Session
Late-breaking Clinical Trials I
Study: Intracoronary infusion of bone marrow–derived progenitor cells in acute myocardial infarction: a randomized, double-blind, placebo-controlled multicenter trial. Reinfusion of Enriched Progenitor Cells And Infarct Remodeling in Acute Myocardial Infarction (REPAIR-AMI)
Presenter: Dr Volker Schachinger, Goethe University, Frankfurt am Main, Germany
Background: Despite advances in therapy for acute myocardial infarction, mortality and morbidity related to post–myocardial infarction (MI) left ventricular dysfunction remain high. To date, the clinical tools for preventing post-MI heart failure have been limited to rapid reperfusion and postinfarction drug therapy. Recently, there has also been considerable interest in novel approaches aimed at preventing reperfusion injury and improving infarct healing, including stem cell therapy. Several preclinical studies1,2 and small clinical trials3-5 have demonstrated the potential benefit of bone marrow–derived cell-based therapies in the treatment of post-MI left ventricular dysfunction. These studies have focused on the whole mononuclear cell fraction of bone marrow, because it is unclear which cell type or combination of cell types may be responsible for the promising early results.
The REPAIR-AMI trial was the largest, randomized, double-blind, placebo-controlled study to evaluate the effects of intracoronary delivery of progenitor cells after primary percutaneous coronary intervention (PCI) for ST-segment elevation MI. The study involved 204 patients at 17 medical centers in Germany and Switzerland. After bone marrow aspiration, patients were randomized to receive an intracoronary infusion of the infarct-related artery with autologous mononuclear progenitor cells (BMC group) or placebo medium, 3 to 6 days after acute MI. The primary end point of the study was absolute increase in left ventricular ejection fraction (EF) as measured by repeat left ventricular angiography at 4 months.
Results: There were no differences in baseline characteristics between the groups, with 69% of patients having left anterior descending coronary artery territory infarctions and 84% of patients undergoing primary PCI. A mean of 236 million cells were delivered an average of 4 days after PCI. At baseline, EF was similar between groups (48% BMC group vs 47% placebo group). Ejection fraction was higher in both groups at 4 months compared with baseline, but the increase in EF was statistically significantly higher in the BMC group compared with the placebo group (5.5% vs 3.0%, P = .014).
In subgroup analyses, the improvement in EF with bone marrow cell infusion was evident among patients with a baseline EF of <49% (7.5% for the BMC group vs 2.5%, P < .01), but was not significant in patients with an EF of >49% (4.0% vs 3.7%, P = NS). In addition, patients treated within 5 days of their acute MI showed no benefit with bone marrow cell infusion compared with placebo, whereas patients treated after 5 days showed a significant increase in EF (7.0% vs 1.9%, P =.004). Although the study was not powered to detect a difference in clinical end points, a trend toward a reduction of the composite of death, MI, or repeat revascularization was seen in the BMC group (21% vs 30%, P = .17).
Interpretation: The REPAIR-AMI trial demonstrated that intracoronary infusion of bone marrow mononuclear cells in patients after acute MI improved left ventricular function at 4 months. In addition, although care should be taken in interpreting subgroup analyses, it is interesting to note that the improvement in left ventricular function was most striking in patients with worse baseline left ventricular EF and in those treated ≥5 days after MI. Furthermore, treatment with bone marrow cells was found to be safe and associated with a trend toward a reduction in major cardiovascular events. In light of these results, the REPAIR-AMI investigators suggest that larger clinical trials designed to detect differences in clinical outcomes are now warranted. Still, the exact mechanism of benefit of the cells remains unclear, and the improvement in left ventricular EF seen in the REPAIR trial was not reproduced in the similarly designed ASTAMI trial, also presented at this year's AHA.
References
1. Amado LC, Saliaris AP, Schuleri KH, et al. Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proc Natl Acad Sci USA 2005;102:11474-9.
2. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation 2001;104:1046-52.
3. Assmus B, Schachinger V, Teupe C, et al. Transplantation Of Progenitor Cells And Regeneration Enhancement in Acute Myocardial Infarction (TOPCARE-AMI). Circulation 2002;106:3009-17.
4. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913-8.
5. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141.
Session
Late-breaking Clinical Trials III
Study: Effect of ACAT inhibition on the progression of coronary atherosclerosis: a randomised controlled trial
Presenter: Dr Steven E. Nissen, Cleveland Clinic Cardiovascular Coordinating Center, Cleveland, OH
Background: The enzyme acyl–coenzymeA:cholesterol transferase (ACAT) is responsible for the esterification of cholesterol in a variety of tissues. Inhibition of ACAT1 is intended to make more free cholesterol available for reverse cholesterol transport that theoretically could reduce lipid accumulation within atherosclerotic lesions. Previous animal models have shown that ACAT inhibition was capable of reducing atheroma volume, presumably by preventing the accumulation of cholesterol within macrophages and thereby inhibiting foam-cell formation.
In the ACTIVATE trial, 534 patients with symptomatic coronary artery disease and coronary angiography with >20% stenosis were enrolled at 52 US hospitals. All patients received recommended therapy, including statins if indicated. Intravascular ultrasound using a 40-MHz transducer and a motorized pullback at 0.5 mm/s through a target segment of >30 mm in length of a single “target” coronary artery was performed at baseline; it was repeated after 18 months to measure the progression of atherosclerosis. Patients were randomized to receive the ACAT inhibitor pactimibe (100 mg/d) or placebo for 18 months of treatment. Approximately 60 patients in each study arm did not return for repeat intravascular ultrasound of the target vessel.
Results: Baseline characteristics between the 2 study arms were similar. The average baseline low-density lipoprotein cholesterol levels were 95 mg/dL in both treatment arms. Regarding the primary efficacy parameter (change in percent atheroma volume), both treatment groups showed a statistically significant progression although the increase in percent atheroma volume was slightly greater in the pactimibe group compared with the placebo group (0.69% vs 0.59%, respectively, P = .77).
However, both the secondary efficacy parameters (change in atheroma volume in the total artery and then in the most diseased segment) showed proatherogenic effects with pactimibe treatment. Normalized total atheroma volume showed regression in the placebo group, −5.6 mm3 (P = .001 compared with baseline), and no regression in the pactimibe group, −1.3 mm3 (P = .39 compared with baseline). The between-groups' P value was .035. The change in the atheroma volume in the most diseased 10-mm subsegment showed similar results with a −3.2-mm3 regression in the placebo group and −1.3-mm3 regression in the pactimibe group (P = .01). Adverse cardiovascular outcomes neither increased nor decreased with pactimibe therapy (study not powered for clinical outcomes).
