doi: 10.1161/01.CIR.0000047676.70066.2D
(Circulation. 2002;106:e211.)
© 2002 American Heart Association, Inc.
ESC Meeting Highlights |
Meeting Highlights
Highlights of the 24th Congress of the European Society of Cardiology
From St Luke’s Episcopal Hospital, Texas Heart Institute, Houston, Tex.
Correspondence to James J. Ferguson, MD, Cardiology Research, Texas Heart Institute/St Luke’s Episcopal Hospital, 6720 Bertner Ave, MC 1-191, Houston, TX 77030. E-mail jferguson{at}heart.thi.tmc.edu
Acute Coronary Syndromes
MAGnesium In Coronaries (MAGIC)
Presenter:
Elliot M. Antman, MD (Brigham and Women’s Hospital, Boston, Mass)
Purpose:
To examine the effect of early administration of magnesium therapy in high-risk patients with ST-elevation acute myocardial infarction (AMI).
Study:
High-risk patients presenting with ST-elevation AMI were enrolled within 6 hours of presentation and included both those who were >65 years of age and eligible for reperfusion (Stratum I) as well as those in all age groups who were eligible for reperfusion (Stratum II). Cardiogenic shock, high-grade AV block, and severe renal failure were exclusion criteria. The patients were randomized in double-blinded fashion to receive either magnesium (n=3110, 2-g bolus over 15 minutes followed by an infusion of 17 g over 24 hours) or (volume-matched) placebo (n=3098). The primary end point was 30-day mortality.
Results:
The incidence of death by 30 days was not significantly different between the magnesium-treated (n=475, 15%) and placebo-treated (n=472, 15%) patients with an odds ratio of 1.0 (CI 0.9 to 1.2, P=0.96). Similarly, there was no difference with magnesium-therapy in the secondary end points of defibrillation (5% in both groups), pacemaker requirement (2% in both groups), or requisite therapies for congestive heart failure (18% vs 19%).
Summary:
The early administration of magnesium in high-risk patients with ST-elevation myocardial infarction has no benefit on 30-day mortality or on secondary outcomes of arrhythmia or congestive heart failure. No subgroups showed benefit in this study. There appears to be no indication for the routine administration of magnesium to patients with ST-elevation myocardial infarction at any level of risk. However, as no apparent harm was identified in this study (confirming prior studies), magnesium may continue to be administered for repletion of documented electrolytes deficits.
Randomized Intervention Trial of Unstable Angina (RITA 3) Interventional Versus Conservative Treatment for Patients with Unstable Angina or Non–ST-Elevation Myocardial Infarction
Presenter:
Keith A.A. Fox, MBChB (Royal Infirmary of Edinburgh, Edinburgh, Scotland)
Purpose:
To test the hypothesis than an early interventional strategy is superior to a conservative approach within a moderate risk unstable angina patient population.
Study:
A multicenter trial from November 1997 to October 2001 enrolling 1810 patients from 45 hospitals in England and Scotland with non–ST-elevation acute coronary syndromes. The patient population was carefully defined as patients presenting with chest pain who concomitantly had convincing evidence of coronary artery disease (CAD) defined by at least one of the following: ischemic ECG changes (ST-segment depression, transient ST elevation, preexisting left bundle branch block, or T-wave inversion), pathological Q-waves indicative of prior MI, or known CAD by prior cardiac angiography. All patients with an evolving acute myocardial infarction (including those in whom reperfusion therapy was indicated) were excluded, as were patients with recent MI (<1 month), recent percutaneous coronary intervention (PCI, <12 months), or prior CABG. Additionally, new pathological Q-waves or CK/CK-MB values twice that of normal values were exclusion criterion. Only 2% of patients in each study arm were included on the basis of an elevated troponin (the protocol was designed before the standard diagnostic use of troponin for MI) in the absence of other entry criteria. Eligible patients were randomized to either early intervention or conservative therapy. Enoxaparin was utilized as the anticoagulant of choice in both treatment arms. Two composite primary end points were utilized: (1) a composite of death, nonfatal MI, or refractory angina at 4 months, and (2) a combined rate of death or nonfatal MI at 1 year. Refractory angina was defined as rest angina despite maximal medical therapy accompanied by new ECG changes that resulted in an emergent revascularization (within 24 hours). The analysis was performed by intention-to-treat. No patients were lost to follow-up.
Results:
Given evolving clinical scenarios, 38 of the 895 patients (4%) randomized to the invasive approach did not undergo angiography; of the 96% of patients treated per protocol, 55% underwent revascularization as a result of the randomized angiogram with either PCI (35%) or CABG (21%). Of the 915 patients randomized to the conservative strategy, 440 ultimately underwent angiography by 1 year (representing a 48% requisite eventual crossover rate) with 252 patients requiring either PCI (16%) or CABG (12%). At 4 months, a significant reduction in death, MI, or refractory angina was identified within the invasively treated (9.6%) vs the conservatively managed patients (14.5%, P=0.001). This difference was primarily driven by a reduction in refractory angina with the invasive approach (4.4% vs 9.3%, P<0.0001) rather than by any significant effect of intervention on either mortality (2.9% vs 2.5%, P=0.61) or on nonfatal MI (3.4% vs 3.7%, P=0.68). This lack of significant reduction in the risk of death or MI with the interventional approach persisted at 1 year (7.6% vs 8.3%, P=0.58). The benefit in the decreased rate of refractory angina—defined here as readmission for recurrent chest pain associated with new ECG evidence of ischemia—persisted at 1 year among the invasively managed patients (6.5% vs 11.6%, P=0.0002).
Summary:
In moderate-risk patients presenting with unstable coronary disease, an invasive strategy is preferred over a conservative strategy and is associated with a 50% reduction in the risk of subsequent refractory angina without an associated increased risk of death or MI. Five-year follow-up data acquisition is planned.
