Effectiveness of Probucol in Preventing Restenosis after Percutaneous Transluminal Coronary Angioplasty Young Joon LEE, MD, Hiroyuki DAIDA,MD, Hisashi YOKOI,MD, Hiroshi MIYANO,MD, Junshi TAKAYA,MD, Hidehiko SAKURAI,MD, Hiroshi MOKUNO,MD, and Hiroshi YAMAGUCHI,MD SUMMARY Lipid lowering therapies were employed to prevent restenosisfollowin electivepercutaneous transluminal coronary angioplasty(PTCA). The effecto probucol was compared to that of Pravastatin in 141 coronary atherosclerosi patients. Probucol (750mg/day) was administeredfor at least 30 days prior to PTCA (34 patients, group P-1) or less than 14 days prior to PTCA (27 patients, group P-2). Pravastatin (10mg/day) was administered for at least 30 days prior to PTCA (38 patients, group V-1) or less than 14 days prior to PTCA (42 patients, group V-2). In group P-1, the patient restenosisrate was 17.6% and lesionrestenosis rate was 14%. These rates were significantlylower than those of group V-1, which were 44.7% and 40.4% respectively(p<0.05). The re- spectivevalues were 48.1% and 51.8% in group P-2 (p<0.05, vs group P-1) and 35.7% and 34% (p<0.05, vs group P-1) in group V-2. Probucol seems to work, not only by lowering cholesterolbut also by its antioxidativeproperties when administeredfor a sufficientperiod prior to PTCA. (Jpn Heart J 1996; 37: 327-332) Key words: Lipid loweringtherapy Restenosisafter PTCA Probucol Antioxidant Pravastatin RESTENOSIS within 6 months after PTCA is still a clinical problem and its pathophysiology continues to be discussed. Although the pathologic fea- tures of restenosis are different from spontaneous atherosclerosis in the absence of lipid laden cells,1)activated macrophages may play an important role in both pathologic processes by producing cytokines which regulate cellular growth. Be- cause oxidized low-density lipoprotein (LDL) is an important activator of mac- rophages1) and platelets3),we hypothesized that to prevent restenosis it is crucial to maintain the antioxidant concentration around the intima high enough at the From the Department of Cardiology, Juntendo University, School of Medicine, Tokyo, Japan. Address for correspondence : Hiroyuki Daida, MD, Department of Cardiology, Juntendo University 2-1-1 Hongo, Bunkyo-Ku, Tokyo, 113, Japan. Received for publication September 14, 1995. Accepted January 26, 1996. 327 Jpn Heart J 328 LEE ET AL May 1996 time of PTCA so as to minimize message induction for cellular growth. In this study we administered probucol, a lipid lowering drug which has antioxidative properties as well as the ability to inhibit cytokine secretion, to candidates for elective PTCA to determine whether probucol can prevent restenosis after PTCA. We compared its activity to pravastatin, a HMG-CoA reductase inhibi- tor, which has no antioxidative activity but clearly causes a lowering of serum cholesterol. METHODS A prospective controlled study was conducted in 141 consecutive coronary atherosclerosis patients with or without previous myocardial infarction (121 males, 20 females, 60.4•}8.6 years old, 164 vessels attempted). Patients were di- vided into four groups classified by lipid lowering therapy which was added to the following routine medication for PTCA: 80mg/day of aspirin, 150mg/day of dipyridamole, 180mg/day of diltiazem, 40mg/day of isosorbide dinitrate. In the first half of the study, all candidates were given probucol (750mg/day) for either at least 30 days prior to PTCA (34 patients, group P-1) or less than 14 days prior to PTCA (27 patients, group P-2). In the second half of the study, all candidates were given pravastatin (10mg/day) for either at least 30 days prior to PTCA (38 patients, group V-1) or less than 14 days prior to PTCA (42 patients, group V-2). The medication was continued in all candidates until coronary angiographic evaluation 5 months after PTCA or until restenosis was confirmed, by coronary angiography. The following criteria were applied to angiographic evaluation: a lesion with more than 75% luminal stenosis but without total occlusion was indicated for PTCA; PTCA by which luminal stenosis became less than 50% without major complication at the end of a procedure was successful, and lesions which developed more than 50% luminal stenosis by angiographic follow-up study were considered to have restenosed. No adverse drug effects developed and no patients required urgent coronary bypass surgery during this study. Blood samples were taken at baseline, the time of PTCA and angiographic follow-up study to determine plasma levels of total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol. The values of low-density lipoprotein (LDL) cholesterol were calculated by Friedewald's formula. Student's t test and Chi square test were used for statistical analysis. RESULTS The clinical characteristics of each group at baseline are shown in Table I. There were no differences among the groups with respect to age, gender,,body mass index, mean blood pressure, prevalence of smoking, and hemoglobin Alc. Vol 37 PROBUCOL