American College of Cardiology

Late-Breaking Clinical Trials II

Mammoth Hypertension Study Nixes Conventional Beta Blockers

(ORLANDO)—A large randomized trial comparing newer antihypertensive treatment strategies to conventional ones has recommended that beta blocker-based treatment be withdrawn “where appropriate” and substituted with newer antihypertensive therapy with calcium channel blockers and ace inhibitors.

There has been continuing debate about whether newer antihypertensive strategies that use calcium channel blockers and ACE inhibitors are superior to older treatments with beta blockers and diuretics. However, despite several large studies and meta analyses, the question remained unsettled, said Peter S. Sever, M.D., Imperial College, London.

In ASCOT-BPLA, some 20,000 hypertensive patients aged 40 to 79 were randomized to receive the calcium channel blocker amlodipine with or without the ACE inhibitor perindopril, or the beta blocker atenolol with or without the diuretic bendroflumethiazide. The target blood pressures were <140/90 mmHg (<130/80 mmHg for patients with diabetes). The primary endpoint was non-fatal myocardial infarction and fatal coronary heart disease, with other prespecified endpoints including all coronary events, fatal and non-fatal stroke, all cardiovascular events and procedures, cardiovascular mortality and all-cause mortality.

The reduction in stroke, coronary events, cardiovascular death and all-cause mortality was so much greater in the amlodipine/perindopril arm that the data safety and monitoring board (DSMB) recommended to the ASCOT Steering Committee that ordered the trial be stopped, fearing it would be unsafe for patients in the beta blocker-diuretic arm to continue, Dr. Sever said.

In addition, there was a substantial excess of new diabetes in the beta blocker/diuretic arm, noted Dr. Sever. “This has been reported in quite a few studies now. It’s clear that patients on any regimen containing a beta blocker, and even worse, if it also contains a diuretic, are 30% more likely to develop diabetes. Something about this drug combination induces diabetes, and this is not good news at all, given the worldwide epidemic of diabetes.”

Dr. Sever is scheduled to present the results of the ASCOT-BPLA trial at 8:45 a.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Buflomedil reduces amputations in patients with peripheral arterial occlusive disease

(ORLANDO)—Long-term treatment with the vasoactive drug, buflomedil, has been shown to improve claudication and reduce clinically important complications such as lower limb amputation in patients with peripheral arterial occlusive disease (PAOD), an international trial concludes.

The Limbs International Medical Buflomedil Trial randomized 2078 Fontaine stage II PAOD patients with an ankle brachial index (ABI) between 0.3 and 0.8 to buflomedil or placebo. Most patients also received aspirin, and a minority received another antiplatelet agent and an oral anticoagulant. After a median of 2.75 years follow-up, trends in favor of buflomedil were observed, Alain Leizorovicz, M.D., School of Medicine, RTH, Leenec, France reported.

Patients on buflomedil had fewer lower limb amputations, cardiovascular death, and total death. In addition, they had significant improvements in intermittent claudication compared to controls.

Dr. Leizorovicz is scheduled to present the full results of the trial here at 8:30 a.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

Can Rimonabant Keep the Weight Off?

(ORLANDO)—Rimonabant has been shown to help overweight and obese slim their waistlines and improve their lipid and cardiovascular risk profiles. But can the selective canabinoid receptor blocker (CB1) keep the weight off? The two-year results from RIO-Europe should give the answer.

Last year, one-year results showed that rimonabant 20mg/day resulted in a significant decrease in body weight and waist circumference (WC), a marker of cardiovascularly dangerous visceral fat, as well as improvements in HDL-cholesterol, triglycerides and the prevalence of metabolic syndrome in overweight/obese patients. The current trial is attempting to show whether extending administration of rimonabant for two years maintains these important improvements.

“There is weight loss and there is weight maintenance,” said Luc Van Gaal, M.D., Antwerp University, Antwerp, Belgium. “Maintenance is a more important issue, because many patients can follow a weight loss regimen for six months or a year. But keeping that going for two years is usually much more difficult,” said Dr. Van Gaal. He added: “If we can show that the weight loss of approximately 10 kilos and the waist circumference change of roughly 10 centimeters, which we have seen at one year, together with all the benefits that we have previously described for the second year, this would be big news.”

Dr. Van Gaal will present the two-year results of RIO-Europe at 9:45 a.m., Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Implantable Monitor May Guide Therapy for Advanced Heart Failure

(ORLANDO)—A device the size of a small pacemaker that continuously records intracardiac pressures when implanted into the chests of patients with advanced heart failure (HF) may help clinicians hone their treatment of this serious condition.

