CDU Washington Editor and
CDU Contributing Writer

WASHINGTON The late-breaking clinical trial sessions of the 24th annual scientific sessions of the North American Society of Pacing and Electrophysiology (NASPE; Natick, Massachusetts), which were held here in mid-May, focused on studies designed to refine the understanding of drugs and devices for major cardiac problems. In particular, there was great interest is the relationship between atrial fibrillation (AF) and congestive heart failure (CHF).

It is widely known that proper atrial function significantly improves cardiac output in CHF patients. As well, it is accepted that AF significantly contributes to an increase in mortality in CHF patients. The results of the highly-anticipated AFFIRM (Atrial Fibrillation Following Investigation of Rhythm Management) trial, reported in the Dec. 5, 2002, issue of the New England Journal of Medicine, concluded that "management of atrial fibrillation with the rhythm-control strategy offers no survival advantage over the rate-control strategy, and (that) there are potential advantages ... with the rate-control strategy."

As a result, pacing for the treatment of AF has become more accepted, whether alone or in conjunction with medical management. In a NASPE session at the Washington Convention Center, attendees heard the latest results of several trials aimed at evaluating the safety and effectiveness of advanced feature settings for pacing and defibrillation therapies, as well as for drugs to treat AF and CHF.

Dr. Willem de Voogt of St. Lucas Andreas Hospital (Amsterdam, the Netherlands) presented the outcomes of the Overdrive Atrial Septum Stimulation in Patients with Paroxysmal Atrial Fibrillation with Class 1 and 2 Pacemaker Indication (OASES) trial. Overdrive pacing is a technique in which the pacing rate is set higher than the heart's normal intrinsic rhythm, which generally causes the pacemaker to pace continuously. The pacemaker typically gains control of the patient's heart, which has the benefit of eliminating or preventing certain arrhythmias such as AF. One major question in pacing therapy has been where to position the pacing leads and therefore, where to stimulate the heart. Interestingly, the OASES study, involving 255 patients with a mean age of 70 years, assessed the differences in AF patients paced in the right atrial appendage (RAA) vs. patients paced in the lower region of the atrial septum and compared these to a control group.

This trial clearly achieved its primary endpoint of reducing AF episodes. According to de Voogt, "It was clear that pacing the lower septum was significantly better than pacing the RAA while dynamic overdrive pacing was turned on as reflected by a greater reduction of AF episodes." He also noted that there was an improved quality of life (QOL) for this group.

Dr. Steven Singh, chief of cardiology at the Veteran Affairs Medical Center (Washington), presented the results of the Sotalol Amiodarone (Atrial) Fibrillation Efficacy Trial (SAFE-T). This Veterans Affairs cooperative study was designed to determine optimal medications to maintain normal sinus rhythm in patients with persistent AF once they were converted back into normal sinus rhythm. It compared the length of time it took persistent AF patients to convert back to AF while being treated with either amiodarone or sotalol once they were converted to normal sinus rhythm either pharmacologically or electrically (i.e., cardioverted). Persistent AF patients were placed on a given antiarrhythmic medication. If no conversion to normal sinus rhythm occurred within four weeks, then the patient was electrically cardioverted according to the protocol.

The primary endpoint of the study was time to first recurrence of AF. The patient population included 685 veterans with persistent AF being treated with either amiodarone or sotalol after being cardioverted. There were 287 patients randomized to amiodarone therapy, 261 patients to sotalol therapy and 137 patients on placebo. Median times to AF recurrence after normal sinus rhythm restoration were 809 days for patients on sotalol, 209 days for those on amiodarone and 14 days for placebo patients. This important direct comparison of amiodarone to sotalol will help physicians to a better understanding of AF recurrences while on medications.

