NEW ORLEANS, Louisiana Presenters revealed some stunning data in coronary and peripheral revascularization during a press conference on late-breaking trials at the American College of Cardiology's (ACC; Bethesda, Maryland) annual scientific sessions in early March. The presentations at the Ernest N. Morial Convention Center included results from the three iterations of the ARCHeR (Acculink for Revascularization of Carotids in High-Risk Patients) trial, which is focused on treatment of carotid artery disease. The three trials tested the safety and efficacy of the Acculink stent developed by Guidant (Indianapolis, Indiana). Guidant, which sponsored the trial, said in a press release that approval for use of stents for the carotid artery could come late this year or early in 2005.
The ARCHeR 1 and 2 trials enrolled 158 and 278 high-risk patients, respectively. Patients in ARCHeR 1 were treated with the over-the-wire Acculink Carotid Stent System. Patients in ARCHeR 2 received both the stent system and the over-the-wire Accunet Embolic Protection System, designed to trap particles of atherosclerotic plaque. The 12-month composite primary endpoint of all death, stroke and myocardial infarction (MI) in the first 30 days, plus any ipsilateral stroke (strokes in the same territory of the lesion) between 31 days and one year was 8.3% in ARCHeR 1 and 10.2% in ARCHeR 2. By comparison, the data associated with the high-risk surgical historical control group indicated a rate of incidence of these events of 14.5%. "We found a significant improvement over that," said William Gray, MD, of the Swedish Heart Institute (Seattle, Washington), a lead researcher of the study.
The ARCHeR 3 trial enrolled 145 high-risk patients and was designed to show equivalence in the safety and performance of the next-generation rapid exchange (RX) versions of Acculink and Accunet with the first-generation over-the-wire devices used in ARCHeR 2. The combined death, stroke and myocardial infarction rate at 30 days was 8.3%, establishing equivalence with the devices used in ARCHeR 2.
An important safety parameter in any stroke prevention trial is the rate of major stroke and death. At 30 days, the rate of major stroke and death across ARCHeR 1, 2 and 3 was 3.8%, 2.5% and 2.8%, respectively. From 31 days to one year, there were no major ipsilateral strokes in ARCHeR 1, and just one in ARCHeR 2.
According to Gray, carotid artery stenting could eventually replace carotid endarterectomy surgical procedures, particularly in high-risk groups. "The results were very good. Carotid stenting is a new technology which very well could supplant surgery in these high-risk patients," he said. Carotid endarterectomy requires an incision in the patient's neck and artery to remove plaque and debris from inside the vessel wall. About 167,000 carotid endarterectomies are performed each year in the U.S. Gray said he believes that once carotid stenting has been approved for use in high-risk patients, it could quickly be adopted as the standard of care. "Certainly if I were a patient and I saw those numbers, I wouldn't want the surgery," he said.
In a study that could have significant implications on how drug-eluting stents (DES) are placed, Jeffrey Moses, MD, of the Lenox Hill Heart and Vascular Institute (New York) suggested that a more DIRECT approach to stenting might have advantages over the traditional balloon-first approach known as angioplasty. According to Moses, the DIRECT trial first came about after a small European study suggested that such an approach might have advantages over pre-dilitation stenting.
The study was designed to assess the safety and effectiveness of direct stenting using the sirolimus-eluting Bx Velocity stent, also known as the Cypher stent from Cordis (Miami Lakes, Florida), which also was the study's sponsor. The U.S. study involved 225 Cypher patients who received direct stenting, meaning without angioplasty. It showed the subsequent buildup of scar tissue in their stents was virtually the same as that seen in Cypher stents during the earlier SIRIUS trial also sponsored by Cordis in which patients had first undergone the balloon procedure.
The investigators concluded that direct stenting was as safe and effective as pre-dilitation stenting and also that it was associated with less restenosis at the edges of the stent, which could help to alleviate the early concerns about edge effect.
The in-lesion rate in the SIRIUS trial, a landmark study that was a benchmark for the DIRECT study, was 9%. "What we see is that when we place the stent directly, we reduce restenosis even further down to 6% so that margin effect now is significantly reduced, going from about a 6% rate down to approximately a 3% rate, and that's an important finding on that issue," Moses said.
