This Week in Circulation
Interleukin-18 Predicts Coronary Events
Circulating interleukin (IL)-18 was shown to be an independent predictor of coronary events in 10 600 healthy, middle-aged European men followed up for 5 years, according to a report in the current issue of Circulation (Circulation. 2003;108:r115–r121OpenUrl).
In the analysis, 335 cases with a coronary event were compared in a nested case-control manner with 670 age-matched controls. At baseline, levels of IL-18 were significantly higher in the men who developed a coronary event than in the controls, said researchers led by Stefan Blankenberg, MD, of Faculté de Médecine Pitié-Salpétrière in Paris, France. In fact, the researchers said that determining the levels of circulating IL-18 might improve prediction of coronary events, at least in a similar population.
Late-Breaking Clinical Trials From the 2003 Scientific Sessions of the American Heart Association
ORLANDO, Fla—Mickey Mouse may reign supreme in this Florida city, but everything was serious during the 2003 Scientific Sessions of the American Heart Association, attended by an estimated 27 000 participants. Thousands of scientists, physicians, researchers, and others interested in the heart crowded into a variety of sessions to learn the latest information. Of particular interest were the late-breaking clinical trials, which covered everything from primary prevention in low-income populations to groundbreaking information about the use of automated external defibrillators by trained members of the public to the newest in drugs and the use of implanted cells to save failing hearts.
On the Mend in an Underserved Population. . .
ORLANDO, Fla—An innovative and aggressive program reduced multiple cardiovascular disease risk factors in a medically underserved population, said researchers from the Oregon Health and Science University who reported on the trial at the 2003 Scientific Sessions of the American Heart Association held here November 9–12, 2003.
The case management approach to reducing risk had already been shown to reduce risks effectively in people with good access to medical care, said William L. Haskell, PhD, Associate Professor of Medicine in the Division of Cardiology at the Oregon Health and Science University in Portland. “What is missing are data that such systems can be modified to reach the medically underserved,” he said.
In this study, 149 people at high risk for cardiovascular disease were identified among low-income people in Santa Clara County, Calif, who had little or no health insurance. They were screened and assigned on a 2-to-1 basis to the case-management approach to risk reduction and usual care. The yearlong case-management system used a physician-directed, nurse and dietitian case management system that included both lifestyle change and medical management.
The study included people who were Hispanic (57%), Asian (10%), African-American (7%), Caucasian (16%), and other (10%). Only 33% of the patients were fluent in English, and 45% spoke no English at all. Fifty-four percent of the patients were type II diabetics, 38% were obese, 67% had high cholesterol and/or high triglycerides, and 70% were hypertensive.
Study participants averaged 6.3 clinic visits during the first year. Each visit was 60 minutes long and included a reassessment of where the individuals were compared with the goals. They were counseled about lifestyle changes, and medication regimens were changed for those who needed it.
Medication provided in the program came from existing indigent care programs and as donations from drug companies, Dr Haskell said. The study was funded by the Health Trust of Santa Clara County, which focuses on providing health care to people who cannot afford it,
At 1 year, the case-management program significantly reduced major cardiovascular disease risk factors when compared to the usual-care population, said Dr Haskell. That included blood pressure, low-density lipoproteins, total cholesterol, high-density lipoprotein–low-density lipoprotein ratio, and control of blood sugar, he said.
“One area that challenged us all was reduction in body weight, and it remains a significant challenge,” he said.
Overall, he said, the program was a success. In part, that was because its design made care available to the patients.
“We attempted to minimize any kind of barriers or delays in getting people the services they needed,” said Dr Haskell. “We attempted to provide those services immediately. What we did goes against popular wisdom. One should not confuse lack of education and resources with a lack of intelligence and motivation.”
Providing the kind of care given in this study is not expensive but could not be done widely in the system of health care current in the United States, he said.
George Mensah, MD, of the Cardiovascular Disease Branch of the US Centers for Disease Control and Prevention in Atlanta, Ga, agreed that “while these findings are impressive, what factors would help us translate these findings from the research setting to real practice to help the 75 million people in the United States who lack health insurance” at one time or another during a 2-year period?
