American Heart Journal
Volume 148, Issue 2 , Pages 254-262, August 2004

Highlights from the American College of Cardiology Annual Scientific Sessions 2004: March 9–12, 2004

  • Svati H. Shah, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • Corresponding Author InformationReprint requests: Svati Shah, MD, Duke Clinical Research Institute, PO Box 17969, Durham, NC 27715, USA.
    • ,
  • Jean-Pierre Dery, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Michael C. Fischi, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • John F. Heitner, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Geoffrey A. Kunz, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Trip J. Meine, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Manesh R. Patel, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Anne Marie Valente, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Richard E. Waters, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA
    • ,
  • Jonathan Yager, MD

      Affiliations

    • Duke Clinical Research Institute, Durham, NC, USA

Article Outline

 

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Session 

Echocardiography and imaging in pediatric and congenital heart disease 

Study 

Creation of an atrial septal defect in utero for fetuses with hypoplastic left heart syndrome and intact or highly restrictive atrial septum

Presenter 

Dr Wayne Tworetzky, Children's Hospital, Boston, Mass

Background 

Greater than 10% of newborns with hypoplastic left heart syndrome (HLHS) have an intact or highly restrictive atrial septum (RAS). These infants have a high neonatal mortality, estimated to be at least 50%. The left atrial hypertension that is present predisposes these infants to pulmonary parenchymal changes and pulmonary vascular remodeling and subsequent pulmonary hypertension. The management of these infants involves left atrial decompression urgently after birth, and palliative surgery.

A retrospective chart review by Rychik et al documented their experience over 7 years and identified 18 patients with HLHS and RAS, of whom 6 survived (33%).1 All of the survivors had an obstructed decompressing vein. On histological review of those who died, there was arterialization of the pulmonary veins. Therefore, the objective of this study was to create an atrial septal defect (ASD) in utero to fetuses identified with HLHS and RAS or intact atrial septum. Exclusion criteria included twin gestation, presence of other congenital anomalies, maternal medical problems, and/or gestational age >34 weeks.

The methods included percutaneous access to the right atrium obtained through an intercostal space, as a modification to the previously described procedure for cardiocentesis. The ultrasound-guided technique used a 19-gauge cannula with sylet, and a 22-gauge ultra sharp Chiba needle, a 0.014-inch floppy wire and 3 mm coronary balloon. The needle was introduced through the abdomen, right atrial wall, and atrial septum and then advanced into the left atium. The wire was passed into a pulmonary vein and the balloon was then inflated in the left atrium, partially deflated, and pulled back into the cannula. Acute success was defined as balloon inflation across the atrial septum and improvement of color Doppler flow across the septal defect.

Results 

Seven procedures were performed between September 2002 and November 2003. The median gestational age was 30 weeks, with a range of 26 to 34 weeks. Four fetuses had a severely restrictive atrial septum, and 3 had intact atrial septum with an obstructed decompressing vein. Two fetuses were hydropic, and 6 were referred from other institutions.

Percutaneous procedures were performed in all 7 subjects. Acute success was obtained in 6 subjects. The remaining fetus was deemed a technical failure due to suboptimal fetal positioning and suboptimal imaging. In all subjects, the pulmonary venous Doppler flow was unchanged. There were no maternal complications and no episodes of fetal bradycardia. One fetal demise occurred, in a 27-week gestation fetus in which an 18-gauge cannula was used. Persistent ASD was documented by echocardiography in 5 of the 6 remaining patients.

The postnatal outcomes included 6 live births. Of these, 4 underwent neonatal left atrial compression. One subject had an adequate ASD at birth, and 1 hydropic subject received no postnatal therapy. Five of the neonates underwent stage I palliative surgery, and 2 of those 5 survived to hospital discharge.

Interpretation 

The conclusions of this pilot study were that the creation of an ASD in fetuses with HLHS with RAS can be performed with low maternal and fetal acute complications; however, there was no improvement in postnatal survival. In conclusion, neonates with HLHS with restrictive or intact atrial septum have a high mortality; however, new approaches are being developed to address their management.

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Session 

Late-breaking clinical trials 

Study 

Final composite end point results for the ARCHeR study 1-year results: ACCULINK for revascularization of carotids in high-risk patients

Presenter 

Dr William A. Gray, Swedish Medical Center, Seattle, Wash

Background 

Carotid endarterectomy (CEA) is the standard of care for the treatment of high-grade carotid artery stenosis in both symptomatic and asymptomatic individuals. However, individuals with high-risk anatomical or medical characteristics are often considered poor surgical candidates and have been excluded from prior CEA trials.2, 3 Carotid artery stenting with distal embolic protection may offer a less invasive and potentially safer therapeutic alternative for these high-risk patients.

