Highlights from the XXII Congress of the European Society of Cardiology: August 26 to 30, 2000☆☆☆

Study: 

Global Use of Strategies To Open Occluded Coronary Arteries IV in Acute Coronary Syndromes (GUSTO IV ACS)

Background: 

The Chimeric 7E3 Antiplatelet Therapy in Unstable Angina Refractory to Standard Treatment (CAPTURE) trial was the first study in non-ST elevation acute coronary syndromes (ACS) to examine the impact of an 18- to 24-hour infusion of a glycoprotein IIb/IIIa inhibitor before planned percutaneous coronary intervention (PCI) in patients with angina refractory to medical management. CAPTURE was terminated early because of a clear benefit in patients treated with active therapy (abciximab) versus placebo (29% reduction in 30-day primary composite end point of death, myocardial infarction [MI], or urgent intervention, P < .012). In a subgroup analysis abciximab reduced the incidence of acute MI by 71% during the pre-PCI treatment period (0.6% vs 2.1%, P < .029). Subsequent clinical trials in non-ST elevation ACS have demonstrated a therapeutic benefit with glycoprotein IIb/IIIa inhibition regardless of subsequent management (medical therapy or revascularization).

GUSTO IV ACS was designed as a randomized, double-blind, placebo-controlled trial to evaluate the safety and efficacy of abciximab in non-ST elevation ACS patients for whom PCI was not planned. Entry criteria included 5 minutes of cardiac ischemic chest pain within 24 hours of presentation with either ST segment depression 0.5 mm or positive levels of troponin T or I. Patients were excluded if they were found to have any of the following: PCI within the previous 14 days, acute ST segment elevation MI, thrombolytic agent within the previous 48 hours, contraindication to heparin or abciximab, standard bleeding risks, or PCI or coronary artery bypass grafting (CABG) planned within 30 days after enrollment. A total of 7800 patients were randomized to one of three treatment arms: (1) placebo bolus plus two consecutive 24-hour placebo infusions, (2) abciximab bolus followed by a 24-hour abciximab infusion, followed by a 24-hour placebo infusion, or (3) abciximab bolus followed by two consecutive 24-hour abciximab infusions. The primary hypothesis was that both 24- and 48-hour infusions of abciximab compared with placebo (aspirin and heparin alone) would reduce the composite end point of death or MI (creatine kinase [CK] fraction MB 3× upper limits of normal [ULN]) at 30 days.

Results: 

Baseline characteristics between the three treatment arms were similar. Median age was 65 years and men constituted 63% of the population. The average incidence of prior MI was 31%, diabetes 22%, prior PCI 10%, and prior CABG 9%. Each arm exhibited similar enrollment characteristics with the following average incidences: 59% were troponin positive, 80% had ST depression, 32% had both positive troponin and ST depression, and 28% had an evolving MI. Concomitant medications were also similar between treatment groups with an average incidence of aspirin 97%, unfractionated heparin 85%, LMWH (dalteparin) 13%, β-blocker 77%, calcium channel blockers 22%, intravenous nitrates 60%, and angiotensin-converting enzyme (ACE) inhibitors 35%.

No difference was observed between placebo and 24- or 48-hour infusions with abciximab in the primary composite end point of death or MI at 30 days (8.0% vs 8.2% vs 9.1%, respectively). There was a nonsignificant trend for increased event rates in the 48-hour treatment arm. Revascularization rates were quite low: only 128 patients (1.6%) underwent any revascularization through 48 hours and no differences were seen among the placebo and two treatment groups. At 7 days, 10.7% of patients had a PCI and at 30 days, 19.3%. For troponin-positive patients, there was no statistical difference in the primary composite end point between placebo and 24- or 48-hour infusions with abciximab (9.7% vs 10.2% vs 11.7%, respectively). For patients with ST depression, there was no statistical difference in the primary composite end point between placebo and 24- or 48-hour infusions with abciximab (8.4% vs 8.5% vs 9.9%, respectively).

Abciximab was associated with increased bleeding. Major bleeding and transfusion were statistically significant for the 48-hour abciximab infusion only. Minor bleeding was statistically significant for both the 24- and 48-hour infusions of abciximab. No statistical difference was seen in intracranial hemorrhage.