The Glucose-Insulin-Potassium Study (GIPS)
Presenter:
Felix Zijlstra, MD, PhD (De Weezenlanden, Zwolle, the Netherlands)
Purpose:
To evaluate the use of glucose-insulin infusions for myocardial protection—in addition to full anticoagulants, antiplatelet agents, and modern revascularization techniques—in patients with ST-elevation myocardial infarction.
Study:
A total of 940 patients presenting with acute ST-elevation myocardial infarction were randomized to receive an infusion of either glucose-insulin-potassium or no infusion (no placebo infusion). The treatment arm received a 20% glucose infusion at a rate of 3 mL/kg/h in a potassium concentration of 80 mmol per 500 mL with a concomitant insulin drip (adjusted hourly per serum glucose level per routine). The primary end point was 30-day mortality and major adverse cardiac events (MACE)—including reinfarction and repeat revascularization.
Results:
In the overall study population, although exhibiting a trend in 30-day mortality in favor of glucose-insulin-potassium administration (4.8%) over untreated patients (5.8%), this difference failed to reach statistical significance (P=0.10). Similarly, there was no significant effect of treatment on MACE, incidence of reinfarction, or need for repeat percutaneous coronary intervention. Subsequent carefully defined subset analyses were performed in 3 distinct patient populations in whom the therapy intuitively may provide more relative benefit: patients with successful reperfusion, patients without diabetes mellitus, and patients without congestive heart failure (excluding patients with Killip Class II-IV). There were no differences in the primary end points (as defined above) between treated and control patients with successful reperfusion or in nondiabetics. However, significant treatment benefit was conferred to the subset without congestive heart failure; the 30-day mortality rate in this subgroup of Killip Class I patients—representing 91% of the total population—was only 1.2%, compared with 4.2% in the untreated patients (P=0.01); similarly, a significant reduction in MACE was identified within treated patients with congestive heart failure (4.2% vs 8.4%, P=0.01).
Summary:
Although metabolic protection with a glucose-insulin-potassium infusion offers no convincing additional therapeutic benefit beyond standard-of-care in the overall patient population presenting with acute ST-elevation myocardial infarction, subset analysis reveals superior results in treated patients without congestive heart failure. Although this finding—as a subset analysis—is only hypothesis generating rather than definitive, it provides further impetus for studying the potential benefit of metabolic protection during uncomplicated ST-elevation myocardial infarction.
PRimary Angioplasty in AMI patients from General community hospitals transported to PTCA Units Versus Emergency thrombolysis (PRAGUE 2)
Presenter:
Petr Widimsky, MD, DrSc (University Hospital Vinohrady, Prague, the Czech Republic)
Purpose:
To compare the outcome in patients presenting to small community hospitals with an acute myocardial infarction (AMI) who receive immediate thrombolysis versus urgent transport to tertiary centers for primary angioplasty.
Study:
A multicenter study that enrolled 850 patients from September 1999 to January 2002 presenting to one of 44 community hospitals (without cardiac angiography capabilities) within 12 hours of their presentation with an ST-elevation AMI. Contraindication to thrombolysis was an exclusion criterion. These patients were randomized to immediate thrombolysis versus urgent transport to a designated tertiary center for primary angioplasty; a total of seven separate tertiary centers were utilized. The primary end point was 30-day mortality (intention-to-treat analysis). The secondary end points were: death, reinfarction, or stroke at 30 days; 30-day mortality in subgroups treated 0 to 3 hours vs 3 to 12 hours after symptom onset; and the 30-day mortality reanalyzed by actual treatment received. The thrombolysis (n=421) and primary angioplasty (n=429) groups were closely matched for age (64 vs 65 years old), distribution of infarction (anterior 39% vs 41%), prior infarction (11% vs 14%), prior revascularization (1.9% vs 1.4%), comorbidities (diabetes mellitus 23% vs 25%; hypertension 47% vs 49%), and acute congestive heart failure (Killip II-IV 17% vs 18%).
Results:
A trend was identified in 30-day mortality favoring primary angioplasty (6.8%) over thrombolysis (10.0%, P=0.12). When analyzed by subgroup analysis, the patients who benefited most from primary angioplasty were enrolled 3 to 12 hours from symptoms onset (6.0% vs 15.3%, P<0.02); more acute presentation (0 to 3 hours from symptoms onset) revealed similar mortality between primary angioplasty (7.3%) and thrombolysis (7.4%, P=NS). As several patients crossed over between groups, reanalysis of overall 30-day mortality by treatment received revealed a significant reduction with primary angioplasty vs thrombolysis (6.0% vs 10.4%, P<0.05). Similarly, the secondary end point of death/reinfarction/stroke was significantly decreased in patients treated with primary angioplasty (8.4%) when compared with thrombolysis (15.2%).
Summary:
Urgent inter-hospital transport for primary angioplasty in the setting of acute ST-elevation myocardial infarction is a feasible and safe management scheme that improves the 30-day prognosis of the patients when compared with thrombolysis in the community hospital setting.
GRupo de Análisis de la Cardiopatía Isquémica Aguda (GRACIA)
Presenter:
Francisco F. Avilés, MD, PhD (Instituto de Ciencias del Corazón, University of Valladolid, Spain)
Purpose:
To evaluate the potential benefits of an early post-thrombolysis interventional approach in the modern era of coronary stenting with adjunctive GP IIb/IIIa inhibition.
Study:
A multicenter, randomized trial in patients with ST-elevation acute myocardial infarction (AMI) treated with thrombolysis comparing an early invasive strategy to conservative management (post-thrombolysis ischemia-guided intervention). A total of 500 patients from 23 centers with ST-elevation AMI who were successfully treated with thrombolytic therapy were randomized from March 2000 to September 2001 to receive either early coronary angiography (within 24 hours of thrombolysis) or ischemia-guided treatment. When indicated, percutaneous coronary intervention (stenting with adjunctive abciximab) or coronary artery bypass graft surgery was performed before discharge in the invasively managed patients. Aspirin, ß-blockade, and intravenous heparin were provided to all patients per standard of care. The primary end point was the composite incidence of death, myocardial infarction, or ischemia-driven revascularization at 30 days and 1 year; notably, revascularization of conservatively managed patients before discharge was not considered an event.
