(Circulation. 2003;108:2723.)
© 2003 American Heart Association, Inc.
Late-Breaking Clinical Trial Abstracts
Heart Disease on the Mend: A Multifactor Risk Reduction Program in the Medically UnderservedWilliam Haskell, Kathy Berra, Annette Clark, Dianne Christopherson, Shauna Duff, Jan George, Linda Klieman, Jeff Myll, Stanford University School of Medicine
Background: Risk factors contributing to increased risk for cardiovascular disease (CVD) are well defined. Clinical trials have shown that multifactor risk reduction (MRR) reduces CVD morbidity and mortality. The challenge is to implement cost-effective MRR programs, especially for ethnic minority and low-income populations. Purpose: To test the effectiveness of an MRR program in the medically underserved. Methods: Persons at high risk for CVD were identified in settings where low-income patients obtain medical care in Santa Clara County, Calif. Medical history and clinical screening confirmed eligibility. Eligible participants were randomized (2:1—treatment [T] versus usual care [UC]) into the Heart Disease on the Mend (HDOM) yearlong MRR program. The MRR program used a physician-directed, nurse and dietitian case management approach that included lifestyle change and medical management. Results: Of the 149 persons randomized, 56% were female, with mean age of 57 years (s.d.=20.4). Ethnicity included 57% Hispanic, 10% Asian, 7% African American, 16% Caucasian, and 10% other. Patient fluency in English: none=45%, moderate=22%, and fluent=33%. Presence of type II diabetes (54%), dyslipidemia (67%), hypertension (70%), and obesity (38%) were the most common CVD risk factors at baseline. Data at 12 months were collected on 91% of patients. The MRR program produced significant reductions in major CVD risk factors during follow-up for T vs UC. Risk status was lower at follow-up (6-month plus 12-month values) for T vs UC (ANCOVA) for the following risk factors: TC (mg/dL)—UC=199, T=184 (P<0.01); LDL-C (mg/dL)—UC=116, T=104 (P<0.01); TC/HDL-C—UC=4.8, T=4.2 (P<0.001); Tg (mg/dL)—UC=193, T=174 (P=0.06); fasting glucose (mg/dL)—UC=142, T=129 (P<0.01); SBP (mm Hg)—UC=137, T=128 (P<0.001); DBP (mm Hg)—UC=81, T 77 (P<0.001); physical activity risk score—UC=11.6, T=7.9 (P=0.02); and nutrition risk score—UC=14.7, T=13.0 (P=0.02). Conclusion: HDOM achieved excellent retention and participation over 12 months and reduced most CVD risk factors in this low-income, mostly minority population. Such programs can help address the enormous societal need to provide access to known beneficial therapies to improve the health and well being of high-risk, underserved populations.
A Randomized Evaluation of Early Administration of Reteplase Plus Abciximab or Abciximab Alone Prior to Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction
Adnan Kastrati, MD; Julinda Mehilli, MD; Klaus Schlotterbeck, MD; Franz Dotzer, MD; Josef Dirschinger, MD; Stephan Nekolla, PhD; Melchior Seyfarth, MD; Stefan Martinof, MD; Günther Clermont, MD; Christina Markwardt, MD; Christiane Kalina, MD; Claus Schmitt, MD; Markus Schwaiger, MD; Albert Schömig, MD; for BRAVE Investigators
It is not known which is the best antithrombotic strategy to apply in patients with acute myocardial infarction (AMI) during the interval between establishment of diagnosis and primary coronary intervention (PCI). The objective of the Bavarian Reperfusion Alternatives Evaluation (BRAVE) trial was to assess whether reteplase plus abciximab ("combo therapy") is more effective than abciximab alone when given as a pretreatment (pre–cath lab) to patients with AMI intended to undergo PCI ("facilitated PCI"). Methods: This is a randomized, open-label study. Eligible for this study were patients presenting at the admitting hospital within 12 hours from the onset of symptoms of an ST-elevation AMI and having no contraindications to thrombolysis and glycoprotein IIb/IIIa inhibition. Patients were randomized by phone to receive either half-dose of reteplase (2 boluses of 5 U) plus abciximab (bolus followed by a 12-hour infusion), group R+A, or abciximab alone, group A, before transferal to cath lab. A single photon emission computed tomography with 99m technetium sestamibi was performed 5 to 10 days after randomization. Scintigraphy was assessed by operators blinded to the assigned treatment. Final infarct size (% of the left ventricle) was the primary end point of the trial, and the study was designed to have 80% power for detecting a 30% reduction of infarct size with R+A. Results: The study included 253 patients, 125 assigned to R+A and 128 to A: 74% of the patients were randomized in hospitals without interventional facilities and transported to PCI centers situated at an average distance of 39 km where 92% of the patients underwent coronary stenting. The infarct size (median [25th, 75th percentiles]) was 13.0% [3.0%, 28.0%] in group R+A and 11.5% [3%, 26.3%] in group A (P=0.81). Two patients in each group died within 30 days from randomization. The combined 30-day incidence of death, recurrent myocardial infarction, and stroke was 3.2% in group R+A and 1.6% in group A (P=0.66). Major bleeding was observed in 5.6% in group R+A and 1.6% in group A (P=0.16). Separate analyses for patients randomized in hospitals without interventional facilities, for those randomized within 2 hours from symptom start and those with a >90-minute delay from randomization to intervention did not show any superiority of the "combo therapy" over abciximab alone. Conclusions: Pretreatment with reteplase plus abciximab is not superior to abciximab alone in patients with AMI who will undergo a PCI.
