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The high incidence of restenosis has long been recognized as the Achilles heel for percutaneous transluminal coronary angioplasty (PTCA) and other similar techniques, such as arthrectomy. A number of possible mechanisms have been proposed, largely involving vascular remodeling or exuberant cellular proliferation and neointimal formation. Preliminary investigations suggested that oxidative metabolites may play a central role in such processes, and earlier animal studies and smaller clinical trials suggested that antioxidant therapy may prevent restenosis. Tardif and colleagues at the Montreal Heart Institute undertook an ambitious and well-designed factorial study of probucol 500 mg bid vs. pharmacologic doses of beta carotene, vitamin C (500 mg bid), and vitamin E (700 IU bid) vs. the combination of probucol and multivitamins vs. placebo. Approximately 80 patients in each group completed the study. All received treatment starting one month prior to elective PTCA and continuing for six months post. The study was initially planned to have 440 patients; however, it was terminated prematurely when an interim analysis demonstrated highly significant benefits. The primary end point of the trial, reduction in mean luminal diameter as determined by quantitative angiography, was markedly reduced in the patients treated with probucol. Similarly, restenosis rates compared to placebo were reduced by 47% (21% vs 39%; P = 0.003), with a resultant 58% reduction in the need for repeat angioplasty. The pharmacologic doses of anti-oxidant multivitamins failed to show any benefit compared to placebo.
Finally, after 20 years of trying, we have a treatment for restenosis. After attempts with calcium channel blockers, ACE inhibitors, antiplatelet agents, anticoagulants, fish oil, and aggressive lipid lowering with statins, among others, we can now use probucolat least for our elective angioplasty patients, since it would appear it needs to be started early enough to build up levels and penetrate the tissue. Although there is concern about the marked reduction in HDL levels with its use, that shouldn’t be a problem since experimental evidence suggests that the inflammatory processes and remodeling responsible for the restenosis are no longer active beyond six months. The only problem would seem to be that the drug is no longer on the market, having been withdrawn by its maker due to apparent lack of efficacy as a lipid-lowering agent. Anticipating this, the investigators tried pharmacologic doses of antioxidant multivitamins. However, they were no more effective than placebo or any of the other multiple treatments tried before. Bummer.
Now, why am I wasting this space (and your valuable time) reporting on a therapy we are unlikely to be able to use? Although we should be disappointed, we must be excited and encouraged that we are starting to knock on the door of success. This study, and the preliminary investigations that lay the groundwork for it, serve to increase our understanding of the mechanisms responsible for restenosis. It is clear that the lipid-lowering effect of probucol was not responsible for its success. The acute trauma of angioplasty, just as with unstable angina and other acute ischemic syndromes, releases oxidizing metabolites. Oxidized LDL, interacting with cellular components such as neutrophils and platelets, initiates cascades of reactions. The vascular biologists investigating this invoke substances once only of concern to rheumatologists or hematologists. OK, so perhaps we don’t have a way of modifying the interleukin or tumor necrosis factor. Not yet. But, such successes as above demonstrate that we are getting awfully close. And, in the meantime, I must echo the concluding remarks of the accompanying editorial. Treatment of the underlying risk factors to prevent the development of atherosclerosis and thereby eliminating the need for PTCA must remain our primary goal.