Highlights from the American College of Cardiology 49th Annual Scientific Sessions: March 12 to 15, 2000☆☆☆
Article Outline
Session
Late-Breaking Trials in Interventional Cardiology
Study:
High dose eptifibatide (Integrilin) in elective coronary stenting: Results of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial
Presenter:
Dr James E. Tcheng, Duke University Medical Center, Durham, NC
Results:
Several clinical trials have demonstrated that glycoprotein IIb/IIIa receptor blockade improves clinical outcomes after percutaneous coronary intervention (PCI). Only one study,1 however, has formally evaluated adjunctive glycoprotein IIb/IIIa inhibition in the setting of coronary stent implantation, even though stents are now used in more than 80% of all percutaneous interventions. Moreover, in the clinical trials performed to date, eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has appeared to be less potent than the monoclonal antibody abciximab. It has since been recognized that an approximately 4 times higher dose of eptifibatide than that used in the Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis–II (IMPACT-II) trial would be required to achieve maximal platelet inhibition in coronary interventions. The ESPRIT trial was designed to test the safety and efficacy of an adjunctive, high-dose, double-bolus regimen of eptifibatide in coronary stenting. Patients with known coronary artery disease who were scheduled to undergo elective PCI with stent implantation in a native coronary artery and who, in the opinion of the treating physician, would not routinely be treated with a IIb/IIIa inhibitor, were eligible for inclusion. Patients with a myocardial infarction (MI) within 24 hours before randomization were excluded from the trial. Patients were randomly assigned to receive either placebo or eptifibatide started immediately before PCI. Eptifibatide was given as two 180-μg/kg boluses 10 minutes apart and as a continuous infusion of 2.0 μg/kg per minute (or 1.0 μg/kg per minute in patients with serum creatinine >2.0 mg/dL) started at the same time as the first bolus and continued for 18 to 24 hours. All patients received concomitant aspirin. A weight-adjusted heparin regimen was recommended (initial bolus of 60 U/kg, not to exceed 6000 U) with a target activated clotting time between 200 and 300 seconds. Treatment with ticlopidine or clopidogrel was strongly encouraged on the day of the procedure but not before then; the use of a loading dose was also encouraged.
It was originally planned to enroll 2400 patients at sites throughout North America. The trial was discontinued prematurely, however, by the Data and Safety Monitoring Board because of the impressive treatment benefit in the eptifibatide treatment group. Baseline characteristics between groups were similar. The primary end point of death, MI, urgent target vessel revascularization, or thrombotic bailout IIb/IIIa inhibitor therapy at 48 hours was reached in 10.5% of patients treated with placebo (n = 1024) and 6.6% of eptifibatide-treated patients (n = 1040), a 37% event reduction (P = .0015). The composite of death and MI at 48 hours was reduced by 40% (9.2% vs 5.5%; P = .0013). The benefit of eptifibatide in reducing the primary end point was consistent across subgroups including those with diabetes (6.6% vs 3.8%) and women (14.5% vs 6.1%) and was similar between the lowest (10.0% vs 6.1%) and highest (10.3% vs 7.0%) tertiles of activated clotting time. The major and minor bleeding rates in placebo- and eptifibatide-treated patients (by the TIMI classification) were 0.4% versus 1.4% and 1.8% versus 2.8%, respectively, with most bleeding occurring at the vascular access site. Profound thrombocytopenia (<20,000) occurred in 0.2% of eptifibatide-treated patients.
Interpretation:
A new, high-dose 180/2/180 eptifibatide regimen significantly reduced the incidence of death and myocardial infarction in the 48 hours after elective coronary artery stenting. The treatment benefits were not accompanied by any significant increase in severe bleeding complications. Follow-up is ongoing to quantify long-term outcomes.