Drs. John Herre of Cardiology Consultants (Norfolk, Virginia), Steven Kutalek of Hahneman University Hospital (Philadelphia, Pennsylvania) and Bruce Wilkoff of the Cleveland Clinic Foundation (Cleveland, Ohio) each presented some results of the Dual Chamber and VVI Implantable Defibrillator (DAVID) trial. This study was conducted at 37 sites throughout the U.S. and included 800 patients. It addressed the debate of whether patients needing an implantable cardioverter defibrillator (ICD) and having AV nodal block with low ejection fraction should receive bi-ventricular pacing therapy or dual- or single-chamber right ventricular pacing therapy. Half of the participants were randomized to dual-chamber (DDDR) pacing, with the other half assigned to single-chamber (VVI) pacing.

The study's primary endpoint was to determine event-free survival or hospitalization due to CHF and included 1.5 to 3.5 years of follow-up. There were three goals: improving the prognosis of patients with ICDs, increasing the QOL of patients treated with ICDs, and reducing costs of ICD patient treatment. Only the first two endpoints were covered in the NASPE presentation. Patients in the DDDR population fared much worse than VVI pacing, demonstrating a significantly higher mortality or heart failure hospitalization rate. In discussing the results, Wilkoff said "DDDR pacing offered no benefit [to these patients] and the percentage of RV pacing correlated with poor outcomes." Herre added that "it appears that dual-chamber pacing in defibrillator patients worsens survival and heart failure without showing any benefit in QOL or reduction in inappropriate [shock] therapy."

Dr. Isabelle van Gelder of University Hospital (Groningen, the Netherlands) presented the Rate Control vs. Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) trial results, which was conducted in 37 centers in that country. Patients with persistent AF or atrial flutter for greater that 24 hours and less than one year who had received one or two cardioversions in the past two years were randomized to either rate control therapy or rhythm control therapy. Rhythm control included electrical cardioversion, followed by various widely-used AF medications. Rate control, or lowering the heart rate, used beta-blockers, calcium channel blockers or digoxin and oral anti-coagulants.

The primary endpoint was defined as a composite including cardiovascular death, hospitalization due to heart failure, thromboembolic complications, severe bleeding, pacemaker implantation, and severe adverse effects. The results presented included normal sinus rhythm in 14% of the rate control group versus 36% in the rhythm control group. In addition, overall cardiovascular mortality in the rate control group was 11.5% vs. 6.1% in the rhythm control group. However, there was no significant difference in the defined primary endpoint between the two methods of control, van Gelder said.

Sleep apnea an emerging ICD opportunity

In a rare case of harmonious convergence, researchers and device manufacturers appear to be headed in the same direction in regards to future uses for ICDs. Manufacturers are exploring the use of ICDs to treat sleep apnea, and results from a just-released clinical study suggest that patients with pacemakers are at higher risk for the condition.

Manufacturers of ICDs are seeking new indications for the devices to treat the condition, which often goes undiagnosed, said Eric Fain, MD, senior vice president of development and clinical/regulatory affairs at St. Jude Medical (St. Paul, Minnesota).

Results from a sleep apnea study were discussed during a session at the conference as well. The study monitored 52 patients with pacemakers to determine the prevalence of sleep apnea in those patients, as well as determine the patients' quality of life. The study found that in pacemaker patients with or without heart failure, 60% had sleep apnea. The researchers concluded that sleep apnea in pacemaker patients should be a primary target for diagnosis due to the high risk of cardiovascular complications that accompany it.

A similar study found that pacemaker patients are at higher risk of experiencing syncope (loss of consciousness) while driving. Researchers studied the prevalence, patient characteristics and risk predictors of those who faint or lose consciousness while behind the wheel. A group of 3,879 cardiac patients who've experienced syncope both while driving and not revealed clinical characteristics and predictors of patients more likely to experience the problem.

Resynchronization therapy newest HF option

Until recently, patients had few therapeutic options available following heart failure that benefited the heart tissue itself. Advances in medical technology are giving patients more options by providing physicians with the ability to restore the lower chambers of the heart. One option cardiac resynchronization therapy (CRT) uses a strategy of reverse remodeling in an attempt to rehabilitate the heart to its original functioning ability.