The ARCHeR investigators designed 3 prospective, nonrandomized, single-arm registry studies, and enrolled 581 patients from 48 sites in North America (43), Europe (4), and Argentina (1). Inclusion criteria consisted of symptomatic carotid stenosis ≥50% or asymptomatic stenosis ≥80% and at least 1 medical or anatomical high-risk characteristic such as low ejection fraction, uncontrolled diabetes, contralateral carotid occlusion, prior endarterectomy, severe chronic obstructive pulmonary disease, or prior radiation therapy. Individuals with prior severe strokes or recent strokes (<7 days) were excluded. The ACCULINK carotid-stent and the ACCUNET distal-protection filter (Guidant, Indianapolis, Ind) were used. In ARCHeR 1, 158 patients underwent carotid stenting without distal protection, and in ARCHeR 2, 278 patients received stenting with distal protection. Both studies used death, stroke, or myocardial infarction at 30 days plus ipsilateral stroke from 31 days to 1 year as end points and compared this on a noninferiority basis with outcomes expected from weighted historical controls. A new rapid-exchange system was introduced in 145 patients in ARCHeR 3, and 30-day outcomes were compared with those in ARCHeR 2.

Results 

Procedural success was high, with adequate stent deployment in >98% and successful filter deployment and retrieval in >95%. The 30-day death, stroke, or myocardial infarction rate was 7.6%, 8.6%, and 8.3% in ARCHeR 1, 2, and 3, respectively. There was no significant difference in 30-day outcomes after the introduction of the rapid-exchange system in ARCHeR 3. The composite end point of stroke, death, or myocardial infarction at 30 days and ipsilateral stroke at 1 year was 8.3% in ARCHeR 1 and 10.2% in ARCHeR 2, with both comparing favorably to the 14.5% rate of weighted historical controls. The major and fatal stroke rate at 1 year in these 2 arms averaged 3.3%. There were no fatal strokes after the 30-day mark and only 1 major nonfatal stroke and 4 minor strokes. At 1 year, all patients with minor strokes had an NIH Stroke Scale score of 0 to 1. Target lesion revascularization rates of 0.5% at 6 months and 2.5% at 12 months were reported. The outcomes of stenting without distal protection (ARCHeR 1) and with distal protection (ARCHeR 2 and 3) were also analyzed and no statistical difference was found. It was noted, however, that the absence of a higher stroke rate in the distal protection cohort was promising because this group of patients tended to have significantly more vessel angulation and calcification.

Interpretation 

In surgical high-risk patients, carotid stenting, using the ACCULINK carotid-stent system and the ACCUNET embolic protection filter, compares favorably to CEA in historical controls. Major and fatal stroke rates are similar to those seen in prior CEA trials and minor strokes resulted in no significant clinical impact at 1 year. A low rate of target lesion revascularization at 1 year suggests durability. A much larger trial would be needed to detect a statistical difference with and without embolic protection. These data, taken together with the previously reported randomized Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial, make a strong case for the use of carotid stenting in patients at high risk for surgical endarterectomy.4, 5

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Session 

Late-breaking clinical trials 

Study 

Percutaneous transvenous transplantation of autologous myoblasts in the treatment of postinfarction heart failure: The POZNAN trial

Presenter 

Dr Tomasz Siminiak, University School of Medical Sciences, Poznan, Poland

Background 

Despite progress in the treatment of acute myocardial infarction (MI), many MI patients are left with significant systolic dysfunction. As more and more patients survive their index event, the number of patients with post-MI heart failure continues to grow. Although there have been major advances in pharmacologic and mechanical treatments for heart failure, some patients remain symptomatic despite optimal therapy. Studies in animal models have shown that transplanted autologous myoblasts can generate new muscle cells in the heart and improve systolic performance. Based on these promising preclinical findings, intramyocardial transplantation of autologous skeletal myoblasts is being studied as a potential method of regenerating infarcted myocardium for the treatment of post-MI heart failure.