Results:
Invasively managed patients had significantly fewer primary composite end point events at 30 days (0.8% vs 3.7%, P=0.03). Unlike older trials comparing interventional with conservative strategies, the rate of bleeding complications at 30 days was not significantly higher in the interventionally managed patients (all bleeding events 2.4% vs 1.6%, P=0.84; severe bleeding events 1.6% vs 1.6%, P=NS). The duration of hospitalization was significantly shorter with invasive management (7±57 days vs 11±16 days, P=0.0001). One-year follow-up data will be reported at a later date.
Summary:
Early cardiac catheterization post-thrombolysis (with resultant early percutaneous coronary intervention or coronary artery bypass grafting surgery) both decreases the incidence of major adverse cardiac events and shortens the acute hospitalization without increasing the risk of noncardiac events, including bleeding complications. Confirmation at one-year follow-up is awaited.
Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL): Effects of Losartan and Captopril on Mortality and Morbidity in High-Risk Patients After Acute Myocardial Infarction
Presenter:
Kenneth Dickstein, MD, PhD (University of Bergen, Bergen, Norway)
Purpose:
To test the hypothesis that the angiotensin II receptor antagonist losartan would be superior or noninferior to the ACE inhibitor captopril in decreasing mortality in high-risk patients with acute myocardial infarction.
Study:
A multicenter (329 centers in 7 European countries) trial that enrolled 5477 high-risk patients from February 1998 to February 2002 with documented acute myocardial infarction (diagnosed by at least two of the following: a history of typical chest pain lasting >20 minutes, ST elevation on ECG, or an increase in cardiac markers above the diagnostic level). High-risk infarction patients were defined as being aged >50 years with either resultant congestive heart failure (as defined by one or more of the following: requisite treatment with diuretic or vasodilator therapy, presence of rales or third heart sound on examination, persistent sinus tachycardia, or radiographic evidence of pulmonary congestion) or evidence of decreased myocardial reserve (left ventricular ejection fraction <35%, left ventricular end-diastolic diameter >65 mm, new anterior wall Q-waves, or reinfarction with preexisting anterior Q-waves). Significant hypotension (SBP <100 mm Hg), active ACE or angiotensin II inhibition, unstable angina (without infarction), significant valvular stenosis, hemodynamically significant dysrhythmia, and planned coronary revascularization were exclusion criterion. Eligible patients were randomized to receive either losartan (n=2744, titrated to a target dose of 50 mg daily) or captopril (n=2733, titrated to a target dose of 50 mg 3 times per day). The primary end point was all-cause mortality within an intention-to-treat analysis. The secondary end point was a composite of sudden cardiac death or resuscitated cardiac arrest, and the tertiary end point was fatal or nonfatal reinfarction.
Results:
By the completion of a mean follow-up of 2.7 years, a nonsignificant trend favoring a reduction in mortality with captopril therapy over losartan therapy was identified (16.4% vs 18.2%, P=0.07). Similarly, a trend favoring captopril was identified in cardiac death/arrest (7.4% vs 8.7%, P=0.072). No significant difference was identified between captopril or losartan therapy in fatal/nonfatal reinfarction (13.9% vs 14.0%, P=0.72). The incidence of the other clinically important outcomes—need for revascularization (n=1672, P=0.62), stroke (n=272, P=0.59), and all-cause hospitalization (n=3580, P=0.36) were essentially identical between the groups. As anticipated, losartan was significantly better tolerated than captopril therapy leading to increased compliance of the former: only 458 patients within the losartan group (17%) discontinued therapy (with one patient lost to follow-up), as compared with 624 captopril patients (23%, P<0.0001).
Summary:
In high-risk patients with acute myocardial infarction, there is a mortality trend favoring captopril over losartan. Accordingly, losartan noninferiority is not supported, suggesting that ACE inhibition should remain first-line therapy within this patient population. The issue of higher losartan doses will have to be examined in the future.
Congestive Heart Failure
The Extended Studies of Left Ventricular Dysfunction (XSOLVD): Enalapril Improves Survival and Life Expectancy in Patients With Reduced Left Ventricular Ejection Fractions
Presenter:
Salim Yusuf, MBBS, DPhil (McMaster University, Hamilton, Ontario, Canada); Philip Jong (McMaster University, Hamilton, Ontario, Canada)
Purpose:
To determine whether the previously identified mortality reductions with enalapril in the landmark SOLVD trial were sustained beyond the active trial period out to 12-year follow-up.
Study:
The SOLVD trials randomized two distinct patient populations to enalapril vs placebo: the Treatment Trial enrolled 2569 patients with symptomatic congestive heart failure, whereas the Prevention Trial enrolled 4228 patients with asymptomatic left ventricular systolic dysfunction. At the completion of both trials (at an average of 3.2 years of follow-up), the incidence of myocardial infarction and congestive heart failure admission were reduced, but only the Treatment trial demonstrated a significant decrease in mortality (with a nonsignificant trend in the mortality curves favoring enalapril therapy in the Prevention trial). XSOLVD extended the survival follow-up to 12 years to determine whether the mortality benefit in the Treatment trial was sustained and whether the initial reduction in morbidity documented in the Prevention trial were translated into a survival benefit over time. The investigators were able to determine the vital status of 99.8% of the original participants. The average duration of follow-up was 12.1 years in the Treatment trial and 11.2 years in the Prevention trial.
