Late-Breaking Trials From the American College of Cardiology
The troubles with stents and how to solve them, diabetes as a cardiovascular disease, elderly patients and how to treat them, and evidence-based medicine and quality care took center stage at the 51st Annual Scientific Sessions of the American College of Cardiology in Atlanta, Ga, from March 17 to 20, 2002.
Thin Is In
In a spare presentation during the first late-breaking clinical trials session of the conference, Helmut Schuhlen, MD, of the German Heart Center in Münich confirmed the oft-quoted Babe Paley (who opined that one could never be too thin or too rich) when he revealed that the second Intracoronary Stenting and Angiographic results—Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO-2) trial demonstrated that stents with thin struts were associated with better outcomes than were those with thicker struts.
The finding, said Dr Schuhlen, could significantly impact today’s practice. “It could also guide future device development. Stent design has now been brought forward by the fact that stent thickness may impact treatment enormously,” he said.
Of course, thin and thick are a matter of context. The thin struts measured no more than 50 μm, whereas the thick ones were ≈140 μm, said Dr Schuhlen.
A total of 5 German hospitals participated in the study, which enrolled 611 patients who were randomized to one of two types of stent. The two stent types were of similar design but different strut thicknesses. The patients enrolled had small lesions, measuring <2.8 mm in diameter. They were randomly assigned to receive either the Guidant ACS RX MultiLink stent, with a thickness of 50 μm, or the Cordis BX Velocity stent, with a strut thickness of 140 μm.
At baseline, there was no significant difference between the two groups, and the stents were placed with at least 99% success in both groups. The device success rate for the thin-strut device was 87.6%, versus 98.7% in the thick-strut stent. At baseline, the angiographic results were almost identical, with a final diameter of the stented area of 4.3 mm in the thin-stent group versus 4.2 mm in the thick-stent group.
However, at 6-month follow-up, the late lumen loss was significantly lower in the thin-strut group, said Dr Schuhlen (0.94 versus 1.20 mm). The restenosis rate by angiography was 18.9% in the thin-stent group versus 31.6% in the thick-stent group. The target vessel revascularization rate was 12.3% for the thin-stent patients versus 21.2% for the thick-stent patients. There was no difference in the combined rate of death and myocardial infarction after a year.
No COASTing for Heparin-Coated Stents
Seeking again to open small arteries with target lesions between 2 and 2.6 mm, researchers in the Heparin-coated Stents in Small Coronary Arteries (COAST) trial randomized 605 patients to receive balloon angioplasty alone, an uncoated stent, or a stent coated with heparin, said Michael Haude, MD, of the University of Essen in Germany. Although some results were higher for the two stent groups, there was essentially no difference in restenosis at 6 months (a primary end point) among the three groups.
The restenosis rate was 32% for the balloon angioplasty group, 25% for the uncoated stent group, and 30% for the coated stent, according to Dr Haude. Event-free survival rate was essentially the same for the 3 groups—between 84% and 88%.
A total of 21 European centers participated in the trial.
Spencer King, MD, an American College of Cardiology moderator, summed up the study: “For small vessels in this study, whether it was a balloon or a stent with or without heparin, they all did the same.”
Dr Haude said, “I see no chance that the heparin-coated stent would be of clinical benefit. I think the door is closed.”
Antibiotic Treatment to the “Max” Proves Ineffective
Two studies designed to test the hypothesis that short-term treatment with the antibiotic azithromycin would be beneficial to patients with acute coronary syndrome who had had a prior infection with Chlamydia pneumoniae showed no benefit. The finding was a surprise to researchers who had thought that the antibiotic would not only have an effect on the organism but would also have an anti-inflammatory effect in the patient.
The trials Azithromycin in Acute Coronary Syndrome (AZACS) and Weekly Intervention with Zithromax for Atherosclerosis and its Related Disorders (WIZARD) showed no significant difference between groups that received the drug and those that received placebo.
“We have to conclude that in patients admitted with unstable angina or acute MI, short-term treatment with azithromycin did not reduce recurrent ischemic events or deaths during the following months,” said Bojan Cercek, MD, of Cedars-Sinai Medical Center in Los Angeles, Calif, during his late-breaking presentation on March 18, 2002, at the American College of Cardiology Scientific Sessions in Atlanta, Ga.