Cardiac resynchronization therapy can bring hope to thousands of patients with moderate-to-severe heart failure and potentially improve the lives of hundreds of thousands more in the future, said Walid Saliba, MD, an implant physician in the cardiac pacing and tachyarrhythmia devices unit at The Cleveland Clinic. Saliba spoke about his facility's experiences in the Multi-center InSync Randomized Clinical Evaluation (MIRACLE) study using Medtronic's (Minneapolis, Minnesota) InSync 8040 device. The InSync device is a small, surgically implanted biventricular pacemaker that sends tiny electrical impulses to the heart muscle in an attempt to resynchronize the contractions in the lower chambers of the heart.

Resynchronizing the contractions of the lower chambers helps it pump blood throughout the body more effectively, Saliba said. As a result, common symptoms associated with heart failure, such as fatigue, shortness of breath and swelling in the feet and ankles are reduced. Using the device in conjunction with drug therapy, dietary and lifestyle changes, patients can experience multiple dimensions of improvement in their quality of life, he added. The Cleveland Clinic's heart center was one of 45 centers in the U.S. and Canada to participate in the clinical trial, which is the largest study on CRT to date. Results from MIRACLE trial showed that CRT helps patients with moderate to severe heart failure live better, more active lives despite their condition, Saliba said.

Research see-saw difficult on docs

Cardiologists taking part in a research roundtable session said the dilemma between academic and "industry" research is a double-edged sword. The battle physicians feel they are fighting, however, could be resolved in a simple meeting of the minds, if the medical technology industry would only listen, according to a panel of physician experts. That was the consensus from a panel of leading research veterans who discussed the trends in current science research and possible solutions during a NASPE roundtable session.

Physicians are faced with the dual interests of academia and the industry when it comes to research dollars, and the balancing act between the two is still a problem, said Michael Cain, MD, of Washington University School of Medicine (St. Louis, Missouri).

"We need to work with the medical device industry to make their research better and more meaningful for practicing physicians," said Mark Josephson, MD, of Columbia University (New York). Elaborating, he said that cardiologists often lack long-term data from newer devices, and the long-term benefit for a patient is unknown.

"Physicians, in collaboration with the NIH [National Institutes of Health; Bethesda, Maryland], should work with the industry to develop clinical trials with the most benefit for the patient and the research, as well as follow-up," Josephson urged. That collaboration would help create a much-needed clinical network between research and practice, he added. Josephson proposed that NIH, not the FDA, maintain a registry of coronary devices so that the data "will help doctors in the long term, which is not available now." But a lack of funding to NIH could prove to be a difficult proposition, said Cain.

Lack of long-term clinical data proved to be a contentious issue among those in attendance at the NASPE session during a question-and-answer period. The reality in research on sudden cardiac death, however, is that the device industry has taken the lead, said John Camm, MD, of St. George's Hospital Medical School (London).

"The fact is, the industry has found a way to buy research through finding physicians to agree to the research. They are going into areas where the government hasn't gone to. The industry already has quite a few secrets unlocked that academia does not, and they have the advantage in creating a clinical network," he said.

One panelist embraced industry-oriented research, and his words may carry greater significance than others on the panel. Peter Spooner, of the NIH's National Heart, Lung & Blood Institute, said that the medical device industry was "disenfranchised" in the research process. "The device industry has been shunned. We need to bring them back into the clinical research arena," he said. Getting input from the device industry would help bring the academic and clinical interests together, Spooner added.

Systematic approach to ICD problems

In a session focused on potential problems with ICDs, experts emphasized that the key to managing patients having difficulty with an ICD is to approach shocks in a systematic way. That's the advice Richard Fogel, MD, a consultant and practicing physician with the Case Group (Indianapolis, Indiana), had for electrophysiologists during one NASPE session. "Patients with phantom or pseudo shocks could be experiencing them due to external factors, but it could also be an idiosyncrasy with the device itself," he said.