Results 

The POZNAN study (named after the city in Poland in which the study was conducted) was designed as a phase I safety and feasibility trial to evaluate the effects of injecting skeletal myoblasts into areas of postinfarct myocardial scar. The investigators used a percutaneous catheter-based system to inject cells into the heart. An intravascular ultrasound (IVUS)-tipped catheter was passed retrogradely from the femoral vein into a cardiac vein adjacent to the area of infarction. Using IVUS guidance, a needle was advanced through the wall of the vein and into the scar, and skeletal myoblasts were injected. The myoblasts had been previously prepared from muscle biopsies taken from the patients in the weeks before the procedure.

Ten patients were enrolled in the study. All patients had post-MI heart failure, no viable myocardium, and perfusion to the infarct zone from either a revascularized artery or collateral vessels. One patient had an implantable cardioverter-defibrillator (ICD) in place; the other 9 were treated with prophylactic amiodarone due to the concern for ventricular arrhythmias. Cellular transplantation was successful in 9, and was abandoned in 1 patient in whom the cardiac veins could not be accessed.

Heart failure class improved in all 9 successfully transplanted patients. Of the 6 patients who had completed 6-month follow-up, 4 experienced an increase in left ventricular ejection fraction of 3% to 8%. The patient with an ICD had several episodes of ventricular tachycardia requiring ICD shocks; there were no significant arrhythmias among the amiodarone-treated patients.

Interpretation 

This pilot study demonstrates that autologous skeletal myoblasts could be transplanted into areas of myocardial scar using a catheter-based system with relative safety. Larger randomized trials of myoblast transplant with blinded or objective outcome measures are needed to confirm the clinical benefits that were observed in this small patient series.

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Session 

Late-breaking clinical trials 

Study 

Primary angioplasty in acute myocardial infarction with distal protection of the microcirculation: Principal results from the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberalized Debris (EMERALD) trial

Presenter 

Dr Gregg W. Stone, Lenox Hill Hospital, New York, NY

Background 

The use of distal protection devices has been shown to improve outcomes of patients undergoing percutaneous coronary intervention (PCI) of saphenous vein grafts.6, 7 Whether the use of such devices is beneficial in patients undergoing primary PCI for ST-elevation myocardial infarction (STEMI) is unknown. EMERALD was a multicenter, prospective, randomized, clinical trial evaluating infarct size and ST-segment resolution in patients with STEMI who presented within 6 hours of symptom onset and were randomized to a strategy of primary PCI with the adjunctive use of the GuardWire Plus Temporary Occlusion and Aspiration System (Medtronic AVE, Santa Rosa, Calif) or conventional PCI without distal protection. The primary end points were infarct size assessed by sestamibi SPECT imaging at days 5 to 14 and complete (≥70%) ST-segment resolution 30 minutes after the last contrast injection measured with continuous ST-segment monitoring. Secondary efficacy end points included frequency of normal grade-3 myocardial blush and 30-day major adverse cardiac events (MACE) (death, new-onset severe heart failure, new-onset sustained hypotension, and readmission for left ventricular failure).

Results 

A total of 501 patients were enrolled in the study. Debris was recovered in 76% of patients treated with the GuardWire distal protection device. Total procedure time was significantly longer with embolic protection (58 min vs 42 min; P < .0001). Platelet glycoprotein (GP) IIb/IIIa inhibitors were used in 83% of patients in each of the treatment arms. There was no significant difference in the occurrence of the primary and secondary end points with the use of distal protection compared with conventional PCI (Table I).

Table I.
End pointGuard Wire (n = 252)Control (n = 249)P
Infarct size (% of left ventricule)17.1%14.3%.09
Complete ST-segment resolution62.2%60.6%.77
Grade-3 myocardial-blush60.1%52.7%.13
MACE14.0%13.1%.79

Embolic protection with the GuardWire Plus Temporary Occlusion and Aspiration System did not reduce infarct size nor did it improve microvascular flow or MACE in patients undergoing primary PCI for STEMI.

Interpretation 

These disappointing results are unlikely to be the consequence of an underpowered study because EMERALD had >90% power to show a significant difference in infarct size and >98% power to show a benefit in complete ST-segment resolution. It is possible, however, that the longer procedural times may have blunted the beneficial effect of distal protection in this patient population. Tissue necrosis, edema, and other humoral factors may be more important in the pathophysiology of reperfusion injury than embolic debris itself.

