Low molecular weight heparin (reviparin) in percutaneous transluminal coronary angioplasty. Results of a randomized, double-blind, unfractionated heparin and placebo-controlled, multicenter trial (REDUCE trial). Reduction of Restenosis After PTCA, Early Administration of Reviparin in a Double-Blind Unfractionated Heparin and Placebo-Controlled Evaluation.

OBJECTIVES: The specific objective of the REDUCE trial was to evaluate the effect of low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). BACKGROUND: Unfractionated heparin and its low molecular weight fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies. METHODS: The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single-lesion coronary artery obstructions suitable for PTCA. Three hundred six patients received reviparin as a 7,000-U bolus before PTCA, followed by 10,500 U as an infusion over 24 h and then twice-daily 3,500-U subcutaneous application for 28 days. The 306 patients in the control group received a bolus of 10,000 U of unfractionated heparin followed by an infusion of 24,000 U over 24 h. These patients then underwent 28 days of subcutaneous placebo injections. The primary end points were efficacy (defined as a reduction in the incidence of major adverse events [i.e., death, myocardial infarction, need for reintervention or bypass surgery]), absolute loss of minimal lumen diameter and incidence of restenosis during the observation period of 30 weeks after PTCA. RESULTS: Using the intention to treat analysis for all patients, 102 (33.3%) in the reviparin group and 98 (32%) in the control group have reached a primary clinical end point (relative risk [RR] 1.04, 95% confidence interval [CI] 0.83 to 1.31, p = 0.707). Likewise, no difference in late loss of minimal lumen diameter was evident for both groups. Acute events within 24 h occurred in 12 patients (3.9%) in the reviparin group and 25 (8.2%) in the control group (RR 0.49, 95% CI 0.26 to 0.92, p = 0.027) during or immediately after the initial procedure. In the control group, eight major bleeding complications occurred, and in the reviparin group, seven were observed within 35 days after PTCA. CONCLUSIONS: Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.

The induction of liver peroxisomal proliferation by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16).

Treatment of rats by beta,beta'-methyl-substituted hexadecanedioic acid (MEDICA 16) resulted in a dose- and time-dependent increase in liver peroxisomal enoyl-CoA hydratase and cyanide-insensitive palmitoyl-CoA oxidation with a concomitant increase in the volume density of peroxisomes as determined by morphometry. The induced peroxisomal proliferation was sustained as long as treatment was maintained and was accompanied by an increase in liver weight. Incubation of cultured rat hepatocytes in the presence of MEDICA 16 added to the culture medium resulted in a dose-dependent increase in peroxisomal beta-oxidation activities with a concomitant elevation of the volume density of peroxisomes. The induction of peroxisomal proliferation by MEDICA 16 in culture could be prevented in the presence of carnitine palmitoyltransferase inhibitors added to the culture medium, e.g. 2-bromopalmitate, 2-tetradecylglycidic acid or 2-[5-(4-chlorophenyl)-pentyl]oxirane-2-carboxylate. The induction of liver peroxisomes by MEDICA 16 conforms to the previously defined requirement for an amphipathic carboxylate in initiating peroxisomal proliferation. The prevention of peroxisomal proliferation by carnitine acyltransferase inhibitors may implicate the involvement of this acyltransferase in the induction of peroxisomal proliferation by xenobiotic or native amphipathic carboxylates.

The short- and long-term effects of bezafibrate in the rat.

Bezafibrate is a potent hypolipidemic agent, which causes marked proliferation of peroxisomes in rat liver. At the same dosage, bezafibrate is more effective in male than in female rats. This is probably related to divergent pharmacokinetics, which cause differences in drug level in serum and liver. The volume density of peroxisomes and several of their enzymes such as carnitine acetyl transferase and acyl-COA oxidase increase in a dose-related fashion. The hypolipidemic effect of bezafibrate, however, does not correlate with the used dosage. This implies that peroxisomal proliferation may play only a minor role in the hypolipidemic action of bezafibrate. In animals treated for 26 months with 300, 750, or 1500 ppm bezafibrate, the relative liver weight and serum triglycerides did not differ significantly from controls. Peroxisomal proliferation varied in different cells, being most prominent in single hepatocytes. The liver catalase activity was significantly reduced, but carnitine acetyl transferase was increased. Abnormal peroxisomes and mitochondria with longitudinal cristae were quite frequent. In one focus, catalase activity was severely diminished ahd peroxisomes were markedly reduced. The incidence of liver tumors was the same (1-3%) in treated animals as in controls.