Interpretation: 

Because of the wealth of data demonstrating a modest benefit with glycoprotein IIb/IIIa inhibitors in non-ST elevation ACS, the lack of benefit (and trend toward harm) of abciximab is surprising and has stirred considerable controversy. Currently no firm conclusion explains these unexpected findings. However, GUSTO IV ACS did enroll a patient population that differed from previous non-ST elevation ACS trials. GUSTO IV was the first non-ST elevation ACS trial to include the use of troponin as an entry cardiac marker. False elevations in troponin are not uncommon and therefore may lead to a lower-risk population. Fewer interventions were performed in this study than in previous non-ST elevation ACS trials. Additionally, abciximab had not previously been evaluated during a 48-hour infusion, and the effects of prolonged platelet inhibition with abciximab are unknown. Furthermore, the treatment effect in previous trials has been modest and the current trial may have been insufficiently powered to detect this small difference. Despite the difficulty of evaluating subgroups in a negative trial, future subgroup analyses may provide some insight into potential factors, such as regional enrollment populations and outcomes, that may help explain the surprising results of this non-ST elevation ACS trial.

Study: 

Benefit of 1-month oral glycoprotein IIb/IIIa inhibition with lefradafiban is maintained through 6-month follow-up: results from the Fibrinogen Receptor Occupancy Study (FROST)

Background: 

The Fibrinogen Receptor Occupancy Study (FROST) was a prospective, randomized, parallel-group, placebo-controlled, Phase II dose-finding and safety study evaluating lefradafiban, an oral GP IIb/IIIa antagonist, compared with placebo for the treatment of patients after an episode of non-ST elevation ACS.

At the time of presentation for ACS, patients were randomized to one of 4 treatment strategies, including 3 dosing strategies of lefradafiban (20 mg, 30 mg, or 45 mg three times daily) or placebo. Study drug was administered for 30 days after enrollment. All patients received aspirin and heparin therapy by protocol. End points of the study included measures of safety, pharmacokinetics/dynamics (PK/PD), and a composite efficacy end point of death/MI/revascularization evaluated at 30 days and at 6 months of follow-up. Thirty-day results were previously reported.1

Results: 

A total of 531 patients were enrolled in the trial. Although not powered for efficacy assessment, a trend toward clinical benefit reported at 30 days in the 30-mg lefradafiban arm compared with placebo in the primary composite end point of death/MI/revascularization was maintained through 6 months of follow-up (38.5% vs 56.7%, respectively; P = .01).

Associations between pharmacokinetic (fibrinogen receptor occupancy [FRO]) and pharmacodynamic (% platelet inhibition) measures and clinical efficacy were suggested. The highest risk appeared to occur at increasing levels of FRO and between 35% and 60% platelet inhibition. Analyzing the timing of clinical efficacy end points relative to the interval since the last dose of study drug, event rates favored lefradafiban compared with placebo at <8 hours since last dose (9.5% vs 16.9%) and at >12 hours since the last dose (1.5% vs 3.9%). However, between 8 and 12 hours from the previous dose, the event suggested an increased risk with lefradafiban versus placebo (6.7% vs 3.1%).

Conclusions: 

The benefit trend of the 30-mg dose reported at 30 days was sustained through the 6-month follow-up. The correlation between clinical events and PK/PD measures, along with the relationship between timing of events relative to the last dose of study drug, indirectly supports the hypothesis previously put forth that these drugs may have a paradoxical prothrombotic effect. The class of drugs is worthy of continued research and development.

Interpretation: 

The efficacy trend with one of the 3 doses of lefradafiban provides a ray of hope for this drug and for the class of oral GP IIb/IIIa inhibitors. However, results from 4 previous randomized clinical trials assessing the efficacy of 3 separate oral GP IIb/IIIa antagonists have been negative1-3 and when meta-analyzed demonstrated a statistically significant increase in mortality (odds ratio [OR] 1.35, 95% confidence interval [CI] 1.16-1.60). With this history of the oral GP IIb/IIIa antagonists and the fact that only 1 of 3 doses of lefradafiban trended in the right direction, the efficacy data should be interpreted very cautiously; because the trial was not powered to evaluate clinical efficacy, the finding may represent a statistical artifact.