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Session 

Late-breaking clinical trials 

Study 

CAPITAL AMI—Combined Angioplasty and Pharmacological Intervention vs Thrombolytics Alone in Acute Myocardial Infarction

Presenter 

Dr Michel R. LeMay, University of Ottawa, Ottawa, Canada

Background 

Not long ago, the previous administration of thrombolytics was considered to be a relative contraindication to performing immediate percutaneous coronary intervention (PCI). This was based on 10-year-old data showing that “facilitated PCI” was associated with increased bleeding complications without improved ischemic outcomes. Pharmacologic therapy and device technology have evolved greatly in the intervening years. Modern interventions use weight-based nomagrams to guide heparin and lytic dosing. Smaller profile catheters and refined techniques reduce vascular complications. With these advances, a gap developed in the literature guiding cardiologists as to the ideal time to invasively follow-up on a lysed acute myocardial infarction (AMI) patient.

The PACT trial suggested that patients treated with low-dose rtPA and facilitated PCI had achieved earlier Thrombolysis in Myocardial Infarction (TIMI)-3 flow in the infarct-related artery compared with intervention-alone patients—and without additional bleeding risk.8 The results of that study encouraged the CAPITAL AMI investigators to determine the outcomes of high-risk AMI patients treated with full-dose fibrinolysis and facilitated PCI compared with lytics without planned PCI.

A total of 170 high-risk, ST-elevation AMI patients (primarily with anterior wall infarctions) who presented within 6 hours of symptom onset were randomized to fibrinolysis alone with full-dose tenecteplase (TNK) or full-dose TNK with immediate transfer to the Ottawa Heart Institute for angiography and possible PCI. Those randomized to the fibrinolysis-only group were also transferred for PCI if they failed lytic therapy. Inclusion criteria were anterior ST-elevation MI, severe nonanterior ST-elevation MI, or the sum of ST-elevation >20 mm. Patients with Killip Class III heart failure and new left bundle branch block (LBBB) were included. Patients with contraindications to fibrinolysis, prior bypass surgery, cardiogenic shock, contrast allergy, or heparin within the previous 6 hours were excluded. The most common cause for exclusion was small MI. No patients received glycoprotein IIb/IIIa inhibitors.

Results 

The primary end point of 30-day death, MI, stroke, or recurrent ischemia was significantly reduced in the facilitated PCI group (9.3% vs 21.4%, P = .034). This was primarily driven by a reduction in recurrent ischemia (7.0% vs 17.9%, P = .037), as there was no significant reduction in death, MI, or stroke. Notably, there was no difference in TIMI major bleeding (9.3% vs 8.3%, P = NS). Final ejection fraction or 30-day exercise test tolerance was not different between groups. There was a weak trend toward less heart failure in the facilitated PCI group (10% vs 14%) and shorter duration of hospital stay (2 days vs 3 days).

Interpretation 

This was a small study, but the ramifications could be dramatic, especially if they are supported by larger, similarly designed, randomized trials. According to Dr LeMay, one of the CAPITAL AMI primary investigators, “All high-risk STEMI patients treated with TNK should be transferred for immediate PCI.”

The upcoming, 4000-patient ASSENT-4 trial comparing facilitated PCI versus PCI alone will help to further define the role of thrombolysis as an adjunct to PCI.

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Session 

Late-breaking clinical trials 

Study 

The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial

Presenter 

Dr Barry M. Massie, University of California–San Francisco and the Department of Veterans Affairs Medical Center, San Francisco, Calif

Background 

Patients with chronic heart failure have an increased risk of thromboembolism and stroke9 due to vascular abnormalities, hypercoagulability, and impaired blood flow. Many different antithrombotic agents have been used as therapy in patients with chronic heart failure, and retrospective data have shown a benefit in anticoagulation with warfarin.10 However, the optimal pharmacologic regimen for preventing thrombotic events in the general heart failure population has yet to be determined. Furthermore, concerns have been raised about potential interactions between angiotensin-converting enzyme inhibitors (ACEI) and aspirin because of their antagonistic effects on the formation of vasodilatory prostaglandins.11

The WATCH trial sought to answer the following questions: (1) Is warfarin better than aspirin in preventing thrombotic events in patients with chronic heart failure? (2) Does aspirin have an adverse effect in these patients? The primary study design of the WATCH trial was a randomized, double-blinded, non-placebo–controlled trial comparing chronic therapy with warfarin (target international normalized ratio [INR] of 2.5–3.0), aspirin 162 mg daily, and clopidogrel 75 mg daily. Inclusion criteria included patients aged >18 years, New York Heart Association (NYHA) class II to IV heart failure, left ventricular ejection fraction (EF) <35%, and treatment with ACEI and diuretic therapy. Exclusion criteria included contraindication to study medications, indication for study medications (ie, recent myocardial infarction [MI], recent percutaneous coronary intervention, atrial fibrillation), unstable patients, expected cardiac transplant, or concurrent severe illness. Patients were enrolled in the Unites States, Canada, and the United Kingdom (UK). Patients were followed-up at 3-month intervals and with INR checks as mandated by standard care. Analyses were by intention-to-treat. Initially, the WATCH trial had 80% to 90% power to detect a 20% difference in the primary composite end point of death, nonfatal MI, and nonfatal stroke. The secondary end point was a broader composite of these events plus hospitalization for worsening heart failure, unstable angina, or peripheral or pulmonary embolism. The study investigators had planned on randomizing 4500 patients; however, the final enrollment was only 40%. The trial was discontinued prematurely in June 2002 because of issues with low enrollment.