Researchers also reported that the direct approach seemed particularly helpful in diabetics and those with small vessels, reducing their restenosis rate by half. "Direct stenting is a commonly used strategy with ordinary stents," Moses said, "but there were virtually no data indicating that it was a proper procedure for drug-eluting stents. We were concerned that if you put the stent in the vessel directly without opening it up a bit [with a balloon] first that the drug may be scraped off, or lose its potency on the way through the blockage. But this didn't occur." Moses noted that this trial suggests patients with direct stenting "have similar or better outcomes" than those who first received angioplasty. He estimated that only one-third of drug-coated stents are currently placed without the balloon procedure. He predicted that percentage could "easily double" in the next year, as results of the DIRECT trial become more widely known.
A randomized comparison between off-pump, or beating-heart, coronary bypass surgery and on-pump "standing" heart coronary bypass surgery has concluded that both are equally safe and effective. In the PRAGUE-4 trial, 400 cardiac surgery patients were randomly assigned to the more recent off-pump bypass surgery technique performed while the heart continues to beat, or to classic on-pump bypass surgery. Coronary angiography was performed in 255 patients at one-year follow-up. Patients in both groups showed similar one-year bypass patency, although the patency of arterial grafts was substantially better than one-year patency of venous grafts, according to Petr Widimsky, MD, of Charles University (Prague, Czech Republic).
"Beating-heart surgery is comparable to classic surgery," Widimsky said, "and this can be an advantage for high-risk patients." The high occlusion rate of venous grafts one year after surgery "is at least comparable to, or higher than, the risk of restenosis after PCI [percutaneous coronary intervention]. Most patients with venous graft occlusion remain asymptomatic or have only minimal symptoms," he added.
Drug-eluting stents, widely acclaimed for the treatment of de novo lesions, or newly diagnosed atherosclerotic lesions in large coronary arteries, are equally impressive in the revascularization of small coronary arteries, according to another trial. Widening smaller vessels, either with balloon angioplasty or stent implantation, has been an enormous problem for interventional cardiologists. Most vessel narrowing occurs in the smaller arteries, but attempts to reopen these vessels would fail 50% of the time, according to Diego Ardissino, of the University of Parma (Parma, Italy).
In the SES-SMART trial, 257 patients with a lesion in a small vessel were randomly assigned to treatment with a stent that had been coated with the drug sirolimus or a standard bare-metal stent. Patients who received the sirolimus-eluting stent had significantly less in-stent restenosis and major cardiovascular events. "The sirolimus-eluting stent reduced the restenosis by 80%," Ardissino said. He added, "We have had no effective means of revascularizing the small coronary arteries. Now we do." He noted that this is particularly important "because two-thirds of the vessels that we are revascularizing are small, and drug-eluting stents are especially useful in this setting."
Guidant cites clinicals, 'good science' of others
In the wake of the successful results reported in the U.S.-based ARCHeR trial, Guidant updated recent clinical achievements during an analyst meeting at the Hilton Riverside Hotel. Guido Neels, group chairman, office of the president, said the session was put together to give an update, from the company's perspective, of the clinical results that were published during the ACC meeting, both from the company and its competitors. "There have been some significant clinical achievements published in the last couple of days," Neels said. He specifically mentioned two areas stroke and heart failure, "that mean significant progress for patients and for physicians and for the industry alike." Neels said stroke affects nearly 1 million people worldwide every year and heart failure impacts the lives of nearly 10 million people across the globe.
While he emphasized that Guidant is working hard to meet the clinical needs in these two areas, he also wished to note that it is "an achievement of the industry that we have now made it to SCD-HeFT [Sudden Cardiac Death in Heart Failure Trial] and COMPANION [Comparison of Medical, Resynchronization and Defibrillation Therapies in Chronic Heart Failure]. We have continued more clinical information and relevance for the therapies that we are working in," particularly over the last three years.
Beverly Huss, president of the Endovascular Solutions unit of Guidant, discussed stroke prevention therapies. She noted that there are about 700,000 strokes a year in the U.S. 500,000 new strokes and 200,000 recurring strokes and that about every 45 seconds, somebody has a stroke in this country and every three minutes, somebody dies of one. "You might think that these are people who are 85 or 90 years of age," Huss said, "[but] the reality is about a third of these patients are under 65 years of age." She also noted that it is the third leading cause of death in the U.S.
According to Huss, there is a need for therapies to help reduce the financial burden of taking care of stroke survivors, of which she said there are more than 4.4 million alone in the U.S. "It is the leading cost of inpatient Medicare costs and it costs about $90,000 per patient per stroke. The annual cost to our healthcare economy is over $50 billion a year."