. . .but Failing in Women
ORLANDO, Fla—A systematic program to prevent coronary heart disease in women was unsuccessful, said its principal investigator, as she presented the Secondary Prevention Beyond Hospital Walls IntervenTion Trial In Women (WITTI) at the 2003 Scientific Sessions of the American Heart Association here November 9–12, 2003.
A total of 304 women (average age, 62.3 years) hospitalized with coronary heart disease were randomized to 2 groups—one systemic intervention to maximize adherence to 8 AHA secondary prevention goals and usual care directed at the same target, said Lori Mosca, MD, MPH, PhD, Director of Preventive Cardiology at New York Presbyterian Hospital. The intervention group received counseling by a prevention facilitator/educator about lifestyle, risk factors, and preventive medications during hospitalization, and members were contacted at 2 weeks, 4 weeks, 3 months, and 6 months after discharge.
A summary score for meeting the 8 goals was the primary end point. Goals included were weight reduction; low-density lipoprotein levels; blood pressure; smoking cessation; physical activity; and use of aspirin/anticoagulants, β-blockers, and angiotensin-converting enzyme (ACE) inhibitors. At 6 months, there was no significant difference in the summary score between the intervention and usual-care group.
Dr Mosca said that 10% to 15% of women were lost to medical follow-up.
“Part of the reason that women have a bad prognosis is that they don’t see a doctor at all,” she said. “I suspect with women that transportation is often an issue.”
BRAVE Trial Favors Abciximab Alone While Awaiting Percutaneous Intervention
ORLANDO, Fla—The glycoprotein IIb/IIIa receptor inhibitor abciximab alone was as effective as abciximab plus the thrombolytic reteplase in treating acute myocardial infarction patients who experience delay in undergoing percutaneous intervention, said German researchers participating in the BRAVE (Bavarian Reperfusion Alternatives Evaluation) trial. The results were presented at the first late-breaking research session at the 2003 Scientific Sessions of the American Heart Association here November 9–12, 2003.
“There is often unavoidable delay between establishment of a diagnosis for acute myocardial infarction and percutaneous intervention,” said Adnan Kastrati, MD, Senior Cardiologist at the Deutsches Herzzentrum in Munich, Germany. “We don’t know the best antithrombotic strategy in these patients.”
Of the 253 patients who arrived at the hospital within 12 hours from the onset of symptoms of an ST-elevation acute myocardial infarction, 125 were randomized to receive reteplase and abciximab, and 128 were assigned to abciximab alone while they awaited percutaneous intervention. Seventy-four percent of patients were randomized at community hospitals that lacked percutaneous intervention facilities, and the rest were randomized at the interventional hospitals.
Infarct size measured by scintigraphy did not differ significantly between the two groups. Combined 30-day incidence of death, recurrent myocardial infarction, and stroke was 3.2% in the combined group and 1.6% in the abciximab-alone group.
“After treatment, we saw no difference between the two groups in TIMI3 flow rates,” said Dr Kastrati.
Frans van der Werf, MD, PhD, Department of Cardiology, University of Leuven in Belgium, noted that in this study, delays in treatments were as short as 90 minutes in one half the patients.
“In the real world, delays are much longer,” he said. “It is now well accepted that time to first balloon inflation is as important as time to lysis. In view of the delays incurred, giving a lytic agent makes sense.”
He noted that in the BRAVE trial, patency rates before percutaneous intervention were higher with the combination therapy than with monotherapy. It did not translate into benefit in this small population, said Dr van der Werf.
“Which pharmacological treatment should be given will have to come from larger studies,” he said. “At present, we don’t have convincing evidence that facilitated PCI (pretreatment combined with percutaneous intervention) is better. It is a pity that BRAVE did not include primary PCI without prior treatment in their otherwise excellent study.”
Omega-3 Fatty Acids Fail Arrhythmia Test
ORLANDO, Fla—Patients with implantable defibrillators and a history of arrhythmia who received fish oil or n-3 polyunsaturated fatty acids did not have fewer or delayed arrhythmic events than similar patients who received placebo, said Oregon researchers at the first late-breaking research session of the 2003 Scientific Sessions of the American Heart Association here November 9–12, 2003.
“This, of course, was an unexpected result,” said Merritt Raitt, MD, of the Oregon Health and Science University in Portland.
