By DON LONG
Cardiovascular Device Update Executive Editor
And MARK McCARTY
Cardiovascular Device Update Washington Editor

WASHINGTON — Healthcare in general and cardiovascular medicine in particular must declare all-out war against heart failure.

That was the clarion call issued by Gale Pearson, chief of heart development and structural diseases of the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health at the 11th Annual Scientific Meeting of the Heart Failure Society of America (HFSA; St. Paul, Minnesota) here in early September.

And the HFSA, one of the leaders in this war, brought together a range of clinicians engaged in this fight at the Marriott Wardman Park Hotel to present research and explore issues, but also — to a very large extent — vent their frustrations concerning what they repeatedly said is poor progress in this battle.

The lack of progress was reflected in various ways at the scientific sessions: in a presentation contradicting and undercutting Pearson's optimistic message and tone; in presentations highlighting the inability of diagnostics to predict sudden cardiac death and worsening disease; in presentations emphasizing the slow progress in developing drug and device therapies for cardiovascular disease; and parallel slow progress in the pharmacogenomics efforts in this sector.

The sessions also included the usual early-stage reports on stem cell therapies for the heart. And one of the investigators in that sector provided Cardiovascular Device Update an umbrella observation of progress in that field that just as well summarizes the entire cardio sector — that it still "has miles to go" before accomplishing the "Holy Grail" goals of exact diagnostics, truly effective therapies and the regeneration of heart muscle and coronary vasculature that will accomplish true healing.

But the news out of the conference wasn't all dismal.

Some investigators reported good progress in device development and safety, previously contradictory guidelines given improved consensus, and exhibitors, as usual, enthusiastic about their newest product offerings.

'... so many things to measure'

Emphasized throughout the sessions was the crying need to develop improved diagnostics that provide some real confirmation and accuracy in identifying those at greatest risk for cardiovascular fatality, the specific type and degree of heart disease and, of course, the earliest signs of heart disease in order to provide early treatment.

During a Presidents' Forum and symposium on this issue, Stefan Anker, MD, of Applied Cachexia Research (Berlin), focused on the emerging area of chemical biomarkers for early assessment and said that there are "so many things to measure — far too many. We need to reduce the number."

Anker provided figures to support that: the number of research studies ballooning over the past 50-plus years from one such study in 1960 to more than 900 in 2007, he said. Given this proliferation, he said that a critical need is greater guidance in focusing on the biomarkers and research directions that are most important.

Among the studies he reviewed were those involving the use of the traditional ECG measurement, and the more recent exploration of chemical markers such as BNP and NT-proBNP and other physiological indicators. In all of these, he said there remain large areas of "uncertainty" and the need for the diagnostician's "clinical judgment."

"How do you assess the added prognostic value" of such markers? Anker asked, giving at least a partial answer that greater emphasis on clarifying the "grey areas of analysis" is needed — a comment tending to put the key focus on the ultimate use of clinician judgment, despite its subjectivity.

Disappointments more than advancements

The frustration of prediction — especially when trying to peer into the future, as one waggish guru, once put it — was further emphasized in the realm of adverse cardiovascular events during a conference session on "Devices for Arrhythmias, Resynchronization, and Heart Failure Remodeling."

David Rosenbaum, MD, chief of the Division of Cardiology at Case Western Reserve University (Cleveland), tackled the issue of examining markers of ventricular dysfunction and ejection fraction as indicators for the need to provide implantable cardioverter defibrillator (ICD) therapy, in his presentation "Identification of Arrhythmia Risk: Advances and Disappointments."

His emphasis tended to be on the inevitable disappointments, underlining the fact that it requires many ICD implants to prevent a single sudden cardiac death — describing this unbalanced ratio as an indication that you can "win the battle and lose the war, based on the methods we have right now .... We must do better than ejection fraction."

