Use of collagenase to facilitate guide wire crossing in total arterial occlusions

Abstract

The use of a collagenase containing formulation for degrading collagen within an occlusive atherosclerotic plaque in a chronic fibrotic occlusion, chronically occluded animal tube or cavity. A medical-related apparatus is provided comprising a medical-related device having provided thereto a therapeutic amount of a collagen degrading composition comprising a proteiolytic enzyme containing formulation. A method is provided for treating chronically occluded animal tubes and cavities by administering a therapeutic effective amount of a proteolytic enzyme-containing formulation adjacent to an occluding atherosclerotic plaque, waiting for a pre-angioplasty waiting period, followed by crossing the plaque with an angioplasty guide wire.

Description

The present invention relates to the field of percutaneous interventions of occluded arteries using local infusion of collagenase or a combination of enzymes that include collagenase. BACKGROUND OF THE INVENTION Scope of Problem: Chronic total occlusions (CTO) are an extremely common finding in patients undergoing diagnostic catheterization. Up to 20% of patients undergoing angiography have been reported to have one or more chronic total coronary occlusions1. Balloon angioplasty is one treatment modality for CTO with the first successful report appearing in 19822. Percutaneous coronary interventions (PCI) continue to increase annually with >1 million procedures world-wide in 19983, and CTO currently account for approximately 10%-15% of PCI4-7. However, since PCI have severe limitations in this patient subset, clinicians frequently decide to refer these patients for bypass surgery or persist with (often ineffective) medical therapy. The presence of one or more CTO of vessels su...

AI Technical Summary

Benefits of technology

The use of a collagenase containing formulation has been identified for degrading collagen within an occlusive atherosclerotic plaque in a chronically occluded animal tube or cavity. More particularly, a collagenase containing formulation is used as an infusion preparation for administration and retention of a therapeutic dosage of collagenase adjacent to or into the atherosclerotic plaque during a formulation exposure waiting period.

A medical-related apparatus is provided for degrading collagen within an occlusive atherosclerotic plaque in a chronically occluded animal tube or cavity comprising a me

Problems solved by technology

However, since PCI have severe limitations in this patient subset, clinicians frequently decide to refer these patients for bypass surgery or persist with (often ineffective) medical therapy.

The main limitations of PCI for CTO are the decreased procedural success rates compared to stenotic (but not totally occluded) arteries, and a high restenosis rate.

Thus a purely mechanical approach of designing stiffer and more powerful guide wires to try and push through fibrotic total occlusions has only limited efficacy.

Although thrombolytic therapy is effective in acute coronary occlusions, only a small number of native artery chronic occlusions have been treated with prolonged thrombolytic infusions with limited results and this strategy has largely been abandoned.

Consequently, significant angina pectoris represents the most common cause of attempted PCI in the setting of CTO.

The situation of inadequate blood supply to viable myocardium (termed “hibernating myocardium”) is also a major cause of potentially reversible myocardial dysfunction leading to heart failure.

Moreover, there is accumulating data that CTO portend a poorer prognosis.

Release of various enzymes (trysin or papain alone or in combination with collagenase) frequently resulted in not only dissolution of the plaques but also caused extensive damage to the media of the artery.

Moreover, none of these studies address the unique clinical situation of a chronically occluded artery in which a long segment of artery is completely occluded and will not permit the passage of guide wires which are an absolute requirement for performing balloon angioplasty and stenting.

Experimental studies of chronically occluded arteries have been limited by the lack of a suitable animal model.

Infusion therapy with collagenase and urokinase were attempted, but patentcy was not restored in any animal and attempts at the passage of a guide wire through the occlusion were unsuccessful.

However, these methods of enzyme delivery would likely only be relevant for non-occluded arteries, particularly for generalized atherosclerosis disease.

In this setting, much higher concentrations of enzymes are required which can only be achieved through a localized delivery system.

However, this application of the fibronolytic matrix metalloproteinase is not relevant to the problem of performing angioplasty in chronically occluded arteries, which contain extensive collagen and other extracellular matrix components and very minor amounts of fibrin or fibrinogen.

In addition, as stated above, the systemic delivery method is not relevant to local delivery into arterial occlusions.

In summary, CTO remain an important subset of PCI lesions with quite limited success, predominantly due to inability of crossing the occlusion with a guide wire.

The vast majority of patients with symptomatic chronic total occlusions are either treated by medical therapy with often limited effectiveness or undergo invasive bypass surgery.

In addition to causing significant angina, there is strong evidence that CTO are also associated with poorer left ventricular function and possibly worse survival than stenotic (but not occluded) lesions or successfully dilated chronic occlusions.

Thus, the current evidence suggests that opening total occlusions by percutaneous interventions is underutilized and necessitates new approaches.

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