The data regarding an increased risk of cardiovascular events within an intermediate range of platelet inhibition and during the intermediate interval since the last dose of study drug provide the strongest support yet for the hypothesis of prothrombosis associated with PK/PD nadirs of this class of drugs. These data suggest that the development of oral GP IIb/IIIa antagonists with longer PK/PD half-lives and with higher affinity for the GP IIb/IIIa receptor may improve results. However, the data presented are indirect and are post-hoc subanalyses with little statistical power. Therefore they serve only to strengthen the research question, not answer it.

References 

Alexander JH, Al-Khatib S, Cantor W, et al. Highlights from the American College of Cardiology 48th Annual Scientific Sessions: March 7 to 10, 1999. Am Heart J 1999;38:175-90.

SYMPHONY Investigators. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. Lancet 2000;355:337-45.

O’Neill WW, Serruys P, Knudtson M, et al. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization: EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events. N Engl J Med 2000; 342:1316-24.

Study: 

COHORT registry: Swedish National Register of Cardiac Intensive Care

Background: 

Lipid-lowering therapy with statins is well established in the primary and secondary prevention of coronary events. However, the optimal time in which to initiate statin therapy after an ACS has not yet been defined. Prospective, randomized, placebo-controlled clinical trial data have demonstrated a reduction in recurrent cardiovascular events only in patients who were clinically stable at least 3 months after an acute coronary event. Additionally, the impact of early revascularization in patients after ACS remains controversial.

The Register of Information and Knowledge for Swedish Heart Intensive care Admission (RIKS-HIA) is a national registry that includes every ACS patient admitted to 58 participating Swedish hospitals. The current study evaluated patients below age 80 years who survived 14 days after their first register-recorded acute myocardial infarction (AMI). The objective of this study was to evaluate the impact on 1-year mortality of early initiation of cholesterol-lowering therapy as well as early revascularization in the first 14 days after AMI presentation. Significance of effects on outcome was analyzed by Cox regression. All available variables known to influence outcome were used as the covariates and adjusted for in the analysis.

Results: 

In the 58 participating centers there were large differences regarding the use of different types of medical treatment and revascularization procedures. A total of 6273 patients received a statin by post-AMI day 14. Patient demographic data varied between the statin and no-statin groups in relation to age, congestive heart failure (CHF), atrial fibrillation, LMWH use, and discharge use of aspirin or β-blockers. No difference was seen in sex, hypertension, diabetes, revascularization, thrombolysis, reinfarction, or discharge use of ACE inhibition. Cox regression analysis of statin use at discharge revealed a significant 1-year mortality benefit. The adjusted relative risk (RR) was 0.66(P < .001).

A total of 2436 patients received an early revascularization procedure by post-AMI day 14. Patient demographic data varied between the early revascularization and no-revascularization groups in relation to age, diabetes, admission aspirin or statin use, intravenous nitrate use, and discharge use of aspirin and ACE inhibitors. Reinfarction rates were higher in patients who underwent revascularization, whereas the incidence of CHF was lower. No difference was seen in sex, hypertension, current tobacco use, previous MI, previous revascularization, or discharge use of β-blockers or statins. Cox regression analysis of revascularization within 14 days post-AMI revealed a significant 1-year mortality benefit. The adjusted RR was 0.64 (P < .001).

A separate analysis was performed to evaluate the impact of each individual intervention and the combination of the two therapies. For patients who received both statin therapy and a revascularization procedure (n = 760), the RR was 0.36 (P < .001) compared with the reference population.

Conclusions: 

In addition to aspirin, β-blockade, and ACE inhibition, initiation of statin treatment and early revascularization procedures will have a major impact on survival after AMI.

Interpretation: 

Given the paucity of data regarding the post-ACS initiation of statin therapy, the results of this retrospective analysis are intriguing. The characteristics of the patients receiving either statin therapy or early revascularization differed markedly from patients who did not receive either therapy. Overall, they were much healthier than the patients who did not receive either statin or revascularization. Statistical adjustments were made to compensate for 27 factors recorded at admission and during the hospital stay that may affect patient outcomes. The results of these statistical analyses demonstrate significant treatment differences with the use of statins or early revascularization in AMI and additive effects when used in combination. Although this registry is subject to the biases inherent in retrospective analyses, it provides further evidence that this question needs to be answered in a prospective randomized trial. Two such trials, Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering (MIRACL) and the currently enrolling A to Z trial, should provide further insights into the early initiation of statins after ACS.

