Fish Oils and Low-Molecular-Weight Heparin for the Reduction of Restenosis After Percutaneous Transluminal Coronary Angioplasty
The EMPAR Study
Background Percutaneous transluminal coronary angioplasty (PTCA) is complicated by restenosis within 6 months in >40% of patients. Theoretical, animal experimental, and human epidemiological and clinical trial findings have suggested that fish oils (n-3) might reduce restenosis. Low-molecular-weight heparin (LMWH) has reduced cellular proliferation and restenosis in several experimental systems.
Methods and Results We randomized 814 patients to fish oils (5.4 g n-3 fatty acids) or placebo a median of 6 days before PTCA and continued for 18 weeks. At the time of sheath removal, 653 patients with at least one successfully dilated lesion were randomized to LMWH (30 mg SC BID) or control for 6 weeks in a 2×2 factorial design. Follow-up with quantitative coronary angiography (QCA; target, 18 weeks) was interpretable on 96% of these patients. Restenosis rates per patient were for n-3, 46.5%; placebo, 44.7%; LMWH, 45.8%; and control, 45.4%. Restenosis rates per lesion were for n-3, 39.7%; placebo, 38.7%; LMWH, 38%; and control, 40.4%. At follow-up QCA, mean minimal lumen diameters were (mm) for n-3, 1.12; placebo, 1.10; LMWH, 1.12; and control, 1.10. Fifteen percent of patients permanently discontinued n-3/placebo before study completion, and 21% of patients discontinued LMWH early. There were no significant differences in the occurrences of ischemic events. Bleeding was more common with LMWH, usually was mild, and led to early discontinuation of study medication in only 0.9% of patients. Gastrointestinal side effects were more common in patients receiving n-3 than placebo.
Conclusions There is no evidence for a clinically important reduction of PTCA restenosis in this trial by either n-3 or LMWH. Evaluation of the results for n-3 in the context of previously published data on the reduction of PTCA restenosis indicates that n-3 is not efficacious and that further trials are unwarranted.
The incidence of restenosis after PTCA has decreased little since the earliest days of angioplasty and remains at >40% by 6 months.1 2 More than half the affected patients have a recurrence of angina sufficient to warrant repeated PTCA or coronary artery bypass surgery.2 No medical intervention has emerged as clearly efficacious in reducing the risk of restenosis.3
Coronary events may be less frequent among populations consuming large amounts of n-3 polyunsaturated fatty acids (fish oils),4 and clinical trials among survivors of acute myocardial infarction have demonstrated a reduction in subsequent coronary events by an increased consumption of fatty fish5 or α-linoleic acid (a precursor of n-3 fatty acids derived from vegetable sources).6 An increase in dietary n-3 fatty acids in relation to arachidonic acid alters platelet prostaglandin and leukocyte leukotriene pathways, resulting in potentially beneficial limitation of the smooth muscle cell proliferative response underlying angioplasty restenosis.4 7 The prevention by fish oils of proliferative atherosclerosis in the coronary-balloon-injury cholesterol-fed pig model suggested that such a benefit might accrue in humans.8 Five trials of fish oils for the reduction of PTCA restenosis reported by 1989 suggested an overall benefit,9 10 11 12 13 but deficiencies in their design and conduct prompted us to undertake a large clinical trial with sufficient power to evaluate definitively the efficacy of fish oils among patients undergoing elective PTCA.
The effort and expense of conducting the trial prompted us to maximize the utility of our undertaking by evaluating a second potentially beneficial therapy using a factorial design. This approach allows assessment of a second therapy at relatively modest additional cost and effort and represents an efficient use of resources.14
Various heparin fractions are effective in preventing smooth muscle cell hyperplasia after experimental arterial injury.15 16 17 The antiproliferative effects appear to be independent of molecular size and anticoagulant effect17 ; because LMWH fractions are about one third the size of standard heparin, they may be capable of greater inhibitory activity than unfractionated heparin for an equivalent anticoagulant effect. In venous thrombosis, LMWH produces less bleeding for an equivalent antithrombotic effect than unfractionated heparin.18 We decided to evaluate both LMWH and fish oils for the limitation of PTCA restenosis using a 2×2 factorial design.