Results 

A total of 1587 patients were randomized to warfarin, aspirin, or clopidogrel. The mean follow-up was 23 months, comprising 3068 patients-years, making WATCH the largest trial of antithrombotic therapy in chronic heart failure patients. The mean INR was 2.6, with 31% of patients achieving the target mean INR of 2.5 to 3.0 and 70% of patients with mean INR of 2.0 to 2.5. The mean age was 63 years, 85% of patients were male, and 11% were black. Seventy-two percent of patients had ischemic cardiomyopathy, 48% had hypertension, and 34% had diabetes. The intervention groups were similar in all aspects except for an imbalance in the incidence of diabetes (34%, 31%, and 38% in the aspirin, clopidogrel, and warfarin groups, respectively). Overall, the population was maintained on an appropriate heart failure medication regimen, with 88% treated with ACEI, 11% with angiotension-receptor blockers (ARB), 99% on diuretics, and approximately 70% on β-blockers. Thirty-five percent of patients had been hospitalized within the previous 6 months, 54% to 58% had NYHA class III to IV heart failure, and the mean EF was 24%.

Due to premature termination of the trial, the study investigators chose to focus on the comparisons of warfarin versus aspirin and clopidogrel versus aspirin. In the warfarin versus aspirin comparison, the trial found no difference in the primary composite end point (19.8% vs 20.5%). The incidence of nonfatal MI was nonsignificantly lower in the aspirin group and nonfatal stroke was nonsignificantly lower in the warfarin group (P = .06). There was a statistically significantly increased incidence of heart failure hospitalizations in the aspirin group versus the warfarin group (22.2% vs 16.1%, P = .01). When comparing clopidogrel versus aspirin, the trial once again found no difference in the primary composite end point (20.5% vs 21.8%, P = .68) and a nonsignificant trend towards increased heart failure hospitalizations in the aspirin group. Proportional hazards ratio modeling showed no difference in hazard ratios (HR) for the secondary composite end point for warfarin compared with aspirin (HR 0.94) and for clopidogrel compared with aspirin (HR 1.03). The trial also evaluated major and minor bleeding events in all groups. There was a statistically significantly higher incidence of major bleeding events in the warfarin group compared with clopidogrel or aspirin (30 events vs 13 and 19, respectively).

Given the premature termination of the WATCH trial and concerns over insufficient power, the study investigators conducted post-hoc power calculations showing 41% power to detect the primary composite end point of death, nonfatal MI, or nonfatal stroke, and 69% power to detect the secondary composite end point of death, MI, heart failure hospitalization, unstable angina, or thrombotic event. Based on these calculations, the study investigators conclude that 10% to 15% differences in the end points in the warfarin compared with aspirin groups were excluded with 90% to 95% confidence.

Interpretation 

In this group of relatively sick chronic heart failure patients, there was no difference in the primary or secondary composite end points for warfarin or clopidogrel compared with aspirin. Therefore, although the WATCH trial was insufficiently powered to definitively conclude that warfarin or clopidogrel is similar to aspirin in preventing thrombotic events, it was able to exclude a large difference in the primary and secondary composite end points between warfarin or clopidogrel compared with aspirin. The finding of a 31% higher rate of heart failure hospitalization in the aspirin group compared with warfarin and a trend in the same direction compared with clopidogrel must be interpreted cautiously, but it is consistent with data from a previous smaller trial (WASH)12 and observational studies, and it lends support to the hypothesis that prostaglandin inhibition may have an adverse effect in chronic heart failure patients. Overall, these results suggest warfarin and clopidogrel are as efficacious as aspirin in preventing death, nonfatal MI, and nonfatal CVA in patients with chronic heart failure, and that aspirin may cause increased heart failure hospitalizations in this patient population.