A total of 1439 patients were randomized receive either azithromycin in a standard dosage for 5 days or placebo. Of these, 710 in the placebo group and 702 in the treatment group completed treatment and follow-up.
In evaluation of the primary end points of death, nonfatal myocardial infarction, urgent revascularization, or recurrent ischemia, there was no difference between the two groups, nor was there any significant difference between the groups in the secondary end points of worsening ischemia requiring hospitalization, new cardiac heart failure, or worsening disease, according to Dr Cercek.
The WIZARD trial involved >7500 patients who had had a heart attack and were randomized to receive azithromycin or placebo for 12 weeks. They were followed up for 2 years.
Christopher O’Connor, Associate Professor at Duke University Medical Center, Durham, NC, said that the short-term azithromycin therapy was associated with a 7% reduction in the primary end points (all-cause mortality, rehospitalization for an acute coronary event, or urgent revascularization), but the statistic did not reach statistical significance.
There was no statistically significant difference between the groups when any of the primary end points were considered singly or together, he said.
“These results neither confirm nor refute the hypothesis” that the antibiotic would reduce the number of primary events in the treated population, he said. He hopes that ongoing studies will clarify the role of antibiotics in longer-term studies of patients with atherosclerotic heart disease.
Low–Molecular Weight Heparin INTERACTs to Prove Its Worth
The Integrilin and Enoxaparin Randomized Assessment of Acute Coronary syndrome Treatment (INTERACT) trial showed that use of low–molecular weight heparin resulted in less major bleeding than did the use of unfractionated heparin, said Shaun Goodman, MD, of St Michael’s Hospital in Toronto, Canada, in a late-breaking presentation at the American College of Cardiology Scientific Sessions on March 18, 2002.
In the study, all patients received the glycoprotein IIb/IIIa inhibitor eptifibatide, but 366 received unfractionated heparin, and 380 received enoxaparin or low–molecular weight heparin. There was major bleeding in 4.6% of patients receiving the unfractionated heparin and 1.8% of those who received enoxaparin. However, he said, there was a slightly higher rate of minor nuisance bleeding with the low–molecular weight heparin.
In addition, he said, there were fewer ischemic episodes in the low–molecular weight heparin group and lower rates of death or myocardial infarction. However, he said, the study was open-label and the sample size was modest, indicating that further study probably is needed.
How Low Can It Go?
Expected to be the “definitive” studies of the endothelin antagonist bosentan in congestive heart failure, the identical Endothelin Antagonist Bosentan for Lowering cardiac Events in heart failure (ENABLE) trials carried out in Europe and North America proved a disappointment, said Milton Packer, MD, of the Columbia Presbyterian Medical Center in New York, NY.
“Long-term treatment with bosentan did not reduce risk of death or hospitalization or the risk of death alone in patients with severe chronic heart failure,” said Dr Packer. “The lack of benefit may have been related to early and sustained development of fluid retention, which had prognostic implications.”
For the drug to continue into development, he said, physicians would have to find a way to minimize fluid retention or attempt a lower dose of bosentan. He did not know if another trial with the drug would be attempted.
An early trial of bosentan used doses in the range of 1000 to 2000 mg daily. In the ENABLE trial, patients received 62.5 mg twice daily for the first 4 weeks and then 125 mg twice daily after that. There were 808 patients in the placebo group and 805 in the bosentan group. All of the patients had severe heart failure and were receiving appropriate medications for their disease.
A total of 321 patients in the placebo group and 312 in the bosentan group died or were hospitalized for heart failure. “The hazard ratio was nearly one,” Dr Packer said, indicating that there was essentially no difference between the two groups. In addition, he said, initiation of treatment with bosentan was associated with an early risk that persisted for more than 1 year. The risk primarily was increased likelihood of hospitalization for heart failure.
A total of 173 patients in the placebo group and 160 in the bosentan group died during the study—again, a hazard ratio of nearly one, said Dr Packer. There was no difference in subgroups that were analyzed.
However, the early and sustained fluid retention was a prognostic hazard. “The greater the risk of fluid retention during the first 2 weeks of therapy, the greater the risk of an adverse outcome,” he said.
