CD&D Washington Editors

A new guidance from the FDA concerning the treatment of atrial flutter (AFl) is the second this year from the agency mandating clinical trial design for a specific device in a specific application.

Earlier this year, FDA published the guidance for drug-eluting stents (DES), while the latest guidance deals with catheter ablation for AFl and at least in one respect, differentiates between radio frequency (RF) ablation and cryogenic ablation.

The guidance indicates that the agency is targeting different specifications for testing for AFl and for atrial fibrillation (AF). That, of course, offers increased complexity in seeking PMA approval, but at least one industry voice says the separation of flutter and fibrillation as indications, and hence as PMAs, makes sense.

FDA also says it will consider study designs other than randomized, controlled trials (RCTs) in the evaluation including a single-arm study using performance goals but the agency often expresses skepticism concerning such trials in advisory committee hearings. For AFl trials, FDA recommends a primary efficacy endpoint using a chronic success measure such as freedom from recurrent flutter at six months. However, the document says that "there is sufficient scientific evidence to indicate that acute procedural success (defined as the creation of bi-directional block at the cavo-tricuspid isthmus) is predictive of chronic success," and hence may be used in lieu of a chronic primary efficacy endpoint.

However, this provision is said to apply only to RF ablation, apparently leaving out makers of cryoablation equipment. Even in the case of RF ablation, the surrogate endpoint is of no help if the patient has to go on anti-arrhythmic drugs "in the follow-up period," in which case that patient should be counted as a study failure.

Suggested safety endpoints include freedom from cardiac perforation/tamponade, death, infarction and pulmonary embolism. Sponsors should base enrollment on the larger of the numerical requirement imposed by safety and efficacy, and minimum follow-up requirements are at seven days on the phone, and office visits at 30 days and six months. Any patient who is likely to experience flutter at the time of treatment should be on anti-coagulant therapy for three to four weeks prior unless an echocardiogram of the trans-esophageal area presents no evidence of left atrial appendage thrombus.

Jean-Pierre Desmarais, chief scientific officer at Cryocath Technologies (Montreal), told Cardiovascular Devices & Drugs that he did not consider it unduly burdensome to require separate PMA standards for AF and AFl because, he said, the syndromes are "so different." He said that doctors sometimes see both AFl and AF in the same patient and that AFl "can induce fibrillation," but they are distinctly different in terms of treatment and prognosis.

As to the rationale for allowing a surrogate endpoint for RF devices and not cryogenic units, Desmarais said, "I believe there are four RF devices approved," for AFl and only one cryogenic unit. As a result, a sponsor "can put forward a case that RF devices can be evaluated with a surrogate endpoint."

Desmarais speculated that for a single-arm trial with a performance criterion, rather than an RTC, he said, "Typically when you look at a trial with a success rate at 90% ... a sponsor will need 150 to 170 patients." In contrast, an RCT designed to demonstrate superiority might require as many as 700 enrollees. Hence, he said, there is "not much incentive to go for superiority" rather than non-inferiority in an RTC, and "it's less risky as well" to aim for non-inferiority if the data are at all equivocal.

Study: heart rate turbulence a CHF risk

New research reveals that abnormal heart rate turbulence (HRT), an ECG-based risk marker, is a significant risk predictor for sudden death in patients with congestive heart failure (CHF).

Published in the August edition of the Heart Rhythm Journal, the journal of the Heart Rhythm Society (Washington), the study is the first to document abnormal HRT as an indicator of sudden, or arrhythmic death risk in patients with heart failure.

The Muerte Subita en Insufficiencia Cardiaca (MUSIC) Study, a multi-center, Spanish, longitudinal study designed to assess risk markers for sudden death in CHF patients, is being billed as the largest heart failure population ever studied. More than 1,000 patients were enrolled in MUSIC between 2003 and 2004, and several risk markers, including Holter-based, were assessed to predict mortality during nearly four years of follow up.