Session
Late-Breaking Clinical Trials III
Study:Stent-PAMI: 12-month follow-up results
Presenter:Dr Cindy L. Grines, William Beaumont Hospital, Royal Oak, Mich
Results:Implantation of coronary stents has been shown to reduce the incidence of restenosis and target vessel resvascularization (TVR) compared with balloon angioplasty. The major goals of acute myocardial infarction reperfusion trials have been an improvement in Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow and concomitant decrease in mortality rate. The long-term effects of stenting in this population are not known.
In the Stent-PAMI study, patients presenting within 12 hours of an acute myocardial infarction who were stent eligible were randomly assigned to either primary percutaneous transluminal coronary angioplasty or angioplasty and implantation of a heparin-coated Palmaz-Schatz stent. Baseline demographics were not significantly different between the 2 groups. At 1 year there was a significant reduction in ischemic TVR in the stent arm (10.6% vs 21%, P = .0001). There was no difference in the rate of reinfarction or disabling cerebral vascular accident between the 2 groups. Importantly, there was a trend toward increased mortality rate in the stented group of patients (5.8% vs 3.1%, P = .07). This difference was seen primarily in patients who achieved TIMI 3 flow (4.5% vs 2.3%, P = .075). Significant predictors of increased 1-year mortality rate included in-hospital coronary artery bypass grafting, TIMI grade 0 to 2 flow, age >70 years, female sex, and left anterior descending coronary artery infarct. When these high-risk variables were considered, the trend toward increased mortality rate in the stented group persisted (9.1% vs 4.9%, P = .057).
Interpretation:Although stenting for acute myocardial infarction reduced the rate of ischemic TVR at 1 year, it was associated with a disturbing trend toward increased mortality rate (5.8% vs 3.1%, P = .07). Increased mortality rate in stented patients was associated with a lower achievement of TIMI grade 3 flow, though this did not fully account for the increase in the number of deaths. Even in patients achieving TIMI 3 flow, mortality rate was higher in the stented group.
Glycoprotein IIb/IIIa use was only 5% in the trial. Whether this adjunctive therapy will reverse the trend seen in Stent-PAMI awaits the final results of the CADILLAC trial, which had arms in which patients were randomly assigned to stenting plus IIb/IIIa inhibitor therapy.
Session
Late-Breaking Trials in Interventional Cardiology
Study:Intracoronary Stenting or Angioplasty for Restenosis Reduction in SMall ARTeries (ISAR-SMART)
Presenter:Dr Adnan Kastrati, Deutches Herzzentrum, Munich, Germany
Results:Although previous clinical trials have demonstrated a reduction in restenosis after stent deployment in percutaneous coronary intervention compared with plain angioplasty, eligibility for such studies has included a vessel diameter of 3 mm or greater. Whether the same advantage extends to stenting lesions in smaller arteries—which represent up to half of the coronary arteries treated with catheter-based techniques—remains controversial.
The German ISAR-SMART trial was designed to compare rates of restenosis with the strategy of routine stenting versus angioplasty with provisional stenting. The study randomly assigned 404 patients to either stent deployment (ACS Multi-Link) or routine angioplasty with the primary end point of angiographic restenosis (>50% stenosis) at 6-month follow-up. Inclusion criteria were evidence of ischemia in native vessels with a diameter of 2.0 to 2.8 mm. Fewer than 20% of the patients assigned to angioplasty underwent provisional stenting. All patients received periprocedural abciximab followed by aspirin and ticlopidine for 2 to 4 weeks. Despite significantly greater acute luminal diameter gain with routine stenting, no significant differences in rates of restenosis (35.7% stent, 37.5% percutaneous transluminal coronary angioplasty [PTCA]; P = .73) or target vessel revascularization (20.1% stent, 16.5% PTCA; P = .35) occurred between treatment strategies at 6 months. Survival free of myocardial infarction at 6 months also did not significantly differ (97.0% stent, 96.6% PTCA; P = .80).