Rosenbaum also reviewed the use of T-wave Alternans, a method for examining the variations in beat-to-beat heart rhythms. He said that there is a growing body of evidence supporting this diagnostic technique, and he cited the Alternans Before Cardioverter-Defibrillator (ABCD) trial of the method as just as effective as invasive angiography for identifying the risk of sudden cardiac death.

But he also cited the technique's limitations, including the inability to do ambulatory testing and that "heart failure doesn't give you alternans."

He said also that while T-wave Alternans measures the risk for sudden cardiac death, it does so for only two years out, and then is no better than angiography, and so suggesting the need for periodic retesting. Thus, he said there is a great need for "concomitant, synergistic information."

Further acknowledging this current state of diagnostic unreliability, Rosenbaum said that the result is the "inefficiency of using ICDs for primary prevention of sudden death."

"Ninety-three percent of patients will never get a shock — never need use of the device," he said, but that implantations continue apace, given physicians' asking the predictable question: "What if I fail to implant?"

Another session, "Device Therapy for Heart Failure: New discoveries, New Directions," provided further discussion of ICD and ICD/CRT (cardiac resynchronization therapy) implantation, further underlining the guesswork involved in patient selection.

Some of their conclusions:

• John Boehmer, MD, of the Milton S. Hershey Medical Center (Hershey, Pennsylvania): Though ICD therapy may be indicated for even older patients, medical therapy may be just as useful. "We have no data to suggest we need to put this [device] in quickly."
• Jagmeet Singh, MD, a Boston cardiologist: Successful use of CRT therapy "extends across all age groups" and the "impact is equal" across age groups, but that the exact patients who will benefit is "a moving target." He added that the most important benefit of an ICD is to enhance the quality of life. "And ICD shifts the mode of death. Clinical judgment is still key."
• Justin Ezekowitz, MD, director of the Heart Function Clinic at the University of Alberta (Edmonton): ICD plus CRT "reduces all-cause mortality," producing a 26% reduction in all-cause cardiac death."

Good conclusion but a meta-analysis

The statement from Ezekowitz was derived from a meta-analysis he and other researchers performed for the Agency for Healthcare Research and Quality (AHRQ; Washington) on a series of 1,100 articles appearing in the literature on the use of CRT which treats arrhythmias in both ventricles, in conjunction with ICDs in treatment of left ventricular systolic dysfunction (LVSD).

As perhaps a nod to some of the criticisms of using meta-analysis, he also acknowledged that his conclusions might be controversial.

While noting the reduction in mortality, Ezekowitz said that "the incremental benefit of CRT plus ICD over CRT alone in patients with LVSD remains uncertain." And he admitted that good news is often over-reported.

"There tends to be publication bias because you want to report something good for your institution," he said, and that evaluation of community use "is better than in a randomized clinical trial" in giving a real-world picture of the impact of electrophysiology (EP) implants.

As a comparison of the two EP functions, Ezekowitz said that ICDs reduce mortality in patients with NYHA Class II and III disease with a left ventricular ejection fraction of 35% or less, but that it takes 20 patients a total of 35 months to prevent one death with a moderate safety risk.

CRT used in patients with NYHA Class III/IV disease will prevent one death in 23 patients after six months, but the disease set is more severe than that he described for ICDs.

Ezekowitz recommended that patient experiences with CRT be included on a mandatory basis in the national ICD registry, the National Cardiovascular Data Registry, maintained by the American College of Cardiology (Washington).

As for safety, Ezekowitz said he had seen data from implantations of ICDs in 6,300 patients in France that demonstrated a risk of infection of about .01%, "which is good," but he emphasized that the cardiologist's procedural experience is critical.

"Those who are putting in less than 30 devices a year" have more infections and device complications. "If you don't do it a lot, you're not going to be able to do it very well."

Glucose-type monitoring needed?

Rosenbaum offered one of the more intriguing possibilities concerning the best strategy for determining the early risk of sudden cardiac death, the prediction of those most likely to benefit from ICD use and identifying and increased problems from heart failure.