Getting the correct dosage might solve the problem, however. “Doses 75% lower than these may still block the endothelin receptor,” he said.
Preclinical studies in animals did not reveal the fluid retention problem. “We do not know why there was a discrepancy between the experimental data and clinical data. This mechanism was not seen in the preclinical studies. It has to be studied if we are ever to find a role for these drugs in heart failure.”
The landmark Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart failure (REMATCH) trial that demonstrated a survival advantage for heart failure patients who received a left ventricular assist device (LVAD) compared with those who received optimum medical therapy (N Engl J Med. 2001;345:1435–1443) (November 15, 2001) also demonstrated that the LVAD was of major benefit to patients who were on intravenous inotropic therapy at the time of randomization, according to Lynne Warner Stevenson, MD, of Brigham and Women’s Hospital in Boston, Mass.
“The immediate extension of VADs to a less sick population would not have as big an effect as seen for the whole population in REMATCH,” she said. She said it would be important in the future to determine the best populations in whom to use the device before such devices proliferate.
“As we anticipate continuing device development, we must also develop new alternative therapies for these populations, including the adaptation of hospice to provide compassionate care for heart failure at the end of life,” said Dr Stevenson.
Breathing Not Properly
A point-of-care test to identify B-type natriuretic peptide (BNP) in the blood of patients who come to emergency departments because of severe shortness of breath should be added to guidelines for the management of patients with congestive heart >failure, said Alan S. Maisel, MD, of the University of California at San Diego and principal investigator of the Breathing Not Properly Multinational trial. “The time has come,” said Dr Maisel during the late-breaking trial sessions at the American College of Cardiology (ACC) Scientific Sessions on March 19, 2002. “BNP is the most significant advance for diagnosing heart failure in the past 20 years.”
The Breathing Not Properly trial evaluated the test for BNP as diagnostic of congestive heart failure in 1586 patients who came to the emergency department with dyspnea. In the end, he said, the test was 81.1% accurate in identifying those patients who had heart failure.
The test, performed at the bedside with a small machine, is currently used by 500 hospitals nationwide. There is, as yet, no laboratory-based test for BNP, said Dr Maisel.
A breath test that identifies the alkanes and methylated alkanes that are the metabolic byproducts of the rejection of a donated heart can determine if a person is not suffering from rejection, said Michael Phillips, MD, of Menssana Research Inc, in Fort Lee, NY. The method was tested on 539 heart transplant recipients as part of the Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (HARDBALL) study.
The transplant recipients had all been scheduled for a heart biopsy, said Dr Phillips. What researchers found was that the test was not a good indicator of how serious a patient’s rejection status was. In fact, readings for patients whose rejection class was the most serious were lower than readings for others whose rejection class was less serious. Dr Phillips hypothesizes that the rejection in those sickest patients had induced not only the production of alkanes but also the enzyme that metabolized them.
However, he noted, the breath test had a high negative predictive value. That means it identifies patients who are not in rejection.
“How might the test benefit patients?” Dr Phillips asked during his late-breaking presentation. “If a patient tests positive on the breath test, he or she should go for a biopsy. But a negative breath test means no biopsy.”
He predicted that such a test could reduce biopsies >50% and false negative tests from 2.3% to 1.6%.
Implanted Defibrillators MADIT-II
The use of implanted defibrillators in patients with prior myocardial infarction and reduced ejection fraction resulted in a 31% reduction in mortality and improved survival in the Multicenter Automatic Defibrillator Trial (MADIT-II), Arthur J. Moss, MD, of the University of Rochester in New York, reported in a late-breaking session of the ACC on March 19, 2002. “Prophylactic implanted defibrillator therapy is now ready for prime-time use in patients with coronary heart disease and left ventricular dysfunction,” said Dr Moss. He estimated that as many as 2 million people in the United States would benefit.
“From this study, I would say that electricity is better than drugs,” said Douglas P. Zipes, MD, the outgoing president of the ACC. And although Dr Moss said the healthcare system could handle the $40 000 to $60 000 cost of such therapy in a large population, Dr Zipes noted, “It has profound implications for the healthcare budget, and I don’t think that’s escapable at the current cost of the implanted defibrillator.”