Interpretation:The ISAR-SMART trial demonstrated that for lesions in small coronary vessels, use of glycoprotein IIb/IIIa inhibition with systematic stenting or plain angioplasty with provisional stenting is associated with equally favorable results. Further study is needed to explain why these results conflict with another contemporary trial (BESMART), which showed a benefit with small-vessel stenting.
Session
Late-Breaking Trials in Interventional Cardiology
Study:FGF-2 Initiating Revascularization Support Trial (FIRST)
Presenter:Michael Simons, Beth Israel Deaconess Medical Center, Boston, Mass
Results:As angioplasty sites restenose and bypass grafts fail, the segment of patients with coronary artery disease not amenable to conventional revascularization procedures will continue to grow. Many such patients are candidates for novel revascularization therapies such as treatment with angiogenic growth factors, yet early trial results with vascular endothelial growth factor (VEGF) have been disappointing.
The FGF Initiating Revascularization Support Trial (FIRST) is a phase II multicenter, placebo-controlled, double-blind comparison of 3 doses of recombinant fibroblast growth factor 2 (FGF-2) for patients with coronary artery disease ineligible for angioplasty or bypass surgery. The median age was 63 years; most patients were men with significant risk factors such as diabetes, hypercholesterolemia, prior infarction, or previous bypass surgery. Three hundred thirty-seven patients received placebo or a single intracoronary infusion of either 0.3, 3.0, or 30 μg/kg of FGF-2. The primary end point, exercise capacity measured by the exercise treadmill time at 90 days, did not significantly improve among treatment arms. However, patient and physician perceptions of angina assessed by the Seattle Angina Questionnaire (P = .057) and Canadian Cardiovascular Society Angina Classification appeared to improve with treatment (P = .09). Older patients and those with the greatest symptom impairment at baseline appeared to derive the greatest benefit. Overall, treatment was not associated with a reduction in nuclear perfusion parameters.
Interpretation:Similar to previous experience with VEGF, the FIRST trial failed to show improvement with FGF-2 for the primary end point of exercise treadmill time. Still, improvement in health-related measures of quality of life holds promise for further investigation with angiogenic growth factors. Since such therapies are likely designed to improve symptoms, further studies should clarify whether functional measures such as angina are a more discriminative end point than exercise time.
Session
Cardiac Function and Heart Failure
Study:Survival rates are similar between African-Americans and other races with heart failure
Presenter:Dr Stephanie H. Dunlap, University of Illinois, Chicago
Recently, published data from the Studies of Left Ventricular Dysfunction (SOLVD) prevention and treatment trials demonstrated that blacks with mild-to-moderate left ventricular dysfunction have a higher risk of death from heart failure and all-cause mortality than whites in both the prevention and treatment arms. Although the 2 groups were similar overall, blacks were more likely to be female, have a nonischemic cause of their left ventricular dysfunction, hypertension, diabetes, and prior stroke. Yet blacks were less likely to be treated with β-blockers than whites. The purpose of this study was to examine retrospectively the prognosis of blacks compared with whites among 680 patients with symptomatic heart failure from the University of North Carolina Heart Failure Database. Three-hundred and six (45%) of the subjects were black compared with 374 “other,” the majority of whom were white (360, or 96%); 210 (31%) patients were female and most had impaired left ventricular function (ejection fraction 25% ± 13%). Mean follow-up was 1.9 ± 2.1 years.
Results:Consistent with the results of the SOLVD investigators, blacks were more likely to have hypertension (67% vs 38%) and causes other than ischemia for their heart failure (14% vs 45%); however, left ventricular ejection fraction (26% ± 14% vs 26% ± 12%) and New York Heart Association class (2.8 ± 0.7 vs 2.9 ± 0.7) were similar in the 2 groups. Incidence of diabetes was not significantly different between blacks and whites (22% vs 23%, P = not significant). Coronary artery bypass graft surgery rates were significantly lower in blacks than whites (3% vs 45%, P < .01). This was caused by the marked difference in etiology of heart failure between the races, with 40% of blacks having hypertension as the sole identifiable cause compared with 12% in whites (P = .001). Unadjusted analysis found that blacks had a significantly lower mortality rate than whites (relative risk, 0.76; 95% confidence interval, 0.590-0.977; P = .032). Adjusted analysis, which included ejection fraction, age, sex, cause of heart failure, and New York Heart Association class found no difference in survival between blacks and whites (relative risk, 1.097; 95% confidence interval, 0.830-1.451; P = .514).
