The XXIII Congress of the European Society of Cardiology opened to cool blue skies in Stockholm, Sweden, on September 1, 2001, as >20 000 cardiologists, scientists, and other healthcare providers gathered for the largest heart-related meeting on the continent. With “Hotline” sessions spotlighting the latest research spanning 3 days, the Congress drew large morning crowds to hear their colleagues explain the newest studies.
Those spotlighted included:
On September 1, 2001, the day before scientific presentations began, Martin Simoons, MD, president of the European Society of Cardiology, predicted the results reported at the first Hotline for the newest information would change the way he and his staff treat acute myocardial infarction. After the session on September 2, 2001, he said he would add the use of low-molecular-weight heparin to his armamentarium.
Uwe Zeymer, MD, of the Staedtische Kliniken in Kassel, Germany, reported that the sodium hydrogen exchange inhibitor eniporide did not add to the positive effects of thrombolysis in patients with acute myocardial infarctions. His trial, the Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction (ESCAMI), involved 2 stages. The first was designed to prove efficacy and safety and to select 2 doses for the second stage of the trial. The stage 2 part of the trial was designed to select the dose for a large-scale mortality trial. In that trial, ≈320 patients in each group received placebo, 100 mg of eniporide, or 150 mg of eniporide (the 2 doses chosen from phase 1).
In the study, patients with acute myocardial infarction were scheduled for the reperfusion therapy of their physicians’ choice: thrombolysis or primary percutaneous transluminal angioplasty (PTCA). Eniporide was given later with the goal of reducing the size of the infarct and saving heart muscle. Dr Zeymer noted that, “The overall result of the study was negative.”
Although he had hoped that the drug would increase the protection of the left ventricle, “the overall message is that these drugs will not work in this setting. In this setting, that’s it for this compound.”
Although the Comparison of Primary Angioplasty and Prehospital Thrombolysis In Patients with Acute Myocardial Infarction (CAPTIM) trial could not accrue the 1200 patients its originators thought it would need to prove efficacy, Paul Touboul, MD, of the Hopital Cardiovasculaire et Pneumologique Louis Pradel in Lyon, France, said the trial showed that there was no difference in efficacy between the use of prehospital thrombolysis and primary percutaneous intervention (PCI). “CAPTIM means that whatever strategy we use, the one that allows us to reperfuse the patients as soon as possible may be the best,” said Dr Touboul.
However, it would be wrong to consider the prehospital thrombolysis group, which received tissue plasminogen activator (tPA), a drug-only treatment. Instead, 33% of the patients in that arm required urgent angioplasty because of incomplete thrombolysis, continuing pain, and other problems related to their disease.
Of the patients enrolled in the study, 410 received prehospital thrombolysis and 426 underwent primary PCI. In the study, 8.2% of those who received the prehospital thrombolysis died, had a second heart attack, or a disabling stroke—conditions that made up the trial’s combined primary end point. In the PCI group, 6.2% of patients experienced one of the primary end point conditions. However, the difference was not statistically significant. When the conditions were considered separately, no significant differences were found.
Dr Touboul said CAPTIM shows the prehospital administration of both thrombolytics and primary PCI might be considered to treatment of acute myocardial infarction, depending on the situation. In areas that have medical centers capable of performing the percutaneous intervention, that treatment might be better, whereas in areas where such in-hospital care is not possible, prehospital thrombolytics might offer a benefit.
In the Global Utilization of Streptokinase and tPA for Occluded Coronary Arteries V (GUSTO V), 16 588 patients treated for an acute myocardial infarction within 6 hours of symptom onset were randomly assigned to one of 2 groups: those who received a standard dose of reteplase (two 10-U boluses 30 minutes apart) and those who received a half dose of reteplase plus a full dose of abciximab (0.25 mg/kg bolus and 0.125 μg/kg per minute for 12 hours). Patients were also given standard aspirin therapy, but heparin treatment varied between the arms of the study. Any other adjunctive medications were used at the discretion of the physician.
At 30 days, all-cause mortality was 4.88% in the reteplase alone group and 4.68% in the combined therapy group. There were no differences between the groups in terms of confirmed cerebrovascular events or nonfatal disabling stroke. However, said A. Michael Lincoff, MD, of the Cleveland Clinic, the risk of complications short of death, such as reinfarction or need for urgent percutaneous intervention, was lower with the combination of reteplase and abciximab. However, there were more bleeding complications and thrombocytopenia with the combined therapy.
Dr Lincoff said the study, which was published in The Lancet in June, raises the issue of how much improvement can be expected by decreasing the time to opening the occluded vessel (Lancet. 2001;357:1905–1914).
The Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT-3) study of 6095 patients with acute myocardial infarction compared 3 regimens: full-dose tenecteplase and enoxaparin (low-molecular-weight heparin) for as long as 7 days; half-dose tenecteplase with weight-adjusted low-dose unfractionated heparin and a 12-hour infusion of unfractionated heparin; and full-dose tenecteplase with weight-adjusted, unfractionated heparin for 48 hours (standard therapy). Investigators found that there were significantly fewer patients who suffered death at 30 days, in-hospital reinfarction, or refractory ischemia, with or without intracranial hemorrhage or major bleeding complications, in the experimental arms of the study, said Frans Van de Werf, MD, of Gasthuisberg University Hospital in Leuven, Belgium (Lancet. 2001;358:605–613).
“There was a clear benefit for the two experimental arms of the study, with little difference between them for the experimental end points,” said Dr Van de Werf. These options are “attractive for use in the emergency department with its hectic environment and even in prehospital treatment.”
In their article published in the Lancet, Dr Van de Werf and his ASSENT-3 colleagues concluded, “Taking into account efficacy and safety, the combination of full-dose tenecteplase and long-term administration of enoxaparin emerged as the best treatment in this trial. Because of additional advantages, such as the ease of administration and the lack of need for monitoring of anticoagulation, this combination should be regarded as an attractive alternative pharmacological reperfusion strategy deserving further study.”
The Hirulog Early Reperfusion/Occlusion (HERO-2) study failed to show a reduction in mortality among the >17 000 patients enrolled in the trial worldwide. The patients from 539 hospitals in 46 countries were randomized to receive unfractionated heparin or bivalirudin after experiencing a heart attack.
The key result was that there was no mortality difference in the 2 groups, said Harvey D. White, MD, of Green Lane Hospital in Auckland, New Zealand. However, the numbers of in-hospital myocardial infarctions were reduced in the bivalirudin group. Dr White noted that bivalirudin is “a valuable addition to the range of treatments now available.”
The Warfarin-Aspirin Re-Infarction Study (WARIS-II) was designed to compare the efficacy of warfarin to that of aspirin in secondary prevention after myocardial infarction, said Harald Arnesen, MD, PhD, of the Ulleval University Hospital in Oslo, Norway. A total of 3630 heart attack patients from 20 Norwegian hospitals were randomized to receive daily aspirin, warfarin designed to reduce clotting, or both medications.
The patients were followed for 4 years. Of patients in the combined treatment group, 181 died or suffered a nonfatal heart attack or hemorrhagic stroke. A total of 203 patients in the warfarin-alone group and 241 patients in the aspirin-alone group suffered one of these events. “Our conclusion is that the combined treatment with warfarin plus aspirin is more significant in reducing the combined end points than aspirin alone,” said Dr Arnesen. “Warfarin was significantly more effective than aspirin alone. However, the incidence of nonfatal bleeding was seen 4 times more frequently in the warfarin-treated patients, even though the incidence of such events was low.”
Researchers identified no difference in the incidence of death, nonfatal myocardial infarction, or other ischemia-driven morbidities in the Tenax for the Prevention of Restenosis and Acute Thrombotic Complications, a Useful Stent Trial in Patients with Acute Coronary Syndromes (TRUST) study, which randomized 485 patients to receive either a normal stent or a silicone carbide–coated one, said Christian W. Hamm, MD, of the Kerckhoff Heart Center, Bad Nauheim, Germany.
The study drew its patient population from 12 European countries, Canada, and Israel. A total of 238 patients received the Tenax-coated stent, and 247 received the reference stent. Patients were on concomitant medications such as aspirin, clopidogrel, β-blockers, and ACE inhibitors, but only a few received glycoprotein IIb/IIIa inhibitors because this medication was discouraged in the trial, said Dr Hamm.
Dr Hamm noted that most of the patients underwent treatment with the sent within the first day after admission, and adverse events in the hospital were “strikingly low.” However, in the group of sicker patients (rated Braunwald IIIB), the study showed a statistically significant difference that favored the Tenax stent at 6 months. However, at 9 months, the significance was lost.
The study indicates that further studies are needed to determine the potential of silicone carbide–coated stents, said Dr Hamm.
Matthias Pfisterer, MD, of the University Hospital in Bern, Switzerland, and his colleagues in the Trial of Invasive versus Medical Therapy in the Elderly (TIME) investigated the optimum care for a population often overlooked in clinical studies: those older than 75 years of age.
Their conclusion was that patients >75 years who suffer from angina, even if they are receiving standard drug therapy, should at least be offered an invasive evaluation (coronary angiography), although the risk of the test and subsequent invasive treatment is increased 3- to 4-fold in the population.
“If the coronary anatomy is suitable for revascularization, they should be revascularized to reduce symptoms and improve quality of life,” said Dr Pfisterer. Patients and physicians should weigh the benefits of taking fewer antianginal drugs against the increased, although still small, risk of intervention.