Results:
The cumulative 12-year survival among patients in the Prevention trial was significantly improved with enalapril therapy; although this survival benefit was only marginal at the original (average of 3.2 years) completion of the active phase of the trial (86% vs 84%), this benefit persisted and widened beyond the active phase of the trial with 77% vs 73% at 5 years and 47% vs 41% at 12 years; analysis of the 12-year Kaplan-Meier survival curves revealed a significant improvement in survival with enalapril therapy (P=0.001). The average increase in median life expectancy from enalapril therapy was 9.2 months (95% CI 0 to 19.2 months, P=0.05). In contrast, the benefit from enalapril in the Treatment trial was most pronounced at the (average 3.2 years) completion of the active phase of the study (64% vs 60%)—a benefit which persisted for 4.9 years—with a subsequent decreasing incremental benefit (convergence of curves) of enalapril therapy over time, including 53% vs 49% at 5 years and 21% vs 20% at 12 years. Despite this diminishing clinical benefit, analysis of the 12-year Kaplan-Meier survival curves again revealed an overall significant benefit associated with enalapril therapy (P=0.01). The median increased life expectancy within enalapril-treated patients in the Treatment trial was 8.6 months (95% CI 1.0 to 17.3 months, P=0.03). Combined analysis of these protocols revealed a 9.4-month increase in median life expectancy (95% CI 2.8 to 16.5 months, P=0.004). This decrease in mortality was primarily driven by an enalapril-associated decrease in cardiovascular death (47% vs 51.2%, P=0.0001).
Summary:
Extended follow-up of the SOLVD patient populations demonstrate sustained mortality benefit at 12 years in both the Prevention Trial and the Treatment Trial.
Endothelin Antagonist Receptor Trial in Heart Failure (EARTH)
Presenter:
I.S. Anand, MD, DPhil (Veterans Affairs Medical Center, Minneapolis, Minn); Thomas F. Lüscher, MD (University Hospital, Zurich, Switzerland)
Purpose:
This trial sought to determine the effect of treatment with the endothelin A antagonist darusentan (in addition to standard therapy with angiotensin converting enzyme inhibition and ß-blockade) on left ventricular remodeling in congestive heart failure.
Study:
642 patients with left ventricular ejection fraction <35% and class II-IV congestive heart failure were randomized to receive either darusentan (1 of 5 doses: 10 mg, 25 mg, 50 mg, 100 mg, or 300 mg daily) or placebo. 458 of these participants completed the 24-week treatment phase of the trial. The primary end point was change in left ventricular end-systolic volume as assessed by high resolution MRI. The secondary end points included 6-minute walk distance.
Results:
Although a dose-related trend was demonstrated favoring reduction of left ventricular end-systolic volume with darusentan therapy, this effect was weak and nonsignificant. Similarly, the results of the 6-minute walk also nonsignificantly favored darusentan therapy. There were no apparent adverse effects associated with darusentan therapy.
Summary:
No convincing benefit of endothelin antagonism (on top of standard therapy) was identified in these patients with dilated cardiomyopathy with respect to either LV remodeling or exercise tolerance.
Carvedilol ACE Inhibitor Remodeling Mild CHF EvaluatioN (CARMEN)
Presenter:
Willem J. Remme, MD, PhD (STICARES Cardiovascular Research Foundation, Rhoon, the Netherlands)
Purpose:
To determine the relative individual and additive effects of carvedilol monotherapy, enalapril monotherapy, and combination therapy on left ventricular remodeling and function in patients with mild congestive heart failure.
Study:
A total of 572 patients with mild congestive heart failure who were on stable doses of diuretics and digoxin were randomized into one of 3 double-blinded treatment arms: carvedilol/enalapril, carvedilol/placebo, or enalapril/placebo. After two up-titration phases, the patients were monitored for 18 months. The primary end point was the comparison of the left ventricular end-systolic volume index (LVESVI) between treatment arms.
Results:
In examining the effect of treatment over time, only carvedilol monotherapy and the combination therapy experienced a decrease in the LVESVI over time. There was a nonsignificant trend favoring improvement with carvedilol monotherapy over the least beneficial therapy of enalapril monotherapy. Combination therapy (carvedilol/enalapril) resulted in significant improvement in LVESVI versus enalapril monotherapy (P<0.002).
Summary:
Combination therapy with carvedilol and enalapril results in significant improvement in LVESVI, a marker of left ventricular remodeling and function. All three treatments arms showed a very similar safety and tolerability profile, which argues against the common perception that ß-blockade is less tolerated than ACE inhibition in this prevalent disease.
Trans-European Network—Home Monitoring Study (TEN-HMS)
Presenter:
John G.F. Cleland, MD (University of Hull, Kingston-on-Hull, Great Britain)
Purpose:
To test the hypothesis that the use of an outpatient telemonitoring system would lead to clinical improvement when compared with standard-of-care management in patients with moderate to severe congestive heart failure (CHF).
Study:
The study population consisted of patients with class II-IV New York Heart Association CHF actively treated with loop diuretics (
40 mg daily of furosemide or equivalent) with known ventricular dilatation (left ventricular end-diastolic diameter 30 mm/m2) and left ventricular systolic dysfunction (left ventricular ejection fraction <40%). Additionally, this patient population had unstable CHF—as defined by a planned or recent (<6 weeks prior) hospital discharge for decompensated CHF and either one or more admissions in the past 2 years—or severe CHF (as defined by a left ventricular ejection fraction of <25% or a furosemide requirement of >100 mg daily). Eligible patients were randomized to receive one of three outpatient treatment strategies: (1) interactive health care services by telemonitoring (as described below); (2) outpatient standard-of-care for CHF (usual care arm, administered by the patient’s primary care physician); or (3) usual care optimized via monthly telephone contact from a designated CHF nurse specialist assisting the patient’s primary care physician (nurse telephone arm). The telemonitoring arm consisted of automated daily transmittal of the patient’s clinical information (including home blood pressure, daily weight measurements, and a rhythm strip) to a computerized clinical server managed by a nurse and a supervising physician who could respond to the patient either verbally (by phone) or via therapeutic changes administered by a rapid delivery system. The patients were randomized 2:1:2 to the telemonitoring, usual care, and nurse telephone arms of the study. The primary end point was a comparison of a composite of the average days alive out-of-hospital (expressed as a percent of the total number of possible days). The secondary end points were re-hospitalization and duration of hospitalization. The patients were monitored for an average of 450 days after randomization.