Two hundred patients with an implanted defibrillator and recent episode of ventricular tachycardia or fibrillation were randomized to received 1.8 g of n-3 polyunsaturated fatty acids or placebo daily and were seen every 3 months for as long as 2 years. There was a trend toward an increase in incidents of ventricular tachycardia and ventricular fibrillation in patients randomized to fish oil.
“Patients with the highest increase in red cell omega 3 fatty acid levels had the highest risk of ventricular arrhythmias,” said Dr Raitt. “Although not statistically significant, this is associated with findings that omega fatty acids do not have an antiarrhythmic effect in this population.”
Eric Prystowsky, MD, Director of the Clinical Electrophysiology Laboratory at St Vincent Hospital, Indianapolis, Ind, said, “I’m a little surprised to see a trend in the wrong direction. You can’t say it is pro-arrhythmic. That is premature.”
“The big question for all of us is does this study mean we should throw out all the literature on omega 3 fatty acids?” said Dr Prystowsky. “My response is absolutely not. I think it teaches us not to make leaps of faith on mechanism.”
PRIMO-CABG—Trying to Reduce Infarction and Mortality After Bypass
ORLANDO, Fla—The antiinflammatory drug pexelizumab did not significantly reduce death or myocardial infarction at 30 days in the coronary artery bypass patients who received it in this randomized, double-blind, placebo-controlled study, but there were indications of benefit, said its principal investigator during the 2003 Scientific Sessions of the American Heart Association here November 9–12, 2003.
In the PRIMO-CABG (Pexelizumab for the Reduction of Infarction and Mortality in Coronary Artery Bypass Graft surgery) trial, 3099 patients enrolled at 205 centers in North America and Europe, with 1368 randomized to placebo and 1378 to pexelizumab. At day 4, said Edward D. Verrier, MD, Professor of Cardiovascular Surgery at the University of Washington School of Medicine in Seattle, the composite end point of death and myocardial infarction was significantly reduced in the treatment population—26% in the CABG-only group and 24% in the overall population (which included some patients who underwent valve surgery as well).
It also significantly reduced death and myocardial infarction in the total intent-to-treat population at day 180, he said.
“The study did not meet its end point,” said Robert C. Robbins, MD, of Stanford University School of Medicine. He said that while there were indications of success in subpopulations, the effect of the drug was not as significant as would have been expected.
“The lack of dramatic effect means there is a potential need to inhibit more than one component of the inflammatory process,” said Dr Robbins. He said there are plans to study the effects of inhibiting other components of the process, as well.
“One of the most important issues would be to perform a pharmacoeconomic analysis,” he said. He said that on the basis of this study, it would be difficult to justify using such treatments in most patients at this time.
ORLANDO, Fla—The angiotensin receptor blocker valsartan is as effective as the ACE inhibitor captopril in reducing the occurrence of cardiovascular deaths and major cardiovascular events, said the principal investigator of VALIANT (Valsartan in Acute Myocardial Infarction Trial) during a late-breaking research session of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
The study, which was released early by The New England Journal of Medicine on November 10, 2003 (N Engl J Med. 2003;349:1893–1906), randomly assigned 4909 patients to the valsartan arm of the trial, 4885 patients to valsartan plus captopril, and 4909 to captopril alone. Over 24.7 months, 979 patients in the valsartan group died, 941 in the valsartan-plus-captopril group died, and 958 patients in the captopril group died.
Although the drug-related adverse events in the 2 single-drug groups were the same (although the kinds of events differed with the drug), the combination drug group experienced more such events.
“In these patients, valsartan is a clinically effective alternative to an ACE inhibitor,” said Marc Pfeffer, MD, PhD, Professor of Medicine at Harvard Medical School in Boston. “Physicians will have more tools to expand the life-saving use of these inhibitors of the renin-angiotensin system.”
“Bertram Pitt, MD, Professor of Internal Medicine at the University of Michigan at Ann Arbor, called the study a landmark trial.
“Clearly, I would feel confident now using an angiotensin receptor blocker as equivalent in these patients,” he said. However, he said, the trial does not translate necessarily into a class effect without careful trials to establish the equivalent dose.
“The doses are critical,” he said. He said he would also be careful about extrapolating the data to the use of angiotensin receptor blockers in different classes of patients.