Interpretation:Although blacks were similar to whites in terms of their clinical characteristics in both the SOLVD trials and the present study, the prognosis was different. This study found no differences in adjusted survival between blacks and whites; however, it was limited by its small sample size and lack of data on therapy, and it represented a single institution’s experience. Additionally, the unadjusted lower survival in blacks is inconsistent with extensive epidemiologic data that show that blacks have higher cardiovascular mortality rates than whites. Although the results of this study are different from the results of the SOLVD trial, neither study examined whether there is an interaction between race and ischemia or “other” causes of heart failure. In fact, blacks and whites in these 2 studies were more dissimilar than similar with respect to the cause of heart failure and the prevalence of other clinical characteristics. Further studies will need to be conducted to define whether the natural history of CHF and response to conventional therapy is in fact different by race among a more homogeneous group of patients.
Session
Late-Breaking Clinical Trials
Study: Estrogen Replacement and Atherosclerosis (ERA) trial
Presenter:Dr David Herrington, Wake Forest University School of Medicine, Winston-Salem, Durham, NC
Results:Observational data and animal models of atherosclerosis suggest that estrogen therapy after menopause may lower coronary heart disease risk. However, the results of the HERS trial, the only large, randomized clinical trial to date to have addressed this issue, showed no reduction in myocardial infarction or death from coronary heart disease after 4.1 years of conjugated equine estrogen (CEE) and medroxy progesterone acetate in women with established heart disease.1 The Estrogen Replacement and Atherosclerosis trial was designed as a randomized, double-blind, placebo-controlled angiographic trial to study the effect of estrogen on coronary artery disease progression. Postmenopausal women with one or more coronary stenoses ≥30% were randomly assigned to receive estrogen (CEE 0.625 mg/d), estrogen and progestin combined (CEE 0.625 mg/d and medroxy progesterone 2.5 mg/d) or placebo. They were followed up for a mean of 3.2 years. Overall, there were no differences in the rate of progression of coronary disease among the 3 arms. This lack of treatment effect on the primary outcome occurred against a background of significantly beneficial effects of active treatment on cholesterol profile.
Interpretation:In women with established coronary heart disease, progression of coronary atherosclerosis was unchanged by 3.2 years of treatment with either unopposed estrogen or a combination of estrogen and progestin. The effects of hormone therapy in younger, healthy women in preventing the onset of coronary disease are, as yet, unknown.
Session
Late-Breaking Clinical Trials
Study:2nd SYMPHONY: Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post Acute COroNary SYndromes
Presenter:Dr L. Kristin Newby, Duke Clinical Research Institute, Duke University, Durham, NC
Background:Aspirin is effective in reducing the risk of recurrent events after episodes of acute coronary syndromes (ACS), but event rates remain relatively high. Drugs that block the platelet glycoprotein IIb/IIIa (GP IIb/IIIa) receptor are effective in the acute clinical situations of percutaneous coronary intervention and non-ST-segment elevation ACS when delivered parenterally and used short term. Less is known about the safety and efficacy of long-term use of oral GP IIb/IIIa receptor antagonists after ACS, but results from 3 previous trials of this class of drugs have been disappointing, including the SYMPHONY study that demonstrated the lack of superiority of 2 doses of sibrafiban compared with aspirin in the prevention of recurrent cardiovascular events after ACS.1, 2, 3
2nd SYMPHONY was designed to assess the safety and efficacy of long-term therapy (12 to 18 months) with sibrafiban, an oral GP IIb/IIIa antagonist, in high-dose alone or in low-dose combined with aspirin compared directly with aspirin alone in patients after ACS. This randomized, double-blind, prospective, multicenter international clinical trial was terminated early once the negative results of SYMPHONY were known. At that time, 6671 patients had been randomized. Sibrafiban dosing was adjusted by an algorithm that accounted for patient weight and renal function. Patients qualified for enrollment if they were within 7 days of an ACS and had stabilized from the qualifying event. ACS was defined as acute MI or unstable angina, confirmed by elevation of cardiac enzymes or electrocardiographically by ST-segment elevation or depression, new T-wave inversions of >1 mV in at least 2 leads, or new left bundle branch block at presentation. Main exclusion criteria included a high risk of bleeding complications or serum creatinine >1.5 mg/dL.
