Early Plus Delayed Hirudin Reduces Restenosis in the Atherosclerotic Rabbit More Than Early Administration Alone Potential Implications for Dosing of Antithrombin Agents (original) (raw)
Related papers
1998
Background-Arterial injury after percutaneous transluminal coronary angioplasty (PTCA) triggers acute thrombus formation and thrombin generation. Hirudin, a potent and direct thrombin inhibitor, prevents thrombus formation after arterial injury. Two large clinical trials showed marked reduction in acute clinical events but no long-term benefits in reducing restenosis during short-term administration of thrombin inhibitors. Our hypothesis is that adequate, maintained thrombin inhibition, by inhibiting all the thrombin-dependent mechanisms, will reduce neointima formation after PTCA. Methods and Results-Thirty-six pigs received three different regimens of hirudin: bolus (1 mg/kg), short-term (bolusϩ0.7 mg/kg per day for 2 days), and long-term (bolusϩ0.7 mg/kg per day for 14 days). The results on neointima formation at 4 weeks after coronary angioplasty were compared with the control group (100 IU heparin/kg bolus). Hirudin was continuously administered for 2 weeks through an infusion pump. In vivo thrombin generation was persistently increased up to 2 weeks after angioplasty. Inhibition of thrombin activity for 14 days reduced luminal narrowing by 40% (58Ϯ3% versus 35Ϯ3%; PϽ.001). No differences were observed among the bolus and short-term hirudin groups and the control group. Conclusions-Our results indicate that there is a continued, marked thrombin generation that lasts for at least 2 weeks after PTCA. Administration of r-hirudin for 2 weeks significantly reduces neointima formation after PTCA. This observation, if extrapolated to humans, could explain the lack of effect on restenosis observed in the clinical trials with antithrombin agents despite the clear benefits on reducing acute thrombotic complications after PTCA. Therefore an adequate and prolonged administration of thrombin inhibitors is needed to "passivate" the thrombogenic substrate (disrupted arterial wall) and achieve full benefit of this therapeutic approach.
A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty
New England Journal …, 1995
Background. The likelihood of restenosis is a major limitation of coronary angioplasty. We studied whether hirudin, a highly selective inhibitor of thrombin with irreversible effects, would prevent restenosis after angioplasty. We compared two regimens of recombinant hirudin with heparin. Methods. We randomly assigned 1141 patients with unstable angina who were scheduled for angioplasty to receive one of three treatments: (1) a bolus dose of 10,000 IU of heparin followed by an intravenous infusion of heparin for 24 hours and subcutaneous placebo twice daily for three days (382 patients), (2) a bolus dose of 40 mg of hirudin followed by an intravenous infusion of hirudin for 24 hours and subcutaneous placebo twice daily for three days (381 patients), or (3) the same hirudin regimen except that 40 mg of hirudin was given subcutaneously instead of placebo twice daily for three days (378 patients). The primary end point was event-free survival at seven months. Other end points were early cardiac events (with-in 96 hours), bleeding and other complications of the study treatment, and angiographic measurements of coronary diameter at six months of follow-up. Results. At seven months, event-free survival was 67.3 percent in the group receiving heparin, 63.5 percent in the group receiving intravenous hirudin, and 68.0 percent in the group receiving both intravenous and subcutaneous hirudin (P ϭ 0.61). However, the administration of hirudin was associated with a significant reduction in early cardiac events, which occurred in 11.0, 7.9, and 5.6 percent of patients in the respective groups (combined relative risk with hirudin, 0.61; 95 percent confidence interval, 0.41 to 0.90; P ϭ 0.023). The mean minimal luminal diameters in the respective groups on follow-up angiography at six months were 1.54, 1.47, and 1.56 mm (P ϭ 0.08). Conclusions. Although significantly fewer early cardiac events occurred with hirudin than with heparin, hirudin had no apparent benefit with longer-term follow-up. (N Engl
Circulation, 1994
BACKGROUND The major morbidity of percutaneous transluminal coronary angioplasty is acute thrombosis and restenosis of the dilated lesion. Platelet-thrombus deposition occurs within minutes after injury, is primarily mediated by thrombin, causes acute occlusion, and contributes to late restenosis. Experimentally, specific thrombin inhibitors have prevented mural thrombosis. However, local therapy may be more effective than systemic treatment. We tested the hypothesis that high local concentrations of an antithrombin drug at the site of arterial injury following balloon angioplasty inhibit platelet thrombus formation equally or better than conventional systemic treatment and at lower systemic anticoagulant levels. METHODS AND RESULTS Balloon angioplasty of the carotid arteries of 29 pigs was performed using systemic intravenous treatment with heparin (100 U/kg, groups I and II), suboptimal r-hirudin (0.3 mg/kg, group III), and higher-dose r-hirudin (0.7 mg/kg, group IV), which is the...