Interpretation: For patients with coronary disease, treatment with an ACAT inhibitor showed no benefit for the primary efficacy parameter (percent atheroma volume) and adverse effects for 2 major secondary efficacy measures. The results of this study suggest that ACAT inhibition is not an effective strategy for limitation of atherosclerosis and may be proatherogenic.
Session
Late-breaking Clinical Trials IV
Study: Effects on left ventricular function by intracoronary injections of autologous mononuclear bone marrow cells in acute anterior wall myocardial infarction: the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial
Presenter: Dr Ketil Lunde, Rikshospitalet University Hospital, Oslo, Norway
Background: The role of intracoronary infusion of autologous bone marrow cells in the management of acute myocardial infarction (MI) was examined in the ASTAMI trial. (See also the summary of the REPAIR-AMI trial.) The ASTAMI investigators limited enrollment to acute ST-segment elevation MI patients with anterior wall involvement for 2 reasons: (1) it is the region of the myocardium best visualized with noninvasive imaging and (2) anterior wall MIs are associated with a greater risk of post-MI left ventricular dysfunction compared with isolated involvement of other walls.
In the ASTAMI study, 101 patients with acute anterior MI who underwent successful primary percutaneous coronary intervention (PCI) were randomized either to intracoronary infusion of mononuclear bone marrow cells (mBMC) 5 to 8 days after PCI (n = 52) or to control (n = 49).1 In contrast to the REPAIR-AMI trial, the control group did not undergo bone marrow aspiration or repeat cardiac catheterization. All patients underwent single-photon emission computed tomography and echocardiographic imaging at baseline and at 6 months' follow-up. In addition, patients had a cardiac magnetic resonance imaging performed 2 to 3 weeks post-MI and 6 months.
Results: No significant differences between groups were present at baseline (mean age, 57 years; 35% hypertensive, 8% diabetic, 44% smokers, 29% underwent fibrinolysis before PCI). The mean time from symptom onset to PCI was 262 minutes in the mBMC group and 274 minutes in the control group. The cells were infused a mean of 6 days post-MI.
Results of the 3 different imaging modalities showed no differences in ejection fraction between groups at baseline and 6 months' follow-up. Ejection fraction improved in both groups as measured by single-photon emission computed tomography (8% mBMC vs 7% control, P = NS), magnetic resonance imaging (1.2% mBMC vs 4.3% control, P = NS), and echocardiography (3.1% mBMC vs 2.1% control, P = NS). There were also no differences in change in infarct size and end diastolic volume. There were no deaths at 6 months, and adverse event rates did not differ between groups.
Interpretation: In contrast to the REPAIR-AMI trial and several other previously reported studies of bone marrow cell infusion in acute MI, the ASTAMI trial found no benefit for intracoronary infusion of bone marrow mononuclear cells in patients after primary PCI for anterior MI. These discrepant results were noted despite generally similar study methods, including the types of cells used, as well as the timing and intracoronary delivery technique used. Differences between the REPAIR-AMI and ASTAMI studies included the method of measurement of left ventricular function and location of MI. Although the negative findings of ASTAMI are difficult to reconcile, additional analysis of the data may prove insightful. Consideration should be given to analyzing the data in terms of the timing of cell delivery and baseline ejection fraction, given the findings in REPAIR-AMI of greater benefit in patients with lower baseline ejection fraction and those treated later.
Although the results of the ASTAMI may have tempered the enthusiasm generated after the REPAIR-AMI trial, the role of stem cell therapy for cardiac repair remains promising. Ongoing basic science and preclinical research efforts are needed to better define the optimal stem cell type, timing of infusion post-MI, and delivery methods for future clinical trials.
Reference:
1. Lunde K, Solheim S, Aakhus S, Arnesen H, Abdelnoor M, Forfang K, ASTAMI Investigators. Autologous stem cell transplantation in acute myocardial infarction: The ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005;39:150-8.
Session
Late-breaking Clinical Trials I
Study: EArly Discharge After Transradial Stenting of CoronarY Arteries: the EASY study's 6 months' results
Presenter: Dr Olivier F. Bertrand, Laval Hospital, Quebec Heart-Lung Institute, Quebec City, Canada
Background: More than 500,000 percutaneous coronary intervention (PCI) procedures are performed each year in the United States, and it has been estimated that >1,000,000 are performed annually worldwide. The femoral artery has traditionally been the preferred access site for coronary procedures, but this approach has several limitations. It is relatively contraindicated in the presence of peripheral arterial disease, requires postprocedure recumbence, and is poorly tolerated by patients with left ventricular dysfunction, lung disease, or back and hip pain. The rate of complications after PCI via the femoral approach (hematoma, pseudoaneurysm, arteriovenous fistula, or the need for blood transfusion or surgical arterial repair) is 2% to 8%.1,2 Access via the radial artery has potential advantages compared with the femoral approach, including its superficial course and collateral ulnar flow, which could reduce access site complications and provide earlier patient mobilization.
Blockade of the platelet surface membrane glycoprotein IIb/IIIa complex with abciximab, a human chimeric antibody Fab fragment, has been shown to markedly reduce the incidence of acute ischemic complications in the setting of PCI.3-6 However, few studies have addressed the duration of abciximab treatment in this patient population. The EPIC trial evaluated the 30-day composite end point of death, myocardial infarction (MI), or urgent revascularization in patients undergoing coronary angioplasty or atherectomy treated with placebo, abciximab bolus, or abciximab bolus plus infusion. The results of the EPIC study showed that the abciximab bolus plus infusion was superior to abciximab bolus alone with the benefit driven by repeat revascularization (3.6% vs 0.8%, P < .001). However, this study was performed when stents were minimally used.
The EASY study was an open-label randomized study funded by Eli Lilly and Bristol-Myers Squibb/Sanofi-Aventis evaluating the efficacy of same-day hospital discharge after transradial PCI combined with single bolus administration of abciximab. This study was designed as a noninferiority trial where researchers compared same-day discharge with bolus abciximab (504 patients) versus overnight abciximab bolus plus infusion (501 patients). There were 343 patients entered into a registry because of predefined complications after angioplasty that included arterial dissection, suboccluded branch vessels, or insufficient TIMI flow. The registry patients received 12-hour abciximab infusions and hospitalization. The primary composite end point was death, MI, urgent revascularization, repeat hospitalization, major bleeding, access site complications, or severe thrombocytopenia at 30 days. Secondary end points included the composite of death, MI, or revascularization of the dilated vessel at 30 days and 6 months.