The VALIANT investigators “have given us just about all we need to know about the role of ARBs [angiotensin receptor blockers] and ACE inhibitors in acute myocardial infarction, but we have more to learn about chronic heart failure,” said Dr Pitt.
ACTIV in CHF?
ORLANDO, Fla—The vasopressin receptor blocker tolvaptan significantly reduced body weight in patients hospitalized with heart failure in the ACTIV in CHF (Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist in Congestive Heart Failure) trial reported during a late-breaking session of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
Three hundred twenty patients hospitalized for heart failure in the United States and Argentina were randomized within 72 hours of admission to receive daily placebo or one of 3 doses of tolvaptan—30 mg, 60 mg, and 90 mg. The mean ejection fraction was 24%, and all had fluid overload, said Mihai Gheorghiade, MD, Professor of Medicine and Chief of the Cardiology Clinical Service at the Northwestern University Feinberg School of Medicine in Chicago.
Therapy continued for 60 days and was given concomitantly with standard therapy, he said.
“All patients on drug had a significant decrease in body weight compared to placebo,” he said. “The body weight decrease was not dose related, however.”
However, there was no difference in worsening heart failure between the 2 groups, he said.
Mariell Jessup, MD, Associate Professor of Medicine at the University of Pennsylvania School of Medicine, said researchers in the field know that a vasopressin antagonist can be acutely effective.
“In the present study, we were hoping for a little more,” she said. “Clearly, patients diurese and lose water and weight. In patients who were very sick, it might have an impact on mortality. I would argue that it’s a lot to expect in this environment that an additional drug will significantly impact mortality.”
She was disappointed that the study was done only in patients with a low ejection fraction when 50% of patients with heart failure have normal ejection fractions. She hoped that it could be studied in a group that is more varied as to race, gender, and ethnicity.
Bone Marrow Cells May Help Patients After Myocardial Infarction
ORLANDO, Fla—Transfer of autologous bone marrow cells into the coronary artery by catheter was safe and enhanced left ventricular function in myocardial infarction patients after successful percutaneous intervention, said German researchers during a late-breaking research session during the 2003 Scientific Sessions of the American Heart Association held here November 9–12, 2003.
Thirty patients were randomized to receive autologous bone marrow transplantation, and 30 were designated controls in this study, said Kai C. Wollert, MD, of the Hannover Medical School in Hanover, Germany. Bone marrow cells were obtained from the hip bones of patients 4 days after the myocardial infarction and transferred into the patients’ occluded coronary arteries via catheter, said Helmut Drexler, MD, also of Hannover School of Medicine.
Patients in the control group that received percutaneous intervention and optimal medical therapy experience a 0.7% increase in ejection fraction, he said. In the group that received the bone marrow transfer, ejection fraction improved 6%. The difference was statistically significant, said Dr Drexler.
“Patients who present late derive substantial benefit from intracoronary bone marrow cell transfer,” said Dr Wollert. “Bone marrow cell transfer appears to promote greater functional recovery in patients who present late after symptom onset.”
The use of bone marrow cells in these patients is appealing because it is technically simple, said Philippe Menasche of the Hospital Bichat in Paris.
Dr Menasche, a pioneer in the field, said he sees positive features in this randomized trial. The study raises 2 questions, he said. One is which kind of cell is preferable in this kind of treatment—bone marrow cells or some fraction of bone marrow that can be considered stem cells.
The other is that “the benefits of the transplantation in the treated group are magnified by the fact that there was virtually no improvement in the control group. It is surprising and distressing to see such a result,” he said.
His comments do not weaken the impact of the study, he said, “which strongly supports the idea that even if we don’t yet know the type of cells to be used, it supports and reinforces the concept that stem cell transfer is likely to be an effective means of potentiating the efficacy of techniques already available for treating patients with acute myocardial infarction.”