The trial was conducted in four teaching hospitals in southern Ontario, Canada, that together perform PTCA on about 2400 patients yearly. A nurse practitioner employed in each hospital attempted to screen every patient scheduled to undergo PTCA with respect to the following inclusion criteria: a diagnostic coronary angiogram showing at least one localized coronary artery stenosis of ≥50% reduction of lumen diameter by visual analysis and age ≥18 years. The exclusion criteria were as follows: (1) certain characteristics of the coronary artery disease (culprit lesion in a saphenous bypass graft, at the site of a previously dilated restenosis, or involving the left main coronary artery; myocardial infarction <28 days previously, the presence of very unstable angina necessitating PTCA in <48 hours, or the presence of variant angina; or the use of Sones' approach); (2) excessive bleeding risk (recent peptic ulcer or gastrointestinal bleeding, platelets <100 000/mm3, predisposition to intracranial hemorrhage, or blood pressure >180/105 mm Hg); (3) concerns specific to the use of fish oils or LMWH (fish product or LMWH allergy or hypersensitivity, a requirement for anticoagulant therapy, the use of insulin, or significant hepatic or renal disease); or (4) practical patient problems (disease therapy that might interfere with LMWH action or evaluation; concomitant disease likely to limit life span to <6 months; drug or alcohol abuse; or insurmountable geographic, social, or language barrier).
After giving informed consent, patients were randomly allocated fish oils (maxEPA capsules, supplied by R.P. Scherer, each containing 180 mg EPA and 120 mg DHA in the form of a triglyceride), six capsules given three times daily with meals (total, 5.4 g/d n-3 polyunsaturated fatty acids), or identical-appearing capsules of corn oil placebo. The intent was to administer the capsules for not <7 days before PTCA and to continue them for 4 months. Patients with unstable angina were eligible for study entry, provided that the investigator believed that fish oils/placebo could be administered for at least 48 hours before PTCA.
All patients received full-dose standard heparin intravenously during PTCA and were maintained with an aPTT at 1.5 to 2 times control until about 4 hours before removal of the groin sheath. Those patients judged to have had successful PTCAs (residual stenosis <50% diameter by visual assessment in at least one vessel in which PTCA was attempted and no peri-procedural infarct, death, repeated PTCA, or coronary artery bypass graft) underwent a second randomization to LMWH (enoxaparine, supplied by Rhoˆne Poulenc Rorer in prepackaged syringes) self-administered subcutaneously 30 mg BID for 6 weeks or standard therapy. No placebo injections were given to the control group. This group comprised the study cohort of interest and were the only patients followed subsequently.
Patients were reevaluated at weeks 2, 6, and 12, and follow-up coronary angiography was scheduled at 18±2 weeks (mean±SD), at which point participation in the trial would be complete. Physicians were asked to avoid repeated coronary angiography before the 16-to-20-week window if possible and consistent with the patient's best interests. If follow-up angiography was clinically required before 16 weeks and visual examination revealed any study lesion stenosed to <50%, the study drug was continued, and every effort was made to obtain a follow-up angiogram in the 16-to-20-week window. If no subsequent angiogram was done, the results obtained at the early angiogram were to be used in the determination of restenosis. If every study lesion was stenosed ≥50% at angiography before 16 weeks, the study treatment was stopped.
Coronary Angiography, PTCA, and Quantitative Stenosis Severity
Twenty-four hours before PTCA, patients began aspirin 325 mg/d (continued throughout follow-up) and a calcium antagonist (continued at the discretion of the attending cardiologist). Nitroglycerin (100 μg IC) was administered before angiography with the largest-acceptable caliber diagnostic catheter. At least two orthogonal views of each lesion to be dilated were filmed with a 7-in image intensifier and careful centering. Exact angles and distances were recorded for each lesion dilated. Standard heparin (10 000 IU IA) was given just before balloon insertion, repeated (5000 IU) every half hour to hour, and maintained (aPTT, 1.5 to 2) until about 4 hours before sheath removal. After dilatation, repeat cinefilms were recorded to duplicate the pre-PTCA projections, caliber of diagnostic catheter, and intracoronary nitroglycerin. Identical approaches were followed for the 18-week follow-up angiogram.