The COMPASS-HF (Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure) trial implanted 274 NYHA Class III-IV patients with the Chronicle, which provided continuous ambulatory intracardiac pressure monitoring. The data from the device was then transmitted once a week to participating physicians via a home-based remote monitor.

“We know patients who have higher pressures do worse with heart failure but it’s often difficult to measure those pressures, especially with physical examination,” said Robert C. Bourge, M.D., F.A.C.C., University of Alabama at Birmingham, in Birmingham, Ala. “We believe that by knowing this information prospectively and continuously, with the patient at home and uploading their parameters to us, we can adjust their medications and optimize therapy,” said Dr. Bourge.

Dr. Bourge will present the COMPASS-HF results at 8:30 a.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

How Low Can You Go? Treating to New Targets Aims to Find Out

(ORLANDO)—The benefits of lowering LDL cholesterol (“bad” cholesterol) have been established without question. But even when LDL reaches levels between 100 and 130 dl/mg, heart attacks and other coronary events still occur in a substantial number of patients. Could this be because the LDL fraction is still not low enough? The Treating To New Targets (TNT) Study aims to find out.

Optimal treatment targets for patients with coronary heart disease (CHD) are still the subject of substantial debate. The TNT study assessed whether reducing LDL-C levels well below the currently recommended level of 100 mg/dL (1.6 mmol/L) would be beneficial in helping to prevent coronary events.

“The aim was to get them down to a level of about 75 mg/dL,” said John C. LaRosa, M.D., president, SUNY Downstate Medical Center and Chairman of the TNT steering committee. “This is new territory, and the issue is, is there any benefit to this,” said Dr. LaRosa.

In TNT, patients with clinically evident CHD underwent an initial eight-week run-in period during which they were treated with atorvastatin, 10mg/day, to get their LDL-C levels down to 130 mg/dL or lower. After this was achieved, 10,002 patients were randomized to atorvastatin 10 mg or 80 mg/day and followed for an average of five years for the occurrence of a major cardiovascular event, which was defined as death due to CHD, nonfatal myocardial infarction, resuscitated cardiac arrest and fatal or nonfatal stroke.

“Is it useful to get LDL cholesterol levels down so low? And secondly, is it safe? These are landmark questions," said Dr. LaRosa. He will present the results of the TNT trial at 10:30 a.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

Tezosentan Safe, But Does Not Improve Acute Heart Failure: VERITAS

(ORLANDO)—Despite high hopes, intravenous administration of the endothelin receptor antagonist tezosentan failed to improve dyspnea, death or worsening heart failure in patients with acute heart failure (AHF), according to the largest international trial in AHF to date.

Endothelin-1 (ET-1) is a potent, endogenous vasoconstrictor, and its presence is a strong predictor of mortality in AHF. The aim of VERITAS (Value of Endothelin Receptor Inhibition With Tezosentan in Acute Heart Failure Studies) was to determine whether the ET-1 receptor antagonist tezosentan could modulate the effects of ET-1 and relieve shortness of breath, the main symptom of acute heart failure — and in so doing, reduce the morbidity and mortality associated with AHF.

VERITAS actually consisted of two identical, double-blind, randomized placebo-controlled trials. Patients who were hospitalized for AHF with dyspnea at rest and who required intravenous treatment for AHF were randomized to tezosentan or placebo for 24 – 72 hours. The primary endpoint of each trial was change in dyspnea over 24 hours, and the primary endpoint for the two trials combined was the incidence of death or worsening heart failure at seven days. Both trials were stopped for futility following recommendation by the Data and Safety Monitoring Board.

John J.V. McMurray, M.D., F.A.C.C., Western Infirmary, Glasgow, Scotland, will present the final analysis of VERITAS at 8:30 a.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Autologous Myoblast Transplant Safe and Feasible at Three Years

(ORLANDO)—In three-year follow-up, autologous myoblast transplantation (AMT) remains feasible and safe in patients undergoing coronary artery bypass grafting (CABG), according to a U.S. multicenter trial.

In AMT, skeletal muscle cells, or myoblasts, are taken from the patient’s thigh and cultured for several weeks. They are then injected into the heart, at the area of the infarction, to promote the growth of new, viable heart tissue. The ultimate goal of AMT is to heal the heart after MI and improve its pumping ability, said Nabil Dib, M.D., F.A.C.C., at the Arizona Heart Institute in Phoenix.