The SPORTIF V Results
ORLANDO, Fla—The oral thrombin inhibitor ximelagatran was as effective as warfarin in preventing stroke and systemic embolic events in patients with atrial fibrillation in the SPORTIF V (Stroke Prevention using an Oral Thrombin Inhibitor in atrial Fibrillation V) trial, said Jonathan Halperin, MD, Professor of Medicine at Mount Sinai School of Medicine in New York. Dr Halperin presented during a late-breaking clinical trials session at the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
“In high-risk patients with nonvalvular atrial fibrillation, ximelagatran is as effective as warfarin,” said Dr Halperin. “It has the advantages of fixed oral dosing and no need for coagulation monitoring. It is associated with an increase in liver enzymes that went as high as 3 times higher than normal in 6% of the patients.” He said the levels return to normal eventually, whether the drug is stopped or not. He advised monitoring liver enzymes monthly for the first 6 months of ximelagatran administration.
SPORTIF V investigators enrolled 3922 patients at 409 sites. The trial was randomized and double-blinded, with half the patients receiving warfarin in carefully controlled dosages with frequent anticoagulation monitoring and half receiving ximelagatran at a dose of 36 mg twice a day. Each patient remained in the study 12 months, and an aggregate follow-up of 4000 patient-years was required, with 80 patients experiencing a verified primary event. The primary end point was all strokes and/or systemic embolic events based on intention to treat.
The trial was designed to prove that ximelagatran is as effective as warfarin, and it did that, said Dr Halperin. Follow-up was 20 months per patient. There were 37 primary events in the warfarin group and 51 in the ximelagatran, he said.
The difference is not statistically significant, he said. Even though the number of events was smaller in the warfarin group, the study supports the noninferiority of ximelagatran for patients with atrial fibrillation, he said.
“My first impression is that this is a landmark study,” said Michael Ezekowitz, MD, PhD, Professor and Chair of Medicine, Cardiology, at Drexel University College of Medicine in Philadelphia, acting as discussant at the session. “What I found quite remarkable is that the investigators got the dose right. To put that into perspective, it took the field almost 50 years to get the dose right for warfarin.”
He noted that stroke rates in both arms of the trial were unusually low.
“The liver enzyme issue needs to be addressed,” he said. He said more information is needed on the abnormalities found and whether they truly resolve in all patients. A drug that does not cause such problems would obviously be better, and he advised that research in the future should work toward improving on ximelagatran, perhaps moving to a single-dose medication.
ORBITing the Truth About Defibrillators
ORLANDO, Fla—A biphasic rectilinear defibrillator showed no superiority when compared against monophasic defibrillators in converting rhythms after out-of-hospital cardiac arrest with either 1 or 3 shocks, said a Toronto researcher during the late-breaking clinical trials session of the 2003 Scientific Sessions of the American Heart Association here November 9–12, 2003.
The biphasic defibrillator was safe with no complications, said Laurie Morrison, MD, principal investigator and Director of the Pre-Hospital Research Program at Sunnybrook and Women’s College Health Sciences Centre in Toronto. There was no difference in survival between the groups of patients that received the monophasic defibrillation and the biphasic shock in ORBIT (Out-of-hospital Rectilinear Biphasic Investigational Trial).
Randomization was accomplished by assigning a field officer to move the biphasic units from one station to another on a schedule set randomly, said Dr Morrison. The trial was suspended 3 times: during a papal visit, when the field officer had a heart attack and replacement had to be trained, and for 4 days during a Rolling Stones concert tour.
Results from 434 patients enrolled in the trial showed that return of spontaneous circulation in the two groups was the same: 88 in the monophasic group versus 90 in the biphasic. In the monophasic group, 123 arrived alive in the emergency department compared with 125 in the biphasic group. Survival at 24 hours was 46 (monophasic) versus 50 (biphasic) and at 30 days, 14 (monophasic) and 15 (biphasic).
“It is important to mention that these are important public health issues,” said Raymond J. Gibbons, MD, chairman of the American Heart Association Committee on Scientific Sessions Program and Professor of Medicine at the Mayo Clinic Medical School in Rochester, Minn. “Our ability to successfully resuscitate people out of the hospital varies among locations. These trials are difficult to do.”
