Heparin Infusion Prior to Stenting (HIPS) Trial
Heparin Infusion Prior to Stenting (HIPS) Trial
Background: Local delivery of pharmacologic agents or genes at the site of angioplasty is a promising approach to reduce restenosis. However, there are unresolved questions concerning the safety and feasibility of local vascular delivery in clinical practice as well as the efficacy of delivered drug. To this end, the safety, feasibility, and efficacy of local delivery of heparin were evaluated in the Heparin Infusion Prior to Stenting (HIPS) trial.
Methods and Results: A total of 179 patients were enrolled in this multicenter, randomized, prospective, core laboratory-evaluated trial. Patients were randomly assigned to 5000 U heparin either administered to the coronary artery lumen or infused into the arterial wall immediately after angioplasty and before stent placement. End points included procedural events and clinical, angiographic, and intravascular ultrasound events at 6 months. Patient groups were evenly matched. There was no difference in the incidence of arterial injury, defined as an increase in arterial dissection, acute closure, or decrease in Thrombolysis In Myocardial Infarction grade blood flow in the group receiving local delivery. At follow-up there was no difference in the major adverse event rate between intraluminal (22.7%) and local groups (24.7%). There was no difference between intraluminal and local therapy in the angiographic in-stent restenosis rate (12.5%, 12.7%) or the in-stent volumetric analysis by intravascular ultrasound (IVUS) (37.19 ± 20.86 mm vs 43.79 ± 25.52 mm).
Conclusions: Local delivery of 5000 U heparin into the arterial wall before stent implantation is safe and feasible. There was not a favorable effect of locally delivered heparin on clinical, angiographic, or IVUS end points of restenosis. The use of IVUS to measure volume of intimal hyperplasia in a multicenter, core laboratory-controlled trial is feasible.
Restenosis after percutaneous transluminal coronary procedures remains an important long-term limitation. Probucol has demonstrated efficacy in reducing restenosis after percutaneous transluminal coronary angioplasty (PTCA); however, the medication must be started 1 month before the procedure, reducing its feasibility in the majority of patients. Elective implantation of an intracoronary stent reduces the restenosis rate compared with balloon angioplasty, but angiographic restenosis still develops in 22% to 32% of patients. An important limitation of systemic drug delivery of pharmaceutical agents may be the inability to rapidly achieve an adequate drug concentration within the arterial wall. Furthermore, extracardiac side effects limit increases in dosing. An alternative approach is the local delivery of concentrated pharmacologic or genetic agents because this method results in substantially increased arterial wall levels compared with a systemic delivery or delivery through a guiding catheter.
To be a successful therapy, local vascular delivery must not be associated with an increase in periprocedural complications or cause a subsequent increase in intimal hyperplasia as manifested by restenosis. Heparin is an ideal initial agent to evaluate the acute and chronic effects of local vascular delivery because it is used routinely in percutaneous procedures and has a long-established safety profile. In addition to its potent anticoagulative effects, heparin has a variety of biological actions, which include inhibition of smooth muscle cell proliferation and migration and suppression of matrix-degrading protease expression. The effects of the systemic administration of heparin in reducing intimal hyperplasia after angioplasty-induced injury have been contradictory. In the rat carotid and porcine coronary models of arterial injury, heparin reduces intimal proliferation. However, in the baboon model, no effect was observed. Studies evaluating the clinical efficacy of heparin delivered systematically have also shown no effect on restenosis. Alternatively, local delivery of heparin into porcine carotid arteries reduces platelet deposition by 39% in the initial 12 hours after angioplasty-induced injury, a step postulated to reduce eventual intimal area. Therefore the Heparin Infusion Prior to Stenting (HIPS) trial was designed to determine the safety of the local vascular delivery approach and the efficacy of a local delivery of heparin on intimal hyperplasia after elective stent implantation.
Background: Local delivery of pharmacologic agents or genes at the site of angioplasty is a promising approach to reduce restenosis. However, there are unresolved questions concerning the safety and feasibility of local vascular delivery in clinical practice as well as the efficacy of delivered drug. To this end, the safety, feasibility, and efficacy of local delivery of heparin were evaluated in the Heparin Infusion Prior to Stenting (HIPS) trial.
Methods and Results: A total of 179 patients were enrolled in this multicenter, randomized, prospective, core laboratory-evaluated trial. Patients were randomly assigned to 5000 U heparin either administered to the coronary artery lumen or infused into the arterial wall immediately after angioplasty and before stent placement. End points included procedural events and clinical, angiographic, and intravascular ultrasound events at 6 months. Patient groups were evenly matched. There was no difference in the incidence of arterial injury, defined as an increase in arterial dissection, acute closure, or decrease in Thrombolysis In Myocardial Infarction grade blood flow in the group receiving local delivery. At follow-up there was no difference in the major adverse event rate between intraluminal (22.7%) and local groups (24.7%). There was no difference between intraluminal and local therapy in the angiographic in-stent restenosis rate (12.5%, 12.7%) or the in-stent volumetric analysis by intravascular ultrasound (IVUS) (37.19 ± 20.86 mm vs 43.79 ± 25.52 mm).
Conclusions: Local delivery of 5000 U heparin into the arterial wall before stent implantation is safe and feasible. There was not a favorable effect of locally delivered heparin on clinical, angiographic, or IVUS end points of restenosis. The use of IVUS to measure volume of intimal hyperplasia in a multicenter, core laboratory-controlled trial is feasible.
Restenosis after percutaneous transluminal coronary procedures remains an important long-term limitation. Probucol has demonstrated efficacy in reducing restenosis after percutaneous transluminal coronary angioplasty (PTCA); however, the medication must be started 1 month before the procedure, reducing its feasibility in the majority of patients. Elective implantation of an intracoronary stent reduces the restenosis rate compared with balloon angioplasty, but angiographic restenosis still develops in 22% to 32% of patients. An important limitation of systemic drug delivery of pharmaceutical agents may be the inability to rapidly achieve an adequate drug concentration within the arterial wall. Furthermore, extracardiac side effects limit increases in dosing. An alternative approach is the local delivery of concentrated pharmacologic or genetic agents because this method results in substantially increased arterial wall levels compared with a systemic delivery or delivery through a guiding catheter.
To be a successful therapy, local vascular delivery must not be associated with an increase in periprocedural complications or cause a subsequent increase in intimal hyperplasia as manifested by restenosis. Heparin is an ideal initial agent to evaluate the acute and chronic effects of local vascular delivery because it is used routinely in percutaneous procedures and has a long-established safety profile. In addition to its potent anticoagulative effects, heparin has a variety of biological actions, which include inhibition of smooth muscle cell proliferation and migration and suppression of matrix-degrading protease expression. The effects of the systemic administration of heparin in reducing intimal hyperplasia after angioplasty-induced injury have been contradictory. In the rat carotid and porcine coronary models of arterial injury, heparin reduces intimal proliferation. However, in the baboon model, no effect was observed. Studies evaluating the clinical efficacy of heparin delivered systematically have also shown no effect on restenosis. Alternatively, local delivery of heparin into porcine carotid arteries reduces platelet deposition by 39% in the initial 12 hours after angioplasty-induced injury, a step postulated to reduce eventual intimal area. Therefore the Heparin Infusion Prior to Stenting (HIPS) trial was designed to determine the safety of the local vascular delivery approach and the efficacy of a local delivery of heparin on intimal hyperplasia after elective stent implantation.
Source...