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Session 

Late-breaking clinical trials 

Study 

The Superior Yield of the New strategy of Enoxaparin, Revascularization and GlYcoprotein IIb/IIIa inhibitors (SYNERGY) trial: Primary results

Presenters 

Dr Kenneth Mahaffey, Duke Clinical Research Institute, Durham, NC, and Dr James Ferguson, Texas Heart Institute, Houston, Tex

Background 

Current treatment for non-ST–segment acute coronary syndromes (ACS) includes antithrombin, antiplatelet, and anti-ischemic therapies. In addition, an early invasive approach with diagnostic angiography and revascularization compared to a conservative approach was shown to be beneficial in the Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18 (TACTICS-TIMI 18)13 and the Fast Revascularization during Instability in Coronary artery disease (FRISC-II)14 trials. Subsequently, the clinical community has adopted an early invasive approach in high-risk patients with non-ST–segment ACS.

Enoxaparin is a low-molecular–weight heparin that has been studied in patients with non-ST–segment ACS. The Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events (ESSENCE)15 and the TIMI 11B16 trials found enoxaparin to be superior to unfractionated heparin (UFH) in preventing the composite of death or cardiac ischemic events. A prespecified, pooled analysis of the 2 trials showed an early and sustained benefit that led to a 23% relative risk reduction in death and myocardial infarction.17

In spite of these findings, the use of enoxaparin has been limited, likely due to inadequate data on its use in patients treated with glycoprotein IIb/IIIa inhibitors and an early invasive strategy. The revised ACS guidelines assign a IA recommendation to both UFH and enoxaparin, with a footnote for UFH in patients who are likely to undergo cardiac catheterization within 12 hours.18 Therefore, the SYNERGY study was designed as a prospective, randomized, open-label, multicenter trial to evaluate the efficacy and safety of enoxaparin versus UFH when administered with established therapy, including GP IIb/IIIa inhibitors at investigator discretion and aspirin in high-risk patients with non-ST–segment ACS who are to be managed with an early invasive approach.

High-risk ACS patients with angina who met at least 2 of the qualifying criteria (age ≥60 years, transient ST elevation or ST depression, and positive creatine kinase-MB or troponin) were randomized to receive either 1 mg/kg subcutaneous enoxaparin every 12 hours or intravenous heparin (initial dose 60 U/kg; 12U/kg/hour; maximum of 5000 bolus/1000 infusion subsequently aPTT titrated) followed by a recommended early invasive strategy and other therapy, such as aspirin, β-blocker, angiotensin-converting enzyme inhibition, clopidogrel, or a GP IIb/IIIa inhibitor, according to current American Heart Association/American College of Cardiology guidelines. For patients receiving enoxaparin, catheterization could be performed at any time after the last dose. No additional enoxaparin was given if percutaneous coronary intervention (PCI) was performed <8 hours since the last dose, but an intravenous dose of 0.3 mg/kg was given when PCI was performed 8 to 12 hours after the last dose. Intravenous UFH was given with an initial dose of 60 U/kg followed by 12 U/kg/hour. The primary end point was death or MI at 30 days. Primary end point was analyzed by calculating hazard ratios and 95% CI to test for both superiority and noninferiority. Noninferiority was defined as an upper 95% CI <1.1.19

Results 

A total of 10,027 high-risk ACS patients from 467 centers in the United States, Europe, Canada, South America, and Australia/New Zealand were enrolled. The median age was 68 years and 34% of the patients were women. More than 92% of the patients went to the cardiac catheterization lab within a median of 21 hours. There were no significant differences in death, MI, or the combined end points of death and MI at 30 days between the treatment groups. The combined end point of death and MI at 30 days occurred in 14.0% of the enoxaparin group and 14.5% of the UFH group; MI occurred in 11.7% and 12.7%, respectively, and death in 3.2% and 3.1%, respectively. Results showed that the incidence of GUSTO severe bleeding was 2.9% with enoxaparin versus 2.4% for UFH (P = NS). Incidence of TIMI major bleeding was 9.1% in the enoxaparin group versus 7.6% in the UFH group (P = .008), and TIMI non-CABG major bleeding was 2.4% vs. 1.7% (P = .025). There was no difference observed in the incidence of blood transfusions, ICH, or abrupt closure. In a pooled analysis of all trials randomizing patients to enoxaparin versus UFH in ACS (n = 22,000), there was an absolute 0.9% and 9% relative risk reduction that was highly statistically significant in the combined end point of death or MI at 30 days.

