Looking to reverse its U.S. regulatory fortunes in regard to percutaneous myocardial revascularization (PMR) therapy for the relief of angina, CardioGenesis (Foothill Ranch, California) is attempting for the second time to send a premarket approval (PMA) application through the FDA. The company said last month that it had submitted to the FDA new clinical data and a comprehensive analysis in support of its PMR system after the agency's Circulatory Device Systems Panel last summer voted 7 to 2 to deny recommendation of the system, citing adverse events and safety issues as primary reasons for its decision.The new submission, made in the form of an amendment to the pending PMA supplement, is the company's formal response to the FDA's October request for more information.

PMR, which already has the CE mark, is a catheter-based procedure in which physicians use a CardioGenesis laser to create tiny channels in the heart muscle to trigger the mechanisms of angiogenesis, or the creation of new blood vessels in the heart. It is related to transmyocardial revascularization (TMR), a similar laser cardiac procedure developed by the company that is performed by a surgeon and already approved by the FDA in 1999.

Chairman and CEO Michael Quinn said the formal submission was a significant milestone for the company and his staff has worked "diligently" to meet the FDA request for additional information. "We have focused our attention and resources on the questions raised by the FDA and have made a concerted effort to respond completely to all concerns," Quinn said in a company statement.

According to CardioGenesis, more than 2,000 patients have undergone the PMR procedure in Europe and Canada, which it said is an indication of the ongoing interest in the PMR technology. Since the FDA panel's initial rejection, the company has reported long-term positive clinical data that it said proves the mechanism of action of the PMR system is not a placebo effect, another concern of the agency. At the end of February, the company released 12-month follow-up data from its Blinded Evaluation of Laser PMR Intervention Electively for Angina Pectoris (BELIEF) trial, a prospective, randomized, double-blind controlled trial led by Jan Erik Nordrehaug, MD, PhD, chair of the department of heart disease at Haukeland University Hospital (Bergen, Norway).

Data from the completed BELIEF trial showed by independent assessment that patients who underwent PMR experienced a two-fold improvement in significant angina relief compared to patients who received a sham procedure. These results were a surprise even to Nordrehaug, who had originally set out to disprove the validity of the therapy. He said he believed beforehand that the results of the study would prove that the technology wouldn't work. When the data proved the system to be effective, he actually started to re-treat his patients who were in the original sham control group with the PMR system.

Richard Lanigan, vice president of government affairs and business development for the company, said the 12-month data from BELIEF is part of the new FDA submission. He told Cardiovascular Device Update that the company had presented the six-month BELIEF data at last summer's panel meeting, "and clearly, the panel recognized the importance of that information and had mentioned that they did want to see the full 12-month follow-up." He said that the amendment provides significant additional new clinical results, which provides the FDA with "a much larger and significant basis to demonstrate the safety of the procedure, and that was their No. 1 concern."

While the results of the BELIEF study were positive, another study did not reveal as compelling a case for the therapy. An article in the May 15 issue of the Journal of the American College of Cardiology concluded that patients treated with PMR with class III or IV angina caused by chronic total occlusions did not experience any reduction in angina, improvement in exercise duration or survival free of adverse effects compared to patients treated with optimal medical therapy alone.

Lanigan disputes the results of that study. He said for one thing, the system used to treat that study group was different – it used a Holium YAG laser from the Biosense Webster (Diamond Bar, California) division of Johnson & Johnson (New Brunswick, New Jersey) instead of the CardioGenesis system. Additionally, he said it investigated a different treatment group than the company's prior studies, consisting of non-recanalizable chronic total occlusion patients, a patient group with less-extensive coronary artery disease than that in the BELIEF trial. He also noted that the data was only a partial follow-up. He said that in terms of the endpoints of the study, only 50% of the follow-up was reported at six months. "While there wasn't a significant improvement in the patients, the data that was there was trending favorably. So drawing any conclusions based upon that [limited follow-up] would be questionable," especially since the treatment group was less severe than that of BELIEF, which had shown such promise.

Quinn was more blunt in his assessment. "Despite the unwarranted generalizations made regarding our PMR technology based on negative trial results with different systems, we remain resolved to make our PMR technology available to patients with debilitating angina who are not candidates for traditional methods of revascularization."

Janet Fauls, vice president of regulatory affairs, said CardioGenesis has collected additional randomized clinical trial data and has gained significant marketing experience in Europe and Canada to support this major amendment. She said the company has "taken great pains to be as thorough as possible and will take all the necessary steps to support a rapid FDA review." And she noted in regard to the regulatory process going forward that "there are several recent precedents of cardiovascular devices not receiving endorsement from the advisory panel and ultimately receiving FDA approval without a return to panel." Her apparent reference was to Guidant (Indianapolis, Indiana), which in May received FDA clearance for its Contak CD/EasyTrak system for heart failure without the necessity of another panel meeting, after an initial denial by the Circulatory Devices Panel in July of last year.

Aside from the obvious qualifier of if the system will be approved comes the question of when it will happen, and according to Lanigan, there is a fairly broad window of time to consider. "This is a major amendment," he said, "which means the FDA has up to six months to respond." However, he noted that since the company is only amending the clinical results of the PMA, it hopes to get the approval quicker than that.