The TIME study enrolled 301 patients >75 years of age from 14 Swiss centers. These patients were randomly assigned to either drug therapy or left heart catheterization and revascularization (either angioplasty or coronary artery bypass graft), when appropriate.
The primary end point was quality of life rather than life extension, said Dr Pfisterer. However, the investigators did measure death from all causes, major adverse cardiovascular events, hospitalizations, nonfatal myocardial infarction, and acute coronary syndromes, with or without the need for urgent follow-up. Patients were followed for 6 months.
The drug therapy group included 148 patients, and the invasive group had 153 patients. The average age in both groups was 80 years, and almost half of those enrolled were women. As expected, said Dr Pfisterer, all patients had a high-risk profile, with hypertension, diabetes, and history of stroke, acute myocardial infarction, prior revascularization, and extensive comorbidities.
At baseline, patients were taking 2 anginal drugs. Drugs were then increased in number and dosage. During the trial, patients in the drug therapy group were taking 3.5 drugs to control angina, with the dosage of all drugs increased.
A total of 80% of the patients in the invasive group had 2 or 3 blocked coronary arteries. Of the 153 patients in this group, 147 agreed to undergo catheterization, and about three-quarters of them were candidates for a revascularization procedure. In almost 80% of cases, percutaneous intervention was the treatment of choice.
Overall, medically treated patients in this study experienced death, myocardial infarction, and hospitalization for unstable angina 2.5 times more often than did those patients who underwent angioplasty or bypass surgery (48% versus 19%). However, both forms of treatment reduced the pain from angina and improved the patients’ sense of well being.
The investigators concluded older patients should be offered heart catheterization and revascularization when appropriate, just as such procedures are offered to younger patients.
Neuropsychology in the SoS Trial
Although previous studies have demonstrated neurocognitive deficits in patients who have undergone coronary artery bypass grafting, Peter Wahrborg, MD, PhD, found no such problems in a subset of patients studied in the large Stent or Surgery (SoS) trial, which was reported at the American College of Cardiology meetings in Orlando, Florida, earlier this year. Dr Wahrborg’s neuropsychology results were first reported in Stockholm.
In this part of the study, researchers evaluated the neuropsychological outcome of 153 patients from Germany, Sweden, and the United Kingdom who were randomized to receive percutaneous intervention or surgery. A total of 988 patients were enrolled in the overall SoS trial. At baseline, Dr Wahrborg and his colleagues found no neurocognitive or psychological differences between the 2 groups of people. After 6 months, they identified no decline in function and no difference between the 2 groups.
“The assessment was the same at 12 months,” said Dr Wahrborg. “The results are the same as at baseline.”
Dr Wahrborg said he is not sure why his results are so much different from those of others, but the expertise of the surgeons or anesthesiologists could affect the results.
Darusentan, an endothelin A antagonist, reduced blood pressure significantly at 3 different doses in the Hypertension Endothelin Antagonist Trial (HEAT-2), said Roumen Nakov, MD, of the International Institute of Thrombosis and Vascular Diseases in Frankfort, Germany.
Patients were randomized to 1 of 3 doses of darusentan (10, 30, and 100 mg) or to placebo. The trial, which involved nearly 400 patents, involved a placebo run-in period. Once the medication was started, hypertension decreased over the first week in all the treatment groups. The decrease was dose-dependent, and the greatest drop in blood pressure occurred in those patients who were taking 100 mg of darusentan. There was no change in pulse rate in the groups. “It is important that the reduction in blood pressure is not accompanied by an increase in pulse rate,” noted Dr Nakov.
However, adverse events occurred in 14.6% of patients in the 100 mg group but only 6.1% of those in the placebo group. The most frequently observed adverse event seen was headache. Others included flushing and peripheral edema, as well as a mild dose-dependent decrease in hemoglobin and red blood cells seen in the first 2 weeks of treatment. The problems reversed when the drug was discontinued, and they were not clinically relevant.
The higher incidence of adverse events at the 100 mg dose level warrants further study, said Dr Nakov. However, he thinks that the use of selective endothelin A receptor antagonists holds promise as an effective and safe treatment for hypertension.
Lacidipine, a third-generation calcium antagonist, showed promise in slowing the progression of carotid atherosclerosis in an international study (European Lacidipine Study on Atherosclerosis [ELSA]) that pitted it against the β-blocker atenolol, said Alberto Zanchetti, MD, of the University of Milan.
A total of 2334 patients were recruited from 410 clinical units in 7 countries. They were referred for evaluation and treatment to 23 referral centers based in university hospitals. The thickness of the carotid wall was evaluated by ultrasound and validated in an ultrasound coordinating center.
After a month of placebo run-in, patients were randomized to receive either 50 mg of atenolol taken once daily or 4 mg of lacidipine. The doses were increased and a diuretic was added until blood pressure control was achieved. The data were analyzed by a comparison of the final versus the baseline ultrasound.