Phantom shocks most often occur at night, and patients can be dreaming and cause the ICD to shock, he noted. "Shocks are also more predominant in anxious patients." Noise either intrinsic or extrinsic also could cause the ICD to shock the patient, Fogel said, such as some physiological noise within the body. Other problems could indicate that the ICD is oversensing or double-counting, he explained.

Oversensing or undersensing also could signal a problem with the ICD's leads, added Andrea Russo, MD, an electrophysiologist at the University of Pennsylvania Health System and Presbyterian Medical Center (Philadelphia, Pennsylvania). Lead failures are more frequent the longer the ICD has been implanted, she said. Lead failures are most likely the result of the insulation breaking down or a mechanical failure, such as a break or separation, Russo said. "Improvements in lead design is needed, and the industry is responding with improved technology in upcoming ICDs." Leadless ICDs might be an option in patients not needing pacing, she suggested.

In cases where ICDs are recalled or parts are found to be defective, the responsibility of tracking patients and paying for replacement costs should be with the manufacturer, Russo said. "In cases where devices have been recalled, the manufacturers have been very successful at contacting the patients up to several years later," she added.

Design trial to fit the device

Despite the discrepancies in approval processes from the FDA and the Centers for Medicare & Medicaid Services (CMS; Baltimore, Maryland), there still are plenty of incentives for device manufacturers to continue with product development. Only a small number of devices are eventually approved for Medicare reimbursement by CMS, but that shouldn't stop a manufacturer from developing a product, said St. Jude Medical's Fain, one of several panelists during a session focused on the critical elements of successful trial design and the pitfalls of an unsuccessful design.

"There are three clinical trial stakeholders: one is the industry, then there are physicians and then there's the FDA," Fain said. "The industry is concerned with the time to market, the physicians are concerned with the ability to publish and the FDA is concerned with the device's feasibility," he noted.

When it comes to devices and clinical trials, physicians need to remember that "the industry is only interested in bringing a device to market, not to answer a clinical question," said Helen Barold, MD, formerly with the FDA and now employed at the National Naval Medical Center (Bethesda, Maryland). She said that clinical trial designs aren't just about collecting data. "There are in-depth engineering reviews and manufacturing issues and inspections that the FDA wants to include in the trial."

A key problem that can delay the clinical trial process, Barold said, is not following through on protocol. "Follow the rules of the protocol," she advised. "Deviations only delay the process of getting the product approved. Don't enroll the wrong type of patient. Fill out the proper paperwork and ensure that the proper blinding techniques are followed."

When designing a trial, ask yourself what does the device do and specify what are the differences and limitations, Barold advised. Next, manufacturers need to determine what the device does to the disease process and to what extent it influences the disease process, she added. "Let the device guide the clinical trial."

Lastly, manufacturers should be creative in constructing clinical trial design issues. "Use the device's features to design the data collection points. And know the disease process inside and out and know when to ask for help from outside disciplines if you need it," she said.

IT interface alliance

GE Medical Systems Information Technologies (GEMSIT; Milwaukee, Wisconsin) unveiled a strategic alliance with Biosense Webster (Diamond Bar, California). GEMSIT will market and distribute an interface between its CardioLab EP monitoring system and Biosense Webster's Carto XP EP Navigation and Ablation System. Biosense Webster is a Johnson & Johnson (J&J; New Brunswick, New Jersey) company.

"Clinicians have told us they needed a way for monitoring and 3-D mapping systems to communicate," said Mike Genau, vice president of cardiology systems for GEMSIT. "This alliance brings together two world leaders in electrophysiology to fulfill that need." He added, "Biosense Webster is recognized as an innovator in cardiac arrhythmia diagnosis and treatment. We believe this interface will improve clinicians' ability to diagnose cardiac disease and enhance patient care, while reinforcing our companies' leadership positions in electrophysiology."

