The FDA Circulatory System Devices advisory panel early this month grappled with the question of whether a laser alone was as effective in treating patients with blocked arteries as balloon angioplasty and overwhelmingly voted 9-1 against recommending approval of the new indication for Spectranetics' (Colorado Springs, Colorado) CVX-300 excimer laser system. Spectranetics presented data on its laser system, which would be marketed as the CliRpath Excimer Laser Catheter as an alternative for patients with a poor prognosis for surgery. The catheters are constructed from multiple fiber optics arranged around a guidewire lumen and intended to recanalize obstructed peripheral vascular arteries. Spectranetics sought approval of the device to salvage limbs in patients with critical limb ischemia who are poor surgical candidates due to occlusions in the superficial femoral artery, popliteal and infrapopliteal arteries, but are acceptable candidates for revascularization.

The company said that the new indication is the result of advances in design and represents the fifth generation of Spectranetics' device, first approved by the FDA in 1993 for use in coronary arteries. "The laser is very similar to LASIK that is used for refractive surgery in the eye," Chris Reiser, vice president of technology and clinical research at Spectranetics, told the panel. The CVX-300 laser system has been in commercial use in Europe since 1997, Reiser noted. "The laser shaves away small layers of tissue about the width of a human hair without burning or scarring," he said.

Spectranetics presented findings from its multi-center single-arm study, Laser Angioplasty for Critical Ischemia (LACI 2), in addition to findings from an historical control using a non-treatment arm from a randomized trial studying a drug to treat CLI. The control data was taken from the Ischemia Chronica Critica degli Arta Inferiori (ICAI) trial conducted in Italy. The primary effectiveness endpoint for LACI 2 was freedom from amputation at or above the ankle at six months, and the primary safety endpoint was death within six months following the procedure. A total of 145 patients were enrolled in the LACI registry with a total of 155 limbs involved.

FDA staff instrumental in the premarket approval analysis shared their concerns with panel members about the device's effectiveness based on the clinical trial data. "The sponsor's hypothesis that the laser device was equivalent to the current alternative treatment is a conservative estimate that can be disputed," Wolf Sapirstein, MD, clinical reviewer at the FDA, told the panel. "It is conceivable that balloon [percutaneous transluminal angioplasty] alone is effective in treating limb ischemia and that the laser device is superfluous," he added. Warren Laskey, MD, chief of interventional cardiovascular medicine at the National Naval Medical Center (Bethesda, Maryland) and chair of the advisory panel, said, "The outcomes can't be compared between the LACI group and the Italian group because we're not certain similarities exist between the U.S. and Italian patients." Adding to this concern was panelist Sharon Lise-Normand, a biostatistician at the Harvard School of Public Health (Cambridge, Massachusetts), who said, "Looking at it from the beginning, I'd say you have a tough statistical problem, determining some commonality among both groups. My question would be how data collected in both groups were measured the same way. For example, was the data on hypertension and diabetes collected in the same manner?"

Prior to voting on its recommendation, the panel was reminded of current FDA regulations regarding clinical study design. "Earlier today the agency clarified that randomization is not required by law, and sometimes a control group may not be ethical or viable at the time. I'd encourage the panel to keep that in mind for future devices," said Michael Morton, industry representative on the panel and director of regulatory, clinical and quality affairs at Sorin-COBE CV (Arvada, Colorado). "I would ask that the device be used on a compassionate-use basis for patients with no other option than amputation," said Salim Aziz, MD, of the University of Colorado Health Sciences Center (Denver, Colorado), the lone panel member voting against the motion not to recommend approval of the device.

Quantix/OR improves CABG

When it comes to surgery, one assumes mostly science is involved, and this is especially true when it comes to coronary artery bypass graft procedures (CABG), an extremely common cardiac surgery for bypassing occluded arteries. But Brent Larson notes that even in surgery as delicate as CABG, there is at least one very low-tech and relatively unscientific procedure that's quite common. Larson, vice president of finance for Neoprobe (Dublin, Ohio), says that after the bypass vessel has been put in place, the surgeon must determine how well it is working. And in the large majority of cases, he or she does so simply by pressing a finger on the vessel, "feeling the pressure there and assuring that they've got blood flowing through there." But, Larson told Cardiovascular Device Update, with this technique, "Whether there is adequate blood flow, there's no quantification of that," and he says that much then depends on "the art of surgery," rather than the science.