Results: Of the 504 patients in the same-day group, 445 (88%) were discharged the same day. The rate of primary events in the same-day group (13.5%) was not significantly different when compared with the overnight group (10.2%). The rate of the secondary composite end point was not significant, 1.6% in the same-day group compared with 1.8% in the overnight group. At 6 months, the rate of death, MI, or revascularization was 5.9% in the same-day group and 5.6% in the overnight group, which was not significantly different. Both randomized groups had a significantly lower (P < .0001) 6-month event rate (11.7%) than the registry group (20.2%). No deaths occurred throughout the study period.
Interpretation: In this randomized trial, abciximab as a single bolus was shown to be noninferior at 30 days and 6 months to the standard bolus plus infusion after uncomplicated transradial coronary PCI. However, a 3.3% absolute difference in the primary event rate may be a cause of concern clinically because the 2 study populations were small. A large multicenter study would help clarify this question.
A limitation of this study was that the radial approach was not compared with the more commonly used femoral PCI approach. Randomized comparisons of the radial versus femoral approach are needed to compare the complication rate of each approach in the same study cohort and to define the population in which the radial approach is a safe alternative. Criticisms of the radial approach have included difficulties performing this procedure in inexperienced centers and the inability to access the LIMA graft in post–coronary artery bypass graft patients. On the other hand, advocates believe the radial approach would decrease coronary PCI complications and increase patient satisfaction. The radial approach allows for easy compression of the small artery access site resulting in minimal bleeding and earlier mobilization by the patient, earlier discharge, and decreased overall cost. If cost can be reduced by this approach, the funds saved could be reallocated toward the use of drug-eluting stents, which are underused by most health care systems around the world.
References
1. Kiemeneij F, Laarman GJ, Odekerken D, et al. A randomized comparison of percutaneous transluminal coronary angioplasty by the radial, brachial and femoral approaches: the access study. J Am Coll Cardiol 1997;29:1269-75.
2. Choussat R, Black A, Bossi I, Fajadet J, Marco J. Vascular complications and clinical outcome after coronary angioplasty with platelet IIb/IIIa receptor blockade: comparison of transradial vs transfemoral arterial access. Eur Heart J 2002;21:662-7.
3. EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994;330:956-61.
4. EPILOG Investigators. Platelet glycoprotein IIB/IIIa blockade with abciximab with low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997;336:1689-96.
5. CAPTURE Investigators. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997;349:1429-35.
6. EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet 1998;352:87-92.
Session
Late-breaking Clinical Trials III
Study: Smoking cessation efficacy and safety of an α4β2 nicotinic receptor partial agonist: results from the varenicline in cessation therapy: optimizing results
Presenter: Dr Serena Tonstad, Ulleval University Hospital, Oslo, Norway
Background: Smoking is the leading preventable cause of illness and premature death in the United States, claiming 140,000 lives from cardiovascular disease annually. The World Health Organization estimates that 1 year after a smoker quits, the risk of having coronary artery disease decreases by 50%. Within 15 years, the relative risk of dying from coronary heart disease for an ex-smoker approaches that of a lifetime nonsmoker. Varenicline, an α4β2 nicotinic receptor partial agonist, has the potential to relieve nicotine craving and withdrawal symptoms while reducing the reinforcing effects of nicotine.
Methods: In two 3-arm studies, 1025 and 1027 smokers were randomized in a double-blind fashion to receive varenicline 1 mg BID, bupropion 150 mg BID, or placebo, with dosages titrated to those levels over the first week, during which smoking was allowed. Inclusion criteria are male or female outpatient cigarette smokers (average of >10 cigarettes per day during the past year), 18 to 75 years old, motivated to quit smoking. They were instructed to quit on the eighth day, therapy continued out to 12 weeks, and a follow-up nontreatment observational period went out to 1 year. The participants went to a clinic weekly for formal motivational support sessions throughout the study periods. The primary end point was the carbon monoxide–confirmed 4-week continuous quit rate during weeks 9 to 12. The secondary end point was the carbon monoxide–confirmed 4-week continuous abstinence (CA) rate during weeks 9 to 52. In the third study, testing maintenance therapy, 1236 other smokers took the varenicline 1 mg on an open-label basis for 12 weeks; they were told to quit cigarettes completely before day 8. The 1206 people from that group who successfully abstained to week 12 and complied with the motivational support sessions were then randomized to the active drug or placebo and followed for a 28-week nontreatment period. CA rate for weeks 13 to 24 was the primary end point, with CA rate for weeks 13 to 52 as secondary end point. A single puff of a cigarette counted as a return to smoking in the analysis.
Results: In the first 2 studies, the quit rate was 44% in the varenicline group, 30% in the bupropion group, and 17.7% for those on the placebo after 12 weeks. The odds ratio of staying smoking free in the varenicline group compared with placebo was 3.91 and compared with bupropion was 1.96. The CA rate during weeks 9 to 52 was 22.1% in the varenicline group, 16.4% in the bupropion group (P = NS), and 8.4% in the placebo group. Similarly, in the second study, the CA rate was 23% in the varenicline group, 15% in the bupropion group, and 10% in the placebo group. In the third study the rate of CA was 70.6% in the varenicline group compared with 49.8% in the placebo group during weeks 13 to 24 and 44% versus 37%, respectively, during weeks 13 to 52. Observed side effects in the two 3-arm studies were markedly more common in the varenicline group and included mild-to-moderate nausea and abnormal dreams, but the rate of withdrawal because of side effects in the first 2 trials was similar for all 3 groups.
Interpretation: The results of the 3 trials suggest a superior effect of varenicline compared with buproprion, although the rate of adverse effects was also higher in the varenicline group. The side effects, mainly mild to moderate nausea and abnormal dreams, did not result in a drug discontinuation rate significantly higher than bupropion. Despite the significant improvement in the rate of quitters, smoking cessation was obtained in less than half of patients in the varenicline group at the end of the treatment period and in less than a quarter at 1 year. The low rate of success obtained by varenicline in a population motivated to quit smoking calls for further efforts in the field of smoking cessation pharmacological support.
Session
Late-breaking Clinical Trials II
Study: Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-W)
Presenter: Dr Stuart J. Connolly, McMaster University, Hamilton, Ontario, Canada
Background: Atrial fibrillation is a very prevalent condition estimated to affect >2 million people in the United States alone.1 Current standard of care for atrial fibrillation, in most cases, is chronic oral anticoagulation with a target INR of 2.0 to 3.0, to reduce the risk of stroke. Despite the good data supporting its use, warfarin remains a difficult drug to monitor and titrate, and it has a number of drug-drug interactions. Furthermore, it carries a not insignificant risk of bleeding of 1% to 6% per year.2 Interest has naturally arisen in finding an efficacious alternative that is more convenient to administer and potentially safer. The ACTIVE trials were designed to address this question of an alternative to oral anticoagulation.