Antiarrhythmic Effects of n-3 Polyunsaturated Fatty Acids in Survivors of Ventricular Tachyarrhythmias
Merritt Raitt, William Connor, Cynthia Morris, Jack Kron, Blair Halperin, Sumeet Chugh, James McClelland, James Cook, Karen MacMurdy, Robert Swenson, Sonja Connor, Glenn Gerhard, Daniel Oseran, Christy Marchant, David Calhoun, Reed Snyder, John McAnulty, Oregon Health & Science University, Portland, Oregon
Clinical studies of n-3 polyunsaturated fatty acids (n-3 PUFA) have noted a reduction in sudden cardiac death but no effect on myocardial infarction. This information and data from cellular and animal studies suggest that n-3 PUFA may have antiarrhythmic properties. Methods: We report the results of a multicenter, double-blinded, randomized, placebo-controlled trial of n-3 PUFA in 200 patients with an implanted defibrillator (ICD) and a recent episode of ventricular tachycardia (VT) or fibrillation (VF). No patients were taking an antiarrhythmic drug. Patients were randomized to receive fish oil (1.8 gram of n-3 PUFA, 42% EPA and 30% DHA in capsules) or placebo (olive oil capsules) daily, and were seen every 3 months for up to 2 years. All ICD therapy events were downloaded from the ICD for classification. Red blood cell membrane n-3 PUFA levels were measured to assess compliance and to correlate with efficacy. A subset of 49 patients had electrophysiologic studies to measure the ventricular effective refractory period, inducibility of VT or VF, and defibrillation threshold at baseline and after 3 months of therapy. Results: Patients treated with fish oil had an increase in their mean red cell membrane n-3 PUFA level from 4.7% of red cell fatty acid at baseline to 8.3% at 3 months (P<0.001). There was no significant change in placebo patients (4.5% to 4.6%). n-3 PUFA levels remained stable from 3 months through 24 months in both groups. There was a trend toward a higher incidence of VT/VF in patients randomized to fish oil. At 6 months, 1 year, and 2 years, 36%, 41%, and 60% of placebo patients had VT/VF compared to 47%, 51%, and 66% of patients randomized to fish oil (P=0.19). Among patients entered after an episode of VT, there was a significant increase in VT/VF in patients randomized to fish oil (P=0.007). There was a trend toward patients with the highest levels of n-3 PUFA having the highest incidence of VT/VF. An actuarial analysis of time to recurrent events showed that patients randomized to fish oil had significantly more events than patients randomized to placebo (P<0.01). There was no difference in the measured electrophysiologic parameters attributable to fish oil. Conclusion: n-3 PUFA do not have antiarrhythmic effects in survivors of ventricular tachyarrhythmias.
Secondary Prevention Beyond Hospital Walls IntervenTion Trial In (WITTI) Women
Background: Secondary prevention of coronary heart disease (CHD) extends survival and reduces recurrent CHD events and the need for revascularization, yet many patients do not reach optimal prevention goals. "Systems" approaches to improve adherence to comprehensive secondary prevention guidelines have not been rigorously tested. Methods: We conducted a randomized, controlled clinical trial among 304 women (mean age 62.3±12.4 years, 52% minorities) hospitalized with CHD to test the effect of a systematic intervention (SI) vs usual care to increase adherence to AHA secondary prevention goals. The SI group received counseling by a prevention facilitator/health educator about lifestyle, risk factor management, and preventive medications during hospitalization and were contacted on a regular basis for up to 6 months after discharge. The prevention facilitator also assisted with enrollment in cardiac rehabilitation. Progress reports regarding status of reaching prevention goals were sent to the women’s physician(s) at baseline and 6 weeks’ follow-up. Attainment of prevention goals (smoking cessation, weight management, physical activity, blood pressure <140/90 mm Hg, low-density lipoprotein [LDL] cholesterol <100 mg/dL [2.59 mmol/L], use of aspirin/anticoagulants, ß-blockers, and angiotensin-converting enzyme [ACE] inhibitors) was assessed systematically in the SI and usual-care groups. The primary outcome was the difference in a summary score of prevention goals met at 6 months between the SI and usual-care groups. A subgroup analysis was conducted by ethnic group status. Results: At baseline, only 13% of women were at the weight goal, 20% at the exercise goal, and 41% had an optimal LDL cholesterol, in contrast to >2/3 meeting other goals. Minority women were less likely than whites to meet the goals for blood pressure (OR=0.46, 95% CI=0.26–0.80), LDL cholesterol (OR=0.57, CI=0.33–0.94), and weight (OR=0.40, 95% CI=0.20–0.82) prior to the intervention. At 6 months, there was no significant difference in the summary score for goals met or in the proportion of individual goals achieved between the intervention and usual-care groups. Attainment of LDL goal remained <60% in both groups at 6 months. Minority women in the intervention group were 2.4x more likely (95% CI 1.13–5.03) to reach the blood pressure goal at 6 months compared to minority women in usual care. In a logistic regression model, the interaction term for ethnic status and group assignment was significant for achieving the blood pressure goal (P=0.009). Conclusion:A systematic intervention to improve CHD preventive care was insufficient to increase rates of adherence to secondary prevention guidelines over usual care in women overall; however, there was a benefit for blood pressure control among minority women. These data highlight the need for better methods to improve lifestyle and lipid control among women with heart disease, especially among minority women.
Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both
Marc A. Pfeffer, MD, PhD; John J.V. McMurray, MD; Eric J. Velazquez, MD; Jean-Lucien Rouleau, MD; Lars Køber, MD; Aldo P. Maggioni, MD; Scott D. Solomon, MD; Karl Swedberg, MD, PhD; Frans Van de Werf, MD, PhD; Harvey White, DSc; Jeffrey D. Leimberger, PhD; Marc Henis, MD; Susan Edwards, MS; Steven Zelenkofske, DO; Mary Ann Sellers, MSN; Robert M. Califf, MD; for the Valsartan in Acute Myocardial Infarction Trial Investigators*
Background: Survivors of acute myocardial infarction complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme (ACE) inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers (ARB) offers a new, more specific, and theoretically more complete pharmacological mode to inhibit the adverse influence of angiotensin II. The objective of the trial is to determine whether the use of the ARB valsartan alone or in addition to captopril offers a clinical advantage compared to a proven ACE inhibitor. Methods:Patients with acute myocardial infarction (0.5 to 10 days), which was complicated by either left ventricular dysfunction or acute heart failure or both, were randomized to valsartan (4909 patients), valsartan plus captopril (4885 patients), or captopril (4909 patients). The primary end point was death from any cause. Results:During a median follow-up of 24.7 months, 979 patients in the valsartan group died, as did 941 patients in the valsartan-and-captopril group and 958 patients in the captopril group (hazard ratio in the valsartan group as compared with the captopril group, 1.00; 97.5% confidence interval, 0.90 to 1.11; P=0.98; hazard ratio in the valsartan-and-captopril group as compared with the captopril group, 0.98; 97.5% confidence interval, 0.89 to 1.09; P=0.73). The upper limit of the one-sided 97.5% confidence interval for the comparison of the valsartan group with the captopril group was within the prespecified margin for noninferiority with regard to mortality (P=0.004) and with regard to the composite end point of fatal and nonfatal cardiovascular events (P<0.001). The valsartan-and-captopril group had the most drug-related adverse events. With monotherapy, hypotension and renal dysfunction were more common in the valsartan group, and cough, rash, and taste disturbance were more common in the captopril group. Conclusions: Valsartan is as effective as captopril in reducing risk of death as well as subsequent heart failure and myocardial infarction in patients who are at high risk for cardiovascular events after myocardial infarction. Combining valsartan with captopril increased the rate of adverse events without improving survival. In these patients, valsartan should be considered as a clinically effective alternative to an ACE inhibitor.