He said that adverse events begin to manifest themselves at a very subtle level several days or even weeks before obvious symptoms appear in the patient. Thus, he suggested that what might ultimately be required are implantable systems that parallel current advanced developments in diabetes therapy — continuous monitoring that will provide continuous assessment of "glucose-like information" indicating the need for "disease-management strategies."

And he said that such information might be obtained with the use of a pulmonary artery monitor and other hemodynamic measures.

But Rosenbaum too returned to the human element in this effort, saying that even with good information better integration of diagnostic information between specialties is needed through the "interaction between people who do not interact a lot."

Turning specifically to the prediction of worsening heart failure, Oklahoma City cardiologist Philip Adamson, in his presentation "Implantable Monitorng of Heart Failure and Hemodynamics: Hypes, Hopes, and Home Surveillance," addressed the issue of the "congestion" and "volume overload" of heart failure usually measured by tracking unusual increases in weight.

But he assessed the process of stepping on a scale as "poor" and with a large need for more direct measures of basic vital signs that can be used as "surrogates." One of those, ultrathoracic impedance, has been tested for this, he said, but not validated in a prospective clinical trial and requiring further study.

Therapy trials 'neutral or worse'

Of all the frustrations expressed at the HFSA conference, perhaps the most direct was stated by Wilson Colucci, professor of medicine and physiology at Boston University School of Medicine, in his introduction of a symposium on "Pharmacogenomic Applications in Heart Failure" and the use of those applications to develop new drug and device cardiovascular therapies.

Colucci said that he has been "progressively more depressed, even catatonic over the last few years" concerning clinical trials of potential therapies because most recent trial results have been "neutral or worse" — largely negative for drug trials but with some successes in device trials.

"Why so much trouble" for these trials? he asked.

He went on to offer two possibilities: that the therapies were ineffective or, alternatively, that researchers are "overlooking potential benefits" to specific patient sub-groups in the trials. Based on the latter possibility, he suggested the need for a better understanding of individual patient responses that "allow for more effective patient-specific therapy."

Focusing on pharmacogenics as a one of the emerging strategies to evaluate new drug therapies — particularly in terms of targeting sub-groups of patients — the panelists tended to underline the difficulties of the task.

Christopher O'Connor, director of the Duke University Heart Center (Durham, North Carolina), reviewed some key trials based on genetic analysis and said that the main conclusion is that "so many genes may modify heart failure risk," thus providing a daunting list of variables.

Dennis McNamara, MD, of the University of Pittsburgh Medical Center, took another approach to the problem, saying that the best strategy may not be the examination of particular genes but rather an understanding of how genetic variations may effect the pathways of the drugs used to treat cardiovascular diseases.

"When gene types keep popping up with multiple datasets," McNamara said, "you know you're on to something."

Thus he encouraged the use of "more polygenic approaches" as a method for developing targeted therapies. "It makes no sense to treat all patients the same," he said, adding that the primary requirement for researchers and physicians is "smarts about using biology."

McNamara did offer encouraging words on the subject though, saying that the search for targeted therapies is just a matter of time. "We'll get there. We're not quite there, but we'll get there."

VAD news is good

The members of this panel acknowledged that device therapies have had greater success in clinical trial, and one of those therapies is the use of ventricular assist devices (VADs). The "VAD news" is that the current generations of these devices, many of which make use of an Archimedean screw, are an improvement over their pressure-pump predecessors.

During a panel on "Mechanical Circulatory Support in Heart Failure," Leslie Miller, MD, chief of the Integrated Divisions of Cardiology at Georgetown University Hospital (Washington) and the Washington Hospital Center, reviewed the progress that these devices have made in dealing with partial or total heart failure and listed "three major milestones" in the development of devices that assist the heart in pumping blood.

The first, he said, was in the transition from external pumps to internal pumps; the second was the move from devices that depend on pneumatic power to push blood from the ventricle to the atrium to the use of electrical power sources.