ACTIVE-W planned to randomized 6600 patients with atrial fibrillation and at least one other risk factor for stroke to receive either oral anticoagulation with target INR 2.0-3.0 or clopidogrel 75 mg/d along with daily aspirin (recommended daily dose 75-100 mg). Patients who were enrolled in ACTIVE-W were eligible for further randomization into ACTIVE-I comparing irbesartan and placebo. The study was planned to have a mean 3-year follow-up. The primary end point of ACTIVE-W was the occurrence of a vascular event, defined as stroke, non–central nervous system systemic embolism, MI, and vascular death.
Results: ACTIVE-W was stopped prematurely by the data safety and monitoring board after approximately 2 years of follow-up due to clearly higher efficacy of the warfarin arm. At the time of termination, a total of 6706 patients had been enrolled. The annual rate of vascular events (the primary end point) was 5.64% in the combination antiplatelet group compared with 3.93% in the warfarin group (relative risk 1.45, P = .0002). Rates of major bleeding were no different between groups, being 2.4% per year for clopidogrel/aspirin and 2.2% per year for warfarin (relative risk 1.06, P = .67). Approximately 75% of patients had been on warfarin before randomization in ACTIVE-W. Subset analysis of these patients previously on oral anticoagulation showed a statistically significant increase in the vascular event rate when they were subsequently randomized to clopidogrel/aspirin, with a relative 1.50-fold excess risk (P = .0006).
Interpretation: Despite the fact that warfarin is cumbersome to use, it remains the most effective drug available for the prevention of vascular complications arising out of atrial fibrillation. The hope, not borne out in ACTIVE-W, was that an alternative regimen of duel antiplatelet agents would be as efficacious as warfarin or at least with a safety profile in terms of bleeding that could support its role in atrial fibrillation. Somewhat surprisingly, ACTIVE-W found no less major hemorrhage with the combination of clopidogrel and aspirin than with warfarin.
Although the routine use of dual antiplatelet agents cannot be recommended for patients who are candidates for warfarin, it is important to recognize that the other 2 arms of ACTIVE are still ongoing. ACTIVE-I is investigating the role of irbesartan on vascular end points, whereas ACTIVE-A is comparing the combination aspirin and clopidogrel versus aspirin alone in patients who are either unable or unwilling to take warfarin. The exact role of the combination regimen remains to be decided, but warfarin remains the standard of care for atrial fibrillation in patients who are candidates for therapy.
References
1. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults. National implications for rhythm management and stroke prevention: the Anticoagulation and Risk Factors In Atrial Fibrillation (ATRIA) Study. JAMA 2002;285:2370-75.
2. Levine MN, Raskob G, Beyth RJ, et al. Hemorrhagic complications of anticoagulant treatment: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126:287S-310S.
Session
Late-breaking Clinical Trials
Study: Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial
Presenter: Dr Anthony Keech, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia
Background: Patients with type 2 diabetes mellitus (DM) are at increased risk of cardiovascular disease, partly owing to dyslipidemia, which can be amenable to fibrate therapy. In patients with type 2 DM, rates of coronary heart disease are 3- to 4-fold higher than in those without type 2 diabetes. Patients with type 2 DM often have a lipid profile that is high in tryglycerides, low in high-density lipoprotein (HDL), and somewhat normal in low-density lipoprotein cholesterol. Fibrates lower tryglycerides and raise HDL cholesterol; hence, they have been a logical treatment by many physicians for their patients with type 2 DM. Both the Helsinki Heart Study and the Veterans Affairs Lipoprotein Cholesterol Intervention Trial demonstrated a reduction in recurrent events in patients with coronary heart disease, and especially in patients with the metabolic syndrome. The FIELD study thus addressed the effect of fenofibrate on cardiovascular disease events in patients with type 2 DM. FIELD was set up as a multinational randomized controlled trial with 9795 subjects aged 50 to 75 years. After an initial fenofibrate run-in phase, patients were assigned to receive 200 mg fenofibrate (n = 4895) or placebo (n = 4900) if they met inclusion criteria of total cholesterol/HDL > 4.0 or had a triglyceride concentration of 1.0 to 5.0 mmol/L . The primary outcome was coronary events (coronary heart disease death or nonfatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularization). Analysis was by intention to treat.
Results: Patients receiving fenofibrate had a significant 24% reduction in nonfatal myocardial infarction (0.76, 0.62-0.94; P = .010) and a nonsignificant increase in coronary heart disease mortality (1.19, 0.90-1.57; P = .22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; P = .035). This finding included a 21% reduction in coronary revascularization (0.79, 0.68-0.93; P = .003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (P = .18). Fenofibrate was associated with less albuminuria progression (P = .002) and less retinopathy needing laser treatment (5.2% vs 3.6%, P = .0003). There was a slight increase in pancreatitis (0.5% vs 0.8%, P = .031) and pulmonary embolism (0.7% vs 1.1%, P = .022), but no other significant adverse effects.
Interpretation: Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer nonfatal myocardial infarctions and revascularizations. The higher rate of starting statin therapy in patients allocated to placebo might have masked a moderately larger treatment benefit.
The results from this trial do not warrant a recommendation for increased fenofibrate use in patients with diabetes, nor do they provide convincing evidence of the benefit of fenofibrate therapy in patients already at target serum low-density lipoprotein cholesterol.
References
1. Taskinen MR. Diabetic dyslipidaemia: from basic research to clinical practice. Diabetologia 2003;46:733-49.
2. De Backer G, Ambrosioni E, Borch-Johnsen K, et al. Executive summary. European guidelines on cardiovascular disease prevention in clinical practice: Third Joint Task Force of European and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 8 societies and by invited experts). Atherosclerosis 2004;173:381-91.
3. American Diabetes Association. Standards of medical care. Diabetes Care 2005;28:S4-S36.
4. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32.
5. The FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): a randomised controlled trial. Lancet 2005; published online Nov 14. DOI:10.1016/S0140-6736(05) 67667-2.
6. Colhoun HM, Betteridge DJ, Durrington PN, for the CARDS Group. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685-96.
7. Collins R, Armitage J, Parish S, for the Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo controlled trial. Lancet 2003;361:2005-16.