Quantitative measurements were made at the Ottawa Heart Institute by use of a customized Siemens Digitron 3.61 analytical program. An Arripro projector was used to optimally magnify the image 2.8 times and to allow centering of the region of interest. From the projections indicated by the angiographer, end-diastolic frames were chosen from the cardiac cycles with best opacification of a given segment, converted to video, and digitized. Operator and computer interaction was used to draw a centerline through the area of interest, allowing edge detection and measurement of the minimal lumen diameter and a reference diameter within 1 cm proximal or distal to the lesion. Calibration markers embedded in a transparent plate placed over the image intensifier tube allowed determination of a calibration line and calculation of vessel diameters in millimeters. The diameters of each segment were calculated from the mean of two orthogonal views. Film sets (before, after, and follow-up) were analyzed at the same time by a single technologist blinded to the treatment allocation. The validity of the system had been assessed previously by filming of dye-filled Plexiglas channels, yielding a test-retest SD of 0.054 mm and a correlation of .997 with the true diameter. All measurements in the study were done by a single technologist. Replicate measures on the same patient film yielded coefficients of variation of the minimal lumen diameter of .19, .15, and .17, whereas reliabilities, expressed as interclass correlation, were 85% to 95%.
We planned to conduct both patient-based and lesion-based analyses of restenosis. In the patient-based analysis, patients were classified as having restenosis if any of their successfully dilated lesions met the definition for restenosis. The lesion-based analyses treated each successfully dilated lesion as a separate observation. The primary definition of restenosis for a lesion was a loss of ≥50% of the gain of luminal diameter achieved by PTCA based on the mean stenotic diameters of the available orthogonal views. In some situations, the post-PTCA image did not allow the quantitative assessment of gain or occasionally failed to indicate any quantitative gain. In these situations, a secondary definition of restenosis was used that required percentage stenosis (with respect to a reference diameter within 1 cm of the lesion) to be ≥50% at follow-up.
We postulated a restenosis rate of 30% in the untreated patients and sought to detect a relative reduction of 50% in this rate. Choosing a two-sided α of 0.05 and β of 0.10, we calculated a sample size of 148 patients per group (total, 592) available for follow-up angiography, necessitating the randomization of >800 patients. Differences between the treatment groups for the various clinical and laboratory outcome variables were tested by the χ2 test or t statistic. A patient was considered to have restenosis if any successfully dilated lesion was restenosed at follow-up. The restenosis rates in the patient-based analysis were compared by use of the Mantel-Haenszel test stratified by the number of successfully dilated vessels. A lesion-based analysis included only lesions for which QCA was available and compared rates of restenosis by use of a Mantel-Haenszel χ2 test. Mean minimal lumen diameters (also lesion-based) were compared by use of ANOVA.
The patients were recruited between June 1990 and June 1993, and the last follow-up coronary angiogram was done in November 1993. There were 814 patients randomized to fish oils/placebo, which they received for a minimum of 2 days and a median of 6 days before PTCA (Table 1⇓). The subgroup of patients with unstable angina received the study treatment for a minimum of 2 days and a median of 3 days before PTCA. Of patients randomized to fish oils/placebo, 7% were subsequently found to be ineligible or had their PTCAs canceled for a variety of reasons. PTCA was attempted in 756 patients and was successful in 668 (88%), among whom there were 3 peri-procedural events and 12 patients who withdrew for other (mainly consent) reasons. There were 653 patients who continued to receive fish oils/placebo and then were randomized to LMWH or control. Intravenous heparin was discontinued on the day of PTCA in 5% of patients, on the morning after PTCA in 83%, and later than the morning after PTCA in 12%. The mean interval between stopping intravenous heparin and beginning LMWH was 10 hours.
The four groups resulting from the second randomization were quite comparable, with no statistically significant differences in the proportions of any relevant baseline characteristics (Table 2⇓). There were no statistically significant differences among the proportions of various characteristics and distributions of the successfully dilated lesions among the four treatment groups (Table 3⇓).