Acute and Chronic Therapeutic Impact of a Vasopressin 2 Antagonist in Congestive Heart Failure (ACTIV in CHF): A Placebo-Controlled Trial in Patients Hospitalized With Heart Failure
Mihai Gheorghiade, Christopher M. O’Connor, Kirkwood F. Adams, Jr, Wendy A. Gattis, Alejandro Barbagelata, Uri Elkayam, Frank McGrew, Jalal K. Ghali, Raymond L. Benza, Marc Klapholz, Cesare Orlandi, for the ACTIV Trial Investigators
Background: In the US, there are 1 million admissions/year for heart failure (HF) with a 20% to 30% readmission rate within 60 days. Often, these patients are volume overloaded. Diuretics (D) are the mainstay of therapy; however, they cause electrolyte abnormalities. Tolvaptan (TLV) is an oral, daily vasopressin V2 receptor blocker that is known to decrease body weight (BW) in HF patients without adversely affecting electrolytes or renal function. Methods: Three hundred twenty patients hospitalized in US and Argentina with HF were randomized within 72 hours of admission to once-daily placebo (PLC) or TLV 30 mg, 60 mg, or 90 mg that was continued for 60 days, in addition to standard therapy that included D (97%), ACE inhibitors (80%), digoxin (70%), and ß-blockers (40%). The primary end points were changes in BW at 24 hours and worsening HF (death, hospitalization, or unscheduled visit for HF) within 60 days after randomization. Results: Greater BW reductions at 24 hours were observed in all TLV patients compared to PLC (2.0 vs 0.9 kg) (P=0.0003). There were no differences in worsening HF at 60 days between the two groups. All-cause mortality was 5.4% and 8.7% in the in TLV and PLC groups, respectively (P=0.18). In patients with hyponatremia (<136 mEq/L), BUN >29 mg/dL, and severe congestion, the mortality was 13.2% vs 18.7%, 9.1% vs 20%, and 5.5% vs 17.8%, in the TLV and PLC groups, respectively. Conclusion: TLV in addition to standard therapy decreases BW at 24 hours, with no changes in worsening HF at 60 days. The effects of TLV on mortality in patients hospitalized with HF are being tested in an ongoing international trial (Effects of Vasopressin antagonists in hEart failuRE: outcome Study with Tolvaptan; EVEREST).1 
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Randomized Controlled Clinical Trial of Intracoronary Autologous Bone Marrow Cell Transfer Post Myocardial Infarction
Kai C. Wollert, Gerd P. Meyer, Joachim Lotz, Stefanie Ringes-Lichtenberg, Christiane Breidenbach, Peter Lippolt, Lubomir Arseniev, Thomas Korte, Burkhard Hornig, Michael Galanski, Bernd Hertenstein, Arnold Ganser, Helmut Drexler, Departments of Cardiology and Angiology (K.C.W., G.P.M., S.R.-L., C.B., P.L., T.K., B.H., H.D.), Radiology (J.L., M.G.), and Hematology and Oncology (L.A., B.H., A.G.), Hannover Medical School, Hannover, Germany
Experimental data and small, open, uncontrolled clinical feasibility studies have suggested that transplantation of autologous bone marrow cells (BMC) to the ischemic area may enhance LV function after myocardial infarction (MI). However, data from prospectively designed, controlled clinical trials are lacking. We performed a randomized, controlled trial in patients after acute ST-elevation MI and successful primary or rescue percutaneous coronary intervention (PCI). The change in left ventricular ejection fraction (LVEF), as determined by magnetic resonance imaging (MRI; assessed by two investigators blinded for treatment assignment), 5 to 6 months after MI as compared to baseline was defined as the primary end point. Patients with hypokinesia or akinesia of 
2/3 of the LV anterior, septal, lateral, or inferior wall (as determined by angiography immediately after PCI) were eligible for the trial. After providing informed consent, patients were randomized to the control (CON, n=30) and BMC (n=30) groups and underwent MRI to determine baseline LVEF. In the BMC group, 128±33 mL of bone marrow was then obtained. Nucleated BMC were enriched by 4% gelatin-polysuccinate sedimentation and were transplanted (4 to 8 days post MI) into the infarct-related coronary artery through the central lumen of an over-the-wire balloon catheter (25±9 x108 nucleated BMC, 9.5±6.3 x106 CD34pos cells). After 5 to 6 months, MRI was repeated in all patients. There were no significant differences between the CON and BMC groups with regard to age, infarct localization, time to PCI (median 8.0 vs 9.8 h), maximum creatine kinase levels, and baseline LVEF (51.3±9.3 vs 50.0±10.0%). After 5 to 6 months, LVEF in the CON and BMC groups had improved by 0.7±8.1% and 6.7±6.5%, respectively (P<0.01, all data are shown as mean±SD). There was no evidence for proarrhythmic effects in the BMC group, as determined by repeated Holter monitoring and an electrophysiological study 5 to 6 months after BMC transplantation. The results from this randomized, controlled trial indicate that intracoronary transplantation of autologous BMC is safe and enhances LV function in patients post MI and successful PCI.