Session
Late-breaking Clinical Trials III
Study: The Incremental Decrease in Clinical Endpoints Through Aggressive Lipid Lowering (IDEAL) Trial1
Presenter: Dr Terje R. Pedersen, Ulleväl University Hospital, Oslo, Norway
Background and Methods: The Scandinavian Simvastatin Survival Study (4S trial)2 demonstrated a 30% reduction in total mortality and a 39% reduction in nonfatal myocardial infarction (MI) in patients with known coronary heart disease (CHD) who were randomized to simvastatin 20 mg daily compared with placebo. The IDEAL study investigators sought to determine whether further low-density lipoprotein (LDL) cholesterol lowering below the level achieved in the simvastatin arm of the 4S trial would result in a further reduction in CHD events. The IDEAL trial was an open-label, blinded, end point trial that was conducted in 190 ambulatory centers in Denmark, Finland, Iceland, the Netherlands, Norway, and Sweden. A total of 8888 patients with a prior history of MI but with stable CHD at baseline were randomized in a 1:1 fashion to receive atorvastatin 80 mg daily or simvastatin 20 mg daily (with titration to 40 mg if needed for sufficient LDL cholesterol lowering). The primary end point was the time to first occurrence of a major coronary event, defined as coronary death, hospitalization for nonfatal MI, or cardiac arrest with resuscitation. Key secondary end points were also prespecified (see table). Analyses were performed on the intention-to-treat principle, and the median follow-up was 4.8 years.
Results: The median baseline LDL cholesterol level was 122 mg/dL (76% of patients were already taking statins at baseline). During treatment, the median achieved LDL cholesterol levels were 104 mg/dL in the simvastatin arm and 81 mg/dL in the atorvastatin arm (for an observed difference of 23 mg/dL, which was less than the expected difference of 40 mg/dL). Overall adherence to assigned statin treatment was exceptional (89% adherence in the atorvastatin arm and 95% in the simvastatin arm), despite the fact that patients in the IDEAL trial partially bore the cost of their statin medication. The table below summarizes the results of the primary and key secondary end points. Overall rates of myopathy and transaminase elevation in either statin arm were very low. The rate of permanent discontinuation of high-dose atorvastatin was higher than that of simvastatin (9.6% vs 4.2%, P < .001).
Interpretation: In the IDEAL trial, high-dose atorvastatin reduced the incidence of the primary composite end point by 11% compared with simvastatin therapy, but this difference was not statistically significant, likely because the difference in LDL cholesterol levels achieved was less than anticipated. Other lipid-lowering trials have similarly failed to show a statistically significant reduction in the primary clinical end point when the difference in LDL cholesterol levels achieved between 2 groups was less than expected.4,5 However, all of the key secondary end points in the IDEAL trial were met, which supports the concept that “lower LDL cholesterol is better” when interpreted in the context of other recently reported trials of aggressive LDL cholesterol lowering.3,6
The IDEAL trial also provides additional data that aggressive LDL cholesterol lowering is safe. Although the rate of discontinuation of atorvastatin (9.6%) was more than twice that of simvastatin (4.2%), this may be partially due to bias from the open-label design of the trial, in which 50% of patients were already taking and tolerating simvastatin at baseline (compared with only 11% use of atorvastatin at baseline). More importantly, the IDEAL study showed no difference between groups with respect to noncardiovascular mortality, which reassures us that the slightly higher noncardiovascular mortality rate in the atorvastatin 80-mg arm in the TNT trial3 was likely due to the play of chance.
From a practice standpoint, the IDEAL study (in addition to the TNT and PROVE IT-TIMI 22 trials3,6) supports the recently revised National Cholesterol Education Program Adult Treatment Panel III guidelines,7 which suggest an LDL cholesterol target of ≤70 mg/dL in patients at very high risk for a vascular event. These trials also suggest a new approach to managing high-risk patients with statin therapy: instead of starting a statin at a low dose and titrating it to achieve a specific LDL cholesterol target, it is reasonable to start a high dose of a powerful statin, carefully monitor for side effects, and reduce the dose only if side effects occur. This latter strategy is more likely to result in a larger proportion of patients achieving their LDL cholesterol targets (at the cost of few muscle or liver reactions), which could have substantial public health impact by reducing the burden of cardiovascular disease at the population level.
References
1. Pedersen TR, Faergeman O, Kastelein JJ, et al, for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin versus usual-dose simvastatin for secondary prevention after myocardial infarction. JAMA 2005;294:2437-45.
2. Scandinavian Simvastatin Survival Study (4S) Group. Randomized trial of cholesterol-lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383-89.
3. Larosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary heart disease. N Engl J Med 2005;352:1425-35.
4. de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs. a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA 2004;292:1307-16.
5. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin versus usual care: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA 2002;288:2998-3007.
6. Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-1504.
7. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:227-39.
Session
Late-breaking Clinical Trials II
Study: Effects of eicosapentaenoic acid (EPA) on major cardiovascular events in hypercholesterolemic patients: the Japan EPA Lipid Intervention Study (JELIS)
Presenter: Mitsuhiro Yokoyama, MD, PhD, Kobe University School of Medicine, Kobe, Japan
Background and Methods: Epidemiological studies have demonstrated that an increased intake of long-chain polyunsaturated n-3 fatty acid rich in fish is protective against mortality and morbidity of coronary heart disease. The Diet and Reinfarction Trial showed that patients who increased the dietary intake of fish at 2 times per week had a 29% decrease in all-cause mortality over 2 years.1 The GISSI prevention trial showed a 20% decrease in all deaths, 30% decrease in cardiovascular deaths, and 45% decrease in sudden deaths associated with a daily supplement of n-3 PUFAs (1 g/d) in patients with recent myocardial infarction (MI).2
The JELIS study was a prospective, randomized, open-label, blinded end point clinical trial designed to test the hypothesis that treatment with highly purified (>98%) eicosapentaenoic acid (EPA) 1800 mg/d together with HMG-CoA reductase inhibitor would be more effective than treatment with HMG-CoA reductase inhibitor alone in reducing major coronary events in hypercholesterolemic patients.3 A total of 18,645 patients were randomly assigned to receive EPA plus HMG-CoA reductase inhibitor (n = 9326) or HMG-CoA reductase inhibitor alone (n = 9319). The primary prevention stratum was defined as participants who had (1) no history of MI or angina pectoris and neither angioplasty/stenting nor coronary artery bypass graft (CABG) surgery until randomization and (2) no clinical manifestation of angina pectoris or ECG abnormalities until randomization. The secondary prevention stratum was defined as those who had a history of well-documented MI or angina pectoris with neither angioplasty/stenting nor CABG until randomization and/or stable, controlled angina pectoris at randomization.