Device option added for hypertension

Cardiovascular treatments generally come in a variety of flavors: invasive, minimally or less-invasive and noninvasive. Then too, there are drugs. Now, developmental firm InterCure (Princeton, New Jersey) has added another option to the noninvasive, non-drug category with its RESPeRATE device for the treatment of high blood pressure, with the company pointing, further out, to develop the system for even more difficult-to-treat cardiovascular problems. RESPeRATE recently was cleared by the FDA for over-the-counter (OTC) sales, and its approach might be called interactive or even "out of body," since it requires only listening to and following instructions for breathing exercises to control and reduce blood pressure.

The clearance is backed by the company's clinical testing demonstrating that patients can significantly lower their blood pressure – by an average of 14 mmHg systolic and 9 mmHg diastolic. InterCure said that reduction has been demonstrated after only an eight-week regimen of use, 15 minutes per day, three to four times each week. Even greater reductions were produced in older patients, or patients with higher baseline blood pressures, beyond those provided by other therapies, according to InterCure.

RESPeRATE first was cleared by the FDA for prescription sales in May 2000, Paul Sheils, president and CEO of InterCure, told Cardiovascular Device Update, but the company has waited until receipt of the OTC sales clearance – offering immediate access to the broader consumer opportunity – before making full product launch. During this period, the company has been testing the product with doctors and reports its appeal as "very strong among both physicians and consumers," Sheils said. He noted that physicians are struggling to deal with large populations of hypertensive patients and that with a non-drug device in their arsenal, physicians "don't have to prescribe another beta blocker."

About the size of a paperback book, RESPeRATE is battery operated and can be used anywhere. Users place an elastic belt that holds a respiration sensor around their torsos, above the clothing and listen to the instructions with standard headphones. The device then analyzes the user's breathing rate and pattern and then guides the wearer through a breathing exercise that slows the breathing from a normal rate of 14 to 18 breaths per minute to a 10-breath per minute "therapeutic zone" via prolonged exhalation. Breathing returns to normal after each session and the benefits accumulate to reduce blood pressure, a reduction that is sustained, according to InterCure.

An obvious question, of course, is the patient's willingness to use this device – that is, compliance. "It's better than medications," Sheils said. "And certainly far better than certain lifestyle modifications," such as diet changes or the exercise regimens that so many persons dread and often fail to follow through on. What especially supports compliance is that better breathing and lowered blood pressure makes people feel good, he said. "We're hanging our hat on the notion that this therapy happens to make you feel like a million bucks – it relaxes you." He quoted an unsolicited testimonial by one female user who reported "it was the best 15 minutes of her day."

While forecasting success for the device in the hypertensive market, Sheils said the opportunities could be far greater in even more important cardiovascular markets, primarily congestive heart failure (CHF), and for various pulmonary applications, such as asthma – sectors he calls "multiple verticals in healthcare." The uses in CHF are "obvious with a training device like ours," Sheils said. "We've already done tests that demonstrate that we can normalize the blood oxygen level, which is a huge issue for CHF patients. They have apneas and terribly volatile breathing patterns, or shallow patterns. RESPeRATE coaches breathing in prolonged fashion with deep exhalation." And he says that the device has produced effects in raising blood oxygen levels similar to the reductions in blood pressure.

Another "pure play" device treatment of cardiovascular ills received a boost last month with the release of follow-up data from Vasomedical (Westbury, New York), supporting use of its enhanced external counterpulsation (EECP) system to reduce the symptoms of angina in patients with left ventricular dysfunction (LVD). EECP therapy consists of placing inflatable cuffs around the patients' legs and thighs and then inflating and deflating these to provide a pulsing action counter to that of the heartbeat. That action, according to the company, provides an improved supply of oxygen to the heart and lowers its need for oxygen.

The study, looking at outcomes of the International EECP Patient Registry, followed 103 angina patients with LVD and found significant reductions in the severity of the patients' angina, with corresponding improvements in health status and overall quality of life. Vasomedical also is sponsoring the Prospective Evaluation of EECP in Congestive hEart Failure (PEECH) trial, a controlled study to assess improvement in exercise ability and quality of life in heart failure patients in order to support Medicare approval for EECP.

Zoll establishes AED foundation

Zoll Medical (Burlington, Massachusetts) last month reported making an educational grant to establish the AED Instructor Foundation. The foundation is designed, it said, "to help initial emergency care instructors provide critical training and support services for CPR and early defibrillation, as well as provide access to a new, affordable automated external defibrillator (AED) specifically designed for laypeople who are likely to be designated responders to victims of sudden cardiac arrest in public gathering places."

Richard Packer, Zoll's president and CEO, noted the growing presence of AEDs and said that "with the establishment of the new AED Instructor Foundation, we can help instructors expand AED access to smaller venues, where these lifesaving devices are desperately needed but often not available."

Zoll said affiliation with the AED Instructor Foundation "will be free and open to anyone engaged in initial emergency care training." Affiliates must have completed prescribed instructor training for a state or nationally approved initial life support and/or AED training program. The AED Instructor Foundation will offer affiliates a variety of services through its website, www.aedinstructorfoundation.org, including training materials, professional development opportunities and financial support. The foundation also will give instructors access to AEDs in many more communities.

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