The role of platelets, thrombin and hyperplasia in restenosis after coronary angioplasty
Journal of the American College of Cardiology, 1991
Coronary angioplasty has gained wide aeceptancc as the proecdttre oi choice in many patients aith coronary artery disease Gtce its first introduction in I977 (1). Inttially restricted to patients with single vessel disease and stable angina. its use has been expanded to unstable angina. acute myocardisl infarction and multivessel coron~y artciy Jlrease Despite impmvementr in cquipmcnt nn~! ircnmque. acute reocclusion alter succcssf~l Lgiopla5ty occur\ m approximately 5% of palientr and Me re\tenoG\ Igcilerall) in.53 month& the most important problem after coronar) angioplasty. occurs in 25% to :iR of patients. We reccmly reviewed (1) the mechimiaas of acute wxluion and rc~tcnusis after angioplarty, and the currenity available pharmucologic approaches for their prevention. In thir report. me summarize our current understanding of the process of poangioplasty occlusion and resteno\i\. with \p+cial attention to the contributory role of olateletr. thrombtn and thrombosis. orgaoizUion and incor&xaion of the thrombw and subsequent intimill hyperptwia. proliferation: and Jl the rote of currem pharmacologic rhcrapy and powble future approachcr. Mechanisms of Dilalion of Stenotie Lesions htwhanisms. Experimenta! and clinical observations 131 wgge\t that four mechanisms may be involved in succesrful angiopbw First. balloon inflation results in tears. fractures ad crack\ in the Qmotic plaqile. entargmg the channel ihmugh which blood is able to Row and improving ve-.set patmcy. Secunu. because plaque tears at the point of least re\~.mce. dissection rhrough the intima into the media cawes enliwgrment of the vessel lumen. With further balluon expansion. the media and adventitia of the artery may stretch to conform with the outer diameter of the inflated balloon. A thtrd mechanism by which bslloa angioplasty may \rorh i) through redibtributmn and compression of the pkique. nprcially plaque composed mainly of tbrombotic dcpuril>. fm&. depending on the degree ofeccentricity of the plequc and its composition. balloon i&lion may rewlt in di*tenGon or stretching of only the disease-free arc of the normid vc\w4 wll and produce little or no damage to the plaque itvlf. Although an initial increment in luminal diameter occurs. 11 may he to>1 within hours. days or seeks after the ddatlon as a result of gradual rclaxadon of the over-\Irexhed segment tre,titution of tone or elastic recoil). Recent observation\ IJI derived from microscopic euminalion of athcrcctomy specimens suggest that this mechanism m;by occur in up to !S% ofangioplasty procedures claartfied a> succc4ui bawd on the milial ang!ognm. Restenobis
Atherosclerosis, 1998
PTCA is a well-established intervention to reduce the severity of atherosclerotic coronary stenosis. Its primary success rate is seriously handicapped by the high incidence of late restenosis. Given the clinical and social importance of this proliferative process, new strategies are needed to prevent or reduce restenosis. Several animal models as well as different arteries have been used to study neointimal proliferation after arterial injury. A number of agents have shown to reduce neointimal proliferation after arterial injury in the carotids and iliac arteries of rodent