The disease progressed in both groups, but progression was greater in the group receiving the β-blocker, said Dr Franchetti. Progression was reduced 40% in the lacidipine-treated group.
There were 17 myocardial infarctions and 17 deaths in the atenolol group and 18 myocardial infarctions and 13 deaths in the lacidipine group. In total, there were 201 serious events in the atenolol group and 186 in the lacidipine group.
ELSA is the largest prospective, randomized, double-blind trial of its kind ever performed, said Dr Franchetti. “The principal statistical analysis showed the effectiveness of lacidipine in this population when compared to atenolol.”
The use of an ACE inhibitor called perindopril reduced the risk of recurrent stroke in patients who took part in the Perindopril Protection Against Recurrent Stroke study (PROGRESS). The study recruited 6105 former stroke patients from 172 centers around the world. They were randomized to treatment with perindopril and the diuretic indapamide or to placebo, and their course was followed over 5 years.
There was a 28% reduction in recurrent stroke in the group that received perindopril and indapamide. Their outcomes were compared with a group that received placebo. In addition, said John Chalmers, MD, of the Institute for International Health in Sydney, Australia, major coronary events were reduced 26% in the treatment group. The treatment group also experienced a reduction in severe cognitive decline and dementia.
“The absolute benefits are substantial,” said Dr Chalmers. “We have eliminated one stroke for every 23 patients treated over 5 years. We have eliminated one major vascular event for every 11 patients treated for 5 years.”
“This treatment should be considered for all patients who have had a stroke or transient ischemic attack, regardless of the stroke type, initial blood pressure, other treatments and drugs, region, ethnicity, age, and sex. This study should have important implications for guidelines, for regulatory authorities, and treating doctors,” he said.
Treatment with the angiotensin II receptor antagonist irbesartan resulted in a significant reduction in the risk of kidney disease for patients with hypertension and type 2 diabetes, said Marc A. Pfeffer, MD, of Harvard Medical School in Boston.
In the Irbesartan Diabetic Neuropathy Trial (IDNT), 1715 patients from 210 clinics around the world were randomly assigned to receive 300 mg/d irbesartan, 10 mg/d amlodipine, or a antihypertensive medication that was not an ACE inhibitor, other angiotensin II receptor antagonist, or calcium-channel blocker (control group). Hypertension was defined as a blood pressure >135/85 mm Hg or documented treatment with antihypertensive medications. Patients also had to have a 24-hour protein excretion ≥900 mg to be enrolled.
After following patients for 2.5 years, Dr Pfeffer and his colleagues found that patients receiving irbesartan progressed to end-stage renal disease or death more slowly than those in the other groups. “Using irbesartan buys you 6 months before you progress to end-stage renal disease or death,” he said.
However, irbesartan had no effect on the incidence of major cardiovascular incidents. The three treatment regimens seemed to have a similar effect on the risk of cardiovascular disease. The population studied is at high risk for both kidney failure and heart disease. When patients are this sick, noted Dr Pfeffer, “no one wins. Patients do poorly on all outcomes.”
In this study, which added cardiac resynchronization therapy to an implanted defibrillator using a device called Contak CD, researchers found no significant clinical effect on heart failure, although peak oxygen uptake improved in all patients, said James Coman, Jr, of the University of Oklahoma School of Medicine at Tulsa.
Dr Coman said that study showed that there was functional benefit in the sickest patients, but that there was a lack of efficacy in standard heart failure measurement. All patients in the study received implanted defibrillators that remained on. However, one group received an additional lead that initiated cardiac resynchronization. A total of 581 patients were implanted with the defibrillator system, and 490 received resynchronization.
The trial showed that the combination of cardiac resynchronization and an implanted cardiac defibrillator is feasible and safe. However, in July, the US Food and Drug Administration elected not to approve the combination implanted cardiac defibrillator/cardiac resynchronization device Contak CD made by Guidant Corp.
The intravenous dual endothelin receptor antagonist tezosentan had no apparent advantage over placebo in a randomized, double-blind, placebo-controlled multicenter trial that involved 669 patients suffering from acute heart failure. Patients in the Randomized Intravenous Tezosentan (RITZ-1) study received standard treatment for acute heart failure plus tezosentan or standard treatment plus placebo.
There was no significant difference in the 2 groups in measurements of dyspnea, a major problem in acute heart failure. When researchers measured time to heart failure or death, they again found that the drug had no benefit over placebo, said John R. Teerlink, director of the Heart Failure Clinic at the San Francisco Veterans Affairs Medical Center. There were some adverse events in the treated group, including headache, hypertension, nausea, and renal impairment or failure. There was no difference in deaths between the 2 groups.
“The question is why?” asked Dr Teerlink. “I think the study design was a problem.” In addition, he thinks that the dose of tezosentan was too high. Future studies will evaluate lower doses.