Results:
Although the results exhibited a trend in the composite end point (combining mortality as well as frequency and duration of hospitalization) favoring the nurse telephone (77%* alive and out-of-hospital) and telemonitoring treatment (80%*) when compared with usual care (65%*), there was no specific difference favoring either of the former two modalities over the other. Also, annual mortality was reduced from 25% in the usual case group to 13% in the nurse telephone and telemonitoring groups (P<0.03). However, additional analyses showed superiority of telemonitoring over phone contact alone with respect to the total number of days hospitalized (
12 days vs 16 days during the first 360 days of the study).
Summary:
Close outpatient monitoring (either by scheduled monthly contact or with telemonitoring) leads to improved clinical outcomes in patients with moderate to severe congestive heart failure.
*Interval 0–360 days.
Interventional Cardiology
EUROpean Sonotherapy Prevention of Arterial Hyperplasia (EURO-SPAH)
Presenter:
Patrick W. Serruys, MD (Thoraxcenter, Rotterdam, the Netherlands)
Purpose:
To investigate whether intravascular sonotherapy decreases the restenosis rate in patients undergoing de novo stenting.
Study:
A multicenter (23 centers in 9 countries) study that enrolled 403 patients undergoing de novo stenting. The patients were randomized to receive either adjunctive intravascular sonotherapy or a sham procedure (in which the sonotherapy catheter was introduced into the lesion, but not activated). Importantly, the study was double-blinded (in that neither the patient nor the treating physician had knowledge of whether adjunctive sonotherapy was administered). All patients were treated with a 30-day course of antiplatelet therapy post-stenting per standard-of-care. The patients were monitored for clinical events for 6 months. The primary end point was late luminal loss (with the goal that sonotherapy would decrease the late luminal loss by 25%). The secondary end points were mortality, major adverse cardiac events (MACE), and repeat revascularization.
Results:
In total, 95.3% of the patients randomized to receive adjunctive sonotherapy successfully received the treatment. Angiographic follow-up was obtained in approximately 90% of the study population. Although the study failed to demonstrate a significant reduction in late luminal loss after sonotherapy, a trend favoring sonotherapy was exhibited with a 0.08-mm reduction in late luminal loss. Additionally, although there was no difference between the groups with respect to mortality, a 27% reduction in MACE was identified within the sonotherapy-treated group. Most strikingly, sonotherapy was associated with a significantly decreased rate of requisite repeat revascularization (despite blinding of therapeutic arm to both the individual patients and treating physicians)—as determined by clinical and angiographic determinants—with 14.4% of the treated and 23.4% of the sham patients undergoing revascularization (RR 0.61, 95% CI 0.4 to 0.9, P=0.02), representing a 39% reduction in the rate of repeat revascularization with adjunctive sonotherapy. There were no complications associated with the sonotherapy.
Summary:
Although failing to demonstrate a significant angiographic reduction in late luminal loss, adjunctive sonotherapy (to reduce restenosis) was associated with a significant reduction in MACE and repeat revascularization. The larger-scale Sound Wave Inhibition of Neointimal Growth (SWING) trial (within which the patients from EURO-SPAH will be included) will further clarify the potential benefit of this technique.
Balloon Equivalent to Stent Study (Best); Intravascular Ultrasound-Guided Balloon Angioplasty Compared With Systematic Stent Implantation: Immediate and 6-Month Results of the Multicenter, Randomized Best Study.
Presenter:
Francois Schiele, MD, PhD (University Hospitals of Besançon, Besançon, France)
Purpose:
To compare the intravascular ultrasound (IVUS), clinical, and angiographic outcome of systematic stent use when compared with IVUS-guided balloon angioplasty with the idea that the latter (if as clinically effective acutely) may avoid the risk of subsequent in-stent restenosis.
Study:
A randomized, multicenter, one-sided, noninferiority design comparing systematic stenting (n=122) with IVUS-guided balloon angioplasty (n=132). The equivalence lower boundary was set to a <8% difference in restenosis rate. The criteria dictating the crossover from IVUS-guided balloon angioplasty to stenting were defined by both on-line quantitative angiography (set at a >30% residual stenosis) and by IVUS measurement (a >30% area stenosis or a minimal cross sectional area of <6 mm2); notably, TIMI III blood flow and dissection were not criteria for crossover to stenting. Stent implantation was performed under angiographic guidance per standard of care. In the balloon group, balloon sizing was determined by IVUS (pre-PTCA) measurements with the balloon inflation pressure dictated by its compliance curve for diameter. The four clinical end points were: (1) the 6-month angiographic restenosis rate; (2) the 6-month angiographic minimal luminal diameter; (3) the 6-month IVUS minimal lumen cross sectional area; and (4) the 1-year clinical event-free rate.
Results:
The baseline minimal luminal diameter (1.07-mm PTCA vs 1.08-mm stent, P=NS) and lesion length (10.6-mm PTCA and 9.7-mm stent, P=NS) were similar between groups. The procedural outcomes were different between the PTCA and stenting groups in several ways. IVUS-guided balloon sizing allowed for a significantly larger balloon nominal size in the PTCA group (3.60 mm) when compared with the stenting group (3.37 mm, P=0.003), which may be even more significant when the non-negligible stent width is added to this difference. However, non-IVUS stenting allowed for significantly shorter procedure duration (39 vs 51 min, P=0.001), less associated fluoroscopy time (9 vs 11 min, P=0.02), less total contrast (158 vs 192 cc, P=0.01), increased maximal inflation pressure (14.5 vs 13.3 ATM, P=0.02), and decreased residual stenosis (13% vs 18%). GP IIb/IIIa inhibition was not significantly different between groups (11.3% in PTCA group and 6.5% in stenting group, P=NS). Importantly, 44% of the PTCA group required crossover to stenting (by the predefined criteria, as above). At 6-month follow-up, no significant difference was identified between the IVUS-guided PTCA and stent groups in the minimal luminal diameter (1.97 vs 2.03 mm, P=0.38), or residual stenosis (31% vs 28%, P=0.14). Although significantly less in-stent restenosis occurred in the PTCA group (5.0% vs 15.6%, P=0.045) due to 56% less stent placement during revascularization, the overall restenosis rate was comparable between the groups (16.8% vs 18.1%, P=0.70).