Fish oils/placebo capsules were permanently discontinued in 100 patients (15%) before the normal end of study at 18 weeks (median duration, 9 weeks). The rate of early discontinuation was similar in active and placebo fish oils groups. LMWH injections were discontinued in 68 of 325 patients (21%) before the normal end of treatment at 6 weeks (median duration, 1 week). Most early discontinuations were attributed to intercurrent ischemic events, adverse experiences, or the patient's lack of cooperation. Before cessation of study therapy (either early or at normal end of treatment), 77% of patients consumed ≥90% of their study capsules, and 88% of patients used ≥90% of their LMWH syringes.
Clinical Events and Complications
There were no significant differences in ischemic events among the treatment groups. Bleeding was less frequent in patients taking fish oils than those taking placebo and was more frequent in patients taking LMWH than among control subjects. Most bleeding was mild, leading to permanent discontinuation of study medication in only six patients (0.9%), and no transfusions were required. Most spontaneous bleeding was characterized by bruising, and most peri-procedural bleeding consisted of excessive oozing at the femoral puncture site. Gastrointestinal side effects, most commonly bloating and burping, were reported more often by patients taking fish oils than those taking placebo (37% versus 30.8%, P=.07) but only occasionally resulted in early withdrawal from study medication. Complaints related to the LMWH injection site were reported by 24.6% of patients, sometimes leading to early withdrawal from study medication. Table 4⇓ summarizes the clinical and laboratory outcomes during follow-up.
A comparison of laboratory test mean changes from baseline to 18 weeks between the fish oils and placebo groups yielded statistically significant differences only in hepatic enzymes and serum triglycerides. Both aspartate aminotransferase and alanine aminotransferase were increased by 11% to 12% at 18 weeks with fish oils, whereas the levels in patients in the placebo group decreased slightly. As expected, fish oils reduced serum triglycerides by about 33%; by comparison, the triglycerides of placebo patients decreased by 9% over the 18-week period. LMWH did not significantly affect any of the laboratory tests.
Follow-up angiograms yielding QCA measurements were available for 625 of the 653 patients (96%): 49 (8%) were done before 16 weeks for clinical reasons, 461 (74%) fell within the protocol window of 16 to 20 weeks, and 115 (18%) were done late. Of the 28 patients for whom QCA measurements were not available, 6 had technically uninterpretable angiograms, 20 refused a follow-up angiogram, and 2 patients died. The 653 patients had a total of 894 successfully dilated lesions; follow-up QCA measurements were available for 824 (92%).
In Table 5⇓, the primary efficacy comparison for fish oils is based on the row totals; for LMWH, it is based on the column totals. From the patient-based analysis, 46.5% of patients treated with fish oils experienced restenosis of one or more successfully dilated lesions compared with 44.7% of placebo patients (1.7% absolute difference; 95% CI±7.8%, P=.6). The restenosis rates with and without LMWH were almost identical (P=.8). The formal test of interaction (ie, the tendency for the effect of one treatment to depend on the presence or absence of the other) was not significant.
The results for the lesion-based analysis (Table 5⇑) show much the same picture. The slight variation in restenosis rates over the four treatment combinations is quite consistent with the null hypothesis of “no real difference” as manifest by nonsignificant P values for all comparisons.
The Figure⇓ displays the cumulative distributions of mean minimal lumen diameters for successfully dilated lesions before PTCA, after PTCA, and at follow-up. The corresponding tabulated means and SDs are summarized in Table 6⇓, which also shows the equivalent summary statistics for the reference diameters. The virtual coincidence of the cumulative distributions and the similarity of tabulated means at each time point show no evidence of a treatment effect for either fish oils or LMWH.
In this randomized, factorial trial of fish oils versus placebo and of LMWH versus control among patients undergoing PTCA, there was no reduction in restenosis rate with either agent alone or in combination. The outcome was particularly unexpected for fish oils, given a strong experimental rationale and a meta-analysis of previous trials suggesting a reduction of the rate of restenosis.4
The trials reported before9 10 11 12 13 and during19 20 21 22 the conduct of EMPAR had defects in design, including relatively low dose of n-3 fatty acids,21 22 short or absent preprocedural treatment period,10 12 19 22 follow-up assessment that used nonquantitative angiography9 10 11 19 or nonangiographic criteria,12 13 19 and inadequate sample size.9 10 11 12 13 19 20 21 22 The EMPAR Trial was designed to avoid these defects.
