Fish Oil Supplements and Restenosis After Percutaneous Transluminal Coronary Angioplasty The study by Milner et al’ reported a lower incidence of clinical restenosis in patients treated with fish oil supplements after percutaneous transluminal angioplasty (PTCA). These findings differ from those of 2 placebo-controlled trials, by our group2 and by Grigg et a1,3which revealed no benefit of fish oil. We believe that the methodology of Milner et al limits the applicability of their findings. First, the study was unblinded, and used subjective endpoints (symptoms and exercise testing). There was no difference in the single objective endpoint, angiographic restenosis, between the 2 groups (18 vs 26% and 20 vs 26% by intention to treat). Other endpoints (such as the exercise test) were apparently interpreted with knowledge of the randomization status, and by a mix of both the investigators and by other physicians as well. Second, patients were chosen for the study after PTCA, leading to potential selection bias in not approaching patients with lessthan-favorable (although successful) PTCA results. Third, study medication was started 1 dav after PTCA and no biologic assessmeni of compliance was undertaken. Membrane levels of n-3 fatty acids adequate to inhibit platelet function and alter eicosanoid formation are achieved only several days to several weeks after initiation of fish oil therapy,?,’ whereas platelet aggregation and release of growth factors is greatest in the first 4 days after experimental balloon injury.h For this reason, a large National Institutes of Health-supported trial of fish oil in patients undergoing PTCA will apparently have patients initiate study medication 2 weeks before scheduled PTCA. For these reasons, and because several studies, including our own, have demonstrated increases in low-density lipoprotein cholesterol levels with fish oil supplementation, we continue to urge that fish oil not be administered to patients undergoing PTCA, pending results of further studies. Richard
Gregg 1. Reis, MD C, Pasternak, MD
Boston, Massachusetts 14 August 1989 1. Mimer MR, Gallino RA, Leffingwell A, Pichard AD, Brooks-Robinson S, Rosenberg J, Little T, Lindsay J. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal angioplasty. hn J Cardiol 1989;64:294-299.
Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
2, Reis GJ, Sipperly ME, Boucher TM, Silverman DI, McCabe CH, Bairn DS, Sacks FM, Grossman W, Pasternak RC. Randomised trial of fish oil for prevention of restenosis after coronal y angiopiasty. Lance1 1585;2:177-181. 3. Grigg LE, Kay TWH, Valentine PA, Larkins R, Flower DJ, Manolas EG, O’Dea K, Sinclair AJ, Hopper JL, Hunt D. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaneoic acid on incidence of coronary artery restenosis after angioplasty. JACC 1988;12:1073-1078. 4. Von Schacky C, Fisher S, Weber PC. Longterm 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. 5. Von Schacky C, Weber PC. Metabolism and effects on platelet function of the purified eicosapentaneoic and docasohexaneoic acids in humans. J Clin Invest 1985;76:2446-2450. 6. Steele PM, Chesbro JH, Stanson AW, Holmes DR, Dewanjee MK, Bademon L, Fuster V. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res 1585;57:105-112.
We agree that further studies are needed to assess the role of omega 3 fatty acids (“fish oil”) in preventing restenosis after successful percutaneous transluminal coronary angioplasty (PTCA). As our article states, and as Reis and Pasternak note, 2 randomized trials demonstrated no benefit from omega 3 fatty acid supplements when compared to “placebo.” ‘J There are, in addition to our study, 2 that suggest a benefit from fish oil supplements.‘,4 Of these 5 trials, only 2 used cardiac catheterization as the endpoint for assessing success or failure.2J The results for these 2 trials were discordant. It is possible that the lack of placebo may have introduced ascertainment bias in our trial and 2 others.),4 In fact, neither placebo-controlled studyr.2 demonstrated a benefit from fish oil suoolements. There is, however, a question as’ to what an appropriate placebo might be. Both placebo studies used olive oil (alone, or with corn oil), a product high in monounsaturated fats, substances that in themselves may have antiatherogenic effects.j Reis et al’ reported a catheterization restenosis rate in the placebo group of 23%, a rate rather better than is usual after PTCA.6 In addition, true blinding may be impossible because of the distinct breath, odor and taste accompanying fish oil ingestion. Our study was limited to subjects with typical angina before PTCA. This design was chosen to provide a clear clinical marker for restenosis, namely return of angina. As cited in our article, silent recurrence is to be anticipated but should occur with equal frequency in treated and control patients in a randomized trial. With regard to the potential for selection bias, randomization to fish oil or control was carried out after entry into the study so that patients with favorable clinical or angiographic features were evenly distributed. As Reis and Pasternak state, fish oil therapy was not initiated before PTCA. We do not believe fish oil primarily affects REPLY:
platelets or spasm, the bases for early (48 hours) reclosure. (Note: Agents such as calcium antagonists and aspirin, which are more potent fOi spasm prevention or platelet inhibition, do not lower the 6month restenosis rate.) Rather, we suspect that its major effect on preventing restenosis is due to the inhibition of smooth muscle proliferation.‘~* Since restenosis occurs usually 1 to 6 months after PTCA, perhaps omega 3 supplements decelerate the growth of the coronary plaque during this time period. Moreover, the peak effect of fish oil supplements usually does not occur for 3 to 6 weeks. Therefore, beginning fish oil supplements 1 to 7 days before PTCA may have no major advantage over initiating therapy the day of PTCA. It would seem ideal to have a clinical trial that initiated fish oil supplements 3 to 4 weeks before PTCA (as has been done in animal experiments9). Finally, it is clear that low-density lipoprotein cholesterol may increase with administration of fish oil supplements.‘0 This finding is usually noted when fish oil is given as supplements alone, and not when there is, in addition, a decrease in dietary fats. It is interesting that populations with a high fish intake have a lower incidence of coronary disease for any given level of serum cholesterol, suggesting that the risk of a specific cholesterol level may depend on the dietary sources of fatty acids.” In summary,
Gregg 1. Reis, MD C, Pasternak, MD
Boston, Massachusetts 14 August 1989 1. Mimer MR, Gallino RA, Leffingwell A, Pichard AD, Brooks-Robinson S, Rosenberg J, Little T, Lindsay J. Usefulness of fish oil supplements in preventing clinical evidence of restenosis after percutaneous transluminal angioplasty. hn J Cardiol 1989;64:294-299.
