This Week in Circulation
Patients with blood containing high levels of antibodies to heat shock protein 65 (hsp65) were found to be at increased risk of subsequent cardiovascular events, independent of other cardiovascular risk factors and inflammatory markers, according to researchers from Semmelweis University and the Hungarian Academy of Sciences in Budapest, Hungary, and McMaster University in Hamilton, Ontario, Canada, in a study appearing in this week’s issue of Circulation (Circulation. 2002;106:2775–2880).
In this study led by Amarilla Veres, MD, from Semmelweis University, researchers used blood samples from the Heart Outcomes Prevention Evaluation (HOPE) study and conducted a nested case control study of 386 people with cardiovascular events and compared them with 386 age- and sex-matched controls from the same study. They attempted to determine the relationship between heat shock protein antibodies, anti-cholesterol antibodies, and the incidence of myocardial infarction, stroke, and cardiovascular death during a 4.5-year follow-up. High levels of anti-hsp65 antibodies were found to be predictive of cardiovascular events with an odds ratio of 2 to 1. High levels of anti-cholesterol antibodies appeared to be protective of stroke in this report.
The authors concluded, “Measurement of anti-hsp65 antibodies may improve the prediction of future CV [cardiovascular] events in secondary prevention studies and provide additional insight into the role of heat shock protein in human atherosclerosis.”
American Heart Association Celebrates 75th Anniversary of Scientific Sessions in Windy City
Chicago, Ill—An unexpected flurry of snow greeted the more than 30 000 attendees at the opening day of the 75th Scientific Sessions of the American Heart Association on November 17, 2002, but the snow dissipated before the opening session ended in early winter darkness. New information was presented about inflammation, tissue engineering, angiogenesis, and a host of new drugs as new results came flying out of the auditoriums and smaller meeting rooms of the massive McCormick Center where the meeting was held through November 20, 2002.
Among the most eagerly attended sessions were the late-breakers in which the most recent information on clinical trials was revealed by the investigators themselves.
Heart Health in Elderly PROSPERs on Statin
Statins are not just for the middle-aged any more, according to Jim Shepherd, MD, of the University of Glasgow, Scotland, who presented the results of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial on November 18, 2002. Results of the trial demonstrated a statistically significant benefit for patients with an average age of 75 years who were taking pravastatin as part of the trial.
“The numbers of people aged ≥65 years will swell to >300 million in the next 30 years,” said Dr Shepherd. “With the growth of the elderly come problems. We anticipate an increase in myocardial infarctions, strokes, and disability as well as dependency on society and dementia.”
“The PROSPER trial was designed to determine whether these clinical issues could be tackled with statins,” he said. “PROSPER is good news for the senior citizen. The treatment, which is currently applied to the middle aged, is equally applicable to the elderly in our population.”
The PROSPER trial enrolled 5804 people, 3000 of them women, aged from 70 to 82 years. They were randomized to two groups. One half of the people were given 40 mg of pravastatin per day and the other half received placebo. Subjects were monitored for 3 to 3.5 years.
“The trial was shorter than most statin trials because the individuals involved were coming close to the end of their lives,” said Dr Shepherd. Because the trial was short, the investigators did not expect to find a mortality benefit.
The primary end point was fatal and nonfatal heart attacks and strokes combined. “We were not trying to add to the quantity of life but to the quality,” he said.
During the course of the study, there were 604 deaths overall. Pravastatin reduced the low-density lipoprotein concentrations by 34% and reduced the primary end points 15%—from 437 events in the placebo group to 408 in the treatment group. However, most of the benefit was seen in the coronary heart disease events, said Dr Shepherd. There was a 19% reduction in the fatal and nonfatal myocardial infarctions and a 24% reduction in deaths from coronary disease in the treatment group.
“In the highest risk groups, you had to treat 25 patients to avoid one heart attack, fatal or not,” said Dr Shepherd.
Surprisingly, there was no effect of statins on stroke, as had been expected from previous studies. However, Dr Shepherd said that might be because the trial was too short to have a stroke effect or an effect on cognition as seen with previous studies. He said that even though patients were taking, on average, 3.6 drugs per day, no adverse drug-drug interactions were seen. The investigators also saw no increase in myopathy, rhabdomyolysis, or problems with the liver.
However, during questioning from journalists at the press conference, Dr Shepherd admitted that there was a 25% increase in cancer of all kinds in the study.
“I don’t believe the cancer finding has relevance to the situation,” he said. During the 3.5 years, researchers saw 199 new cancers in the placebo group and 245 in the pravastatin group.