Summary:
IVUS-guided PTCA with IVUS-guided provisional stenting is safe and is associated with long-term results comparable with routine stenting despite avoiding stent use in 56% of cases. Although the rate of in-stent restenosis is lower when fewer stents are employed, the overall restenosis rate was not improved by this method. The cost savings associated with less stent deployment come at a cost of a more complex, operator-dependent, and longer procedures with the additional caveat that the operator must be comfortable leaving dissections unstented. The impact of this strategy may need to be further evaluated in the coming era of drug-eluting stents.
Cardiovascular Surgery
Transplantation of Autologous Skeletal Myoblasts-Feasibility Study and Phase I Clinical Trial Results
Presenter:
Tomasz L. Siminiak, MD, PhD (University School of Medical Science, Poznan, Poland)
Purpose:
This study examined the safety and feasibility of utilizing a technique for implanting autologous skeletal myoblasts into infarcted segments during concomitant surgical revascularization in patients with postinfarction heart failure.
Study:
Low-risk patients scheduled for coronary artery bypass grafting (CABG) with postinfarction heart failure were enrolled in this Phase I study. The patients underwent simple muscle biopsy before elective CABG which allowed establishment of a myoblast cell culture. Thereafter, skeletal myoblast transplantation was performed via injection of these cells into an (nonrevascularizable) infarcted segment intraoperatively (during concomitant CABG) which was determined to be either akinetic or dyskinetic on preoperative dobutamine transthoracic echocardiographic stress testing. These patients were subsequently monitored for clinical events and, additionally, underwent repeat, postoperative dobutamine stress echocardiography.
Results:
Ten low-risk patients with postinfarction heart failure requiring elective surgical revascularization underwent the skeletal myoblast transplantation procedure, as outlined above. One death occurred on postoperative day 7 that was attributed (by autopsy) to a new infarction in a nontreated, previously normokinetic segment. The primary complication identified was sustained ventricular tachycardia in two patients that were successfully treated with cardioversion and perioperative amiodarone. Prophylactic amiodarone in subsequent patients prevented the further occurrence of arrhythmia. Follow-up echocardigraphy revealed increased contractility in several treated segments; the left ventricular ejection fraction rose postoperatively in all 9 surviving patients.
Summary:
This phase I trial of skeletal myoblast transplantation (intraoperatively during concomitant surgical revascularization) in low-risk patients with postinfarction heart failure demonstrates the feasibility and relative safety of this approach and warrants further investigation. Phase II trials of this procedure are presently being initiated.
PRAGUE 4 Beating Heart (Off-Pump) Versus Classical (On-Pump) Coronary Bypass Surgery
Presenter:
Petr Widimsky, MD, DrSc (University Hospital Vinohrady, Prague, the Czech Republic)
Purpose:
To compare the clinical outcomes between off-pump (no aortopulmonary bypass) to standard on-pump techniques during coronary artery bypass grafting (CABG) surgery.
Study:
A randomized, open, single-center study in nonselected (consecutive) patients requiring CABG (including patients presenting with acute coronary syndromes) randomized to either the standard on-pump or to the evolving off-pump technique. The primary end point was the 30-day incidence of death, myocardial infarction, stroke, or hemodialysis.
Results:
Of the 208 patients randomized to the off-pump procedure, 204 patients underwent surgery with 31 patients crossing over to the on-pump procedure. Conversely, of the 192 patients randomized to the on-pump procedure, 184 patients underwent surgery, with 12 patients crossing over to the off-pump procedure. There was no significant benefit in primary end point (as defined above) between groups in the intention-to treat analysis (3.8% on-pump, 2.9% off-pump). Analysis by the actual treatment utilized revealed a trend in the primary end point favoring the off-pump technique (1.6%) over the on-pump technique (4.9%, P=0.12). The off-pump procedure resulted in beneficial indices with respect to length of intubation (4.5 vs 12.9 hours), hospital duration (5.8 vs 6.8 days), estimated blood loss (623 vs 782 mL), and total cost (3777 vs 5757 Euro). The on-pump procedure, however, allowed for more distal anastomoses (2.8 vs 2.1).
Summary:
In this relatively small, randomized experience, off-pump surgery appears to be at least as clinically effective and safe as on-pump surgery at a lower economic cost.
Arrhythmia
Anticoagulation for Cardioversion with Enoxaparin (ACE)
Presenter:
Christoph Stellbrink, MD (University Hospital Aachen, Germany)
Purpose:
To test the hypothesis that anticoagulation with subcutaneous enoxaparin is as clinically effective for thromboembolic prophylaxis as the standard method of unfractionated heparin (UFH) bridging to oral anticoagulation in patients with atrial fibrillation (AF).