In both strata, the primary end point was the composite incidence of sudden cardiac death, fatal and nonfatal MI, and unstable angina pectoris including hospitalization for ischemic episodes and events of angioplasty/stenting or CABG. All analyses followed an intention-to-treat approach.
Results: At a mean follow-up of 4.6 ± 1.1 years, the composite incidence of the primary end point in the EPA plus HMG-CoA reductase inhibitor group was significantly lower than that of the HMG-CoA reductase inhibitor alone group (2.8% vs 3.5%, hazard ratio 0.81, 95% confidence interval [CI] 0.69-0.95, P = .0113) (table). A prespecified subgroup analysis that looked at the effect of adding EPA to statin therapy in primary and secondary prevention CAD patients showed that in the primary prevention cohort there was an 18% reduction in the risk of major coronary events with EPA-plus-statin therapy when compared with the control group, although the results did not achieve statistical significance (1.4% vs 1.7%; 95% 0.632-1.062, P = .1318). In the secondary prevention cohort, there was a statistically significant 19% reduction in the risk of coronary events (8.7% vs 10.7%, 95% CI 0.657-0.998, P = .0476). Like the primary analyses, the reduction in risk was driven primarily by a reduction in the risk of unstable angina. The significant reduction in LDL cholesterol levels at 5 years was 26% in both groups (LDL-C 133 mg/dL). HDL cholesterol levels showed 5% and 3% increases by treatment with EPA plus HMG-CoA reductase inhibitor and HMG-CoA reductase inhibitor only, respectively. Measurement of the plasma fatty acids fraction revealed changes in the EPA/AA ratio from 0.63 at baseline to 1.23 at 5 years in the EPA plus HMG-CoA reductase inhibitor group and from 0.60 to 0.59 in the HMG-CoA reductase inhibitor group. There were slightly more adverse events related to gastrointestinal distress and skin abnormalities and abnormal liver enzyme elevations in the EPA group.
Interpretation: This study further supports the beneficial effect of omega-3 fatty acid in patients with known coronary artery disease. The addition of EPA to HMG-CoA reductase inhibitor therapy can provide additional benefits in preventing major coronary events mainly through a cholesterol-independent mechanism. A higher dose of EPA compared with that used in previous trials might exert its benefit by stabilizing unstable plaque. Compared with the GISSI trial, where the reduction of sudden death was seen within 6 months, in the JELIS trial, this effect occurred after 1 or 2 years, which is consistent with an atherosclerosis-related mechanism of action.
 | Outcome (%) | Statin alone (n = 9319) | Statin plus EPA (n = 9326) | Hazard ratio (95% CI) | |
| Major coronary events | 3.5 | 2.8 | 0.81 (0.69-0.95) | |
| Sudden cardiac death | 0.2 | 0.2 | 1.06 (0.55-2.07) | |
| Fatal MI | 0.2 | 0.1 | 0.79 (0.36-1.74) | |
| Nonfatal MI | 0.9 | 0.7 | 0.75 (0.54-1.04) | |
| Unstable angina | 2.1 | 1.6 | 0.76 (0.62-0.95) | |
| CABG or PTCA | 2.4 | 2.1 | 0.86 (0.71-1.05) | |
| | |
References
1. Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet And Reinfarction Trial (DART). Lancet 1989;2:757-61.
2. GISSI Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447-55.
3. Yokoyama M, Origasa H. Effects of eicosapentaenoic acid on cardiovascular events in Japanese patients with hypercholesterolemia: rationale, design, and baseline characteristics of the Japan EPA Lipid Intervention Study (JELIS). Am Heart J 2003;146:613-20.
Session
Late-breaking Clinical Trials I
Study: Efficacy and safety of edifoligide for the prevention of vein graft failure in 3014 patients undergoing coronary artery bypass graft surgery: primary results of the PREVENT IV randomized clinical trial1
Presenter: Dr John H. Alexander, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC
Background and Methods: Despite recent advances in coronary artery bypass graft surgery (CABG), major adverse cardiac events (MACE) after CABG are common, in part due to the high incidence of vein graft failure. The PREVENT IV investigators sought to determine whether the incidence of vein graft failure and subsequent MACE could be reduced by treatment of vein grafts with edifoligide, an oligonucleotide decoy that binds to and inhibits the E2F family of transcription factors that have been implicated in the development of neointimal hyperplasia in vein grafts. PREVENT IV was a phase III randomized, double-blind, placebo-controlled trial that enrolled a total of 3014 patients undergoing first CABG with at least 2 autologous vein grafts and without concomitant valvular surgery. Patients were assigned in a 1:1 ratio to have all vein grafts treated ex vivo with edifoligide or placebo, using an external pressure-mediated delivery system. Grafts were treated after being harvested but before grafting to the coronary arteries. All 3014 patients were in the safety cohort. The first 2400 patients were enrolled in an angiographic cohort, in whom quantitative coronary angiography was scheduled 12 to 18 months after the index CABG to ascertain vein graft patency. The primary angiographic end point was the occurrence of death or failure of one or more vein grafts (defined as ≥75% stenosis) on a per-patient basis in the angiographic cohort. The primary clinical end point was the occurrence of the composite of death, nonfatal myocardial infarction, or coronary revascularization with vein graft failure at 5 years in all 3014 patients, for which follow-up is ongoing; however, MACE rates at 1 year by treatment group were also presented.
Results: The baseline characteristics of the 3014 patients enrolled in PREVENT IV were very similar to those of patients who undergo CABG in “real-world” practice, according to the Society of Thoracic Surgery database.2 The internal mammary artery was used in 92% of patients in the trial. A total of 1920 (80%) patients in the angiographic cohort either underwent follow-up angiography (n = 1829) or died (n = 91) before angiography could be performed. The primary end point occurred in 436 (45.2%) of 965 patients randomized to edifoligide treatment and 442 (46.3%) of 955 patients randomized to placebo (odds ratio 0.96, 95% CI 0.80-1.14, P = .66). There was also no difference in any of the secondary angiographic end points (including rates of vein graft failure on a per graft basis, or rates of vein graft occlusion on a per patient basis). Rates of MACE at 1 year similarly did not differ (6.7% in the edifoligide arm vs 8.1% in the placebo arm, HR 0.83, 95% CI 0.64-1.08, P = .16). There were no differences in the rates of adverse postoperative events between treatment groups.