Studies of the cancers showed no evidence that one particular form of tissue or organ system had been affected, he said. Because many of the cancers were diagnosed in the first year of the study, Dr Shepherd said he thought that patients were “bringing cancer into the PROSPER trial.”
In the comment portion of the session, Stephen Fortmann, MD, of Stanford University School of Medicine in Palo Alto, Calif, said that although statins have had “a remarkable safety profile, PROSPER did find a higher rate of some cancers. It does bear careful watching because this is the first trial in this age group.”
He did feel that the study gave physicians good reason to treat older patients.
A New CREDO for Antiplatelet Therapy?
Adding clopidogrel to aspirin as a long-term treatment after percutaneous intervention appears to reduce the risk of death, myocardial infarction, and stroke by 27%, according to Steven R. Steinhubl, MD, Associate Professor of Medicine at the University of North Carolina at Chapel Hill and researcher for the Clopidogrel for the Reduction of Events During Observation (CREDO) trial.
“The clinical implications of this are potentially enormous,” said Dr Steinhubl. He said that the diffuse nature of coronary artery disease is often underestimated, but that aggressive antiplatelet therapy might provide a long-term benefit in treating such disease.
In the study, 2116 patients scheduled for percutaneous intervention in 99 centers throughout the United States and Canada were randomized to two groups. The treatment group received a 300-mg loading dose of clopidogrel 24 hours before the beginning of the procedure. The control arm received a placebo-loading dose.
Both arms of the study received the standard of care of clopidogrel at a dose of 75 mg for 28 days after the procedure. The treatment group that had received the loading dose then continued to receive 75 mg of clopidogrel for a year, whereas those in the control arm received placebo. Both groups were on aspirin throughout the study.
There was no statistically significant difference seen in death, myocardial infarction, or urgent target vessel revascularization at 28 days, said Dr Steinhubl. However at 1 year, there was a significant 27% reduction in the combined risk of death, myocardial infarction, or stroke. The absolute reduction in these areas was 3%. In the placebo group, 11.5% of patients experienced one of the events (death, myocardial infarction, or urgent target vessel revascularization), whereas only 8.5% of the treatment group did.
“Virtually all major bleeding was associated with a major surgical procedure,” said Dr Steinhubl, “and most of that was related to coronary artery bypass grafting. One-half of the patients from both groups who underwent CABG had a major bleed. There was no difference between the groups in terms of minor bleeding.”
“CREDO is the first trial to demonstrate the benefits of therapy with long-term clopidogrel and aspirin treatment. If the results of CREDO were applied to the 1.5 million people who undergo percutaneous intervention worldwide, there would be 50 000 fewer patients who suffered heart attacks, strokes, and death.”
“The benefits observed in this trial by combining clopidogrel and aspirin will impact the way we manage patients with coronary artery disease,” said Valentin Fuster, MD, of Mount Sinai Medical Center in New York. At the same time, he said physicians would have to look for episodes of excess bleeding, particularly in patients who are predisposed to do so.
“Long-term treatment with clopidogrel and aspirin will probably become standard of care for the first year after PCI [percutaneous intervention],” said Dr Fuster. “However, because of cost, a long-term trial comparing clopidogrel and aspirin to anticoagulants and aspirin should be urgently considered.”
He said the clopidogrel as a pre-procedure loading agent is also likely to become standard of care but that the use of a higher loading dose in patients treated in the 6 hours before the procedure should be considered and tested.
The report was published online by the Journal of the American Medical Association on the day of the presentation and will be available in an upcoming print edition of the publication (JAMA. 2002;288:2411–2420).
Looking For a CARDINAL Rule
Treating patients with pexelizumab, a complement-inhibiting factor, appears to reduce mortality in patients who have suffered myocardial infarction even though it failed to reduce the size of the infarct as had been anticipated, according to Christopher B. Granger, MD, of Duke University Medical Center in Durham, NC, speaking on behalf of the Complement and ReDuction of INFarct size after Angioplasty or Lytics (CARDINAL) trial investigators.
The trial actually consisted of 2 separate phase II randomized, double-blind, placebo-controlled trials designed to determine the effect of pexelizumab on the size of the infarct in patients who received thrombolysis and on those who received primary percutaneous intervention. The patients with ST-elevation acute myocardial infarction within 6 hours of the onset of symptoms were randomized to receive either placebo or the drug pexelizumab at a dose of 2 mg/kg bolus over 10 minutes or pexelizumab 2.0 mg/kg bolus over 10 minutes plus a 1 mg/kg/hr infusion over 20 hours.