The PRIMO-CABG Study: Pexelizumab for the Reduction of Infarction and MOrtality in Coronary Artery Bypass Graft surgery
Edward D. Verrier, Div. Cardiothoracic Surgery University of Washington, Seattle, Wash on Behalf of the PRIMO-CABG Steering Committee and the PRIMO-CABG Investigators
Background: PRIMO-CABG was a Phase III, randomized, double-blind, placebo-controlled study of pexelizumab on all-cause mortality or myocardial infarction (MI) in patients undergoing coronary artery bypass graft (CABG) surgery with cardiopulmonary bypass. Methods: Approximately 3100 patients were enrolled at 205 centers in N America and W Europe. Patients underwent CABG with or without concomitant valve surgery. The primary end point was a composite of the incidence of death or MI (death/MI) through day 30 in the CABG-only population (n=2746). Secondary analyses included death/MI in the CABG-only population at day 4, death/MI in the overall study population (n=3099) at day 4 and day 30, and death at day 90. Six different analyses of myocardial infarction were also prespecified as a sensitivity analysis. Results: The number of patients experiencing adverse events (AE) was similar in both treatment groups (85.2% placebo, 85.5% pexelizumab). The most frequent AEs in both groups were atrial fibrillation, nausea, pleural effusion, postprocedural pain, anemia, hypotension, and postoperative wound infection. There was a nonsignificant reduction in the primary end point of death/MI in CABG-only patients at day 30 (P=0.069). For the overall study population, there was significant reduction of death/MI at Day 30 (P=0.030). The death/MI composite was significantly reduced in the CABG-only (P=0.014) and overall study populations (P=0.008) at day 4. There was a trend toward a reduction in death with pexelizumab in the overall population (P=0.096) at 90 days. Pexelizumab significantly reduced myocardial infarction and myocardial injury in both the CABG-only and overall population. Conclusions:Pexelizumab significantly reduced early and late postoperative myocardial infarction in all populations. In the overall study population, pexelizumab significantly reduced death or MI, showing a durable effect through day 90. Pexelizumab was safe and well tolerated.
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A Randomized Controlled Trial Comparing Safety and Efficacy of Rectilinear Biphasic Versus Monophasic Defibrillators in Out-of-Hospital Cardiac Arrest: ORBIT
Laurie J. Morrison, MD, FRCPC; Paul Dorian, MD, FRCPC; Jennifer Long, MSc; Marian J. Vermeulen, MHSc; Brian Schwartz, MD, CCFP-EM; Bruce Sawadsky, MD, CCFP-EM; Jamie Frank, BA, EMT-P; Bruce Cameron, EMT-P; Robert Burgess, EMT-P; Jennifer Shield, BA EMT-P; Paul Bagley, EMT-P; Vivien Mausz, EMT-P; James Brewer, Bruce Lerman, MD; on behalf of the ORBIT Investigators; Prehospital and Transport Medicine Research Program, Sunnybrook and Women’s, University of Toronto, Toronto, Ontario, Canada
A recent meta-analysis suggests first shock efficacy for ventricular fibrillation conversion is equal when lower biphasic energy levels are compared with 200J monophasic. The objective of this study was to compare the safety and efficacy of ascending rectilinear biphasic defibrillation (120J, 150J, 200J) with conventional monophasic defibrillation (200J, 300J, 360J) in the termination of ventricular fibrillation (VF) and pulseless ventricular tachycardia (VT) in patients with out-of-hospital cardiac arrest (OHCA) treated by EMT-P paramedics. This was a randomized, controlled trial employing block randomization of device assignment to ambulance station. A blinded Outcome Validation Committee adjudicated all end points. There were 4532 OHCA and 540 with presumed VT or VF. The station randomization compliance was 95%. The data entry error rate was <1%. The loss to follow-up rate for monophasic vs biphasic (n=217 vs 219) was 2% vs 3%. The patients in the 2 groups respectively (blinded analysis) were similar for age (mean [SD]) (67.1 [15.8] vs 67.0 [14.6]), sex (157 vs 155 male [72% : 71%]), VF as initial rhythm (190 vs 190 [88% : 87%]), EMS response interval (7.7 [4.1] vs 7.7 [3.7]), down time (10.6 [4.4] vs 10.9 [4.9]), bystander witnessed (144 vs 146 [67% : 67%]), EMS witnessed (19 vs 20 [9% : 9%]), bystander CPR (69 vs 81 [33% : 38%]), amiodarone (96 vs 86 [44% : 39%]), and different for prior defibrillation (49 vs 34 [23% : 16%]), P=0.05. Conversion to organized electrical activity after one shock was 55 vs 67 (26% : 32%), P=0.2, and after 1 to 3 shocks was 98 vs 119 (45% : 54%), P=0.06. Conversion for first highest energy setting shock was 30 vs 49 (14% : 23%), P=0.02. The rate of return of spontaneous circulation was the same in both groups: 88 vs 90 (41% : 41%). Survival outcomes were alive to emergency department (123 vs 125 [57% : 57%]), at 24 hours (46 vs 50 [22% : 23%]), and at 30 days (14 vs 15 [7% : 7%]). Cerebral Performance Category scores were "Good" (11 vs 16 [9% : 13%]) and "Moderate to Coma" (7 vs 3 [6% : 2%]), P=0.29, with no adverse events. Conclusion: The biphasic waveform was superior for highest energy setting conversion and not superior for conversion to an organized rhythm after first shock or 1 to 3 shocks in a study with 0.86 power to find a 15% significant difference if one existed. This study is not generalizable to all biphasic defibrillators and defibrillation protocols, as it uses the rectilinear waveform in an ascending protocol.