The current standard of care for treating stroke patients is carotid endarterectomy (CEA), Huss noted, with about 170,000 such procedures done in the U.S. She made the case for the CAS market, saying that currently only 2% of all stroke case are treated with carotid artery stents. She said the company believes this market will grow to reach 23% of all cases by 2007. "This is a market that we think will progress probably over three to five years." Obvious drivers to market adoption include more positive clinical results, Medicare reimbursement (which the company said it expects by 1Q05), treatment of more asymptomatic patients than symptomatic patients and greater awareness of the therapy by patients. "Today, we're already finding that patients are seeking out interventionalists doing these procedures because they'd rather have a minimally invasive intervention than open surgery," Huss said.
She also noted the potential to expand the patient pool, noting that there are 2.5 million people in the U.S with carotid disease, the majority of which go undiagnosed and are typically asymptomatic. "They're high-risk patients currently not treated by endarterectomy, patients that are not even referred for endarterectomy and again, patients that want minimally invasive alternatives." In Europe, there is a 9% penetration of CAS, just under 11,000 procedures. About 80% of these procedures utilized not only the company's over-the-wire and rapid exchange Acculink stents, but also the rapid exchange Accunet embolic protection system. Huss said that Guidant enjoys a market leadership position in this market, with a 30% share reported at the end of 2003. The combination stent and embolic protection system is currently listing in Europe at about $2,500.
Joseph Smith, MD, PhD, chief medical officer for Guidant's Cardiac Rhythm Management unit, discussed the role of clinical science that the company has spurred competitors and the government to bring forward. First, he cited the DEFINITE trial, which was designed to get prospective defibrillator benefit in a non-ischemic patient population. The participants in the trial received single-chamber St. Jude Medical (St. Paul, Minnesota) ICDs, including Atlas and PhotonMicro VR devices. "What was viewed as important is that these patients had non-ischemic dilated cardiomyapathy, symptomatic heart failure and an ejection fraction of less than 35%," Smith said. He also noted that "what we learned from the results was that in a non-ischemic heart population there was a 34% reduction in all-cause mortality." Although he noted that since the trial was powered to detect a 50% mortality benefit it "missed its statistical trigger" he said the study showed that Class III heart failure patients "appeared to have a differential benefit."
On SCD-HeFT, Smith said people have done some "interesting math" equating that trial's results to a combination of the MADIT II (Multicenter Automatic Defibrillator Implantation II Trial) study and the DEFINITE trial results. While he noted that there are important differences between the trials in terms of class of heart failure as well as the ejection fraction cut-offs in the patient populations, there is a "certain consistency" to the notion which evolves when one looks at all of the trials together, with MADIT II showing a 31% reduction in all-cause mortality, DEFINITE showing a 34% reduction and then SCD-HeFT, with an overall reduction of 23%.
As for St. Jude Medical's DINAMIT (Defibrillator IN Acute Myocardial Infarction Trial), a prospective randomized trial designed to assess ICD therapy for prevention of death in high-risk patients early after acute myocardial infarction (AMI), Smith said some "important lessons" can be learned from its failure to show statistical significance. He said that the retrospective data had indicated there might be a benefit if ICDs were implanted early after heart attack in high-risk patients.
"The St. Jude investigators were able to then run a prospective test of that retrospective hypothesis and as you know, that trial failed to be conclusive," Smith said. While that may be the case, he said he believes such studies "draw attention to the importance of testing the hypothesis that you generate from retrospective sub-group analysis, to run that forward so that you can actually tell whether that has significance and value." Smith added, "I think the issues going forward are really all about awareness, access, advocacy [and] action. We've got to move toward getting the patients the benefit that we see in the good science that's been brought forward."
Promising results from smaller trials
While much of the hype at this year's ACC meeting was focused on high-profile studies such as SCD-HeFT and ARCHeR, the bread and butter of the ACC is truly smaller, cutting-edge trials. There always is the potential that one of these will hit upon the next big thing in medicine. During the conference, many presenters offered up studies that could shed light on novel catheter-based treatments for patients with severe heart disease as well as new genetic markers for predicting risk of re-narrowing after stenting.
Data from the POZNAN trial, a human feasibility study evaluating the safety of stem cell delivery via a catheter-based system in heart attack patients, was presented by Tomasz Siminiak, principal investigator of the trial and professor of cardiology at the University School of Medical Sciences, District Hospital (Poznan, Poland). He presented the results of the preliminary 10-patient study one of the first human studies of its kind. The objective of the trial was to evaluate the safety of delivering autologous skeletal myoblast stem cells into heart attack patients via a catheter-based system.