PAD Doubles Rate of Survival in Out-of-Hospital Cardiac Arrest
ORLANDO, Fla—Public access defibrillation doubles the survival to hospital discharge of patients who suffer out-of-hospital cardiac arrest, said Joseph P. Ornato, MD, Chair of Emergency Medicine at Virginia Commonwealth University/Medical College of Virginia in Richmond during a late-breaking clinical trials session of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
The long-awaited trial called PAD (Public Access Defibrillation) involved the use of automatic external defibrillators (AEDs) in public locations by trained layperson volunteers. During the 3 years of the trial, Dr Ornato and his colleagues trained 19 762 volunteer rescuers. Some were trained only to recognize a possible cardiac arrest, call 9-1-1 immediately, and begin high-quality cardiopulmonary resuscitation (CPR), he said. Others were trained to recognize cardiac arrest, call 9-1-1, perform CPR, and use an automatic external defibrillator.
Approximately 1000 AEDs were distributed in 24 communities in the United States and Canada. The PAD trial identified 993 community units that met the criteria for high risk and qualified for AED positioning. Data were collected for more than 21 months on the average, said Dr Ornato.
More than 80% of the identified units were in public locations, but 15% to 16% were in multiunit housing areas—either apartments or gated communities. The AED was centrally located, and volunteers were trained to get the AED and run to the location of the presumed cardiac arrest.
There were 1593 events identified in the CPR-alone communities compared with 1891 in the CPR-plus-AED community units. Of those, 228 in the CPR-alone communities and 240 in the CPR-plus-AED communities were presumed cardiac arrests, and 103 in the CPR-alone and 129 in the CPR-plus-AED communities were definite cardiac arrests. Of these, 15 in the CPR-alone and 29 in the CPR-plus-AED communities survived to hospital discharge.
Because of a possible bias with more cardiac arrests being definitely determined in the AED group because of the technology, Dr Ornato and his colleagues decided to base their denominator on the communities in which the two different methods were used.
“Randomizing the community units levels the playing field, resulting in the equal at-risk pool that generates a similar number of out-of-hospital cardiac arrests in each group,” he said.
Because of this leveling, he and his colleagues were able to compare the numbers of survivors in the two groups, thus arriving at the near doubling of survival in the AED group.
In those groups where cardiac arrest occurred in a home, he said, only 1 person in each group survived to leave the hospital.
This finding is significant because in most cities, 80% of out-of-hospital cardiac arrests occur in the home, said Dr Ornato.
“Ultimately, the most important question is the home and can a layperson in the home setting get the job done?” said Dr Ornato. A study now being planned will shed more light on that issue.
Roger D. White, MD, of the Mayo Clinic in Rochester, Minn, called the study “landmark” and noted that its results had been long awaited. He said he would like to know how many people in cardiac arrest had untreatable cardiac rhythms.
“This would have important implications for understanding the benefits of employing AEDs in a public setting,” he said. “We will need to know in which specific locations the maximum benefit could be realized.”
During an earlier briefing, Dr Ornato said that the cost analysis for the study has yet to be completed.
Dr White said that the number of cardiac arrests at the 24 sites during a 2-year period struck him as being low. He said he is already concerned that AEDs are being positioned in spots because of concerns about liability and not because that is where they will do the most good.
“Now home defibrillation looms before us as a relative concern,” he said. “We do not know what role AEDs might have in that setting.”
Implantable Cardioverter Defibrillator Value in Nonischemic Cardiomyopathy Not DEFINITE
ORLANDO, Fla—In the DEFINITE (DEFibrillators In Non-Ischemic cardiomyopathy Treatment Evaluation) trial, implantation of an implantable cardioverter defibrillator (ICD) did not significantly reduce deaths from all causes, but it did have a significant effect on the reduction in deaths from arrhythmias, said Alan Kadish, MD, Professor of Medicine at Northwestern University in Chicago.
During a late-breaker session of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003, Dr Kadish described the trial, in which 458 patients with nonischemic cardiomyopathy were randomized to receive standard therapy including a β-blocker and an ACE inhibitor or that therapy plus an ICD.
Patients were followed up an average of 26 months. During that time, a total of 56 deaths occurred, 33 in the standard therapy group and 23 in the ICD group. At 2 years, mortality was 8.1% in the ICD group and 13.8% in the regular treatment group. The 34% relative mortality benefit in the ICD group did not reach statistical significance, said Dr Kadish.
However, he said, there were 3 arrhythmic deaths in the ICD group and 11 in the regular group, for a 74% reduction in mortality that was statistically significant.