The absence of benefit in this study probably is not attributable to the dose of fish oils or the duration of treatment before PTCA. The dose of fish oils used in the EMPAR Study is sufficient to profoundly change the ratio of n-3 to n-6 fatty acids in the platelet membrane, and the 7-day pre-PTCA treatment period is sufficient for the majority of the eventual n-3 substitution and alteration of platelet function to occur.23 Changes in red blood cell membranes may occur more slowly.24 The 653 patients with visually successful PTCA, of whom 92% had an evaluable follow-up QCA, provided statistical power sufficient that if fish oils could indeed reduce angioplasty restenosis, the likelihood of failing to detect a clinically important reduction of restenosis is extremely low.
Since the completion of EMPAR, an additional study of fish oils for the prevention of angioplasty restenosis has been published, also with negative results.24 The study randomized 551 patients to 6.9 g/d n-3 fatty acids for 12 to 14 days before and 6 months after PTCA. QCA in 447 evaluable patients revealed a restenosis rate of 46% for placebo and 52% for fish oils, even with a higher dose of fish oils for a longer period of time than was used in the present study. It therefore seems clear that the biochemical changes resulting from fish oil supplementation do not lead to a reduction in angioplasty restenosis.
The fish oils option can now be confidently set aside. Despite an appealing experimental rationale, evidence of possible benefit in chronic coronary artery disease, and early promise in small clinical trials in patients undergoing angioplasty, this therapy has not been demonstrated to offer a benefit in the two most recent and optimally designed clinical trials involving a total of 1073 patients, more than were studied in all previous trials. A formal meta-analysis based on the summary results from the 10 published randomized controlled trials among 2106 patients fails to indicate any reduction of restenosis by fish oils (odds reduction, 1%; P=.95). It appears that the epidemiological observations of the reduced rates of ischemic heart disease outcomes and the post–acute myocardial infarction clinical trial results, while possibly being relevant to the progression and development of complications in patients with coronary atherosclerosis, are not relevant to the rapid smooth muscle cell proliferation pathogenesis of PTCA restenosis.
Apart from one small trial of fragmin that reported a favorable trend,25 trials of heparin to prevent PTCA restenosis have been negative,26 27 28 29 30 including the only other reported trial of sustained LMWH after angioplasty.29 In that trial, patients were randomized to enoxaparine 40 mg SC daily or placebo for 28 days. QCA in 394 patients at 24±4 weeks after PTCA revealed restenosis rates of 52% with enoxaparine and 51% with placebo. The EMPAR Study was larger; the dose of enoxaparine was 50% greater and given twice daily; the heparin-free interval was shorter; and the treatment was sustained 50% longer but was also negative.
A number of mechanisms could be responsible for the inhibition of experimental smooth muscle hyperplasia by heparin and its fractions. These sulfated polysaccharides may compete for endoglycosidases released by activated platelets, thereby protecting heparan sulfate on the surface of smooth muscle cells, in turn inhibiting smooth muscle mitogenesis.31 Heparin and its derivatives also have the potential to inhibit smooth muscle mitogenesis by binding to growth factors released from cells at sites of vascular injury32 or by a direct effect on the cell nucleus.33
Although in EMPAR high-dose unfractionated heparin was administered beginning ≈30 minutes before PTCA, experimental evidence exists that the antiproliferative effects of heparin are increased by pretreatment.34 Heparin was discontinued for about 4 hours before sheath removal, creating a gap in the inhibitory effect on smooth muscle cell proliferative factors, possibly at a critical stage. On the other hand, some studies have shown that the inhibitory effects of heparin can be achieved even when it is started after vessel injury.32 Animal experiments indicate that the antiproliferative effects of heparin are dose dependent.17 Recent studies of LMWH in human arterial diseases have demonstrated that doses much higher than those used in trials of venous thrombosis were safe35 and would therefore be feasible after PTCA. It is also conceivable that the treatment period of 6 weeks in this study was insufficient to realize the benefits of LMWH.