Stroke Prevention Using the Oral Direct Thrombin Inhibitor Ximelagatran in Patients with Nonvalvular Atrial Fibrillation (SPORTIF V)
The Executive Steering Committee on behalf of the SPORTIF V Investigators
Background: Anticoagulation with warfarin prevents ischemic stroke in patients with nonvalvular atrial fibrillation (AF), but routine coagulation monitoring, dose adjustments, and bleeding risk limit use. The oral direct thrombin inhibitor ximelagatran represents a potential alternative anticoagulant. Objective: To establish whether oral ximelagatran is noninferior to dose-adjusted warfarin, within a margin of 2%/year, for prevention of stroke and systemic embolic events. Methods: Patients with AF and at least 1 stroke risk factor (n=3922) were randomized to receive adjusted-dose warfarin (target INR 2.0 to 3.0) or fixed-dose oral ximelagatran (36 mg twice daily). Treatment allocation was double blind; patients in the ximelagatran group underwent sham testing and dose variations of dummy warfarin to mimic INR management. The protocol was otherwise identical to the open-label SPORTIF III trial. The primary end point was all strokes (ischemic and hemorrhagic) and systemic embolic events, based on independent, blinded, centrally adjudicated assessment. Primary analysis was based on establishing noninferiority according to intention-to-treat (ITT). Results: During 6405 patient-years exposure (mean 20 months), 88 patients developed primary events. The INR on warfarin (mean 2.4±0.8) was within target range (2.0 to 3.0) 68% of the time and in the extended range (1.8 to 3.2) 83% of the time. Primary event rates were 1.2%/year in the warfarin group and 1.6%/year in the ximelagatran group, an absolute difference of 0.45%/year (95% CI -0.13, 1.03; P=0.13), demonstrating the noninferiority of ximelagatran. By on-treatment analysis, the absolute difference in primary event rates was 0.55%/year (-0.06, 1.16; P=0.089), and when all-cause mortality was included with the primary events, the rate difference between groups by ITT was 0.10%/year (95% CI -0.97, 1.18; P=0.86). Rates of disabling or fatal stroke, hemorrhagic stroke, and major bleeding did not differ significantly between groups, but combined minor and major bleeding were lower with ximelagatran (47%/year vs 37%/year; P<0.0001). Serum alanine aminotransferase levels rose transiently above 3 times the upper limit of normal in 6.0% of patients on ximelagatran (0.8% of patients on warfarin; P<0.001) within the first 6 months of treatment but generally returned toward baseline levels whether or not treatment was continued. An 80-year-old patient developed fatal gastrointestinal hemorrhage after corticosteroid treatment for hepatitis associated with ximelagatran treatment. Conclusions: In this large, double-blind trial involving high-risk patients with AF, fixed-dose, oral ximelagatran was at least as effective as well-controlled warfarin for prevention of stroke and systemic embolic events and resulted in less bleeding, confirming the results of the SPORTIF III open-label trial.
The Public Access Defibrillation (PAD) Trial
The Public Access Defibrillation Trial Investigators Presenter: Joseph P. Ornato, MD
Introduction: Over 460 000 Americans die each year from out-of-hospital cardiac arrest (OOH-CA). The purpose of the Public Access Defibrillation (PAD) Trial was to determine whether laypersons trained and equipped to call 9–1–1, perform cardiopulmonary resuscitation (CPR), and use automated external defibrillators (AEDs) in public and residential locations, compared with laypersons trained only to call 9–1–1 and perform CPR, could increase survival for patients experiencing OOH-CA. Methods:This prospective, community-based, multicenter clinical trial randomized 993 community units at 21 US and 3 Canadian sites to receive volunteer training in CPR (CPR only) or CPR with defibrillation capability (CPR+AED). All volunteer rescuers were laypersons. A 2- to 4-hour course, mostly American Heart Association HeartSaver ABC and Heart-Saver AED training, was provided for CPR-only and CPR+AED arms, respectively. Eligible study units had to have an estimated 50% risk of experiencing one OOH-CA per year. The primary patient population was defined as individuals (age 8 years) with confirmed, treatable OOH-CA of cardiac etiology. The primary end point was the number of these patients surviving through hospital discharge. A subgroup comparison of residential versus public facilities was prespecified. The primary comparison, per the protocol, utilized a stratified 2-sample t test, with site and public/residential as strata. However, since exposure time varied substantially (std. dev.= 5 mo), a secondary analysis and analyses of other outcomes used a Poisson generalized linear model treating facility exposure-months as an offset. Results: A total of 19 762 volunteer rescuers (17.5/CPR-only unit vs 23.0/CPR+AED unit, P=0.001) consented to participate in the trial prior to January 1, 2003. Study units consisted of the following types of locations: shopping (24%); recreation (24%); residential (15%); entertainment complexes (9%); community centers (7%); office complexes (7%); and hotels, factories, transit centers and other facilities (14%). There was a difference between CPR-only and CPR+AED groups with respect to number of OOH-CA (103, .118/unit/yr vs 129, .138/unit/yr), and the difference occurred in the public (69 vs 96) rather than residential (34 vs 33) units (this difference is likely due to differential ascertainment and was an expected result that prompted our a priori decision to use the number of successful resuscitations rather than rates). Characteristics of the events were not different: patient age (72+15 vs 69+15 yrs); % male (65% vs 70%); indoor location (82% vs 76%); nonsedentary activity at time of arrest (66% vs 66%); witnessed (68% vs 76%); initial rhythm ventricular fibrillation (47% vs 39%). Adverse events did not differ between treatment arms (0.2% vs 0.3%). No inappropriate shocks were delivered by lay rescuers. Successful resuscitation in residential units with either CPR-only or CPR+AED was rare (1 vs 1). There were fewer survivors in the CPR-only vs CPR+AED group (15 vs 29, P=0.042 adjusted for sequential monitoring; P=0.039 adjusted for exposure-months and sequential monitoring). Conclusion: The number of survivors from OOH-CA in public locations approximately doubles when laypersons trained in CPR are also trained in and provided access to early defibrillation using an AED. The survival rate in residential units was very low (less than 3%) whether or not an AED was available. Finally, the PAD Trial supports the notion that a large number of trained laypersons can use AEDs to provide early defibrillation safely. Limitation: As of the time of this writing, 1 potential survivor in the CPR+AED arm was still in hospital, in good health, while undergoing a catheterization and possible percutaneous procedures.