Arthur J. Moss, MD, Professor of Medicine at the University of Rochester (NY) School of Medicine, said that trial “expands the patient population that can benefit from the ICD. It’s a nicely conducted study that meets scientific and statistical scrutiny.”
ORLANDO, Fla—An unanticipated increase in stroke will probably put further development of cariporide on hold, even though the trial itself showed it had benefit in lowering morbidity and mortality after coronary artery bypass surgery and/or valve surgery, said Robert M. Mentzer, Jr, MD, Chair of Surgery at the University of Kentucky at Lexington and principal investigator of the study EXPEDITION (Na+/H+ EXchange inhibition to Prevent coronary Events in acute cardiac conDITIONs).
Dr Mentzer said the use of the sodium-hydrogen exchange inhibitor was designed to reduce ischemia perfusion injury that occurs when blood flow is interrupted as the patient is put on the heart-lung bypass machine. Such injury is most often implicated in the incidence of heart attack and death that follow coronary artery bypass surgery.
A total of 5770 coronary artery bypass graft patients who had risk factors for perioperative myocardial ischemia were randomized to receive intravenous cariporide or placebo. The primary end point of death or myocardial infarction was measured at day 5 and 6 months after surgery. At day 5, the combined death/myocardial infarction rate was 20.3% in the placebo group and 16.6% in the cariporide group. Six months after surgery, the combined rate was 23.9% in the placebo group and 20.2% in the cariporide group. However, at day 5, the death rate in the placebo group was 1.5% and in the cariporide group, 2.2%. However, myocardial infarction rate in the placebo group was 18.9% in the placebo group and 14.4% in the cariporide group. The difference continued in the 6-month statistics.
“An unexpected finding was that there was a small but real difference with regard to stroke,” he said. The stroke rate in the placebo group was 2.7%, compared with 4.8% in the treatment group.
“Clearly this represents an adverse event,” he said. He said plans to take it to market are now on hold because of the stroke issue.
Richard Weisel, MD, of Toronto said most of the treatments that have been used in this population to reduce the risks of death or myocardial infarction had had benefits and risks.
“The solution may be to reduce the dose or to deliver a low dose directly into the heart itself or combine this drug with other agents.”
Just Enough With PAPABEAR
ORLANDO, Fla—Amiodarone almost halved atrial fibrillation or flutter in patients undergoing coronary artery bypass graft surgery, according to L. Brent Mitchell, MD, head of the Department of Cardiac Sciences for the Calgary (Canada) Health Region. His trial PAPABEAR (Prophylactic Amiodarone for the prevention of Arrhythmias that Begin Early After Revascularization) was lauded as having the most creative acronym at the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
β-Blockers are the drugs most extensively studied in this problem, said Dr Mitchell, but they are not used extensively by physicians and patients. Most studies of amiodarone to date have been small and underpowered to prove its value in this population. PAPABEAR was designed to settle the question, he said.
The study’s investigators randomized 601 patients to receive amiodarone at a dose of 10 mg/kg per day or a corresponding placebo for 6 preoperative days, the day of surgery, and for 6 postoperative days. Patients undergoing nonemergency bypass or valve surgery were included in the study. The primary outcome was that atrial fibrillation or flutter occurred in 16.1% of amiodarone-treated patients and 29.6% of patients who received placebo, said Dr Mitchell. Similar benefits were seen in various subgroups, he said.
“The absolute reduction in postoperative atrial fibrillation is 13.5%,” said Dr Mitchell. “You only have to treat 7.4 patients to prevent 1 case of postoperative atrial fibrillation.”
When atrial fibrillation did appear in amiodarone-treated patients, the ventricle’s response was slower, he said. Those in the amiodarone group were also more likely to withdraw from the study because of potential adverse effects, he said.
The results of the PAPABEAR trial are consistent with those of other smaller trials, said Douglas Zipes, MD, of Carmel, Ind.
“What was unexpected was that there was no difference in the number of episodes or the length of episodes or the total atrial fibrillation burden of those who did develop atrial fibrillation while on amiodarone,” said Dr Zipes, a former president of the American Heart Association. “Why did it reduce the total number of patients without having an impact on those who did develop atrial fibrillation? Is there a group of patients responding to amiodarone who don’t develop atrial fibrillation?”
