Regulatory affairs as they affect invasive cardiology.

Over the last several years, the United States Food and Drug Administration (FDA) has significantly improved the time required for the approval of PMA and PMA supplement applications. By the year 1999, the average approval time for PMA applications was 12 months and the average approval time for PMA supplements was only 4 months. In spite of this improved performance by the FDA, it is still advantageous for many products to have their first clinical trial outside the United States.

The impact of stent design and delivery upon the long-term efficacy of radioisotope stents.

Both gamma and beta irradiation delivered via a radioactive catheter-based line source have been shown to have efficacy in reducing restenosis. However, these catheter-based treatments have some limitations, including the safety of handling sources ranging from 30 mCi to 500 mCi. Alternatively, one could use a stent as the platform for local radiation delivery as a means to prevent restenosis. Experimental studies have demonstrated that stents ion implanted with the b-particle emitter 32P can reduce neointima formation. Clinical evaluation of the radioisotope stent began in the fall of 1996. Dose escalation studies have now been completed in approximately 250 patients with 32P, b-particle emitting stents ranging from 0.5 microCi to 24 microCi. Overall, these feasibility trials have demonstrated a clear, dose-dependent reduction of neointimal hyperplasia within the stent structure, but with an unanticipated finding of a relatively high incidence of restenosis at the stent margins. The purpose of this paper is to review the current status of radioactive stents, with an emphasis on the key elements of stent design and stent delivery that could impact the long-term efficacy of this device.

Effects of endovascular radiation from a beta-particle-emitting stent in a porcine coronary restenosis model. A dose-response study.

BACKGROUND: Neointimal formation causes restenosis after intracoronary stent placement. Endovascular radiation delivered via a stent has been shown to reduce neointimal formation after placement in porcine and rabbit iliac arteries. The objective of this study was to evaluate the dose-related effects of a beta-particle-emitting radioactive stent in a porcine coronary restenosis model. METHODS AND RESULTS: Thirty-seven swine underwent placement of 35 nonradioactive and 39 beta-particle-emitting stents with activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 microCi of 32P. Treatment effect was assessed by histological analysis 28 days after stent placement. Neointimal and medial smooth muscle cell density were inversely related to increasing stent activity. The neointima of the high-activity (3.0- to 23.0-microCi) stents consisted of fibrin, erythrocytes, occasional inflammatory cells, and smooth muscle cells with partial endothelialization of the luminal surface. In the 1.0-microCi stents, the neointima was expanded and consisted of smooth muscle cells and a proteoglycan-rich matrix. The neointima of the low-activity (0.15- and 0.5-microCi) stents was composed of smooth muscle cells and matrix with complete endothelialization of the luminal surface. At low and high stent activities, there was a reduction in neointimal area (low, 1.63 +/- 0.67 mm2 and high, 1.73 +/- 0.97 mm2 versus control, 2.40 +/- 0.87 mm2) and percent area stenosis (low, 26 +/- 7% and high, 26 +/- 12%) compared with control stents (37 +/- 12%, P < or = .01). The 1.0-microCi stents, however, had greater neointimal formation (4.67 +/- 1.50 mm2) and more luminal narrowing (64 +/- 16%) than the control stents (P < .0001). CONCLUSIONS: The differential response to the doses of continuous beta-particle irradiation used in this experimental model suggests a complex biological interaction of endovascular radiation and vascular repair after stent placement. Further study is required to determine the clinical potential for this therapy to prevent stent restenosis.

Inhibition of neointimal proliferation with low-dose irradiation from a beta-particle-emitting stent.

BACKGROUND: Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a beta-particle-emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries. METHODS AND RESULTS: Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven beta-particle-emitting radioisotope stents (32P, activity level 0.14 microCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76 +/- 0.37 mm2 versus 2.81 +/- 1.22 mm2, P = .05) and percent area stenosis (24.6 +/- 2.9% versus 36.0 +/- 10.7%, P = .02) within the beta-particle-emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26 +/- 0.04 mm versus 0.38 +/- 0.10 mm, P = .012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the beta-particle-emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index. CONCLUSIONS: A local, continuous source of low-dose endovascular irradiation via a beta-particle-emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.

Ex-vivo results using a new pullback atherectomy catheter (PAC).