Prophylactic Implantation of a Defibrillator in Patients With Nonischemic Dilated Cardiomyopathy
Alan Kadish, Alan Dyer, James Daubert, N.A. Mark Estes, Rebecca Quigg, Kelly P. Anderson, Hugh Calkins, David Hoch, Jeffrey Goldberger, Alaa Shalaby, William E. Sanders, Andi Schaechter, Joseph H. Levine, for the DEFINITE Investigators
Introduction: Patients with congestive heart failure are at substantial risk for sudden cardiac death. However, the utility of the implantable cardioverter defibrillator (ICD) in the primary prevention of sudden death in patients with nonischemic dilated cardiomyopathy is unknown. Methods and Results: A total of 458 patients with nonischemic dilated cardiomyopathy, left ventricular ejection fraction <0.36, and spontaneous premature ventricular complexes or nonsustained ventricular tachycardia were enrolled in a multicenter randomized study. Patients were randomized to standard medical therapy, including angiotensin-converting enzyme (ACE) inhibitors and ß-adrenergic receptor blockers or standard medical therapy plus implantation of a single-chamber ICD. The primary end point of the study was all-cause mortality; a secondary end point was sudden cardiac death. Patients were followed up for a mean of 26±4 months. The mean ejection fraction was 0.21. The vast majority of patients were treated with ACE inhibitors (86%) and ß-blockers (85%). There were 56 deaths: 33 in the standard therapy group and 23 in the ICD group. The hazard ratio was 0.66 (95% confidence interval 0.39–1.12; P=0.06). Mortality at 2 years was 13.8% in the standard therapy group and 8.1% in the ICD group. There were 14 arrhythmic deaths from cardiac arrest: 11 in the standard therapy group and 3 in the ICD group (hazard ratio 0.26, 95% confidence interval 0.072–0.93; P<0.05). The subset of patients with NYHA Class III heart failure had a significant decrease in all-cause mortality (relative risk 0.34; 95% confidence interval 0.13–0.86). Conclusion: Patients with severe left ventricular dysfunction due to nonischemic cardiomyopathy who are treated with ACE inhibitors and ß-blockers have an annual total mortality of 6% to 7%. Placement of an ICD reduces arrhythmic mortality and tends to reduce all-cause mortality. ICD implantation may be useful for selected patients with nonischemic cardiomyopathy.
Effects of Na+/H+ Exchange Inhibition by Cariporide on Death and Nonfatal Myocardial Infarction in Patients Undergoing Coronary Artery Bypass Graft Surgery: The Expedition Study
Robert M. Mentzer, Jr. Univ. of Kentucky, Lexington, Ky, on behalf of the Expedition Study Investigators
Increasing evidence indicates that myocardial infarction (MI) after coronary artery bypass graft (CABG) surgery is more frequent than previously appreciated and is associated with impaired medium- and long-term survival. The EXPEDITION Study addressed the efficacy and safety of Na+/H+ exchange inhibition (NHE-I) by cariporide (CAR) in the prevention of death or MI in patients undergoing CABG surgery. The premise was that NHE-I during CABG surgery–induced myocardial ischemia limits intracellular calcium overload and reduces infarct size. Design: CABG patients (n=5770) with risk factors for perioperative myocardial ischemia were randomized to either intravenous CAR (180 mg/1 h preop loading dose, then 40 mg/h over 24 h and 20 mg/h over the subsequent 24 h) or matching placebo (PLC). The primary composite end point of death or MI was assessed at day 5 and up to 6 months. Results: Death/MI at day 5 was reduced from 20.3% in PLC to 16.6% in CAR (relative risk reduction [RRR] 18.28%; P=0.0002). This reduction was maintained until month 6 (23.9% PLC vs 20.2% CAR; RRR 15.72%; P=0.0005). However, effects in the two end-point components were heterogeneous. Mortality at day 5 increased from 1.5% in PLC to 2.2% in CAR (RRR -53.50%; P=0.028). At month 6, the difference was less pronounced (5.4% PLC vs 6.4% CAR: RRR -18.17%; P=0.11). In contrast, MI declined from 18.9% in PLC to 14.4% in CAR (RRR 23.81%; P=0.000005) at day 5. The difference was maintained at month 6 (18.5% PLC vs 13.8% CAR; RRR 25.58%; P=0.000001). There was, however, an increase in the overall rate of cerebrovascular events from 2.7% in PLC to 4.8% in CAR (P<0.001). Conclusion: This largest drug-intervention study in CABG surgery to date demonstrates, for the first time, the feasibility of pharmacological cardioprotection. Overall assessment of benefits and risks associated with CAR indicates that the imbalances in the safety profile outweigh the reduction in MI observed. Further research is needed to determine whether it is possible to dissociate the adverse from the beneficial effects of NHE-I in order to arrive at a final appraisal regarding the clinical role of this class of drugs to prevent myocardial injury after heart surgery.
Prophylactic Amiodarone for the Prevention of Arrhythmias That Begin Early After Revascularization, Valvular Repair, or Replacement (PAPABEAR): Preliminary Results
L. Brent Mitchell, Derek V. Exner, D. George Wyse, Carol J. Connolly, Gregory D. Prystai, Alexander J. Bayes, William T. Kidd, Teresa M. Kieser, John J. Burgess, André Ferland, Charles L. MacAdams, Andrew Maitland, Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada
Background: Atrial fibrillation (AF) is the most common complication after cardiac surgery and may produce patient discomfort/anxiety, hemodynamic deterioration, stroke and other thromboembolic events, exposure to the risks of antiarrhythmic treatments, prolongation of hospital stay, and increased costs. Previous trials of AF prophylaxis with amiodarone, while promising, have lacked power for the assessment of efficacy in important subgroups and for the evaluation of adverse effects. Purpose: The PAPABEAR trial tests the hypothesis that amiodarone is an effective, well-tolerated, and safe therapy for the prevention of AF after cardiac surgery. Methods: PAPABEAR randomized 601 patients about to undergo cardiac surgery to receive amiodarone or its matching placebo (10 mg/kg per day) for 6 preoperative days, the day of surgery, and 6 postoperative days. The primary outcome variable was >5 minutes of AF that prompted therapy within this postoperative time frame. Secondary outcome variables included AF characteristics, adverse effects, and length of hospitalization. Randomization was stratified to allow separate analysis of each subgroup reported below. Results: Randomized groups were equivalent with respect to demographic/clinical characteristics and surgical variables. Primary-outcome AF occurred less frequently in amiodarone-treated patients than in placebo-treated patients (16.1% vs 29.6%, P<0.001) (HR=0.48, 95% CI 0.34–0.69). Similar benefit was seen in each of the stratified patient subgroups: <65 years of age (11.2% vs 21.2%, P=0.02) (HR=0.51, 95% CI 0.29–0.89), 65 years of age (21.7% vs 41.2%, P=0.001) (HR=0.45, 95% CI 0.28–0.71), having CABG surgery alone (10.9% vs 23.3%, P=0.002) (HR=0.44, 95% CI 0.26–0.74), having valve surgery ± CABG (24.5% vs 41.7%, P=0.006) (HR=0.51, 95% CI 0.31–0.82), with preoperative ß-blocker drug therapy (15.3% vs 25.1%, P=0.03) (HR=0.58, 95% CI 0.36–0.95), and without preoperative ß-blocker drug therapy (16.3% vs 35.8%, P=0.001) (HR=0.40, 95% CI 0.23–0.67). When AF did occur, the ventricular response rate was slower in amiodarone-treated patients than in placebo-treated patients (105±24 vs 131±25 bpm, P<0.001). Potential adverse effects resulting in withdrawal of full-dose treatment were more common in amiodarone-treated patients than in placebo-treated patients (11.4% vs 5.3%, P=0.02). However, there were no significant differences between amiodarone-treated patients and placebo-treated patients in postoperative complications (9.4% vs 11.3%, P=NS) or in-hospital mortality (2.3% vs 3.3%, P=NS). There was a trend for a shorter postsurgical hospital stay in amiodarone-treated patients than in placebo-treated patients (8.2±7.4 vs 8.9±8.1 days, P=0.11). Conclusions: Oral amiodarone prophylaxis of AF after cardiac surgery is effective, well tolerated, and safe. Efficacy for prevention of AF is demonstrated in younger and in older patients, undergoing CABG or valvular surgery, with or without concomitant ß-blocking drug therapy.