Letters (from the United States) concerning a particular article in the Journal must be received within 2 months of the article’s publication, and should be limited (with rare exceptions) to 2 double-spaced typewritten pages. Two copies must be submitted.
2, Reis GJ, Sipperly ME, Boucher TM, Silverman DI, McCabe CH, Bairn DS, Sacks FM, Grossman W, Pasternak RC. Randomised trial of fish oil for prevention of restenosis after coronal y angiopiasty. Lance1 1585;2:177-181. 3. Grigg LE, Kay TWH, Valentine PA, Larkins R, Flower DJ, Manolas EG, O’Dea K, Sinclair AJ, Hopper JL, Hunt D. Determinants of restenosis and lack of effect of dietary supplementation with eicosapentaneoic acid on incidence of coronary artery restenosis after angioplasty. JACC 1988;12:1073-1078. 4. Von Schacky C, Fisher S, Weber PC. Longterm 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. 5. Von Schacky C, Weber PC. Metabolism and effects on platelet function of the purified eicosapentaneoic and docasohexaneoic acids in humans. J Clin Invest 1985;76:2446-2450. 6. Steele PM, Chesbro JH, Stanson AW, Holmes DR, Dewanjee MK, Bademon L, Fuster V. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res 1585;57:105-112.
We agree that further studies are needed to assess the role of omega 3 fatty acids (“fish oil”) in preventing restenosis after successful percutaneous transluminal coronary angioplasty (PTCA). As our article states, and as Reis and Pasternak note, 2 randomized trials demonstrated no benefit from omega 3 fatty acid supplements when compared to “placebo.” ‘J There are, in addition to our study, 2 that suggest a benefit from fish oil supplements.‘,4 Of these 5 trials, only 2 used cardiac catheterization as the endpoint for assessing success or failure.2J The results for these 2 trials were discordant. It is possible that the lack of placebo may have introduced ascertainment bias in our trial and 2 others.),4 In fact, neither placebo-controlled studyr.2 demonstrated a benefit from fish oil suoolements. There is, however, a question as’ to what an appropriate placebo might be. Both placebo studies used olive oil (alone, or with corn oil), a product high in monounsaturated fats, substances that in themselves may have antiatherogenic effects.j Reis et al’ reported a catheterization restenosis rate in the placebo group of 23%, a rate rather better than is usual after PTCA.6 In addition, true blinding may be impossible because of the distinct breath, odor and taste accompanying fish oil ingestion. Our study was limited to subjects with typical angina before PTCA. This design was chosen to provide a clear clinical marker for restenosis, namely return of angina. As cited in our article, silent recurrence is to be anticipated but should occur with equal frequency in treated and control patients in a randomized trial. With regard to the potential for selection bias, randomization to fish oil or control was carried out after entry into the study so that patients with favorable clinical or angiographic features were evenly distributed. As Reis and Pasternak state, fish oil therapy was not initiated before PTCA. We do not believe fish oil primarily affects REPLY:
platelets or spasm, the bases for early (48 hours) reclosure. (Note: Agents such as calcium antagonists and aspirin, which are more potent fOi spasm prevention or platelet inhibition, do not lower the 6month restenosis rate.) Rather, we suspect that its major effect on preventing restenosis is due to the inhibition of smooth muscle proliferation.‘~* Since restenosis occurs usually 1 to 6 months after PTCA, perhaps omega 3 supplements decelerate the growth of the coronary plaque during this time period. Moreover, the peak effect of fish oil supplements usually does not occur for 3 to 6 weeks. Therefore, beginning fish oil supplements 1 to 7 days before PTCA may have no major advantage over initiating therapy the day of PTCA. It would seem ideal to have a clinical trial that initiated fish oil supplements 3 to 4 weeks before PTCA (as has been done in animal experiments9). Finally, it is clear that low-density lipoprotein cholesterol may increase with administration of fish oil supplements.‘0 This finding is usually noted when fish oil is given as supplements alone, and not when there is, in addition, a decrease in dietary fats. It is interesting that populations with a high fish intake have a lower incidence of coronary disease for any given level of serum cholesterol, suggesting that the risk of a specific cholesterol level may depend on the dietary sources of fatty acids.” In summary,