Those concerns aside, “I think there is a sufficient body of data to support routine use of preoperative drugs to prevent atrial fibrillation,” said Dr Zipes. “Now we need a head-to-head comparison of the best therapies. That may prove the answer as to why some patients respond to amiodarone and some don’t.”
Is It the Drug or the LDL? The Dilemma of REVERSAL
ORLANDO, Fla—Is a low-density lipoprotein level below the current recommendations better, or is atorvastatin better than pravastatin? The REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) trial provides a clue, said Steven Nissen, MD, principal investigator and Medical Director of the Cleveland Clinic Cardiac Coordinating Center.
“We designed our trial to find out if there were differences among agents in the drug class and if there were differences in lower LDL levels,” said Dr Nissen, who described his study during a late-breaking clinical trial session of the 2003 Scientific Sessions of the American Heart Association meeting here November 9–12, 2003.
A total of 502 patients were randomized to one of 2 groups. One received 40 mg daily of pravastatin, a moderate lipid-lowering drug, for 18 months. The other group received 80 mg of atorvastatin, a more effective lipid-lowering agent, for the same period.
The total plaque burden was measured at the beginning and end of the trial by intravascular ultrasound. At the end of the trial, baseline low-density lipoprotein cholesterol levels in the pravastatin group were reduced from 150.2 to 110 mg/dL. In the atorvastatin group, subjects started with the same LDL levels but ended up with LDL levels of 79 mg/dL on average, said Dr Nissen. More important, he said, the plaque burden increased 2.7% in the pravastatin group and actually regressed 0.4% in the atorvastatin group, although the change was not statistically significant.
“There was a highly significant difference in progression,” said Dr Nissen. “Virtually the entire group progressed on the pravastatin regimen. You can reduce the progression rate for coronary atherosclerosis to zero, but you have to use the highest dose of the most effective statin. If you undertreat, you don’t affect the progression of disease.”
Even when patients in the pravastatin group were able to lower their LDL levels to 88—almost as low as the average in the atorvastatin group—there was still significant progression, said Dr Nissen.
He cautioned, however, that using intravascular ultrasound to measure plaque is a surrogate marker that is not the equivalent of measuring morbidity and mortality.
“I happen to think that stopping progression of disease is important, but it is not morbidity and mortality,” he said.
Discussant John Hodgson, MD, also of Cleveland, Ohio, was enthusiastic about the trial.
“The REVERSAL study demonstrates that aggressive lipid lowering arrests the progression of atheroma, not just because of LDL but also because of pleiotropic effects,” he said.
How to PREVEND-IT?
ORLANDO, Fla—Treatment with the ACE inhibitor fosinopril appeared to reduce urinary albumin excretion and cardiovascular events, including mortality and hospitalization, as well as end-stage renal disease, said Wiek H. Van Gilst, PhD, Professor of Cardiovascular and Clinical Pharmacology at the University of Groningen in the Netherlands during a late-breaking clinical trials session of the 2003 Scientific Sessions of the American Heart Association held here November 9–12, 2003.
In PREVEND IT (Prevention of Renal and Vascular Endstage Disease Intervention Trial), Dr Van Gilst and his colleagues randomized 864 patients in a 2×2 factorial design. Half the subjects received fosinopril at 20 mg daily or a matching placebo. Half received the lipid-lowering drug pravastatin at 40 mg daily or a matching placebo. The patients all had microalbuminuria but did not have high blood pressure or high cholesterol. They were followed up for approximately 4 years.
“Fosinopril reduced blood pressure and microalbuminuria significantly,” said Dr Van Gilst. “This was associated with a trend to reduce the incidence of the primary end point” of cardiovascular mortality, hospitalization for cardiovascular morbidity, and end-stage renal disease.
Pravastatin had no effect, he said.
Discussant Lars Ryden, MD, of Stockholm, Sweden, said that microalbuminuria “is an indicator not only of increased renal but also of cardiovascular risk. We do not yet know if it is a risk in itself or reflects the presence of other risk factors.”
“The investigators said that PREVEND IT did not give a definitive answer and that the results favor further studies,” said Dr Ryden. “The most important contribution from this study is that it provides knowledge of great value for further studies.”