Dr Zipes said he would urge device manufacturers to find ways to lower the cost of their defibrillators, noting that with the large population that would benefit, device companies could make up profits in sheer volume.
The New England Journal of Medicine released the MADIT-II trial report on its web site early to coincide with the ACC report (N Engl J Med. 2002;346:877–883). The study was published in the journal’s March 21, 2002, issue.
A total of 1232 patients from 76 centers (71 in the United States and 5 in Europe) were enrolled in the study. The only criteria for enrollment were a prior myocardial infarction and an ejection fraction <30%. Most of the patients were on β-blockers and ACE inhibitors.
Patients were randomized to receive an implanted defibrillator or no defibrillator. After 3 years, there was 69% survival rate in the defibrillator group versus 78% in the nondefibrillator group. Of the 490 patients in the conventional treatment group, there were 97 deaths. Of the 742 defibrillator patients, there were 105 deaths.
AFFIRM RACEs to Solve Rhythm-Rate Control Conundrum
Two studies in the late-breaking session of the ACC on March 18, 2002, sought to solve the issue of whether rhythm control or rate control is better in patients with atrial fibrillation. In each instance, they found that rate control was no more dangerous than rhythm control and might be preferable in some populations. D. George Wyse, MD, of the University of Calgary in Alberta, Canada, called atrial fibrillation a problem of the elderly, the population on which the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) concentrated.
The 4060 patients who were selected for the study were >65 years of age or had another risk factor for stroke or death, he said. They were randomly assigned to receive either rate or rhythm control. Patients were followed up for 3.5 years.
There were 306 deaths in the rate control group and 356 in the rhythm control group. The difference did not reach statistical significance, Dr Wyse said. Strokes were also almost the same in the two groups.
“The implication is that in this elderly population with an average age of 70 with risk factors for stroke and risk, the rate control strategy, which had been second best, was at least as good as rhythm control. It should be elevated to a primary approach,” said Dr Wyse.
In the Rate Control versus Electrical Cardioversion for Persistent Atrial Fibrillation (RACE) study, Dutch researchers determined that rate control was “not inferior” to rhythm control in the treatment of patients with persistent atrial fibrillation.
In fact, said Isabelle Van Gelder, MD, of the Interuniversity Cardiology Institute of The Netherlands in Utrecht, “rate control seems an attractive alternative, particularly for patients with a high risk of recurrence of atrial fibrillation or a profile of adverse experience with rhythm control drugs. Harry Crijns, MD, of the University Hospital in Maastricht was the trial’s principal investigator and co-presenter at the late-breaking trials session on March 18, 2002.
Patients who had undergone first angioplasty and then were started quickly on the cholesterol-lowering drug fluvastatin were less likely to die, suffer a heart attack, or be hospitalized for unstable angina than were patients in a control group that had not received the drugs, said Patrick Serruys, MD of the Thoraxcenter, Erasmus University Hospital in Rotterdam, the Netherlands, in describing the results of the Lescol Intervention Prevention Study (LIPS).
“This is a trial that has targeted a neglected population,” said Dr Serruys in explaining his late-breaking trial to the press. In this trial, he said, physicians prescribed 80 mg of fluvastatin. The risk of major adverse clinical events was reduced 22% in the treated group over 4 years.
The patients in the trial had a fairly low LDL level of 131 mg, said Dr Serruys. The drug lowered their LDL to 100 mg. A total of 1600 patients were enrolled in the trial and randomized to receive 80 mg of fluvastatin daily or placebo.
LIFE Brings Surprises
The largest study ever comparing a β-blocker with an angiotensin II antagonist resulted in a 13% risk reduction for losartan when compared with atenolol, according to Bjorn Dahlof, MD, of the University of Goteborg, Sweden. “There was less cardiovascular disease, less stroke, lower onset of new diabetes, better regression of left ventricular hypertrophy,” said Dr Dahlof during his presentation during the last late-breaking session on Wednesday morning March 20, 2002, at the American College of Cardiology Scientific Sessions in Atlanta, Ga. His presentation drew unprecedented applause.