Comparison of Intensive Versus Moderate Lipid Lowering on the Progression of Coronary Atherosclerosis Measured by Intravascular Ultrasound: A Randomized Controlled Trial
Steven E. Nissen, MD, for the REVERSAL Investigators
Background: HMG CoA–reductase inhibitors (statins) reduce both atherogenic lipoproteins and cardiovascular morbidity and mortality. However, the optimal strategy and target level for lipid reduction remains uncertain. Therefore, we compared the effects of intensive vs moderate lipid lowering on changes in atheroma burden measured by intravascular ultrasound (IVUS). Study Design: The study was a double-blind, randomized, active control, multicenter trial comparing the effect of two different statins administered for 18 months on atherosclerotic burden measured by IVUS at 34 community and tertiary care centers in the United States. Methods: Between June 1999 and September 2001, 2163 patients, aged 35 to 78 years, consented; 654 were randomized; and 502 completed the protocol. Patients were randomized to moderate lipid lowering using 40 mg pravastatin or intensive treatment with 80 mg atorvastatin for 18 months. IVUS was performed during baseline catheterization and repeated at study completion. The primary efficacy parameter was the percent change in atheroma volume (follow-up minus baseline). Results: Baseline LDL-C (mean 150.2 mg/dL) was reduced to 110 mg/dL in the moderate lipid-lowering group vs 79 mg/dL in the intensive arm (P<0.0001). C-reactive protein (CRP) decreased 5.2% with pravastatin and 36.4% with atorvastatin (P<0.0001). The primary end point (percent change in atheroma volume) showed progression in the pravastatin cohort; +2.7%, P=0.001 compared with baseline, and was unchanged in the atorvastatin arm (-0.4%, P=0.98 compared with baseline), indicating absence of progression. The progression rate was significantly lower in the atorvastatin arm (P=0.02). Similar differences were observed for secondary IVUS efficacy parameters, including change in total atheroma volume (P=0.02), change in percent atheroma volume (P<0.0002), and change in atheroma volume in the most severely diseased 10-mm subsegment (P=0.01). The atorvastatin arm showed absence of progression in 22 prespecified subgroups. Conclusions: For patients with LDL levels ranging from 125 to 210 mg/dL, intensive treatment with 80 mg atorvastatin halted progression of coronary atherosclerosis, whereas a more moderate regimen using 40 mg pravastatin was associated with progression. These differences may be related to the greater reduction in atherogenic lipoproteins and CRP in atorvastatin-treated patients. More intensive lipid lowering than recommended by current guidelines may be warranted in patients with coronary disease, particularly those at high risk of morbidity and mortality.
Effects of Fosinopril and Pravastatin on Cardiovascular Events in Microalbuminuric Subjects Without Hypertension and Hypercholesterolemia: A Single-Center, Double-Blind, Randomized, Placebo-Controlled Trial With 2x2 Factorial Design (PREVEND IT)
Folkert W. Asselbergs, Gilles F.H. Diercks, Hans L. Hillege, Ad J. van Boven, Wilbert M.T. Janssen, Adriaan A. Voors, D. de Zeeuw, Paul E. de Jong, Dirk J. van Veldhuisen, Wiek H. van Gilst, on behalf of the PREVEND IT Investigators
Background: Microalbuminuria is associated with an increased cardiovascular and renal risk. We assessed whether therapeutic intervention specifically aimed at lowering urinary albumin excretion will reduce cardiovascular and renal events in microalbuminuric subjects without hypertension or hypercholesterolemia. Methods and Results: From the PREVEND cohort (n=8592), 1439 subjects fulfilled the inclusion criteria. From the 864 subjects randomized to fosinopril 20 mg or matching placebo and to pravastatin 40 mg or matching placebo, 854 subjects were eligible for final analysis. The mean follow-up was 46 months, and the primary end point was cardiovascular mortality, hospitalization for cardiovascular morbidity, and end-stage renal disease. Age was 51±12 years, 65% were male, 3.2% had a previous cardiovascular event, 4.8% used cardiac drugs, and the median urinary albumin excretion was 22.9 (25.8 to 41.8) mg/24 h. The primary end point occurred in 42 (4.9%) subjects. Fosinopril reduced urinary albumin excretion by 23% (P<0.001). Patients treated with fosinopril showed a 44% lower incidence of the primary end point (hazard ratio 0.56 [95% CI 0.30–1.04], P=0.07; covariate adjusted 0.53 [0.28–0.995], P=0.048). Pravastatin did not reduce urinary albumin excretion, and patients treated with pravastatin showed a 25% lower incidence of the primary end point than patients in the placebo group (0.75 [0.41–1.38], P=0.35). Conclusions: In microalbuminuric subjects without hypertension or hypercholesterolemia, treatment with fosinopril had a significant effect on urinary albumin excretion. This reduction of urinary albumin excretion was associated with a trend in reducing cardiovascular events. Treatment with pravastatin did not result in a significant reduction in urinary albumin excretion or cardiovascular events.