IN PREVENTING RESTENOSIS AFTER PTCA 329 No 3 Table I. Clinical Characteristics of Each Group Classified by Lipid Lowering Therapy BMI=body mass index; MBP=mean blood pressure; SM=prevalence of smoking; HbAlc=hemoglobin Alc. Table IL Lipid Profiles of Each Group Classified by Lipid Lowering Therapy PTCA=percutaneous transluminal coronary angioplasty; LDL-C=low density lipoprotein cholesterol; HDL-C=high density lipoprotein cholesterol; TG=triglyceride; : p<0.05; *p<0.01. Table III. Angiographic Profiles of Each Group Classified by Lipid Lowering Therapy PCA=right coronary artery; LAD=left anterior descending artery; LCX=left circumflex artery; SVG=saphenous vein graft. Lipid profiles at baseline, and during the PTCA procedure and angiographic follow-up study are shown in Table II. At baseline, there was no significant difference in the lipid profile among the groups except for the LDL cholesterol values between groups V-1 and P-2. At the time of PTCA , LDL cholesterol was significantly lowered in group V-1 by pravastatin as compared to groups P-1 and P-2. In contrast, HDL cholesterol in group P-1 was lower than that in other groups. In the angiographic follow-up study , LDL-cholesterol values Jpn Heart J 330 LEE ET AL May 1996 Table IV. Results of Angiographic Follow-up Study after PTCA LAD=left anterior descending artery; •õ: p<0,05, *: p<0.01. in groups V-1 and V-2 were significantly lower than their counterparts in groups P-1 and P-2. HDL-cholesterol in group P-1 and P-2 were significantly lower than those in groups V-1 and V-2. Angiographic profiles are shown in Table III. Number of diseased vessels, location of target vessel, pre-PTCA lesion stenosis and post-PTCA residual stenosis showed no significant differences among the four groups. LAD com- prised the majority in the target vessels. PTCA was successful and complete angiographic follow up was obtained in all candidates. The results of follow-up angiography in each group are summarized in Table IV. The patient restenosis rate was 17.6% in group P-1, which was signifi- cantly lower than those in V-1 or P-2 (p<0.05). Group P-1 showed a lesion restenosis rate as low as 14.0% and the restenosis rate in the left anterior de- scending artery was 13.0%. These low recurrence rates in group P-1 indicate a statistically significant difference compared with the three other groups. DISCUSSION In the present study, lipid lowering therapies were attempted to prevent restenosis following elective PTCA, and the effects of probucol were compared to those of pravastatin in 141 coronary atherosclerosis patients. When probucol was administered for at least 30 days prior to PTCA, patient restenosis rates were significantly lower than those of the pravastatin groups. An issue in restenosis is the mechanism of proliferation of smooth muscle cells and extracellular matrix. These are apparently more acute (complete in 3- 6 months) after PTCA1) than in spontaneous atherosclerosis. The denudation of endothelium by PTCA exposes the arterial intima to plasma LDL, which is suspected to be ten times higher than in the intima. This might explain to some extent why simple reduction of plasma cholesterol by pravastatin was not effec- tive in preventing rcstenosis after PTCA. LDL, especially when modified, causes aggregation of platelets, on which cyclooxygenase inhibitors have little inhibitory effect,3) and induces expression of several kinds of cytokines and chemotaxins,4) Vol 37 PROBUCOL IN PREVENTING RESTENOSIS AFTER PTCA 331 No 3 such as interleukin-1,5) platelet derived growth factor AA and its surface receptor on smooth muscle cells.5) Furthermore, after ballooning, LDL binds to extracellu- lar matrix intensively at the regrowth region of the endothelium,7) which is now functionally modified. Thus PTCA could result in an area where the oxidation of LDL, activation of macrophages and aggregation of platelets actively take place. Probucol, at concentrations found in the plasma of patients on the drug, prevents oxidation of LDL8) and inhibits interleukin-1 ƒÀ expression9) and macrophage re- cruitment.10) In contrast to pravastatin, probucol seems to prevent restenosis not only by its effects on lipoprotein metabolism, but also by its antioxidative proper- ties and suppression of cytokine expression. Probucol administered for less than 14 days did not reduce the restenosis rate in the present study. Because the pathological processes of restenosis such as platelet aggregation and induction of cytokines and chemotaxins are initiated at the time of vascular injury by angioplasty, premedication early enough before PTCA has been suggested as a way to modify the restenosis process.11) Reaven et al12) reported that it took more than 1 month to obtain adequate plasma levels and antioxidant protection with probucol in humans. Longer than 30 days of premedication of probucol was sufficient to reduce the HDL-cholesterol level in group P-1, which also resulted in a lower restenosis rate compared to group P-2 in the present study.