In the feasibility and safety trial, 24 patients with a prior myocardial infarction and a left ventricular ejection fraction <40% who were scheduled to undergo elective CABG were given AMT injections in one of four escalating doses, ranging from 10 to 300 million cells. Post-procedural monitoring included positron emission tomography (PET) and magnetic resonance imaging (MRI).

With a follow-up extending to three years, the safety of the procedure remains excellent, with no perioperative complications. PET and MRI scans show evidence of new heart tissue formation, and heart function has increased from 21% to 34%, an improvement of almost one New York Heart Association function class, said Dr. Dib.

He is slated to report the full details of the 36-month follow-up at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Autologous Bone Marrow Cell Transfer after Acute MI Tested in Randomized Trial

(ORLANDO)—Can autologous bone marrow cell transplantation, given in addition to state-of-the-art reperfusion therapy, boost the recovery of left ventricular (LV) function after an acute myocardial infarction? Results from a new, randomized, placebo-controlled trial may provide the answer.

Despite optimal pharmacotherapy and stenting, the recovery of LV function after MI remains limited. Although several small phase II studies have suggested that transferring a patient’s own bone marrow cells into the infarcted artery improves LV function, this improvement has not been verified in double-blind, placebo-controlled studies, said Stefan Janssens, M.D., University of Leuven, Belgium.

In the new trial, 67 patients with acute MI were randomized to receive an intracoronary infusion of autologous bone marrow cells or placebo up to 24 hours after successful mechanical reperfusion of the infract-related artery. LV function was assessed with cardiac MRI. To ensure the study was blinded, bone marrow aspirates were taken from all patients, but were frozen in liquid nitrogen for use at a later date in the control group. “If the study showed that patients who received the active treatment had a better LV recovery, we would still have the bone marrow cells for the control group to give at a later time,” Dr. Janssens said.

Regardless of the outcome, the results will yield important information, Dr. Janssens said. “If they show no improved recovery in the active treatment arm, we will have to go back to the bench and learn more about the value of progenitor cells. At any rate, data from this first double-blind, placebo-controlled randomized trial will provide valuable information on the role of bone marrow cells in myocardial functional recovery, as well as on the potential mechanisms involved.”

Dr. Janssens will present data from the trial at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Percutaneous AMT promising, but possibly dangerous, for post-MI HF

(ORLANDO)—A small study of the efficacy and safety of percutaneous autologous skeletal myoblast injection for post-myocardial infarction patients with chronic heart failure (CHF) indicates that the procedures is feasible, and improves ejection fraction and wall motion. However, these benefits come at a price: an increased risk for ventricular arrhythmias.

In the study, 15 post-MI patients with CHF received injections of autologous skeletal myoblasts into the scarred regions of their heart using a fluoroscopy guided injection catheter from 4 to 6 years after their MI. After one year, two patients had died, one at 9 and one at 12 days post procedure. Two patients were implanted with an implantable converter defibrillator (ICD) for ventricular arrhythmia (VA). Left ventricular ejection fraction and wall motion score index improved at rest and at low-dose dobutamine stress, Patrick W. Serruys, M.D., Thoraxcenter, Erasmus Medical Center, The Netherlands, said.

He concluded that randomized, properly powered and closely monitored trials of this procedure are needed to assess its true safety and efficacy in these high risk patients.

Dr. Serruys is scheduled to present full details of the study here at 2:00 p.m., Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

BRAVE 2 Trial May Change Treatment of Acute MI

(ORLANDO)—According to current guidelines, patients who come to the hospital more than 12 hours after they experience symptoms of a heart attack do not receive reperfusion treatment, unless their symptoms persist. But a European multicenter trial is investigating whether aggressive reperfusion strategies are still useful after 12 hours have passed.

“The value of reperfusion in patients with acute myocardial infarction presenting 12 hours or less from the onset of their symptoms is well established, but despite all efforts to get people to the hospital quickly, many still turn up after that 12 hour window has passed,” said Albert Schömig, M.D., Deutches Herzzentrum, Munich, Germany.

BRAVE 2 randomized 365 patients with ST-elevation AMI presenting after 12 hours to receive acute percutaneous coronary intervention (PCI) or to conservative medical therapy. The trial then examined the size of the infarct with scintigraphy performed five to 10 days after patients were randomized.