Focused on shifting the artful approach to a more scientific one, Neoprobe is developing tools for exactly quantifying what is happening in that grafted vessel, and it has received FDA 510(k) approval for the Quantix/OR device for the intraoperative measurement of blood flow. The Quantix/OR's main advantage is its simplicity, says Larson. A surgeon simply places a probe on the vessel, presses a button on the device and gets what Larson terms "a quantified and accurate measurement of blood flow" in the vessel via connection to a nearby console. Besides the measurement of blood flow, the device/console provides information concerning internal vessel size and a variety of data concerning key hemodynamics.

The finger-pressure approach is not done all the time, Larson acknowledges. He says that in about 15% of CABG procedures, the surgeon uses a probe that provides more than an educated guess. But Carl Bosch, vice president of instrument development for Neoprobe, says these competing devices have a variety of disadvantages. They must surround the vessel, requiring the surgeon to strip away other materials from it such as fat or other tissues in essence "skeletonizing" the grafted vessel, he told CDU, to acquire a reading.

The key difference is Neoprobe's use of ultrasound, which it terms "angle-independent" or angle-independent Doppler blood flow (ADBF), a term coined by the company. Explaining, Larson says that the technology "uses two beams of Doppler ultrasound waves. By knowing the angle between those waves, we can measure the inner wall diameter of the vessel as well as the flow profile across the entire vessel." And he says there is no need to guess at the size of probe to estimate outer vessel size, a requirement with other devices.

The company gained FDA clearance of the device, based largely on a predicate device, called the Flowguard, which the company acquired through its 2001 acquisition of Cardiosonix (Hod Hasharon, Israel). The next step is to put the Quantix/OR through its clinical trial paces as a marketing strategy to demonstrate effectiveness. David Bupp, president and chief executive officer of Neoprobe, says that the marketing clearance and commencement of clinical work on the device "will supplement the evaluations already under way in Europe and Asia and will support our efforts to develop a U.S. market for the Quantix/OR through one or more established national sales representative organizations." Overall, Larson says that Neoprobe's focus is on expanding the device approach to this procedure far beyond the current 15% penetration of the market by the competing systems.

Medical Carbon launches aspirin study

Medical Carbon Research Institute (MCRI; Austin, Texas), manufacturer of the On-X Prosthetic Heart Valve, reported launch of a clinical study under an aspirin-only anticoagulation protocol. The protocol was approved by the German Ethics Commission (Freiburg, Germany) and by the individual participating German hospitals' local ethics committees. This is the first aspirin-only study on mechanical heart valves approved by any regulatory agency, MCRI said.

"The significance of this study is that it may prove material and mechanical valve technologies have evolved to make it possible to implant valves for the life of the patient, without the burden of chronic anticoagulation and its associated complications," said Sidney Levitsky, MD, Cheever professor of surgery at Harvard Medical School and director of cardiothoracic surgery for CARE Group (both Boston, Massachusetts). "It appears that the On-X valve's pure carbon surface may not activate the blood's natural coagulation process, making the valve potentially less susceptible to clotting than other types of mechanical valves presently in use. In addition, the valve's unique design reduces blood turbulence that can also cause clotting."

He added that the study is particularly important for elderly patients who show increased complications with the use of warfarin. "This is a well-controlled study that was initiated because of the On-X valve's previous clinical trial results and further supported by interim data from an ongoing clinical trial in South Africa," Levitsky said.

According to the American College of Cardiology and the American Heart Association "Guidelines for Management of Patients With Valvular Heart Disease," three months postoperative aspirin-only anticoagulation therapy is the standard of care for most animal tissue valve replacements. Mechanical valve postoperative anticoagulation mandates the use of warfarin. Although warfarin has a long history of safe use, it has the potential side effect of bleeding.

Studies with antiplatelet agents or no anticoagulation have been conducted with other mechanical valves, but the results have not justified a modification in the postoperative use of warfarin for those mechanical valves. "What makes the On-X valve different is the pure carbon material developed exclusively for this valve as well as the reduced turbulence made possible by the valve's hemodynamic design," said Jack Bokros, PhD, MCRI's founder and chief executive officer. "The study could provide empirical evidence that the On-X valve has crossed the threshold between anticoagulation-related complications associated with other mechanical valves and the limited life of animal tissue valves."