According to Mark Langer, general manager for invasive cardiology at GEMSIT, the two companies planted the seeds for the relationship almost exactly a year earlier at the 2002 NASPE meeting in San Diego, California. "The feedback that we got at our [medical advisory] meeting was fairly unanimous that we really should be working on an interface to Carto," he said. He said that he and other GE reps walked over to the J&J booth and shared that information with the other company. "They said, 'funny you should mention that because we got similar feedback,' and it was fairly unanimous on their side too."

The companies were able to synch up the two systems via a network interface. "It's a bi-directional interface and the two systems basically handshake continuously so that when they do point grabs they move into the chronological log that becomes the final procedure log in CardioLab," Langer said.

GEMSIT said that until now, clinicians conducting EP studies have had to work with physically separate and electronically isolated systems for cardiac monitoring and 3-D mapping, which simultaneously assess the electrical properties of the heart muscle with the anatomy of the heart. To review cases, they have had to shuttle back and forth between workstations.

The CardioLab System Interface with Carto XP System was designed to deliver a complete, integrated EP solution, allowing the monitoring and three-dimensional mapping systems to share information in real time. GEMSIT said it believes that clinicians will be able to share patient demographics between the two systems and access one complete case report form. Langer said that with this combined system, EP docs can go to any point in a study, and go to a specific mapping time endpoint and look at the ECG or go to any point in the ECG data and look at the identical map for that particular point in time in the ECG data. "You've got basically a functional linkage now between your two critical pieces of data your 3-D map and your ECG data." The interface also will streamline patient connections, potentially increasing ease of use and simplifying procedure set-up.

Mark Josephson, MD, chief of the cardiovascular division at Beth Israel Deaconess Medical Center (Boston, Massachusetts), said in a statement that he was pleased to learn that GE and Biosense Webster were working on the interface. "For some time, EP physicians have seen a need for communication between 3-D mapping and monitoring stations," Josephson said. "I believe this interface has potential to provide clinical value and to create workflow efficiencies in the EP lab."

Langer said that on the development side of the alliance, the companies' initial focus is on the interface of the two systems "and then ultimately, we'd like to see an integration." The system, which is currently a fully functional working prototype, is expected to become available in 4Q03. It still requires all customary approvals, including clearance from the FDA.

Virtual office visits

Also at NASPE, Medtronic reported that it has reached an agreement with the Department of Veterans Affairs to equip its medical centers with the Medtronic CareLink Network, the first Internet-based service that connects cardiac device patients and physicians for "virtual office visits." Medtronic said the plan promises greater freedom and flexibility for many of the nation's veterans with ICDs.

"The VA's adoption of the Medtronic CareLink Network demonstrates the government's commitment to providing veterans with the most advanced patient care available," said Reggie Groves, vice president and general manager of Medtronic Patient Management. He said the system "is an especially important benefit for the many VA patients who regularly travel hundreds of miles to have their ICD checked." Groves added that his company "looks forward to working with the VA to expand the availability of the Medtronic CareLink Network throughout the nation's largest integrated healthcare system."

Patients can use the Medtronic CareLink Monitor to collect data about their heart and ICD activity from home or while on vacation anywhere in the 50 states by holding a small "antenna" over their implanted device. The monitor automatically downloads the data and sends it through a standard telephone connection directly to the secure Medtronic CareLink Network. Clinicians access their patients' data by logging onto the clinician website from any Internet-connected computer in their office, home or while traveling. Patients also can view information about their device and condition on their own personalized website, and family members or other caregivers can view this information if granted access by the patient.

The CareLink Network is currently available to some 100,000 patients in and outside the VA network with various Medtronic GEM model ICDs and the Medtronic Marquis DR ICD, which detect and stop fast heart rates and revive patients from sudden cardiac arrest.

Groves said the benefits made possible through the agreement would be expanded to even more veterans as additional implantable Medtronic devices are approved for use with the network.