Copyright © 2008 by the Texas Heart® Institute, Houston Retractable-Needle Catheters An Update on Local Drug Delivery in Coronary Interventions | ||||
Abstract In the treatment of coronary artery disease, local delivery of pharmaceutical substances has long been a goal, yet the technology is still evolving. Coronary stents have become the predominant means of treating obstructive lesions, and the need for additional pharmacologic treatment is evidenced by the popularity of drug-eluting stents. Moreover, stents have residual limitations, in particular in-stent thrombosis and late restenosis. Investigators have recently proposed delivering coronary drugs by means of local injection devices. These innovative devices, which incorporate retractable needles at the tip of a catheter, appear to be ready for clinical testing. In addition to solving many of the limitations of drug-eluting stents, local injection devices may eventually enable interventional cardiologists to treat vulnerable plaques. Herein, we review the evolution and current status of local drug delivery in the coronary arteries, with an emphasis on novel catheters that have retractable needles. Key words: Cardiovascular agents/therapeutic use, coronary artery disease/economics, coronary disease/drug therapy, coronary restenosis/prevention & control/therapy, coronary stenosis/complications, delayed-action preparations/administration & dosage, drug delivery systems/instrumentation/methods, drug implants, equipment design, stents/adverse effects | ||||
In the clinical practice of interventional cardiology, the idea has long been accepted that coronary artery disease (CAD) is chiefly (although not only) a local process, one best treated with local methods. Segmental coronary luminal stenoses, occlusions, or unstable plaques are the most favorable targets for interventions that are aimed at preventing or limiting manifestations of ischemia and myocardial loss, including arrhythmias, congestive heart failure, and death. Coronary interventional treatment has typically consisted of mechanical solutions—surgical bypass and angioplasty. Over the years, however, several systemic pharmaceutical treatments have been introduced to decrease recurrence, stabilize lesions, or cause disease regression at target sites.1 Here, we review the evolution and current status of local drug delivery in the coronary arteries, with an emphasis on novel catheters that have retractable needles. | ||||
Stent-Angioplasty In the late 1980s, angioplasty with the use of bare-metal stents (BMSs) was introduced to obviate the most serious limitations of stand-alone balloon angioplasty: acute elastic recoil, plaque ulceration or dissection, subacute negative vessel remodeling, and fibrocellular proliferation. Angioplasty with BMSs enabled physicians to optimize the early results of vascular recanalization while avoiding elastic recoil and preventing dissection and early reclosure.2,3 Nevertheless, BMS-angioplasty did not solve the biological problems that were created by producing localized coronary trauma with a rigid, metallic device: rare, but catastrophic, postoperative acute stent thrombosis, and, more frequently, delayed in-stent restenosis. Eventually, systemic platelet anti-aggregants, namely clopidogrel and aspirin, proved effective in significantly limiting early stent thrombosis.2,3 Fibrocellular growth (mostly by means of cell proliferation and smooth-muscle-cell migration from the media level), platelet activation and aggregation, inflammation, and fibrin deposition were recognized as the mechanisms that initiate restenosis.4,5 | ||||
Drug-Eluting Stents Subacute in-stent restenosis was not treated effectively until the advent of drug-eluting stents (DESs), which deploy drugs that inhibit fibrocellular proliferation and migration.6,7 These stents are covered with porous polymer coatings that absorb the chosen drug, transport it to the target site, and deliver it over a specified time interval. Such stents are quite effective in repressing intimal growth; they lower the rate of restenosis (or late luminal loss) by 50% to 80%.7–9 Nevertheless, their advent introduced or left unsolved the following limitations:
Some Reasons for the Failure of Drug-Eluting Stents The limitations of DESs are likely related to multiple factors:
Alternative Methods of Local Drug Administration Local administration of pharmacologic agents, genes, or cells was an investigational goal even long before the introduction of DESs.22 However, no single practical solution has been found. The following options have been tested:
Local Injection Devices A novel concept in local drug delivery is a local injection device (LID), which incorporates retractable needles into a catheter device (Fig. 4).30 Two competing LIDs have recently been developed—one by Bavaria Medizin Technologie GmbH (Oberpfaffenhofen, Germany)30 and another by Binlab, Inc. (Webster, Tex). Both devices are patented, but neither is yet approved for clinical use. Each LID prototype consists of a catheter that has 3 or 4 specially designed retractable needles at its distal end. The proximal portion of the catheter houses a control mechanism that causes the needles to deploy and to penetrate the target coronary vascular layer to a predetermined depth—3 to 5 mm by the Binlab catheter, and up to 10 mm by the Bavaria catheter. In pigs, the Bavaria device has been successful in penetrating the adventitial layers29 and, alternatively, the intimal layer31 of coronary arteries. At present, the Binlab catheter has been tested only during preliminary, pilot studies in human cadavers and porcine coronary arteries (Fig. 5); its specially designed metal needles consistently entered the intima, stopped at the medial–intimal interface, and delivered the test solution. When injecting various volumes of the active drug solution over differing time periods, the operator was able to tailor the total quantities of the drug that were delivered at the target sites. The initial experience suggested that by changing the injected volume, the operator could vary the size of the circumferential, drug-filled reservoir (Figs. 5B and 5C) just inside the internal elastic membrane, from which fibrocellular restenotic growth and migration originate.1,4,5,32 After balloon predilation of the target lesion and the use of the LID as described, the general application of a BMS would be expected to complete the procedure. These initial observations suggested that fully circumferential impregnation of a 3- to 5-mm-diameter vascular wall could be achieved with adequate amounts of injected solution when 3 radially oriented needles are used.Although further studies are needed, the LID approach promises to simply and efficiently solve many limitations of current DES. Chief among them are the following:
In addition, LID technology might improve the results of even stand-alone balloon angioplasty for patients in whom stents are contraindicated (for example, in clopidogrel nonresponders or in patients who have superficial femoral artery lesions). By enabling simple local administration of medical therapy or experimental biological substances, LIDs could also be used for the preliminary testing of new drugs and their combinations in animals or human beings, and for cellular or genetic therapy; such testing would be much more cost-effective than the testing of DES models. For instance, the Bavaria LID has been successfully used to establish an interesting experimental model of atherosclerotic plaques in pigs, by the administration of cholesteryl linoleate into the intima.31 The most relevant remaining question regarding the LID approach concerns the possibility of toxic effects if a drug is administered in “excessive doses” in procedures that could be difficult to standardize. In particular, the risk of delayed aneurysm formation or rupture could be a concern.37 | ||||
Conclusions In providing local drug delivery for vascular interventions, catheter-based retractable-needle devices may offer some unique benefits.38 These devices could also presage novel, cost-effective interventions for the treatment of nonocclusive plaques that are considered vulnerable to rapid progression.32,39 Eventually, LIDs might enable plaque stabilization (for example, in an unobstructed left main trunk or a venous graft lesion) by reducing the lipid burden or the inflammatory-cell population, or by locally administering direct antithrombin or tissue-factor inhibitors. These are only some of the possible investigational and therapeutic options that might be realized with these devices. | ||||
Acknowledgments We acknowledge the editorial support of Virginia Fairchild for helping to prepare this article; of Hasitha Samarajeewa for providing the computer renditions of Figures 1 through 4; and of Tomas Klima, MD, for supplying the histologic preparations. | ||||
Footnotes Address for reprints: Paolo Angelini, MD, P.O. Box 20206, Houston, TX 77225-0206. E-mail: pangelini/at/leachmancardiology.com Dr. Angelini holds part ofthe patent rights for the local injection device manu-factured by Binlab, Inc., of Webster, Texas. Dr. Bandula holds part of the patent rights for the same device; he is also Binlab's president and majority stockholder. | ||||
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