Once implanted, stem cells may serve to regenerate and restore damaged heart tissue caused by heart attacks and could help reduce the potential of future heart failure. The procedures in the trial were performed using Medtronic's (Minneapolis, Minnesota) TransAccess Delivery System, a catheter system that incorporates a needle-based delivery system with on-board IVUS (intravascular ultrasound) imaging technology. This combination is designed to allow physicians to precisely deploy therapeutic agents, such as stem cells, via a needle with real time imaging capability through the vascular system into the muscle of the heart. Medtronic acquired the TransAccess catheter technology through its acquisition of TransVascular (Palo Alto, California) last August.
Results from the trial indicate that the stem cell delivery procedure was performed safely in nine of 10 patients, with one procedure suspended due to an inability to place a guide wire. In addition, Siminiak presented six-month follow-up results on six of the nine cases which indicated two major findings: 1) Improvement in New York Heart Association (NYHA) heart failure classification in all six cases and 2) Ejection fraction improvement in four of the six cases. Post-procedure follow up on the remaining three patients continues. "Though this trial included a very limited patient population, I am particularly pleased with the results to date, which support our belief that a catheter-based delivery system can be used safely to deploy stem cells to heart attack patients," Siminiak said during his presentation. "The trial data to date suggests that we can take this method of stem cell delivery to the next phase of human trials to assess the efficacy of this approach. Post-infarction heart failure is a major clinical problem, and thousands of patients could benefit from myocardial regeneration."
To date, precise delivery of stem cells to heart failure patients has been most commonly performed through open surgical procedures. However, catheter-based systems may offer a compelling potential alternative to open surgical procedures since they are minimally invasive and can be more broadly accessed through the vascular architecture.
In patients with end-stage heart failure, the injection of bone marrow cells through a catheter into poorly functioning areas of the heart resulted in sustained improvement, according to a study from Texas and Brazil. According to Emerson Perin of the Texas Heart Institute (Houston, Texas), what was equally important was that the procedure did not provoke any arrhythmias, a problem observed with surgical bone marrow transplantation techniques. The study, which involved 10 patients with abnormal heart function who were unable to have surgery for clogged coronary arteries, evaluated the effect of transendocardial (TE) delivery of autologous bone marrow mononuclear cells (ABMMC) in patients with severe heart failure.
A patient's own bone marrow was aspirated and ABMMCs were isolated. Next, TE injections were performed using the Cordis (Miami Lakes, Florida) Myostar catheter to first detect poorly functioning areas of the heart and then inject the bone marrow cells into the heart muscle. While Perin said that there was "sustained improvement in exercise capacity" evidenced during the study follow-up at two months, six months and one year, he noted that "future studies are needed to further clarify the role of stem-cell therapy in the treatment of ischemic cardiomyopathy." He also noted that an empirical finding of the study was that the rate of arrhythmia was lowered, suggesting the possibility of using the therapy as a treatment for decreasing that condition.
Using a similar approach, a Washington team found catheter injection of autologous bone marrow cells into oxygen-starved heart muscle to be safe and, perhaps, effective in improving the clinical condition of patients with no other treatment options.
Shmuel Fuchs, an investigator from Rabin Medical Center (Petach-Tikva, Israel), said that initial clinical data suggest that intra-myocardial injection of autologous bone marrow may improve myocardial perfusion in patients with obstructive coronary artery disease. The multi-center Phase I feasibility study, which involved 27 relatively young patients average age of 58 involved evenly distributed multiple transmyocardial injections of freshly unfractionated ABM via an electromechanical mapping-guided injection catheter. The injected regions encompassed just under 20% of the total endocardial surface area. "Procedural success was 100%," Fuchs said. After three months, the average amount and severity of chest pain reported by patients decreased significantly. Additionally, he said that the clinical response for the 16 patients available for one-year follow-up was sustained.
Certain forms of a gene involved in the production of the inflammatory protein interleukin-6 can increase the risk of coronary artery re-narrowing after stent implantation by as much as fourfold, according to a study conducted by Tonya Kottman, MD, from the department of cardiology at Heart Center North Rhine-Westphalia (Bad Deynhausen, Germany) and her colleagues. Before undergoing coronary stenting, 96 patients were tested for a variety of genes, including one known as interleukin-6-174G/C. After six months, all patients had angiography to determine whether the treated artery had renarrowed. Researchers found that the rate of renarrowing was 45% in patients who had the -174G/G form of the gene, 30% in patients with the -174G/C form of the gene, and 11% in the -174C/C form of the gene.
Kottman suggested that the information derived from the study could eventually be incorporated into a diagnostic test that could help doctors determine who the best candidates are for drug-eluting stents prior to stent implantation.