In order to evaluate the feasibility of performing definitive atheromatous plaque removal using a novel retrograde cutting (Pullback) atherectomy catheter, pullback atherectomy was performed in 13 severely diseased cadaveric superficial femoral arteries. All experiments were performed using cadaver tissue either mounted in a perfusion/mounting chamber (n = 10) or left in situ (n = 3). In general, a single cut was made with each of three sequentially larger atherectomy catheters (2.5 mm, 3.0 mm, and then 3.5 mm devices). The results were evaluated by angiography and by light microscopy. Nine of the 13 experiments were performed in totally occluded vessels. The mean pre-atherectomy stenosis (all specimens) was 95 +/- 3%, with a final mean postatherectomy stenosis of 21 +/- 5%. There was one vessel performation. We conclude from these preclinical studies that retrograde atherectomy with the Pullback Atherectomy Catheter is a feasible means of performing definitive atherectomy. Despite the promising potential of retrograde atherectomy, little can be said with certainty about the clinical utility of such a device at this early stage.

The programmable implantable medication system (PIMS): design features and pre-clinical trials.

This report describes the clinically significant design features of a variable rate implantable insulin infusion pump, the Programmable Implantable Medication System (PIMS), and its function in pre-clinical trials. PIMS has a number of unique features, including a solenoid, pulsatile pump design requiring minimal power (less than 15 microwatts) and a less-than-atmospheric pressure reservoir. Two-way communication is accomplished by radiotelemetry. The implanted device stores programs, and records its own hourly history of insulin delivery. Limits are set on total insulin delivery over time. Basal rates are adjustable, and patterned prandial insulin delivery curves can be programmed. Initial trials (3.1 dog-years) identified four problems which were corrected prior to final pre-clinical trials: microcracks in the diaphragm, a valve-seating leak, electronic failure of prototype microchips, and insulin aggregation. Sixteen dog-years of final pre-clinical trials with a single system design demonstrated that 5 pumps were still working continuously after up to 3.75 years (mean 3.3 years) without mechanical or electronic pump failure. The longest interval between reservoir refills was 5 months. Remaining potential causes of flow stoppage, however, include blockage of the peritoneal catheter by omentum (which occurred once), and air lock (which occurred two times).

The retrospectroscope-the invention of the rechargeable cardiac pacemaker: vignette #9.

The idea for a rechargeable cardiac pacemaker came to the author in the late 1960s after reading an advertisement stating that a company's batteries were so good they would last two years in a heart pacemaker. This meant that pacemaker patients would have to undergo surgery for their replacement frequently. Having worked on the development of hermetically sealed, nickel-cadmium batteries that could function for a decade or longer in an orbiting spacecraft, the author constructed the first prototype of a rechargeable cardiac pacemaker around 1968 to show cardiologists at Johns Hopkins Hospital that a pacemaker of indefinitely long life and much smaller size and weight could be built readily. The subsequent development and marketing of the device, which came on the market in 1973, is recounted.

A preliminary trial of the programmable implantable medication system for insulin delivery.

We undertook a trial to determine whether an implanted insulin-delivery system, the programmable implantable medication system (PIMS), could be used to treat patients with insulin-dependent diabetes. PIMS is a pulsatile, programmable pump with a battery life expectancy of five years. The reservoir is refilled transcutaneously every two months with a surfactant-stabilized human insulin preparation containing 400 U of insulin per milliliter. Eighteen patients received PIMS-delivered insulin for 4 to 25 months (mean, 18). The total PIMS-implantation experience comprised 28 patient-years. Good glycemic control was established and sustained during treatment (mean plasma glucose level, 7.3 mmol per liter; mean glycohemoglobin level, 8 percent [upper limit of normal, 7.5 percent]), with significantly reduced glycemic fluctuations. The total mean daily insulin dose did not change. Insulin solutions withdrawn from the pump reservoirs contained 92 percent native insulin and preserved biologic activity. There were no surgical or skin complications, severe hypoglycemic episodes, or instances of diabetic ketoacidosis. One pump was replaced because of a manufacturing defect, and four patients had catheter blockages due to omental-tissue encapsulation; two withdrew from the study and two had devices that were repaired successfully. The actuarial rate of survival of catheter function was 78 percent at 1.5 years. We conclude from this pilot study that insulin treatment with an implanted, variable-rate, programmable pump is feasible for periods up to two years.

The invention of the programmable implantable medication system.

The author describes the genesis of his idea for a programmable implantable medication system and the problems encountered in going from idea to the first prototype. He discusses the funding, development, and marketing of his device. He provides some observations on the process of getting medical inventions into public use.

The Johns Hopkins rechargeable pacemaker. Historical aspect.

Several groups have attempted to develop a clinically usable rechargeable cardiac pacemaker. Because of the technical problems, of the 11 reported efforts, only one has met with success, the unit developed at the Johns Hopkins University. A brief review of rechargeable pacemakers is given, along with a discussion of technical problems that required solution before the rechargeable pacemaker could be used clinically. The rechargeable pacemaker, because of its size, should minimize patient problems of discomfort, cosmesis, and skin erosion. The anticipated life of the rechargeable power cell should eliminate the need for pulse generator replacement during the patients's lifetime.