Study:
Enrolled patients had either acute AF (with clinical symptoms for >48 hours) or chronic AF (of 3 months but <1 year duration which included asymptomatic patients) and were suitable candidates for electrical cardioversion. Exclusion criteria included acute neurological symptoms (transient ischemic attack, cerebrovascular accident, or intracranial hemorrhage), other thromboembolic events, aspirin therapy of >325 mg daily, or other indication(s) for permanent oral anticoagulation. Two separate protocols were tested: one without transesophageal echocardiographic (TEE) guidance (Stratum A) and the other with TEE guidance (Stratum B). Stratum A randomized the patients to 21 days of anticoagulation with either subcutaneous enoxaparin or intravenous UFH as a bridge to oral phenprocoumon (PPC) anticoagulation; electrical cardioversion was performed on day 21 followed by an additional 28 days of continued anticoagulation per initial randomization. Stratum B differed by performing a TEE immediately after randomization (again to either enoxaparin or UFH/PPC); if no left atrial thrombus was identified during TEE, the patient proceeded to immediate cardioversion with continuation of assigned anticoagulation; if atrial thrombus was identified, the patient was first treated with the assigned anticoagulation for 21 days followed by repeat TEE; patients with persistent thrombus were excluded from the trial (with clinical continuation of anticoagulation); absence of thrombus on repeat TEE prompted cardioversion with subsequent continuation of assigned anticoagulation for 28 days. The primary end point was a composite of cerebral ischemic neurologic events, systemic thromboembolism, death from any cause, and major bleeding complications. Secondary end points were: successful cardioversion, persistent sinus rhythm at study completion, other (nonmajor) bleeding complications, injection hematomas (>5 cm), or other adverse events. The results were analyzed utilizing a noninferiority design.
Results:
The enoxaparin (n=248) and UFH/PPC (n=248) groups were matched for age (66 vs 65 years old, P=NS), gender (61% male in both groups), underlying coronary artery disease (31% vs 29%, P=NS), hypertension (73% in both groups), left atrial diameter (44 mm in both groups), left ventricular hypertrophy (37% vs 43%, P=NS), AF duration (15 vs 11 days, P=NS), and antiarrhythmic treatment. The only notable difference between the study populations was a higher prevalence of congestive heart failure in the enoxaparin group when compared with the UFH/PPC group (33% vs 24%, P=0.037). Utilizing an intention-to-treat analysis, the combined event rate (as defined above) was similar between the enoxaparin (3.2%) and the UFH/PPC (5.7%) groups; the hypothesis that enoxaparin thromboembolic prophylaxis was not inferior to UFH/PPC anticoagulation was proven with statistical certainty (P=0.016).
Summary:
Enoxaparin for cardioversion of nonvalvular AF provides comparable outcomes to UFH/PPC for the prevention of thromboembolism and is not associated with increased bleeding complications.
EaSyAS (Eastbourne Syncope Assessment System)
Presenter:
Neil Sulke, MD (Eastbourne General Hospital, Eastbourne, Great Britain)
Purpose:
This study was designed to determine whether implantable loop recorders (ILR) could be utilized to increase the diagnostic and therapeutic rate of patients with recurrent syncope.
Study:
Patients who presented during the study period (16 consecutive months) with recurrent (>1 episode) of unexplained syncope were randomized to receive either an ILR (n=103) or routine diagnostic testing (n=98). The patients were monitored for clinical events for at least 6 months (mean 10 months). The primary end point was the time to ECG diagnosis. The secondary end points were the time to recurrent syncope, the time to initiation of therapy (drug/device), and quality-of-life indices.
Results:
ILR patients were significantly more likely to have an etiology of syncope diagnosed (33% vs 4%, P=0.00000005) with the primary diagnoses being bradycardia and vasovagal syndrome. Sixty percent of the cost of the device was saved in hospital-related costs associated with this early diagnosis within 9 months of study enrollment. However, despite the more frequent and earlier definitive diagnoses, there was no change in the quality-of-life indices after 6 months.
Summary:
Although implantation of ILR allowed for more frequent and early diagnosis of dysrhythmia-based recurrent syncope, this information did not improve the quality of life among ILR patients. Additional follow-up data will be forthcoming.
Hypertension
Omapatrilat Cardiovascular Treatment Assessment Versus Enalapril (OCTAVE) Subgroup Analysis of Patients With Atherosclerotic Disease
Presenter:
Michael A. Weber, MD (SUNY Downstate College of Medicine, Brooklyn, New York)
Purpose:
To reexamine the data from OCTAVE to assess whether there may be a more favorable risk:benefit ratio of dual ACE/NEP inhibition with omapatrilat over enalapril in the higher-risk subgroup of hypertensive patients with preexisting atherosclerosis
Study:
Of the 25 000 patients originally enrolled in OCTAVE, 2371 (9%) had documented atherosclerosis (as defined by prior MI, classic stable angina, or history of stroke/TIA). Per the original protocol, this subgroup was further categorized into: (1) those with incident treatment for hypertension (n=368); (2) patients with a history of hypertension who were normotensive on an active antihypertensive regimen (before being switched to the study regimen during randomization, n=1122); and (3) patients with uncontrolled hypertension (failing therapy) before the addition of study drug during randomization (n=793). The patients were treated (with omapatrilat vs enalapril) for 24 weeks per the original OCTAVE protocol design.
Results:
As in the overall OCTAVE population, in the subgroups of patients with atherosclerosis, omapatrilat treatment was associated with a significantly greater reduction in systolic blood pressure (SBP) compared with enalapril but also with increased risk of angioedema. In the subgroup undergoing incident therapy for hypertension, the absolute reduction in SBP was 24.8 mm Hg with omapatrilat vs 20.2 mm Hg with enalapril (P=0.007). Similarly, the subgroups undergoing replacement therapy for controlled hypertensive experienced a significant reduction in SBP (14.5 mm Hg vs 11.8 mm Hg) with omapatrilat (P=0.007) whereas only a nonsignificant trend was present in the uncontrolled hypertensive group (27.6 mm Hg vs 25.7 mm Hg, P=0.117). The overall incidence of angioedema in this high-risk population was 1.18% with omapatrilat compared with only 0.60% with enalapril.
Summary:
In the subgroup of patients with preexisting atherosclerosis, the risk-benefit ratio of omapatrilat therapy is somewhat more favorable than in the general hypertensive population with a reduction of 30 CV events per 10 000 patient-years over enalapril therapy despite a concomitant predicted risk of only 6 resultant cases of severe angioedema.
Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Isolated Systolic Hypertension Subgroup
Presenter:
Sverre E. Kjeldsen, MD, PhD (Division of Hypertension, University of Michigan Hospital, Ann Arbor, Mich, and Department of Cardiology, Ullevaal University Hospital, Oslo, Norway)
Purpose:
To determine whether losartan has a particular protective effect (over atenolol) in patients with isolated systolic hypertension (ISH).
Study:
A retrospective prespecified sub analysis of ISH patients (n=1326) in the LIFE trial (comparing losartan and atenolol in 9193 patients with hypertension); 660 were randomized to losartan therapy and 666 to atenolol therapy. Specific events of cardiovascular mortality, fatal/nonfatal MI, and fatal/nonfatal stroke were compared between treatment groups.
Results:
In ISH patients, the risk of cardiovascular mortality was significantly reduced with losartan treatment (8.7% vs 16.9% with atenolol, RRR=0.46, P=0.01) with Kaplan-Meier survival curves exhibiting early divergence. The risk of fatal/nonfatal stroke was reduced significantly with losartan therapy (10.6% vs 18.9% with atenolol, RRR=0.41, P=0.02). A nonsignificant trend favoring losartan was identified in fatal/nonfatal (RRR=0.13).
Summary:
Losartan is more effective than atenolol for the primary prevention of cardiovascular mortality and stroke in patients with isolated systolic hypertension.
Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Atrial Fibrillation Subgroup
Presenter:
Björn Dahlöf, MD, PhD (University of Göteborg, Göteborg, Sweden)
Purpose:
To determine whether losartan-based therapy has a particular protective effect (over atenolol-based therapy) in patients with atrial fibrillation.
Study:
Reanalysis of the subgroup of patients with atrial fibrillation (n=324) who had enrolled in the previously reported LIFE trial (which randomized a total of 9193 patients with hypertension and left ventricular hypertrophy on electrocardiogram to either losartan or atenolol).
Result:
In patients with atrial fibrillation, losartan was associated with a significant 49% relative risk reduction in the risk of stroke when compared with atenolol therapy. Losartan therapy was also associated with a significant reduction in left atrial dimension when compared with atenolol.
Summary:
In hypertensive patients with atrial fibrillation, losartan therapy is superior to atenolol in reducing left atrial dimension and in decreasing significantly the risk of stroke.
Atherosclerosis
Antibiotic Therapy After an Acute Myocardial Infarction (ANTIBIO)
Presenter:
Ralf Zahn, MD (Herzzentrum Ludwigshafen, Germany)
Purpose:
To reexamine the effect of macrolide therapy (roxithromycin) in the secondary prevention of cardiac events in patients with acute myocardial infarction (AMI).
Study:
Patients with AMI (admitted to the hospital <48 hours after symptom onset) were randomized (within 5 days after admission) to receive either a 6-week course of roxithromycin (300 mg daily) or placebo and were monitored for a total of 12 months. The primary end point was total mortality at 12 months. The secondary end points were major adverse cardiac events (MACE) including death, MI, resuscitation, stroke, or angina leading to hospitalization—both at hospital discharge and at 12-month study completion—as well as recurrent revascularization. Most patients received aspirin, ß-blocker, ACE inhibitor, and statin therapy per standard-of-care.
Results:
Although the study planned enrollment of 3922 patients, slow patient accrual (and lack of clinical benefit) led to termination of the study at 872 patients by the steering committee. No significant difference in overall mortality at 12 months was identified between patients treated with roxithromycin (6.5%) and placebo (6.0%, n=0.74). Similarly, no significant reduction was seen in MACE with macrolide therapy at either discharge from incident hospitalization (18.7% vs 14.1%, P=0.07, a trend favoring placebo) or at 12 months (27.8% vs 23.2%, P=0.110). Recurrent revascularization also was not decreased by macrolide therapy (56% vs 53%, P=0.621).
Summary:
No significant benefit was observed in patients with AMI treated with the macrolide roxithromycin with respect to 12-month mortality, need for revascularization, or total acute or one year MACE.
Perindopril Protection Against Recurrent Stroke Study (PROGRESS) Substudy
Presenter:
Anushka Patel, MBBS, SM (Institute for International Health, University of Sydney, Sydney, Australia)
Purpose:
To reexamine data from the PROGRESS study (in patients with previous stroke or TIA) to determine whether an ACE–inhibitor-based regimen will also favorably impact coronary artery disease and congestive heart failure events.
Study:
The original PROGRESS trial enrolled patients with previous stroke or transient ischemic attack who first participated in a 4-week run-in period on perindopril to establish drug tolerability. Subsequently, eligible patients were randomized to either perindopril 4 mg daily (with the addition of the thiazide diuretic indapamide 2.5 mg daily at the discretion of the study investigators) or matching placebo(s). The primary end points of this sub analysis were major coronary events (nonfatal MI or death due to coronary artery disease) and congestive heart failure events (death, hospitalization, or discontinuation from protocol). The average duration of follow-up was 4 years.
Results:
The incidence of major coronary events was reduced significantly with ACE inhibitor-based therapy (RRR=26%, 95% CI 6% to 42%, P=0.016). Reduction in risk of major coronary events appeared greater with combination therapy (RRR 35%, 95% CI 12% to 52%) compared with monotherapy (RRR 7%, 95% CI -37% to 38%), al- though the confidence intervals were wide, and the statistical test for heterogeneity was nonsignificant. Congestive heart failure events were decreased significantly with ACE inhibitor-based therapy (RRR=26%, 95% CI 5% to 42%, P=0.01).
Summary:
In patients with prior history of TIA or stroke, a drug regimen of perindopril ± indapamide was associated with a reduction in the risk of coronary and congestive heart failure events. Importantly, for all outcomes, the treatment effect was similar in hypertensive and nonhypertensive individuals, as well as in those with or without known coronary artery disease at baseline.
Footnotes
The following studies were presented at the 24th Congress of the European Society of Cardiology in Berlin, Germany, September 1–4, 2002.
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