Interpretation 

The results of the SYNERGY trial, the largest trial in patients with non-ST–segment ACS, provide several new insights. In high-risk patients with ACS who are treated with an invasive strategy, enoxaparin was not superior but at least as effective as UFH. Patients treated with enoxaparin did have a small but statistically significant increase in TIMI major bleeds, with no statistically significant increase in transfusions or GUSTO severe bleeds. Increased bleeding was noted in patients who crossed therapy postrandomization, but the rationale for crossover has not been elucidated, and this finding must be interpreted cautiously as it is a postrandomization event that has inherent biases and confounders.

Lastly, it seems that patients started on an antithrombotic regimen should be continued on that regimen and not switched from one agent to another, due to safety concerns raised from these data.

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Session 

Late-breaking clinical trials I 

Study 

DINAMIT: Defibrillator IN Acute Myocardial Infarction Trial

Presenter 

Dr Stuart J. Connolly, McMaster University, Hamilton, Ontario, Canada, and Dr Stefen H. Hohnloser, JW Goethe-University College, Frankfurt, Germany

Background 

Previous trials of defibrillator therapy have not enrolled patients with a recent myocardial infarction. The MADIT-II trial included patients who had a myocardial infarction ≥1 month before enrollment. In fact, 88% of the patients in that trial received an ICD >6 months after their index myocardial infarction.20 However, it is well-known that 1-year post-MI mortality is high and, therefore, the DINAMIT investigators sought to determine if a strategy of early ICD implantation in post-MI patients was beneficial.

The DINAMIT trial was a multicenter, open-label, randomized comparison of ICD therapy versus no ICD therapy in patients with recent MI (6–40 days), EF <35%, and depressed heart rate variability. Patients with NYHA class IV heart failure, recent CABG or 3-vessel PTCA, or sustained ventricular arrhythmia >48 hours after MI were excluded from the trial. The primary outcome of the trial was all-cause mortality; secondary outcomes included arrhythmic death.

Results 

A total of 674 patients were enrolled in the trial between 1998 and 2002, and average follow-up was 2.5 years. Baseline characteristics were similar in the 2 groups; 72% of patients had experienced an anterior myocardial infarction, and the mean ejection fraction was 28%. Additionally, the majority of patients received optimal medical treatment (ie, >80% received β-blockers and antiplatelet agents, and >90% received ACE inhibitors). There was no difference in the primary end point of all-cause mortality (P = .66). While there was a 58% decrease in the cumulative risk of arrhythmic death in patients treated with ICD therapy, this was offset by a concomitant 75% increase in nonarrhythmic death in these patients.

Interpretation 

This trial helps define the timing of ICD implantation. While the authors speculate that ICD therapy might alter the mode of death from arrhythmic to nonarrhythmic in this population, the lack of overall mortality benefit is most striking. This trial suggests that, in patients with recent myocardial infarction and depressed ejection fraction, there is no benefit to the strategy of early prophylactic ICD implantation.

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Session 

Late-breaking clinical trials 

Study 

SCD-HeFT: The Sudden Cardiac Death in Heart Failure Trial

Presenter 

Dr Gust H. Bardy, Seattle Institute for Cardiac Research, Seattle, Wash

Background 

Patients with heart failure are at increased risk of sudden cardiac death. The recent MADIT-II trial demonstrated that patients with ischemic cardiomyopathy and an ejection fraction <30% derive a mortality benefit from an implantable cardioverter-defibrillator (ICD).21 Similarly, the recently published DEFINITE trial demonstrated a trend toward improved mortality and a statistically significant improvement in arrhythmic mortality in 458 patients with nonischemic cardiomyopathy and an ejection fraction <35%.22

In the setting of these 2 studies, SCD-HeFT's primary hypothesis was to determine if amiodarone or a conservatively programmed shock-only ICD reduces all-cause mortality compared to placebo in patients with NYHA Class II or III heart failure and an ejection fraction <35% regardless of the etiology of heart failure. The study recruited 2521 patients (median age 60.1 years, 23% female, 23% minority) and randomized them evenly to 3 arms: placebo, amiodarone, or ICD therapy. Amiodarone was administered on an outpatient basis, and after a 2- to 4-week loading period was dosed according to the patient's weight: 200 mg per day for patients <150 pounds, 300 mg per day for patients between 150 and 200 pounds, and 400 mg per day for patients >200 pounds. ICDs were Medtronic model 7223 and were programmed for ventricular fibrillation (VF) therapy only.