Dr Granger was only able to present preliminary data during the session’s late-breakers. Among the two groups, which included 920 patients from the thrombolysis population in the trial called Complement Inhibition in Myocardial Infarction Treated with Thrombolytics (COMPLY) and 814 patients from the percutaneous intervention population in the Complement Inhibition in Myocardial Infarction Treated with PTCA (COMMA) trial, there was no difference in infarct size, regardless of the primary treatment for the myocardial infarction.
There was also no difference in the incidence of death, chronic heart failure, cardiogenic shock, or stroke through 90 days in either group, said Dr Granger. However, in the group that underwent percutaneous intervention, those who received the pexelizumab bolus plus later infusion had a lower mortality rate (1.8%) compared with the placebo group (5.9%).
“The results of the trial show that pexelizumab was safe and well tolerated,” said Dr Granger. “It did effectively inhibit complement activity. It is the first trial in a decade to find a nominally significant reduction in mortality when the treatment is added to the standard of care for a heart attack. It warrants further study.” He added that the fact that pexelizumab appeared to have a clinical benefit despite the fact that it did not affect infarct size might show that the drug acts through a novel mechanism.
Christopher Cannon, MD, of The Brigham and Women’s Hospital in Boston, Mass, in his comments, said, “The lists of compounds that don’t work with this approach continue to grow. This is the sixth compound in a large trial to have no impact on infarct size. The result with mortality is intriguing. Now we go back to the basic research laboratory to understand if that finding could be true.”
DIALing Out of the Hospital
An Argentinian program in which trained nurses contacted patients with heart failure on a regular basis to educate them about their disease and their need to take medication and stick with dietary and exercise recommendations reduced the need to hospitalize the patients for their disease, said Daniel Nul, MD, of Buenos Aires, Argentina, who spoke for the Grupo de Estudio de la Sobrevida de la Insuficiencia Cardiaca en Argentina (GESICA), which sponsored the study.
A total of 1518 patients from 51 medical centers in Argentina were randomized to usual care by their personal physicians (758) or by telephone intervention (760). Patients were monitored for an average of 439 days. The primary end point of the study was all cause mortality and/or admission to the hospital for a heart failure-related cause. According to Dr Nul, 26.3% of the patients in the intervention group and 31% in the control group were admitted to the hospital for heart-failure admission or died for some reason. The relative risk reduction was 20%.
However, he said, the difference in the two groups came from the reduction in hospitalizations, not a reduction in mortality, which was 15.3% in the treatment group and 16.1% in the control group. However, hospital admission was 16.8% in the intervention group and 22.3% in the control group
“This is a simple low-cost program,” said Dr Nul. “There was a single center with nurses who phone the patient.”
SAPPHIRE a Jewel in Carotid Stenting?
Carotid stenting with the addition of a special filter during the procedure (ANGIOGUARDXP Emboli Protection Guidewire) proved to have fewer risks than surgical endartarectomy in high-risk patients, according to 30-day results of the Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endartarectomy (SAPPHIRE) trial reported by Jay Yadav, MD, Director of Vascular Intervention of the Department of Cardiology at the Cleveland Clinic, Cleveland, Ohio, on November 19, 2002.
The “filter,” as Dr Yadav terms it, catches the tiny particles that can break off from the wall of the artery during the stenting procedure. When the filter is analyzed after the procedure, about half of its surface is usually covered with the particles, he said.
“Emboli protection devices had made it (carotid stenting) a safer procedure,” he said. “You don’t do carotid stenting without the filters.”
Patients in the SAPPHIRE study had >80% carotid stenosis by ultrasound or >50% carotid stenosis and met high-risk criteria including chronic heart failure, severe chronic obstructive pulmonary disease, previous endartarectomy, severe coronary artery disease, previous radical neck surgery, or radiation therapy. All patients in the study were seen by a team that included a neurologist, a surgeon, and an interventionalist before randomization took place.
A total of 307 patients were placed in two groups—one underwent stenting and the other received surgery. At 30 days after the procedure, the percentage of patients who suffered major adverse events such as death, stroke, or myocardial infarction was 5.8% (9/156) in the stent with filter group versus 12.6% (19/151) in the surgery group.
Dr Yadav said he was unsure how many people in the United States would benefit from carotid stenting, and he pointed out that one-year data are still pending. However, he pointed out that many patients with severe carotid disease are not being treated at all right now because of serious comorbidities.
TETAMI a Wash?
The Treatment with Enoxaparin and Tirofiban in Acute Myocardial Infarction (TETAMI) study had no statistically significant results, according to Marc Cohen, MD, Chief of the Division of Cardiology at New Beth Israel Hospital in Newark, NJ.
