, Chesebra JH. Stanson AW et al. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circulation Res 1985;57:105-112. Austin GE. Raltliff NB. Hallman J. Tabei S, Phillips DF. Interval proliferation of smooth muscle cells as an explanation for recurrent coronary artery stenosis after percutaneous transluminal angioplasty. J Am Coil Cardiol 1985;6:369-373. Johnson DE, Robertson G, Simpson JB. Coronary atherectomy: light microscopic and immunohistochemical study of excised tissues (abstract). Circulation 198X:78:1182. Von Schacky C. Weber PC. Metabolism and effects on platelet function of the purified eicosapentaenoic and docosahexaenoic acid in humans. J Clin Invest 19X5:76: 244662450.