The final milestone, still in play, consists of a transition of the mechanics of the pump itself, from devices that push blood in a pulsatile fashion to devices that drive blood in a continuous flow.

In comparing pump assist devices in broad terms, Miller said that "the characteristic differences between the two are the size, the noise, but most importantly the durability."

He said that continuous-flow devices entail less mechanical activity that involves impact between mechanical surfaces. So they are less subject to wear and tear and hence can be expected to outlast the typical pulsatile device.

Miller said that the REMATCH trial, the now-famous three-year, $25 million assessment of the value of cardiac assists devices, not only was "a landmark in the field," but also "a benchmark" in progress. He said REMATCH demonstrated a "26% absolute reduction in risk" of death at one year (52.1% of patients on VADs vs. 24.7% of patients on medical therapy) and that sepsis and neurological events were also down significantly.

REMATCH also showed that patients on assist devices scored substantially better on depression and other such scores "despite going through a major operation and [having] issues with recovering" from a very invasive procedure.

Miller recommended, however, that "patient selection is, going forward, the most important" element in determining outcomes. "Those who are malnourished are at great risk for complications," Miller said, especially for sepsis.

"These devices provide an incredible platform to study new drug therapy," Miller said, citing clenbuterol as one example of a drug that has shown promise in helping a damaged heart to heal. Not yet FDA-approved, Clenbuterol is a bronchodilator that, in a recent study in the UK, was shown to benefit patients with VADS. Some recovered enough that they were able to leave the hospital and their VADs explanted.

"If we were able to do that with a larger number of patients," Miller said, it would represent "a vital advance."

Newer VADs on the way

Robert Kormos, MD, the medical director of the McGowan Institute for Regenerative Medicine (Pittsburgh) and the director of the artificial heart program at the University of Pittsburgh, described new assist devices in the pipeline and that the DeBakey VAD may be staging a comeback.

The DeBakey left ventricular assist device (LVAD) "enjoyed significant popularity in Europe some years ago," Kormos said, and the company that now sports the DeBakey name, MicroMed (Houston), has come out with new models, including one for children as young as 5.

Kormos said that to date, the DeBakey VAD, using the Archimedean screw, has been implanted in 434 patients around the world, including 151 in the U.S. The longest term of use in a patient is at 808 days. This device has a CE mark as well as a humanitarian device exemption from FDA, and it is the subject of an ongoing bridge-to-transplant trial for adults.

MicroMed did some work on the cannula to improve the inflow of blood, which Kormos said "got rid of some turbulence that may have led to some thrombosis."

He also said that the company has worked on spacing on the device's rear hub that also might have contributed to thrombosis.

"I think it's back," Kormos said.

Australian firm HeartWare (Sydney) offers an LVAD that operates on a centrifugal pump that is tiny enough that it "fits within the pericardial sac," Kormos said. Surgeons have implanted 20 of the HeartWare LVADs, but the device is new. The longest running implant is just over one year, and HeartWare is currently recruiting centers for a bridge-to-transplant trial in pursuit of a CE mark.

Another Australian firm, Ventracor (Chatswood, Australia) offers the VentrAssist, a VAD that operates on a hemodynamically-suspended titanium impeller that is moving into a pivotal trial. "One of the unique things is the flat HQ curve," Kormos said, adding that the device provides a pressure that is "more like our natural heart than a flow device." The VentrAssist has a CE mark, and the current data show an 85% survival rate to two years. Twenty-eight patients are enrolled in a U.S. pivotal trial.

Among the other VADs Kormos discussed was the Impella 2.5 made by Abiomed (Danvers, Massachusetts). The Impella installs percutaneously and straddles the aortic valve to drive blood from the left ventricle to the left atrium.

"The nice thing about this device is that it installs much like an aortic balloon pump," but it has demonstrated no adverse effect on aortic valve.