Results:Baseline characteristics were similar among the treatment groups. At study termination, median follow-up was 95 days (coincidentally similar to the 90-day duration of SYMPHONY). Sibrafiban was associated with a trend toward more early withdrawal of study drug compared with aspirin (low dose + aspirin, 21.0%; high dose, 25.3%; aspirin, 18.4%) and significantly more patients stopped sibrafiban because of bleeding than aspirin (low dose + aspirin, 4.8%; high dose, 5.5%; aspirin, 0.9%). There was no difference between the groups in median duration of study drug exposure (low dose + aspirin, 90 days; high dose, 90 days; aspirin, 91 days). The primary efficacy end point for the trial was time to the composite outcome of death, myocardial infarction, or severe recurrent ischemia (defined as recurrent ischemic symptoms leading to unplanned/unscheduled revascularization), and there was no statistically significant difference between the treatment groups in the incidence of this end point (low dose + aspirin, 9.2%; high dose, 10.5%; aspirin, 9.3%). Importantly, high-dose sibrafiban, compared with aspirin, was associated with a significant increase in the incidence in several important secondary end points, with no significant difference between low-dose sibrafiban plus aspirin and aspirin: the composite of death/myocardial infarction (low dose + aspirin, 6.8%; high dose, 8.6%; aspirin, 6.1%), the incidence of the independent events of death (low dose + aspirin, 1.7%; high dose, 2.4%; aspirin, 1.3%), and myocardial infarction (low dose + aspirin, 5.3%; high dose, 6.9%; aspirin, 5.3%). There was no difference in the incidence of stroke (low dose + aspirin, 0.5%; high dose, 0.6%; aspirin, 0.5%), but the incidence of all-cause rehospitalization was significantly increased for both sibrafiban arms compared with aspirin (low dose + aspirin, 25.1%; high dose, 25.8%; aspirin, 21.5%). The only end point that favored sibrafiban, though not statistically significant, was the incidence of severe recurrent ischemia (low dose + aspirin, 2.8%; high dose, 2.8%; aspirin, 3.7%).
Interpretation:This is the fourth major randomized clinical trial to demonstrate the lack of superiority of oral GP IIb/IIIa antagonists relative to standard therapy.1, 2, 3 Of particular concern is the result of a meta-analysis of the studies reported to date, including 2nd SYMPHONY, that demonstrates a statistically significant increase in the risk of death associated with oral GP IIb/IIIa antagonists (odds ratio 1.35; P = .000112).
Whether the experience to date represents a failure of the class of oral GP IIb/IIIa antagonists or shortcomings of the drugs tested and the trial designs used remains unclear. Careful scrutiny of the results of completed trials and of ongoing clinical work, and further investigation of the basic biological factors of newer drugs before launching large-scale clinical trials, are recommended.
Session
Late-Breaking Clinical Trials II
Study:Heparins and Reperfusion Therapy Trial (HART-II)
Presenter:Dr Allan M. Ross, George Washington University Medical Center, Washington, DC
Results:Several recent clinical trials have established the efficacy of low-molecular-weight heparins (LMWH) in the management of patients with non-ST-segment elevation acute coronary syndromes. Treatment with LMWH rather than unfractionated heparin (UFH) offers the advantages of a more predictable anticoagulant response, less platelet factor 4 inhibition, and a lower incidence of thrombocytopenia. Still, little data exist to support the use of LMWH as an adjunct to fibrinolytic therapy in the management of acute ST-segment elevation myocardial infarction.