models. Unfortunately, these results have not been replicated in humans. We have compared the acute and late response to vascular injury of the carotid and coronary arteries in the pig. Arterial injury was induced by performing balloon angioplasty of the carotid (elastic) and coronary (muscular) arteries in swine. Acute platelet-thrombus formation was evaluated by quantitation of Indium-labeled platelets deposited on the injured segments 1 h after procedure. Measurement of intimal area was performed by morphometry of the most stenotic cross-section at 28 days after balloon angioplasty. Platelet deposition after mild and severe injury in carotids (4 91 and 56 913× 10 6 platelets/cm 2 , respectively) and coronaries (15 95 and 141 9 20 × 10 6 platelets/cm 2 , respectively) are significantly greater in deep, than in mild injury (P B0.005), and significantly greater in coronary than in carotid arteries after deep injury (PB0.05). Likewise, late neointima formation was significantly greater (PB 0.05) after mild and severe injury in coronary (17 9 0.5 and 56 9 2%, respectively) than in carotid arteries (590.5 and 1291%, respectively). Acute platelet-thrombus formation and late neointimal thickening are modulated by the degree of injury induced during the interventions; and after disruption of the internal elastic lamina, coronary arteries always had significantly more acute thrombus and neointimal thickening. This study emphasizes the importance of the animal species, the type of injury and the artery chosen for studies on restenosis post interventions.
Inhibition of Thrombin Attenuates Stenosis After Arterial Injury in Minipigs
Journal of the American College of Cardiology, 1996
Objectives. We sought to determine whether brief, profound inhibition of thrombin or prothrombin activation by factor Xa limits neointimal formation and stenosis after arterial injury. Background. Thrombin has been implicated as a mediator of neointimal formation, but adjunctive administration of anticoagulant agents has not proven effective to decrease restenosis in patients undergoing coronary angioplasty. Methods. We infused recombinant desulfatohirudin (r-hirudin, bolus of 2 mg/kg body weight followed by 2 mg/kg per h, n ؍ 9), heparin (100 U/kg per h, n ؍ 6) or recombinant tick anticoagulant peptide (rTAP, 1-mg/kg bolus followed by 3 mg/kg per h, n ؍ 5), a specific inhibitor of factor Xa, intravenously, beginning 15 min before and for up to 3 h after repetitive balloon hyperinflations sufficient to disrupt the internal elastic lamina in a carotid artery of minipigs with hypercholesterolemia induced by feeding them an atherogenic diet. Results. Partial thromboplastin time was increased six-to sevenfold over baseline levels at the end of the infusions of the anticoagulant agents. Lumen stenosis measured histologically 4 weeks after balloon-induced carotid injury was 29 ؎ 16% (mean ؎ SEM) in r-hirudin-treated, 52 ؎ 19% in rTAP-treated and 76 ؎ 18% in heparin-treated pigs (p < 0.02 for r-hirudin vs. heparin treatment). Conclusions. The marked reduction of stenosis in r-hirudintreated animals indicates that thrombin plays a major role in neointimal formation after balloon-induced arterial injury. A relatively brief interval of profound, direct inhibition of thrombin may be particularly effective to attenuate restenosis after balloon angioplasty.