“We expect to achieve at least a 30% reduction in infarct size in the patients assigned to PCI,” said Dr. Schömig. He added, “If BRAVE 2 shows that aggressive reperfusion strategies are useful after the 12 hour cut-off period, it will help redefine the current guidelines for these late-presenting patients.”

Dr. Schömig is scheduled to present the results of this study at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

Catheter Ablation Plus Medication: Effective Treatment for AF

(ORLANDO)—Catheter ablation combined with antiarrhythmic drug therapy is superior to drug therapy alone in preventing recurrences of atrial fibrillation (AF) in patients with both paroxysmal and persistent AF who have not responded to medication, according to a prospective, randomized, controlled study.

Catheter ablation is a percutaneous procedure performed under mild sedation. Catheters are introduced via the femoral vein into the right and left atria of the heart where they “burn” portions of the heart’s interior in order to stop the electrical impulses which give rise to arrhythmia.

In the Catheter Ablation for the Cure of Atrial Fibrillation (CACAF) study, 137 patients were randomized to ablation plus antiarrhythmic drug therapy, or to drug therapy alone. After a year of follow-up, 63 of the 67 patients (94%) who had been treated with antiarrhythmic medication only had at least one AF recurrence. In comparison, just 26 of the 64 patients (40.6%) in the ablation group had a recurrence of AF.

“All of the patients in our study had a very long history of atrial fibrillation,” said Dr. Emanuele Bertaglia, Civic Hospital of Mirano, and Dr. Giuseppe Stabile, Casa di Cura S. Michele, Maddaloni, Italy. “They had already failed at least two or three antiarrhythmic drugs. They are the worst patients we encounter in clinical practice. Yet they responded after the execution of just one ablation procedure,” said Drs. Bertaglia and Stabile.

Full results of the CACAF study will be presented at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

CPAP Fails to Show Mortality Benefit in Heart Failure: CANPAP

(ORLANDO)—A trial of continuous positive airway pressure (CPAP) for heart failure patients who have central sleep apnea has failed to show CPAP can reduce mortality. But it may have other benefits for HF patients, according to a multicenter trial.

“Central sleep apnea is very common in heart failure and is associated with a substantially higher death rate,” said T. Douglas Bradley, M.D., at the University of Toronto in Toronto, Canada. “We wondered whether treating central sleep apnea would improve outcomes in patients with heart failure, just like targeting their blood pressure does,” Dr. Bradley said.

Building on earlier but smaller studies that had found a trend toward lower death rates in patients who received CPAP, Dr. Bradley and colleagues randomized 258 HF patients who had ejection fractions < 40% on optimal medical therapy to CPAP or no CPAP and followed them for as long as five and a half years to see if they would have a reduced rate of death and heart transplantation. Other variables examined were ejection fraction, sympathetic activity, six-minute walking test distance, hospital admissions and quality of life.

Mortality rates between the two groups were identical. However, patients on CPAP did experience reductions in a number of outcomes. CPAP alleviated central sleep apnea, reduced excessive sympathetic nervous system activity and improved LV function and exercise tolerance, Dr. Bradley said.

“Although there were some very tantalizing improvements in physiological outcomes, they didn’t translate into a reduction in death rates, so unfortunately, we cannot recommend its use. But we will be looking at the data in more detail to determine whether there are particular patients who might derive benefit,” he added.

Dr. Bradley will present the full results from CANPAP here at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session.

Largest Gene Therapy Trial Fails to Translate Safety into Benefit

(ORLANDO)—Despite showing excellent safety and some signs of efficacy in high-risk patients, the largest gene therapy trial to date has failed to show an increase in exercise time for patients with class II to IV angina.

The goal of gene therapy is to grow new blood vessels in patients who have myocardial ischemia. After earlier trials (AGENT and AGENT-2) showed that intracoronary injections of the adenovirus for fibroblast growth factor 4 (FGF-4) showed safety and some favorable effects on exercise tolerance and blood flow to the heart in these difficult patients, investigators had high hopes that AGENT-3 would finally demonstrate some real improvement in their ability to exercise, said Timothy D. Henry, M.D., F.A.C.C. Minneapolis Heart Institute in Minneapolis.

In AGENT-3, 416 patients at 65 centers in the United States were randomized to placebo or low dose and high dose of the adenovirus, delivered via intracoronary injection. The patients did not need immediate revascularization for the angina. Patients were then tested on a treadmill at three months and six months to see if their ability to walk had improved. Despite excellent safety, walking times remained unchanged in all groups.