The HART-II trial randomly assigned 400 patients with acute myocardial infarction within 12 hours of chest pain onset to treatment with aspirin, 100 mg front-loaded tissue plasminogen activator, and either unfractionated, weight-adjusted intravenous heparin or enoxaparin. Enoxaparin was dosed as an initial 30-mg intravenous bolus followed by subcutaneous administration of 1 mg/kg twice daily for at least 3 days. Principal end points included 90-minute infarct-related artery patency, stroke, and bleeding complications.
The study was powered to determine equivalence between the 2 therapies. Infarct-related artery patency at 90 minutes was comparable for patients treated with either enoxaparin (80.1% TIMI 2/3 flow) or UFH (75.1% TIMI 2/3 flow). Grade 3 flow at 90 minutes occurred in 47.6% of patients receiving UFH and 52.9% of patients treated with enoxaparin. Rates of reocclusion assessed by angiography between 5 and 7 days were lower with enoxaparin (5.9%) than with UFH (9.8%). None of these differences achieved statistical significance. Bleeding complications and stroke (intracranial hemorrhage 1.0% for both treatment arms) did not differ between groups. In-hospital and 30-day mortality rate also remained similar, and there were no differences in the need for urgent coronary intervention between treatment groups.
Interpretation:The use of enoxaparin in the HART-II trial demonstrates similar clinical efficacy as UFH with no significant differences in safety end points. Whether other LMWHs are effective adjunct therapy to fibrinolysis remains unknown. Considering the ease of administration and predictability of LMWH, these results are optimistic for the design of larger trials assessing clinical outcomes of LMWH combined with fibrinolytic therapy.
Session
Late-Breaking Clinical Trials II
Study:Optimal dosing of a platelet glycoprotein IIb/IIIa antagonist, lamifiban, using renal-based algorithms, in patients with acute coronary syndromes: Results from the PARAGON B study
Presenter:Dr Robert A. Harrington, Duke University Medical Center, Durham, North Carolina
Background:Previous clinical trials in acute coronary syndromes (ACS) have demonstrated a therapeutic benefit with glycoprotein IIb/IIIa inhibition. Lamifiban is a specific, small molecule, nonpeptide glycoprotein IIb/IIIa antagonist with a rapid onset of action and a renal clearance. PARAGON A was a dose-finding trial that randomly assigned 2282 patients to lamifiban or placebo with a modified 3 × 2 factorial design (2 doses of lamifiban and placebo with and without heparin) that failed to demonstrate a significant reduction in the composite of death or myocardial infarction (MI) at 30 days. However, a 6-month analysis demonstrated a separation in the event rate curves. In addition, retrospective analyses of drug concentrations and event rates at 30 days showed an approximate 50% reduction in a middle-range concentration of lamifiban compared with placebo that was not observed in either the low- or high-concentration ranges.
PARAGON B was planned to evaluate outcomes with an optimal dosing strategy with a renal-based algorithm. PARAGON B was an international, prospective, double-blind, placebo-controlled trial that randomly assigned 5225 patients to lamifiban bolus plus adjusted infusion according to creatinine clearance or placebo bolus plus adjusted infusion for 72 hours. Inclusion criteria were non-ST elevation acute coronary syndromes with chest pain for ≤12 hours and either electrocardiographic changes or positive cardiac markers. All patients received aspirin and weight-adjusted heparin (UFH or LMWH). The primary end point was a 30-day composite of death, MI, or severe recurrent ischemia that led to urgent revascularization. The main secondary end point was death or MI at 30 days. All suspected MI or severe recurrent ischemic events were adjudicated by a blinded clinical events committee. Sample-size calculations were based on a 25% reduction with lamifiban and a primary composite event rate assumption of 16%. Because of a low event rate in the overall population observed at a planned interim analysis, an independent data safety monitoring board recommended enrollment of at least an additional 1000 patients.