Cilostazol for Restenosis Trial: A Randomized, Double-Blind Study Following Coronary Artery Stent Implantation
John S. Douglas, Jr, David R. Holmes, Jr, Dean Kereiakes, Cindy L. Grines, Elizabeth Block, Karen Parker, Jovonne Foster, Paul Kolm, Claudine Jurkovitz, Nancy Murrah, Pamela Hyde, William S. Weintraub, Emory University School of Medicine, Atlanta, Georgia
Background:Restenosis after implantation of coronary stents remains a significant clinical problem. Cilostazol, a phosphodiesterase III inhibitor, reduced restenosis after PCI in several small trials. Therefore, we undertook a study to determine whether cilostazol significantly reduced renarrowing after stent implantation in native coronary arteries. Methods: This was a 19-center, randomized, double-blind, placebo-controlled trial in which 705 patients who underwent successful coronary stent implantation received a study drug for 6 months (placebo or cilostazol 100 mg BID). All patients received clopidogrel and aspirin. Patients with acute MI, thrombus, bifurcation stenoses, or hepatic or renal insufficiency were excluded. Patients had follow-up at 1 and 3 months and underwent coronary angiography at 6 months. The primary end point was minimal lumen diameter (MLD) at 6 months by quantitative coronary angiography; secondary end points included % stenosis, binary restenosis (>50% diameter stenosis), target vessel revascularization (TVR), major adverse cardiac events (MACE), stroke, bleeding, and rehospitalization. Results: Five hundred and seven patients underwent follow-up angiography at 6 months. The MLD of the cilostazol-treated patients (C) was 1.81 mm for the analysis segment (stent plus 5-mm borders) compared with 1.67 mm (P=0.0188) in the placebo group (P). Late loss was 0.52 mm in C compared with 0.70 mm in P (P=0.0035). Binary restenosis (>50% diameter stenosis) occurred within the analysis segment in C less frequently, 20.88%, versus 34.59% in P (P=0.0006), a 39.5% relative risk reduction. In-stent restenosis occurred in 20.08% in C versus 31.37% in P (P=0.0038). Subgroup analysis revealed less restenosis in treated diabetes in C, 16.95%, compared with P, 36.99% (P=0.0108). Restenosis in the analysis segment was also less frequent in vessels <3 mm in C compared with P (21.93% versus 34.38%; P=0.0071). There was no difference in bleeding, rehospitalization, myocardial infarction, TVR, death, or MACE between C- and P-treated patients. Conclusion: In this trial, cilostazol treatment resulted in a significantly larger MLD in the analysis segment and in stent and a significantly lower binary restenosis rate compared with placebo-treated patients. These favorable effects were equally apparent in low- and high-risk subgroups, including diabetic patients and in vessels <3 mm in diameter.
Sirolimus-Eluting Stent to Prevent Restenosis in Diabetic Patients With De Novo Coronary Stenoses: The DIABETES (DIABETes and sirolimus Eluting Stent) Trial—One-Month Clinical Follow-Up
Manel Sabaté, Pilar Jiménez-Quevedo, Dominick J. Angiolillo, Fernando Alfonso, Rosana Hernández-Antolín, Camino Bañuelos, Javier Escaned, Raúl Moreno, Joan Antoni Gómez-Hospital, Francisco Fernández-Avilés, Javier Goicolea, Carlos Macaya, Hospital Clinico San Carlos, Madrid (M.S., P.J.-Q., D.J.A., F.A., R.H.-A., C.B., J.E., R.M., C.M.); Hospital Princeps d’Espanya, Barcelona (J.A.G.-H.); Hospital Clinico, Valladolid (F.F.-A.); and Hospital do Meixoeiro, Vigo (J.G.), Spain.
Patients with diabetes mellitus present higher rates of major adverse cardiac events during follow-up as compared with nondiabetics after coronary stenting. The sirolimus-eluting stent (SES) has emerged as an alternative to the bare metal stent for the treatment of de novo coronary stenoses of low-to-moderate risk of restenosis. The DIABETES (DIABETes and sirolimus Eluting Stent) trial is a prospective, multicenter, randomized, placebo-controlled trial aimed at demonstrating the efficacy of the SES on inhibition of neointimal hyperplasia in diabetic patients. To obtain a 56% reduction in late lumen loss (LLL) (estimated for a LLL of 0.73 mm in the bare metal stent group versus 0.32 mm in the SES group, with a SD of 0.70, 
error of 0.05, ß error of 0.10, and 10% missing values during follow-up), 140 patients have been included in the trial: 70 randomized to SES and 70 to bare metal stent. The primary end point is the in-stent + edges LLL as assessed by quantitative coronary angiography at 9-month follow-up. Secondary end points include restenosis rate at 9 months; in-stent + edges neointimal hyperplasia as assessed by intravascular ultrasound at 9 months; subacute and late stent thrombosis rates; major adverse cardiac events, edge effect, late stent malapposition, and coronary aneurysm at 9 months. Patients were eligible for the study if they were identified as non-insulin– or insulin-dependent diabetics (according to the World Health Organization 1999 report) and had significant coronary stenoses in 1, 2, or 3 vessels with signs or symptoms of ischemia. Besides, there was a subrandomization according to the type of diabetes: insulin- or non–insulin-dependent. The use of abciximab during the procedure was recommended per protocol, and dual antiplatelet therapy (aspirin indefinitely + clopidogrel for 1 year) was routinely prescribed. Eighty-seven patients (62%) were male, and mean age was 67±9 years. Ninety-four patients (67%) were non–insulin-dependent, whereas 46 (33%) were insulin-dependent. Left anterior descending artery was most often treated (44%), followed by the right coronary artery (34%). Thirty-five patients (25%) received multivessel and 17 (12%) multisegment stenting. The number of stenoses treated per patient was 1.4±0.6, and the number of stents implanted per patient was 1.6±0.9. Mean stent length and size were 19.2±7 mm and 2.9±0.9 mm, respectively. No differences in clinical or angiographic baseline characteristics were observed between groups. At 1-month follow-up, in the bare metal stent group, 1 patient died due to a cardiac rupture, and 2 patients developed a non–Q-wave myocardial infarction. In the SES group, no death or myocardial infarction (ie, subacute stent thrombosis) or repeat target vessel revascularization was observed. In conclusion, as compared with bare metal stenting, SES may be safely implanted in diabetic patients without any undesired effect demonstrated at 1-month follow-up. This randomized study will demonstrate whether this therapy is effective on the prevention of restenosis in this high-risk group of patients.
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