Led by principal investigator Antoni Bayes de Luna, MD, this is the first study to document that HRT predicts not only all-cause mortality and heart failure progression, but also sudden death in patients with heart failure.

"Our study documented that HRT might be considered a useful tool to identify heart failure patients at high risk of death, including high risk of dying suddenly," said Iwona Cygankiewicz, MD, PhD, of the cardiology division at the University of Rochester Medical Center (Rochester, New York), the study's lead author. "HRT may help physicians more effectively manage heart failure patients by indicating the need for more frequent follow up visits at specialized heart failure units and more intensely-applied therapy, including ICD implantation in high-risk patients."

Though HRT was proven as an important risk stratifier in post-infarction patients, little is known about its value in patients with heart failure. Previous, smaller studies have proven abnormal HRT as a risk stratifier for all-cause mortality and heart failure progression, but not sudden death.

The researchers said that the MUSIC patients represent a "modern" population of heart failure patients with a broad spectrum of etiologies, including those with heart failure as seen at the ambulatory practice, including a large number with preserved left ventricular ejection fraction (LVEF).

The Heart Rhythm Society said that interest is growing in the survival of patients with preserved LVEF, and that MUSIC marks the first time this sub-group was included in a study evaluating the prognostic value of HRT.

ACC in project battling ethnic disparities

Jack Lewin, MD, CEO of the American College of Cardiology (ACC; Washington), says, "little has been done to improve the delivery of services to ethnic populations." And ACC is one of various groups collaborating in an effort aimed at improving healthcare for traditionally underserved minorities.

The coalition including the ACC, the Association of Black Cardiologists (ABC; Atlanta), the National Kidney Foundation (NKF; New York), Joslin Diabetes Center (Boston), the Johns Hopkins University School of Medicine (Baltimore) and the Institute for Johns Hopkins Nursing (Baltimore) will focus on cardiovascular disease, diabetes, obesity and chronic kidney disease (CKD), conditions that effect minorities especially hard.

Gullapalli and Associates (Jersey City, New Jersey), an educational strategy firm, has been engaged to facilitate the initiative.

The initiative will utilize various experts to develop a curriculum and programs to be marketed to clinicians, said Holly DeVan, managing director of the kidney learning system of the NKF, including online tools and educational resources.

"It's all meant to be very simple and basic, but to reach out to make sure that the people who are working with the populations most affected by the healthcare disparities are aware of their behavior relative to their diagnosis and treatment," DeVan said. "We're sending them a message that 'you need to pay attention to the individuals that you're treating.'"

Because kidney disease is so strongly linked with diabetes and cardiovascular disease, DeVan said the NKF is eager to educate clinicians who are treating heart and diabetes patients and encourage them also to screen patients for CKD.

"The spectrum of clinical implications between hypertension, obesity, diabetes and chronic kidney disease has long been recognized by clinicians, but in recent years they have become a clear focus of considerable preventive and therapeutic attention," said Keith Ferdinand, MD, a clinical professor at Emory University (Atlanta) and chief science officer for ABC. "With this important clinical challenge facing us, however, ethnic disparities limit our ability to provide optimal care."

The ACC's Lewin says that the technology necessary to address disparities in healthcare exists today. "If we can harness these tools and provide training in using them to physicians and their care teams, we will go a long way toward providing evidence-based quality care to all patients regardless of ethnicity."

According to the collaboration, healthcare providers are 40% less likely to order sophisticated cardiac tests for African Americans with chest pain than for Caucasians with identical symptoms. African Americans, Native Americans, Hispanics and American Asians are more likely to develop CKD than Caucasians (respectively, 4.5, 3.6, 2 and 1.6 times); ethnic patients have a rate of end-stage renal disease two to four times higher than Caucasians. Among patients diagnosed with diabetes, African-American patients are less likely (43.6%) than whites (50.4%) to receive an eye exam, a standard for diabetes diagnosis.