First clinical experience with low molecular weight heparin LU 47311 (reviparin) for prevention of restenosis after percutaneous transluminal coronary angioplasty.

Restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains a major problem limiting the clinical efficacy of the procedure. It has been shown that SMC proliferation plays a predominant role in this accelerated atherosclerotic process. In vitro and in vivo experiments with the LMWH reviparin (LU 47311) suggest a pronounced inhibitory effect of this compound on SMC proliferation. To evaluate the safety of reviparin and the incidence of angiographic restenosis in humans a study with increasing dosages was conducted in 41 patients. Repeat coronary angiography was performed 3 months after angioplasty. Restenosis occurred in 5 of 37 evaluable patients (14%) with initially successful PTCA. No major bleeding complication was documented for any of the patients included in this trial. Thus, in this limited series, administration of LU 47311 (reviparin) resulted in a low incidence of restenosis following PTCA without causing major bleeding complications. A randomized trial in a larger population is warranted to define the real impact of this compound for reduction of restenosis in patients who underwent successful balloon angioplasty.

[Low molecular weight heparin, reviparin, after PTCA: results of a randomized double-blind, standard heparin and placebo controlled multicenter study (REDUCE Study]. / Niedermolekulares Heparin, Reviparin, nach PTCA: Ergebnisse einer randomisierten, doppelblinden, Standard-Heparin- und Plazebo-kontrollierten multizentrischen Studie (REDUCE-Studie).

BACKGROUND: Unfractionated heparin and its low molecular fragments possess antiproliferative effects and have been shown to reduce neointimal smooth muscle cell migration and proliferation in response to vascular injury in experimental studies. OBJECTIVES: The specific objective of the REDUCE trial was to evaluate the effect of a low molecular weight heparin on the incidence and occurrence of restenosis in patients undergoing percutaneous transluminal coronary angioplasty. METHODS: The REDUCE trial is an international prospective, randomized, double-blind, multicenter study. Twenty-six centers in Europe and Canada enrolled 625 patients with single lesion coronary artery obstructions suitable for PTCA. Three hundred and six patients received reviparin as a 7000 U bolus before PTCA followed by 10,500 U as an infusion over 24 hours and then twice a day 3500 U s.c. application for 28 days. The 306 patients in the control group received a bolus of 10,000 U unfractionated heparin followed by an infusion of 24,000 U over 24 hours. These patients then received 28 days of s.c. placebo injections. The primary endpoints were efficacy (defined as a reduction in the incidence of major adverse events, i.e., death, myocardial infarction, need for reintervention or bypass surgery), absolute loss of minimal luminal diameter, and incidence of restenosis during the observation period of 30 weeks after PTCA. RESULTS: Using the intention-to-treat analysis for all patients, 102 patients (33.3%) of the reviparin group and 98 patients (32%) of the control group have reached a primary clinical endpoint (relative risk = 0.98; 95% confidence limit, 0.88-1.09; p = 0.707). Likewise, no difference in late loss of minimal luminal diameter was evident for either group. Acute events within 24 hrs occurred in 3.9% of the reviparin group and in 8.2% of the control group (relative risk = 0.49; 95% confidence limit, 0.26-0.92; p = 0.027) during or immediately after the initial procedure. In the control group, 8 major bleedings occurred, and in the reviparin group, 7 major bleeding complications were observed within 35 days after PTCA. CONCLUSIONS: Reviparin use during and after coronary angioplasty did not reduce the occurrence of major clinical events or the incidence of angiographic restenosis over 30 weeks.