Platelet and fibrin deposition on coronary stents in minipigs: Effect of hirudin versus heparin
Journal of the American College of Cardiology, 1993
O~jeetives. The present study was designed to test the hypothesis that the direct thmmbin inhibitor hbxdin is mc~re efficient than beparln in reducing tkrmnhus Formation r&r coronary stenting. Background. Despite aggressive anticoagulatirr~. r&ztl;:e thrombosis of coronary stents is a major mmpticatton associated with these new devices. M&hods. In 19 minipigs indium-lll-tabeled thmmhwyies and ioditw1254abeled Ilbrinogen were injected 14 tn 19 It before commwy implantation of tantalum h&on-expnndable sttents. In group 1 (n = 6, seven rtents), a b&s of hsparin (100 U/kg body wefght) was given before stenting. Group 2 (II = 6. 11 stenls) nnived holh d&ran (500 ml) and hsparin ta 1MUikg bolus followed by P continuous infusion of SO U/kg per h). Ia group 3 [n = 7,J3 statts), birudln (remmbinant desalphatoldrudin HV 1 [CGP 393931 [I mgikg]) was given before stat Implantation, followed by cm lnfuslon of 1 m#kg per h. AU animals were txetreated with aspirin (250 mg intravenmtsly). rtonts in group 3. The aumber of pl*telets on 1 s&e& averz@ 116.2 (range 22 to 5221 x lo" iagrmtp 1,643 (e I1 tn 169) x lo6 in group 2 and 19.7 (range 9 to 38) X l@ in group 3 (p < LX@% vs. grouy 1 and KS. group 2). T&e increase in #&et awxiat?d with medial tear in all gmups, WPS Law& ia group. Simttarty, &&I depositiw was twvst en steats treated animals. reduction achieved with cmnblwd kelrzxin, dext%%n & (J Aa Cdl Canlid 1993,21:2&54) Percutaneous transluminal coronary angioplasty is increasingly applied as the primary revascttlarization procedure in patients with obstructive coronary artery disease (I,Z). However. two major problems limit its immediate and longterm success. Abnrpt coronary occlusion occurs in 2% to II% of patients (3.4) and restenosis of successfully dilated lesions is observed in 20% to 40% of patients (5.61. lntracoronary stents have been suggested as a means to manage both acute occlusion, by pressing obstructive intimal tears to the vessel wall (7). and restenosis, by creating a large smooth-eontourcd lumen, preventing elastic recoil and providing enough space for a reparative vessel response nor restthing in significant lumen obstruction (8.9). Fmm the Departments 01 Cardiology, Nuclear Medicine. Exprrimtnlti AniaUl Research and Nephrology. University Clmic. Cirningen. Germany. This work was supperred by a &znt rrflron Deursche Forschun~~semeinrchaR. SFB 3343. GWngcn. Germany. This work ccmtains part of the Habiiitalian-s_xhrift of Dr. Buchwald. Manuwipl r&vcdJaruary 13. 19% revised manuscript received June 22, 1992. acceplcd June 23. 1592.-[or Amd B. Buchwald. MD, Department of Cardiolagy~Universily Clinic. RoberiXochSkasse 40. WI Gallingen. Gcr.
Determination of the dosage of recombinant hirudin to inhibit arterial thrombosis in baboons
Journal of Pharmaceutical Sciences, 2000
Recombinant hirudin, a potent and direct inhibitor of thrombin, effectively inhibits platelet-dependent thrombosis. Our aim was to establish the plasma concentration at which r-hirudin expresses its optimal antithrombotic effect. We measured the extent of inhibition of 111 In-labeled platelet deposition onto 0.6 cm 2 segments of Dacron vascular grafts. These grafts were incorporated as extension segments into exteriorized permanent femoral arteriovenous shunts in baboons. In six control studies a mean of 1.99 ± 0.26 × 10 9 platelets were deposited at the end of 120 min. In the treatment studies, a thrombus was allowed to form for 10 min in six animals. Treatment for 30 min with r-hirudin at dosages of 140, 70, and 35 g/kg/min, but not 14 g/kg/min, dose dependently interrupted platelet deposition. The relationship between the percent inhibition of platelet deposition caused by r-hirudin and the plasma concentration of hirudin was exponential (i.e., % Inhibition ס 95(1−e 0.23 × [r-hirudin] ) (R 2 ס 0.76). From this, we estimated that 50% inhibition of platelet deposition will occur at a plasma concentration of approximately 3.3 g r-hirudin/mL and 80% at 8.1 g/mL. The relationship between the inhibition of platelet deposition and the plasma concentration of hirudin makes it possible to estimate the dose of hirudin that will result in a given level of inhibition of platelet deposition.