Results:Baseline characteristics were similar between the 2 treatment groups: median age was 64 years, 34% were women, 57% hypertensive, 23% diabetic, 51% hypercholesterolemic, 30% current tobacco users, and 30% with a history of MI. Enrollment characteristics were similar: median 7.4 hours from symptom onset, 57% enrolling MI, 44% ST depression on electrocardiogram, 16% ST elevation on electrocardiogram, 46% T-wave inversion on electrocardiogram, 72-hour median infusion time, 88% heparin use, and >99% aspirin use. Use of cardiac procedures was also similar: cardiac catheterization 64%, percutaneous intervention 28%, stent use during coronary intervention 76%, and bypass surgery 15%. The primary efficacy composite end point for lamifiban and placebo was 11.8% and 12.8%, respectively (P = .329 by logistic regression). The main secondary end point was 10.6% versus 11.5%, respectively (P = .320). No difference was seen in the incidence of major/life-threatening bleeds (1.3% vs 0.9%). However, the increase in intermediate bleeding was significant: 14% versus 11.5% (P = .002). The incidence of transfusion was greater in lamifiban than in placebo (10.3% vs 8.9%). The incidence of intracranial bleeding was identical (<0.01%) and thrombocytopenia was similar (0.7% vs 0.5%).
Preliminary results from a prospectively defined substudy demonstrate a significant decrease in the primary composite end point in patients treated with lamifiban who enrolled with a positive troponin T, as assessed by a core laboratory (11% vs 19%; P = .018). Furthermore, there was a benefit in the 30-day death end point: 1.6% versus 4.3% (P = .007). No benefit was seen in enrolling patients with a negative troponin T (9.6% vs 10.3%). A nonrandomized comparison of interventional strategy in patients on lamifiban versus placebo demonstrated a benefit in patients who received an early percutaneous coronary intervention (11.6% vs 18.5%) but no benefit in late intervention (16.2% vs 15.2%) or no intervention (10.8% vs 11.3%).
Interpretation:Despite a dose-adjusted algorithm with weight and serum creatinine, lamifiban did not significantly reduce the primary composite end point of death, MI, or severe recurrent ischemia at 30 days compared with placebo plus aspirin and heparin. However, in a nonrandomized comparison, lamifiban was associated with a significant reduction in the composite end point of death or MI among patients undergoing early PCI. Furthermore, in a prospectively defined subpopulation, troponin T identified a group of patients at an increased risk of death and MI at 30 days, and lamifiban significantly reduced the death/MI composite in this group of patients. Taken together, these data provide additional sound evidence of the benefit of glycoprotein IIb/IIIa antagonists in high-risk patients with acute coronary syndromes.
Session
Late-Breaking Clinical Trials III
Study:The Bypass Angioplasty Revascularization Investigation (BARI) seven-year results
Presenter:Dr Katherine Detre, University of Pittsburgh, Pittsburgh, Pa
Background:The Bypass Angioplasty Revascularization Investigation (BARI), funded by the National Heart, Lung, and Blood Institute (NHLBI), was a randomized clinical trial designed to compare the effect of percutaneous transluminal balloon angioplasty (PTCA) with coronary artery bypass graft surgery (CABG). The study population included patients who had multivessel coronary disease with angina or objective evidence of ischemia, no prior revascularization, and coronary lesions amenable to either percutaneous or surgical revascularization. The primary results have been previously reported and demonstrated that CABG and PTCA were comparably effective with regard to the primary end point of 5-year all-cause mortality.1 Although mortality rates were similar between the comparative arms among patients without diabetes, PTCA was associated with an almost 2-fold increase in 5-year mortality rates compared with CABG (34.7% vs 19.1%) among the subset of patients with medically treated diabetes.1, 2 These observations led the BARI investigators and the NHLBI to release an urgent NHLBI “Clinical Alert” recommending CABG over standard angioplasty for all patients receiving medical therapy for diabetes with multivessel coronary artery disease requiring initial revascularization.3, 4 The current presentation reports results from the BARI randomized trial through the extended follow-up period of 7 years.