However, some improvement was seen in a subset of very high-risk patients, including those with more severe class III and IV angina, Dr. Henry noted. “These results mean that if you’re not that sick to start with, the gene therapy is not going to make you much better. But it looks as if it is possibly having a better effect in more seriously ill angina patients. In the future, we will probably need to confine this to higher risk patients.”

Dr. Henry is scheduled to present the results of AGENT-3 at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Enhanced External Counterpulsation Helps Improve Congestive Heart Failure

(ORLANDO)—A prospective evaluation of adjunctive treatment with enhanced external counterpulsation (EECP) shows EECP actually improves exercise time and functional New York Heart Association class in patients with congestive heart failure (CHF). EECP is a non-invasive procedure that was shown in a pilot study to be safe.

In the PEECH (Prospective Evaluation of EECP in Congestive Heart Failure) trial, 187 patients were randomized to receive optimal pharmacological care plus 35 sessions of EECP, or to optimal care alone. After six months, exercise time increased by 25+15 seconds in the EECP group, and decreased by 10+13 seconds in the control group. NYHA class improved significantly in the EECP group compared to controls, (31% vs. 16%, p<0.01). Quality of life as reported on the Minnesota Living with HF score also improved significantly among patients who were treated with EECP.

Arthur M. Feldman, M.D., Jefferson Medical College, Philadelphia, is scheduled to present the full results of PEECH at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Novel Compound May Help Preserve Heart Function after AMI

(ORLANDO)—A new class of drug that has the potential to prevent progressive deterioration in left ventricular (LV) function after acute myocardial infarction is being evaluated for the first time in a safety and feasibility phase II trial.

Currently just a number, PG-116800 is a matrix metalloproteinase inhibitor (MMPi) that has shown a significant ability in earlier experiments to reverse LV remodeling, a process in which the infarcted heart undergoes changes in structure and size that ultimately lead to heart failure.

“Metalloproteinases are enzymes within cells that are able to digest proteins, said W. Douglas Weaver, M.D., F.A.C.C., Henry Ford Heart and Vascular Institute, Detroit. “The MMPi stops these enzymes from consuming the structural proteins that keep the integrity of the heart’s shape,” said Dr. Weaver.

The trial randomized 253 patients within 48 hours of their first MI to PG-11680 or placebo for 90 days, in addition to usual care. Serial echocardiographic measurements of LV function and volumes were taken shortly after angioplasty and measured again at 30 and 90 days.

“Expansion of the heart after MI is a surrogate for heart failure, because we know that the bigger the heart gets, the more heart failure progresses. We are hoping that we will show that this new drug will limit this post-MI growth,” said Dr. Weaver.

He is slated to present the results from the multicenter trial at 2 p.m. on Tuesday, March 8, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

Distal Protection No Protection in Acute MI

(ORLANDO)—Hopes that distal protection would improve the outcomes of heart attack patients undergoing coronary angioplasty have been dashed again. But the negative results from a randomized trial may ultimately shed light on the true physiological events that occur during a heart attack, the investigators say.

“Several studies have attempted to show benefit for distal protection devices during direct percutaneous coronary intervention for acute myocardial infarction, but without success,” said Michael Gick, M.D., Herzzentrum, Bad Krozingen, Germany. “However, these studies used endpoints such as ST-segment elevation resolution or other indirect parameters of microcirculation, such as myocardial blush grade. They also looked at infarct size and clinical outcomes to measure benefit,” said Dr. Gick.

In the PROMISE trial, investigators decided to use a direct measure of benefit, improvement of blood flow velocity, by measuring the maximal adenosine-induced Doppler flow velocity in the infarct-related artery in patients with and without distal protection. They also looked at myocardial damage and clinical event rates, but still found no differences between the two groups.

Although the results are negative, they may actually lead to a better understanding of the pathophysiologic process underlying heart attacks, said Dr. Gick. “We were convinced that removing the thrombi and debris with the filters would translate into better flow. Yet, when we remove thrombi we do not see a difference. It seems that letting the debris go into the distal vessel doesn’t matter. We need to find an explanation for this, because it might lead to a better understanding of myocardial infarction.”

Dr. Gick will be presenting the details of PROMISE at 4:45 p.m. on Sunday, March 6, at the American College of Cardiology 54th Annual Scientific Session in Orlando, Fla.

See the news conference schedule for more information.