Interpretation: Edifoligide was no more efficacious than placebo in preventing angiographic vein graft failure 12 to 18 months after first CABG. Although the 1-year MACE rate was slightly lower in the edifoligide arm than in the placebo arm, this difference was not statistically significant and was likely due to the play of chance, given the neutral effect of edifoligide on vein graft failure. Nonetheless, clinical follow-up through 5 years is still continuing.
The percentage of patients who either died or had one or more vein grafts fail at the time of angiographic follow-up was 45.7%, which was higher than the expected rate of 25%. However, the percent of vein grafts that failed by 12 to 18 months was 29%. The investigators acknowledged that it is possible that the use of the pressure-mediated system that was used to deliver the study drug or placebo may have caused damage to vein grafts, thereby prompting higher rates of vein graft failure in both arms. As noted in an accompanying editorial,3 it would have been informative (although logistically difficult) to include a third arm in the study, or replace the placebo-controlled arm with a standard care arm, in which patients underwent no vein graft treatment at all, to determine an unbiased rate of vein graft failure in current practice. However, it is also possible that PREVENT IV provides a more realistic rate of vein graft failure after CABG than previous estimates, because a few prospective CABG studies have been conducted with such high rates of angiographic follow-up.
Despite its negative primary angiographic result, the authors note that PREVENT IV was a model clinical trial of CABG surgery. It tested a novel means of drug delivery (the ex vivo treatment of vein grafts), which allowed for targeted therapy to vein grafts with the potential for limited systemic toxicity.1 Furthermore, it represented a strong collaboration between an academic research organization (the Duke Clinical Research Institute) and the participating sites of a professional society (the Society of Thoracic Surgeons), which facilitated the rapid patient enrollment and high rate of angiographic follow-up (80%). Finally, PREVENT IV will provide a rich database from which the relationships among baseline and surgical characteristics at the time of CABG, 12- to 18-month angiographic follow-up, and 5-year clinical outcomes can be explored.
References
1. The PREVENT IV Investigators. Efficacy and safety of edifoligide, an E2F transcription factor decoy, for the prevention of vein graft failure following coronary artery bypass graft surgery. PREVENT IV: a randomized controlled trial. JAMA 2005;294:2446-54.
2. Alexander JH, Ferguson TB, Joseph DM, et al. The Project of Ex-vivo Vein graft ENgineering via Transfection IV (PREVENT IV) trial: study rationale, design, and baseline patient characteristics. Am Heart J 2005;150:643-9.
3. Conti VR, Hunter GC. Gene therapy and vein graft patency in coronary artery bypass graft surgery. JAMA 2005;294:2495-96.
Session
Late-breaking Clinical Trials II
Study: REVIVE II: multicenter placebo-controlled trial of levosimendan on clinical status in acutely decompensated heart failure
Presenter: Dr Milton Packer, University of Texas Southwestern Medical Center, Dallas, TX
Background: Acute decompensated heart failure (ADHF) is a significant public health problem. In the United States, there are 1 to 3 million hospitalizations for worsening heart failure annually.1 The associated hemodynamic derangements are usually treated with either milrinone or dobutamine, inotropic agents that, in randomized controlled trials, have failed to improve morbidity and mortality and in many instances have resulted in higher mortality for patients with ADHF.2,3 Levosimendan, a calcium sensitizer, is a unique inotropic agent that has a mechanism of action different from conventional inotropic agents, which are typically β-agonists or phosophodiesterase inhibitors. Levosimendan is a positive inotrope and vasodilator. The inotropic action of the drug is mainly attributed to calcium sensitization.4 Levosimendan stabilizes the conformational change in troponin C when it binds to calcium troponin C, a contractile protein that regulates cross-bridging of the actin-myosin filaments. Calcium sensitizers produce an inotropic effect by stabilizing the calcium–troponin C complex and facilitate myocardial cross-bridging.5 During systole, when intracellular calcium is abundant, levosimendan is active.5 During diastole, calcium ions are less abundant and the drug is inactive. For this reason, levosimendan does not impair relaxation.6,7
REVIVE I was a 100-patient pilot study to test a new end point that focused more on global outcomes for use in clinical trials of patients with ADHF.8 Global outcomes were categorized as improved or worsening heart failure. Worsening heart failure was defined as the need for intravenous vasodilators, inotropes, or diuretics. More levosimendan patients improved and fewer experienced worsening heart failure than those administered placebo (overall P = .043). Subjects in the levosimendan treatment arm had a mean reduction of 1 day in the length of intensive care unit and hospital stay.9 REVIVE II was a randomized multicenter placebo controlled trial of 600 patients from 103 sites in the United States, Australia, and Israel. Patients were randomized to levosimendan, administered as a bolus (6-12 μg/kg) followed by a 0.1-0.2 μg/(kg · min) infusion for 24 hours or placebo. The primary end point was the clinical composite that evaluated the clinical course of patients during the first 5 days after randomization. The clinical composite had 3 categories: (1) improved, (2) unchanged, (3) worse, assessed at 6 hours, 24 hours, and 5 days. Patients were improved if they had moderately or markedly improved at 6 hours, 24 hours, and 5 days with no worsening. Patients were unchanged if they neither improved nor worsened. Patients were worse if their clinical status worsened during the first 5 days as judged by death from any cause, persistent or worsening heart failure requiring intravenous medications (diuretics, vasodilators, or inotropes), or moderately or markedly worse patient global assessment at 6 hours, 24 hours, or 5 days. Secondary end points included changes in brain-type natriuretic peptide (BNP) value at 24 hours, duration of initial hospitalization, and specific symptoms at specific time points.
Results: The likelihood of clinical improvement was 33% higher and the likelihood of clinical deterioration was nearly 30% lower in patients treated with levosimendan compared with placebo (P = .015). BNP levels were lower in the levosimendan group at days 1 and 5 relative to the placebo group. The proportion of patients with moderate or marked improvement in their symptoms (global assessment) at 24 hours and 5 days was greater in the levosimendan group compared with placebo. Dyspnea symptoms were similar between the 2 groups at 6 hours, but there was less dyspnea in the levosimendan group at 30 days. The duration of hospitalization was shorter in the levosimendan group. The analysis was not designed or powered to determine mortality outcomes; however, at 6 months there were 49 deaths in the levosimendan group compared with 40 in the placebo group. There were higher rates of atrial and ventricular arrhythmias in the levosimendan-treated patients.