Results:Between August 1988 and August 1991, 1829 patients were randomly assigned to undergo CABG or PTCA at 18 centers in the United States and Canada. Baseline characteristics were similar among the treatment groups. Three hundred fifty-three of the randomized patients had medically treated diabetes mellitus (DM) at study entry. Seven-year survival among patients without DM was not statistically different between the treatment groups (CABG, 86.4%; PTCA, 86.8%; P = .72). Among patients with DM, the statistically significant survival benefit associated with CABG observed at 5 years was maintained (CABG, 76.4%; PTCA, 55.7%; P = .0011), with the survival curves continuing to diverge throughout the follow-up period. These survival trends at 7 years were evident among diabetic patients treated with oral therapy (CABG, 84.1%; PTCA, 60.6%) and those treated with insulin (CABG, 67.8%; PTCA, 49.4%), with insulin therapy associated with worse outcomes in both treatment groups.
Interpretation:Symptomatic patients with multivessel coronary artery disease without treated diabetes have similar 7-year survival with CABG and PTCA. Diabetic patients with multivessel coronary disease requiring revascularization benefit from CABG. For both revascularization procedures, the prognosis is worse for diabetic patients receiving insulin.
The diabetic outcomes of BARI have generated a vigorous debate within the cardiology community and appear to have provided more questions than answers. Despite the BARI diabetic findings, the NHLBI clinical alert and substantial discussion in the medical and popular press, there appears to have been no measurable change in clinical practice patterns in the years since these observations were first publicized, highlighting clinical uncertainty in the wake of BARI.5
Importantly, the optimal treatment for diabetic patients with coronary disease needs to be better defined through additional randomized clinical trials. The BARI observations should be confirmed in a trial specifically designed and powered to assess prospectively the relative safety and efficacy of percutaneous versus surgical revascularization among diabetic patients, especially in the current era of intracoronary stenting and adjunctive glycoprotein IIb/IIIa antagonism. In addition, trials are needed to compare various therapeutic strategies for risk factor and glycemic management among patients with diabetes and coronary artery disease in an ongoing effort to improve the current dismal prognosis among this patient population.
References
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- Double blind, placebo controlled trial of recombinant human vascular endothelial growth factor: the VIVA trial. [abstract] J Am Coll Cardiol. 1999;33(suppl A):384A
- Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA. 1998;280:605–613
- . Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. Lancet. 2000;355:337–345
- . The Evaluation of Xemilofiban in ControllIng Thrombotic Events (EXCITE) trial: 30-day and six-month results. In: Presented at the 48th Scientific Sessions of the American College of Cardiology, New Orleans, Louisiana. March 7 to 10, 1999;
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- . Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med. 1999;335:217–225
- . Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease: the Bypass Angioplasty Revascularization Investigation (BARI). Circulation. 1997;96:1761–1769
- . Clinical alert: bypass over angioplasty for patients with diabetes. www.nlm.nih.gov/databases/alerts/bypass_diabetes.html21 Sept 1995;
- . NHLBI BARI clinical alert on diabetics treated with angioplasty. [abstract] Circulation. 1995;92:3371
- . The influence of the BARI diabetic treatment alert on revascularization selection patterns: The NCN results. [abstract] In: J Am Coll Cardiol. 35:2000;p. 544A
☆ Reprints not available from the authors.
☆☆ Am Heart J 2000;140:181-8.
PII: S0002-8703(00)90257-6
doi:10.1067/mhj.2000.107650
© 2000 Mosby, Inc. All rights reserved.