With the use of a factorial design, the patients were randomized to fish oils or identical-appearing placebo and subsequently randomized to LMWH or standard therapy with no LMWH placebo. Because the comparison of restenosis rates was based on the QCA results performed by a technologist blinded to treatment allocations, minimal bias was anticipated; accordingly, the patient discomfort that would have arisen from placebo injections was judged to be unwarranted.
The potential benefit from LMWH is unclear. The two negative studies involving 1019 patients leave little doubt as to the lack of efficacy with a dose of up to 60 mg/d begun at the time of angioplasty and continued for 6 weeks. Although the impressive results in animal experiments may prompt further clinical trials with appropriate modifications in design, in a recent study in baboons, high-dose LMWH failed to inhibit intimal hyperplasia in a balloon angioplasty model, suggesting that species differences may preclude a beneficial effect of LMWH in humans.36
Is the goal of reduction of restenosis attainable with any intervention? Although numerous trials have failed to demonstrate benefit from steroids, ACE inhibitors, antiplatelet agents, cholesterol-lowering agents, or oral anticoagulants,3 recent studies suggest that stent implantation may be effective in selected patients,37 38 and most recently the platelet-derived growth factor antagonist triazolopyrimidine39 appears to be effective. A meta-analysis of trials of calcium antagonists suggests a benefit,40 although a well-designed single trial is required to provide data that will convince practicing cardiologists. Restenosis continues to complicate 40% to 50% of PTCA procedures; ongoing attacks on this problem are warranted and should be undertaken.
Selected Abbreviations and Acronyms
|aPTT||=||activated partial thromboplastin time|
|EMPAR||=||Enoxaparin MaxEPA Prevention of Angioplasty Restenosis|
|maxEPA||=||fish oil capsules containing 180 mg EPA and 120 mg DHA in the form of a triglyceride (trademarked)|
|PTCA||=||percutaneous transluminal coronary angioplasty|
|QCA||=||quantitative coronary angiography|
The following hospitals and investigators participated in the EMPAR Study. The number of patients enrolled at each center is given in parentheses: Ottawa (Canada) Heart Institute (273): Brian Morton, Jean Franc¸ois Marquis, Bill Williams, Donald Beanlands, Bernie Larocque, Laurie Jozwiak, and Joanne Taylor; Victoria General Hospital, London, Canada (190): Keith Finnie, Ian Penn, Robert Brown, Brendan Foley, Joanne White, and Karen Gier; Hamilton (Canada) General Hospital (182): Douglas Holder, John Gill, Corinne O'Dell, and Chris Basset; Sunnybrook Health Sciences Centre, Toronto, Canada (169): Sal Naqvi, Eric Cohen, Gregory Mishkel, Lynn Baleza, and Neville Arthurs.
Steering Committee: John Cairns (chairman), John Gill, Robin Roberts, Michael Gent, Jack Hirsh, Brian Morton, Keith Finnie, Sal Naqvi, Jean Franc¸ois Marquis, Douglas Holder, Bernie Laroque, Eric Cohen, Robert Brown, and Ian Penn.
External Safety and Efficacy Monitoring Committee: Wayne Taylor (chairman), Graham Turpie, and Leonard Schwartz.
Coordinating and Methods Centre: Robin Roberts, Michael Gent (director), Lorrie Costantini, and Wendy Yacura.
Quantitative Coronary Angiography Committee: Brian Morton (chairman), John Gill, Douglas Holder, Jean Franc¸ois Marquis, and Bernie Larocque.
This work was supported by a grant-in-aid from the Heart and Stroke Foundation of Ontario and by a grant from Rhoˆne Poulenc Rorer. We wish to express our sincere appreciation to our colleagues who performed the cardiac catheterizations and PTCAs, the nurses and technicians in the cardiac catheterization laboratories and radiology departments of the participating hospitals, and Susan Crook for secretarial support.
- Received November 28, 1995.
- Revision received April 11, 1996.
- Accepted April 15, 1996.
- Copyright © 1996 by American Heart Association
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