“Losartan afforded better protection against cardiovascular morbidity and death, including stroke,” he said. In addition, the sicker patients in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE) did better on losartan and saw a greater risk reduction.
According to Dr Dahlof, the study demonstrates that it no longer matters that “we lower blood pressure. It matters how we lower blood pressure because there are benefits beyond blood pressure reduction.”
There were 4605 patients enrolled in the losartan group and 4588 in the atenolol group. Blood pressure control in each group was about the same, but atenolol, as expected, lowered heart rate more. Most patients in the study took a diuretic along with the study drug. Patients were followed up for an average of 4.8 years.
The public health implications of the study are great. “There are 3.9 million people in the United States over the age of 55 with high blood pressure,” Dr Dahlof said. If they were treated with losartan, there would be 70 000 fewer cardiovascular injuries or deaths, 66 000 fewer strokes, and 54 000 fewer cases of type II diabetes, he said.
Danes Prove Value of Percutaneous Coronary Intervention Over Clot-Busters
When the Danes were puzzling over the issue of percutaneous coronary intervention (PCI) versus antithrombolytics, they set up a large study to settle the issue. To make it more complicated, they added in the factor of patient transport.
The Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI)-2 was stopped early because of the clear benefit of PCI, said Henning R. Andersen, MD, of Skejby University in Aarhus, Denmark.
He said the trial showed a 40% relative risk reduction favoring urgent PCI over front-loading with tissue plasminogen activator. The primary end point of the study was death, reinfarction, or disabling stroke. There was a 40% advantage to PCI when the parameters were taken together, and each parameter showed a PCI advantage when considered separately, he said.
When patients were transferred to a university hospital for their PCI, they fared equally as well as patients who stayed closer to home, indicating that transport was not a problem, as long as it could be completed within 3 hours.
The strategy of transferring patients with an ST-elevation myocardial infarction for primary PCI is superior to accelerated tissue plasminogen activator when transfer can be completed within 3 hours, Dr Andersen said.
OVERTURE Strikes a Balance
Hopes that the new drug omapatrilat, a vasopeptidase inhibitor, would prove more valuable than enalapril, an ACE inhibitor, in the treatment of heart failure patients were not realized when leaders of the Omapatrilat versus enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) broke the code on the double-blind study in early March.
Milton Packer, MD, a leader of the study, told attendees at the Wednesday, March 20, 2002, late-breaking session of the American College of Cardiology that there was essentially no difference in primary end points among the 2884 patients who received enalapril and the 2886 who received omapatrilat. In the enalapril group, 973 patients either died or went to the hospital for a cardiovascular-related event, he said. There were 914 deaths or hospitalizations in the omapatrilat group. Patients were followed up for as long as 24 months, he said.
However, he said, omapatrilat met the standard to prove noninferiority, meaning that it is at least equivalent to the ACE inhibitor for the treatment of heart failure.
Don’t Take Those Statins Away
In this week’s issue of Circulation, researchers in the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study found that although patients with acute coronary syndromes who were treated with statins had a better outcome, taking their statins away after the onset of symptoms may have negated the beneficial effect (Circulation. 2002;105:1446–1452).
Christopher Heeschen, MD, of the University Hospital in Frankfurt, Germany, and his colleagues evaluated the effect of statin treatment in 1616 patients in the PRISM study. All the patients had had coronary artery disease and chest pain within the previous 24 hours. The researchers recorded the incidence of death and nonfatal myocardial infarction during a 30-day follow-up.
Of the 1616 patients, 1249 were not on statin therapy, 379 continued statin therapy, and 86 discontinued statin therapy after being hospitalized. Those who continued their statin therapy had a lower risk of death or nonfatal heart attack in the 30-day period than did those who had never been treated (adjusted hazard ratio of 0.49). However, in those for whom the statin therapy was withdrawn, the risk of cardiac event or death was higher than for those who remained on statins (2.93) and tended to be higher compared with patients who had never received the cholesterol-lowering drugs (1.69). Troponin T elevation, ST changes, and continuation of statin therapy were the only independent predictors of patient outcomes.
However, the authors noted that their study is “inherently more ‘hypothesis generating’ rather than ‘hypothesis proving’” because the data were part of a substudy of a randomized trial and because the analysis was performed retrospectively.