The study involved patients with acute myocardial infraction who came in after 12 hours, which was judged to be too late for thrombolytics and percutaneous intervention, said Dr Cohen.
“Unfortunately, many who develop an acute myocardial infarction don’t come in within 12 hours and, even worse, some who do do not receive the traditional therapy of thrombolytics or mechanical intervention,” he said. He estimated that between 25 and 30% of patients with acute myocardial infarction worldwide and in the United States fall into this group.
“In the TETAMI trial, we tried to address how to approach people who do not receive these therapies for their acute myocardial infarction,” he said. “Based on previous trials with low-molecular-weight heparin and tirofiban, a glycoprotein IIb/IIIa inhibitor, we thought they might be advantageous in this population.”
Patients were randomized to one of 4 groups: enoxaparin plus placebo, enoxaparin plus tirofiban, unfractionated heparin plus placebo, and unfractionated heparin plus tirofiban.
“The results were that people on enoxaparin had a trend toward a lower event rate compared to those who received heparin, but it was not statistically significant,” said Dr Cohen. Tirofiban appeared to have no benefit at all, he said.
In the study, 15.4% of patients in the enoxaparin plus placebo group, 16.1% of patients in the enoxaparin plus tirofiban group, 17.3% of patients in the unfractionated heparin plus placebo group, and 17.2% of patients in the unfractionated heparin plus tirofiban group died or suffered another myocardial infarction or recurrent angina. A total of 8.7% of patients in the first group, 8.5% of patients in the second group, 9.2% of patients in the third group, and 8.0% of patients in the fourth group died or had a recurrent heart attack. Again, the difference among groups was not statistically significant.
“We need to think harder about what the tools we have in our basket can and cannot do,” said Dr Cohen. “In the future, we will try to be more discriminating in the focusing on those patients where thrombosis is part of the mechanism as opposed to patients who come in with MI and heart failure.” In the latter patients, busting the clot may not be as important, he said.
“I think, based on TETAMI, one can walk away with a feeling that there are promising avenues for future trials as long as we focus on those who can benefit from antithrombotic therapy.”
Sidney Smith, MD, of the University of North Carolina at Chapel Hill, congratulated Dr Cohen on “presenting what was essentially a negative trial.” He said that such trials are too often not presented and thus the information, which is valuable though negative, is often lost.
The major problem with the study, he said, was that it was underpowered. Although a repeat study with younger patients might be considered, he said, “I think it is impractical and expensive. To my way of thinking, it is time to look at mechanical perfusion in this group.”
Continuous Quality Improvement in CABG
A medical specialty society can address quality issues head on with national trials in quality improvement, said T. Bruce Ferguson, MD, Chair of the Society of Thoracic Surgeons (STS) council of quality assurance and patient advocacy and principal investigator on November 19.
With a $1.2 million grant from the Agency for Health Care Research and Quality, Dr Ferguson led a study of two interventions designed to improve quality of care. The Continuous Quality Improvement in Coronary Artery Bypass Grafting (CQI in CABG) trial sought to increase preoperative β-blocker use and also increase use of the internal mammary artery in patients aged >75 years. A third group of hospitals among the 359 randomized was considered a control.
At each of the intervention hospitals, a physician leader received a call to action to support the intervention. The hospitals received educational products about the change in practice, and longitudinal, nationally benchmarked site-specific feedback about their improvement. Between January 2000 and July 2002, the use of the procedure increased in both intervention hospital groups. β-blocker use increased from 59% before the intervention to 67% after. Use of the internal mammary artery increased from 74% pre-intervention to 85% afterwards.
The improvement in β-blockage before operation was statistically significant, said Dr Ferguson. The increase in internal mammary artery grafts did not reach statistical significance, he said.
The trial was an overall success, however, because it achieved its primary end point of showing that physician-led, low-intensity efforts can have an effect on the quality of care. Dr Ferguson said he hopes it can serve as a model for similar quality improvement efforts in all medical disciplines.
Stormy TEMPEST Review
A new drug called tecadenoson converted most patients with paroxysmal supraventricular tachycardia in the Trial to Evaluate the Management of Paroxysmal supraventricular tachycardia (PSVT) during Electrophysiologic Study with Tecadenoson (TEMPEST) to a normal rhythm within one minute at all 5 doses tested, according to a report from Kenneth Ellenbogen, MD, of the Medical College of Virginia in Richmond during the last set of late-breaking clinical trials on November 20, 2002. In the higher doses, conversion rates approached 90%, he said.