Interpretation: REVIVE II is the first prospective, randomized, controlled trial to evaluate the effects of a drug on the clinical course of patients with ADHF over the duration of a typical hospitalization. In this trial, levosimendan improved the clinical composite score, BNP levels, global assessment, and duration of hospitalization for patients with ADHF. Although the clinical improvement in levosimendan-treated patients is important, the higher rates of atrial fibrillation and ventricular arrhythmias is of significant concern. In addition, there was a trend toward higher mortality in the levosimendan-treated patients at 6 months. Until the risk benefit ratio is further explored in larger clinical trials, levosimendan cannot be recommended as routine treatment for patients hospitalized for ADHF.
References
1. Roger VL, Wesin SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community based population. JAMA 2004;292:344-50.
2. Cuffe MS, Califf RM, Adams KF, et al. Short-term intravenous milrinone for acute exacerbation of chronic heart failure: a randomized controlled trial. JAMA 2002;287:1541-47.
3. Felker GM, O'Connor CM. Inotropic therapy for heart failure: an evidence-based approach. Am Heart J 2001;142:393-401.
4. Earl GL, Fitzpatrick JT. Levosimendan: a novel inotropic agent for treatment of acute decompensated heart failure. Ann Pharmacother 2005;39:1888-96.
5. Brixius K, Reicke S, Schwinger RHG. Beneficial effects of the Ca2+ sensitizer levosimendan in human myocardium. Am J Physiol Heart Circ Physiol 2002;282:H131-7.
6. Hasenfuss G, Pieske B, Castell M, et al. Influence of the novel inotropic agent levosimendan on isometric tension and calcium cycling in failing human myocardium. Circulation 1998;98:2141-7.
7. Janssen PM, Datz N, Zeitz O, et al. Levosimendan improves diastolic and systolic function in failing human myocardium. Eur J Pharmacol 2000;404:191-9.
8. Garratt C, Packer M, Colucci W, et al. Development of a comprehensive new end point for the evaluation of new treatments for acute decompensated heart failure: results with levosimendan in the REVIVE I study [abstract]. Presented at the 24th International Symposium on Intensive Care and Emergency Medicine, March 30 to Aprril 2, 2004, Brussels, Belgium. http://ccforum.com/content/8/S1/P89 [accessed 2005 April 4].
9. Johansson S, Apajasalo M, Sarapohja T, et al. Effect of levosimendan treatment on length of hospital and intensive care stay in the REVIVE I study (abstract). Presented at the 24th International Symposium on Intensive Care and Emergency Medicine, March 30 to April 2, 2004, Brussels, Belgium. http://ccforum.com/content/8/S1/P88 [accessed 2005 April 4].
Session
Late-breaking Clinical Trials IV
Study: The SURVIVE-W trial: comparison of dobutamine and levosimendan on survival in acute decompensated heart failure
Presenter: Dr Alexander Mebazaa, Hopital Lariboisiere, Paris, France
Background: Although acutely decompensated heart failure is a very common cause of hospitalization, accounting for nearly 3 million admissions each year in the US, most treatments commonly used have not been validated in large randomized clinical trials. Inotropic agents currently used for acute heart failure, including dobutamine, milrinone, and nesiritide, have been associated with an increased risk of mortality. Levosimendan is a new agent that induces calcium sensitization for positive inotropic effect and activates vascular smooth-muscle ATP-dependent potassium channels for vasodilatation. The resulting improvement of cardiac function and blood flow may provide a hemodynamic support in patients with acutely decompensated heart failure. The SURVIVE trial was designed to test the effect of levosimendan against dobutamine on death and major clinical events among patients hospitalized for acutely decompensated heart failure.
SURVIVE-W was a double-blind, active control, double dummy, randomized clinical trial. Patients were eligible for inclusion if they had acutely decompensated heart failure, left ventricular ejection fraction <30%, and a clinical need for intravenous inotropic support, as evidenced by an insufficient response to intravenous diuretics and/or vasodilators and at least one of the following: (1) oliguria (mean urine output <30 mL/h for at least 6 h) not due to hypovolemia, (2) persistent dyspnea at rest, (3) mechanical ventilation for heart failure, or (4) invasive hemodynamic demonstration of a pulmonary wedge pressure (18 mm Hg and/or cardiac index ≤2.2 L/(min · m2). A total of 1327 patients were randomized to receive either dobutamine [minimum dose 5 μg/(kg · min) for at least 2 h] or levosimendan [12-μg/kg bolus followed by 0.2 μg/(kg · min)]. The primary end point was all cause mortality within 180 days. The trial was conducted in 8 European countries plus Israel.
Results: The incidence of the primary end point was 26% in the levosimendan group and 28% in the dobutamine group (hazard ratio [HR] 0.91, 95% CI 0.74-1.13). No differences were observed in the incidence of the secondary end point, all-cause mortality within 31 days (12% vs 14% for levosimendan and dobutamine, respectively, HR 0.85, 95% CI 0.63-1.15). A post hoc analysis evaluating all-cause mortality within 5 days showed a trend in favor of levosimendan (4% vs 6%, HR 0.72, 95% CI 0.44-1.16). The trend was stronger among patients with a history of heart failure (HR 0.58, 95% CI 0.33-1.01). No differences were observed in the incidence of hypotension, ventricular tachycardia, and serum creatinine changes. Atrial fibrillation was more common in the levosimendan group while cardiac failure was more common in the dobutamine group. A more marked and persistent decrease in the levels of brain-type natriuretic peptide was observed in the levosimendan group compared with the dobutamine group.
Interpretation: The SURVIVE trial failed to demonstrate benefits of levosimendan compared with dobutamine. In fact, no differences were observed in the occurrence of both the primary and secondary end points. The decreased mortality at 5 days cannot be taken as definitive evidence, because it was based on a post hoc analysis. The possible clinical implications of the decrease in the level of brain-type natriuretic peptide are not clear. The results of the SURVIVE trial should be interpreted together with the results of the REVIVE-2 trial testing levosimendan against placebo in a similar population. The REVIVE-2 trial showed a 33% increase in the proportion of patients with improved symptoms and a 30% reduction in the proportion of patients with worsening heart failure compared with placebo, but at the expense of an increased 90-day mortality (15.1% vs 11.6%) and of a strong increase in adverse events, including hypotension, ventricular tachycardia, and atrial fibrillation. Taken together, the results of the study suggest that levosimendan does not increase mortality more than dobutamine does. Therefore, in patients for whom one of the currently available drugs is clinically indicated, the data of the SURVIVE trial support the use of levosimendan as a possible alternative. However, an optimal therapeutic option for the treatment of acutely decompensated heart failure is yet to come.
FULL TEXT