Patients with ischemic cardiomyopathy comprised 52% of the subjects, and 48% had nonischemic cardiomyopathy. Average QRS duration was 112 ms, and 41% had a QRS >120 ms. Ninety-six percent of the patients were taking either an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) at baseline, 69% were on β-blocker therapy, 19% on spironolactone, 56% on aspirin, 38% on a statin, and 82% on loop diuretics. Statistical analysis was carried out on an intention-to-treat basis, and vital status was available on 100% of patients at a median follow-up of 45.5 months. The study was funded by Medtronic, Inc, Wyeth Pharmaceuticals, and the National Heart, Lung and Blood Institute.

Results 

There was no difference between amiodarone and placebo for mortality, which was 36.1% over 5 years, or 7.2% per year (hazard ratio [HR] 1.06, 97.5% CI 0.86–1.30, P = .529). ICDs reduced mortality by 23% (HR 0.77, 97.5% CI 0.62–0.97, P = .007). This was the same regardless of etiology of heart failure (ischemic or nonischemic). Subgroup analyses hinted that the effect was stronger in patients with QRS >120 ms, those with ejection fraction <30%, those with NYHA Class II as opposed to Class III heart failure, and those on β-blockers, although during his presentation Dr Bardy cautioned that “all subgroup analyses are to be interpreted cautiously.”

Interpretation 

ICDs provide a 23% reduction in all-cause mortality in an “all-comer” population of patients with NYHA Class II and Class III heart failure, regardless of etiology. Amiodarone has no effect in reducing mortality when compared with placebo in this population. This group of patients was already taking good, evidence-based heart failure therapy, including a high use of ACE inhibitors or ARBs, β-blockers, and statins. The argument can now be made that all patients with NYHA Class II or Class III heart failure can benefit from an ICD, without the need for further risk stratification such as an electrophysiology study. The SCD-HeFT investigators are planning economic and quality-of-life analyses from the database, and these will provide even further insight into the cost effectiveness and benefits provided by ICDs.

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Session 

Featured oral session: Clinical utilization of magnetic resonance imaging perfusion and viability 

Study 

Diagnostic utility of contrast enhanced magnetic resonance imaging for screening patients at risk for sudden cardiac death

Presenter 

Dr Igor Klem, Duke University Medical Center, Durham, NC

Background 

The identification of patients at risk for sudden cardiac death (SCD) remains a challenge in the field of cardiology. Invasive electrophysiologic study (EPS) is currently the tool of choice in identifying patients at risk for SCD. Myocardial scar is the substrate for monomorphic ventricular tachycardia. Contrast-enhanced magnetic resonance imaging (ceMRI) has very high spatial resolution in identifying myocardial scar. The hypothesis of this study was that a patient with no evidence of myocardial scar by ceMRI will have a negative EPS.

Eighty-nine patients who were scheduled for an EPS first underwent ceMRI evaluation. There were 49 patients with an ejection fraction ≤40%; 30 (61%) of these patients were classified as having ischemic cardiomyopathy and the other 19 (39%) patients had nonischemic cardiomyopathy. The EPS tracings and the ceMRI exams were reviewed by readers who were blinded to patient data. The EPS tracings were classified into sustained monomorphic ventricular tachycardia (MVT), polymorphic ventricular tachycardia/fibrillation (PMVT/VF), noninducible, and idiopathic ventricular tachycardia (I-VT).

Results 

Twenty-eight (31%) patients had no evidence of myocardial scar by ceMRI, and none of them had inducible MVT, giving a negative predictive value of 100%. There were 49 patients who were noninducible, 19 patients who had MVT, 16 patients with PVT/VF, and 5 patients with I-VT. All of the patients with MVT had some evidence of myocardial scar by ceMRI. Eighteen of the 49 patients who were noninducible had evidence of scar by ceMRI. The amount of scar was significantly larger in the patients with MVT compared with the other group of patients. Scar size was a better predictor of MVT than EF.

Interpretation 

This study demonstrates that a lack of myocardial scar by ceMRI predicts a negative EPS. Interestingly, myocardial scar was a better predictor of MVT than EF. The problem is that there is conflicting data on the predictive value of an EPS. It will be very interesting to see the prognostic value of ceMRI in predicting sudden death, with the potential of determining those patients who would benefit the most from an automatic implantable cardioverter defibrillator.

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PII: S0002-8703(04)00318-7

doi:10.1016/j.ahj.2004.05.028

American Heart Journal
Volume 148, Issue 2 , Pages 254-262, August 2004

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