However, he could not explain the rationale for using a placebo in the trial rather than the standard of care, adenosine. Tecadenoson is an analogue of adenosine designed to affect only the A1-adenosine receptor. The other receptors for adenosine are associated with low blood pressure and bronchospasm and can be activated when adenosine is used, said Dr Ellenbogen. The study was sponsored by Cardiovascular Therapeutics, the drug manufacturer.
The multicenter randomized, double-blind, placebo-controlled study included patients with at least one documented episode of spontaneous, symptomatic tachyarrhythmia consistent with PSVT and the need for an electrophysiological study to evaluate and/or treat PSVT. Patients were randomized to one of 5 doses of tecadenoson or placebo. In the electrophysiological lab, PSVT was induced and sustained for ≥2 minutes. At that time, either tecadenoson or placebo was administered as a rapid IV bolus. If the arrhythmia persisted 1 minute after the drug was given, a second dose was given. If that did not work, then patients were converted by more usual means in the electrophysiology laboratory.
Doses of the drug given were (first dose/second dose) 75 μg/150 μg, 150 μg/300 μg, 300 μg/600 μg, 450 μg/900 μg, and 900 μg/900 μg. According to Dr Ellenbogen, each regimen resulted in significantly higher conversion rates compared with placebo. Two of 30 patients on placebo converted, as well as 16 of 32 on the lowest dose, 17 of 29 on the next dose, 24 of 29 on the next highest dose, 28 of 31 on the next highest dose, 24 of 29 on the second highest dose, and 26 of 30 on the highest dose. The median times to conversion on the three highest doses were all ≤1 minute. Dr Ellenbogen said that time was comparable to those seen with adenosine. However, he said the new drug is safer.
Transient AV block increased with the dose with 7 people experiencing it at the highest dose. One patient required pacing to relieve the AV block, said Dr Ellenbogen.
Asked if he thought a study that compared tecadenoson with adenosine would be required before the new drug receives approval from the US Food and Drug Administration, Dr Ellenbogen said he had no knowledge of what would be required for marketing approval.
ASSENT III Plus an OK for Tenecteplase But Not for Enoxaparin
Acknowledging that the best way to treat acute myocardial infarction is to open the blocked artery by direct angioplasty, Lars Wallentin, MD, Chief of the Research Group in Cardiology at the Uppsala University in Sweden, said that the combination of the clot-buster tenecteplase plus unfractionated heparin given in the ambulance will reduce mortality, at least for that group of people who do not have quick access to a catheterization laboratory.
In describing the results of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen in the Pre-hospital setting (ASSENT III Plus) trial, Dr Wallentin pointed out that many areas in Europe lack the technology necessary to provide angioplasty or stenting quickly. “The main result was that we reduced treatment delay by 45 minutes,” he said. Previously, the average time to treatment was 2 hours and 45 minutes. Now it is 2 hours.
“This will definitely affect outcome,” he said. “It can be given safely in the ambulance.” Tenecteplase has an advantage over other clot-busters because it can be given as an IV bolus rather than an infusion, Dr Wallentin said.
In the study, 1639 patients who called for help <6 hours after the onset of symptoms with ST-segment elevation were randomized to treatment with tenecteplase in combination with enoxaparin as either an IV bolus of 30 mg followed by a subcutaneous dose of 1 mg/kg every 12 hours until discharge or 7 days, or to receive unfractionated heparin as an IV bolus of 60 IU/kg followed by an infusion of 12 IU/kg/h. The primary end points of the study were death within 30 days, reinfarction in the hospital, or in-hospital refractory ischemia. A primary safety and efficacy end point was in-hospital intracranial hemorrhage or major bleeds of other kinds.
In the study, 14.2% of patients who received enoxaparin experienced one of the primary end points, whereas 17.2% in the unfractionated heparin group met that end point, a difference that was not statistically significant. When the safety end point was added, 18.3% of enoxaparin and 20.3% of unfractionated heparin patients reached one of the end points.
One major difference was the rate of intracranial hemorrhage, which was 2.2% in the enoxaparin group and 0.97% in the unfractionated heparin group. Dr Wallentin said that was the reason that death within 30 days was 7.21% in the enoxaparin group and 5.48% in the unfractionated heparin group.
“There was definitely a reduction in reinfarction and severe ischemia with enoxaparin,” he said. “But there was also increased intracranial hemorrhage. These were entirely patients over the age of 75 and almost all of them were women.”
“Use of enoxaparin is feasible but we need a better dosage for the elderly and particularly for older women,” said Dr Wallentin. He said he is looking forward to trials that are planned that will include a lower dosage for elderly people.