The initiative will provide educational interventions in multiple formats to various healthcare providers, ranging from primary care and cardiovascular physicians to specialists such as endocrinologists/diabetologists and nephrologists, nurses, nurse practitioners, pharmacists, physician assistants, and dietitians. A performance improvement system will be used to allow providers to apply quality measurement to their practices and use this data to take action for improving care.

Case in point: disparity in provision of CRT

Among the disparities found in the treatment of heart disease is an inconsistent use of cardiac resynchronization therapy (CRT), a proven treatment for some patients with heart failure, according to research out of Duke Clinical Research Institute (DCRI; Durham; North Carolina). "We looked at figures nationwide, and we found that use of the therapy was extremely variable," said Jonathan Piccini, MD, a cardiologist at Duke University Medical Center and lead study author. He characterized CRT therapy as "extremely valuable," but said that "a lot of people who should be getting the therapy aren't, and some of the people who are getting it may not need it."

The study, appearing in the journal Circulation, showed that only a small percentage of patients with severe heart dysfunction received the device, and those who did were disproportionately younger, white men. Researchers also found that in about 10% of the time, doctors who prescribed CRT did not follow published recommended clinical guidelines.

Study leaders say the findings reveal a troubling picture. It has been estimated that anywhere from a third to a half of all patients hospitalized with heart failure could benefit from CRT. Previous studies have shown that when CRT is used with optimal medical treatment, it can dramatically reduce the need for repeated hospitalization and lower the risk of untimely death.

Two years ago, the American College of Cardiology and American Heart Association (AHA; Dallas) strongly recommended CRT therapy for selected patients with severe heart failure. But until now, it has not been known if the therapy is being used, or if it is being used appropriately.

Investigators examined the records of nearly 34,000 admissions for heart failure from January 2005 to September 2007 in 228 hospitals enrolled in the ACC/AHA's "Get with the Guidelines" program, designed to improve the quality of heart failure care nationwide.

The researchers tracked which patients came into the hospital with CRT in place, and those who had it when they left. They found that the use of the therapy varied significantly, with some hospitals not using it at all, others showing up to 23% of potentially eligible patients receiving the treatment.

They also found that blacks were less likely than whites to receive CRT, even though blacks are twice as likely to suffer from heart failure as whites. In addition, they found that older, sicker patients and those who lived in the Northeast were less likely to receive CRT than younger patients living in other parts of the country.

"Our findings parallel previous studies evaluating adoption of new medical technology in that they show racial disparity in who is receiving the newest therapies," said Piccini. "In contrast to previous studies, however, we didn't find any gender gap in the use of CRT." Men and women received CRT for the first time during their hospital stay about equally.

"We will be watching these trends closely," said Adrian Hernandez, MD, a cardiologist at Duke and the study's senior author. "[T]his study suggests clinically practice varies greatly compared to what it should be."

Cardio immunization potential seen

Low levels of naturally occurring antibodies may represent an increased risk of developing cardiovascular disease, particularly stroke in men, according to a study published recently in the journal Atherosclerosis. The finding points to the possibility of developing an immunization against cardiovascular disease.

It is not known precisely what causes atherosclerosis, but some research suggests that various oxidized forms of bad cholesterol, low-density lipoprotein (LDL), contribute to the development of the disease.

A research team from Karolinska Institute (Stockholm, Sweden), in cooperation with Lund University, has now shown that a particular type of naturally occurring antibodies, anti-PC, which are targeted against the lipid portion of the LDL molecule, play an important role in the development of cardiovascular disease. The findings show that individuals who have low levels of anti-PC are at increased risk of cardiovascular disease. The risk is particularly high in men who develop stroke, with an almost fourfold increase.

This newly discovered risk factor, low levels of anti-PC, is independent of previously known risk factors such as high blood pressure, high blood lipids, diabetes and smoking.