Study: 

Aspirin plus medium-intensity warfarin versus aspirin alone in the prevention of reocclusion after successful thrombolysis for suspected AMI: preliminary results of the Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis (APRICOT)-2 trial

Background: 

After successful thrombolytic therapy, reocclusion of the infarct-related artery occurs in about 30% to 40% of patients within a year after AMI, despite the use of aspirin. The APRICOT-2 trial studied the effectiveness of medium-intensity anticoagulation with warfarin (target international normalized ratio [INR] 2-3) in preventing angiographically proved reocclusion of the infarct-related artery 3 months after thrombolysis for an AMI.

The APRICOT-2 trial was a multicenter, randomized controlled clinical and angiographic follow-up study. Inclusion criteria included patients aged <76 years who had received thrombolytic therapy within 6 hours of symptom onset for a clinically suspected AMI. Patients had to have angiographic evidence of successful reperfusion with Thrombolysis in Myocardial Infarction (TIMI)-3 flow in the infarct-related artery at coronary angiography performed within 48 hours after thrombolysis. Thereafter patients were randomized to receive aspirin 80 mg daily or the combination of aspirin and warfarin with a target INR of 2 to 3.

Results: 

The study randomized 308 patients. Reocclusion (TIMI-2 flow or less) was seen in 30% of patients on aspirin and in 18% of patients on the aspirin/warfarin combination (P = .02, RR 0.6, 95% CI 0.39-0.93). Totally occluded arteries (defined as TIMI-0 or –1 flow) were seen in 19% of the aspirin alone and 9% of the aspirin/warfarin combination treated patients (RR 0.5, P < .05), with a clinical course free from death, reinfarction, or revascularization in 70% and 83% (P < .01) of patients, respectively.

Interpretation: 

The results of this preliminary study suggest that the addition of warfarin with a target INR of 2 to 3 to low-dose aspirin therapy is more effective than low-dose aspirin alone in reducing clinical and angiographic reocclusion after successful thrombolysis for AMI. Data from the ongoing, larger trial are awaited.

Study: 

Carvedilol Prospective Randomized Cumulative Survival Trial (COPERNICUS)

Background: 

Controlled clinical trial evidence continues to accumulate on the benefits of β-blockers for the treatment of all patients with heart failure. The long-term use of relatively β1-selective receptor antagonists such as metoprolol in the Metoprolol Controlled-Release Randomised Intervention Trial in Heart Failure (MERIT-HF) and bisoprolol in the Cardiac Insufficiency Bisoprolol Study (CIBIS)-II led to striking mortality reductions for patients with mild to moderate heart failure symptoms. These robust randomized trial data notwithstanding, debate continues on the safety as well as the utility of β-blocker therapy for more symptomatic patients. The termination of the Bucindolol Evaluation of Survival Trial (BEST) with bucindolol in New York Heart Association (NYHA) class IIIb and IV patients because of the lack of a significant positive result added urgency to understanding the impact of β-blockade in more severely affected heart failure patients. The COPERNICUS trial set out to evaluate the safety, tolerability, and efficacy of carvedilol, a modestly β1-selective agent with potent α-blocking properties, in more severely symptomatic heart failure patients.

The COPERNICUS trial was a double-blind, controlled clinical trial sponsored by Roche pharmaceuticals in 334 centers in 21 countries, which randomized NYHA class IV patients to carvedilol or placebo. All patients enrolled had a left ventricular ejection fraction (LVEF) ≤25%, had clinically stable fluid status on ACE inhibitors and diuretics, were not currently hospitalized in an intensive care unit, and had not been on intravenous vasodilator or inotropic therapy for at least 4 days. Patients randomized to carvedilol received an initial dose of 3.125 mg twice daily and were up-titrated every 2 weeks if tolerated symptomatically without hypotension to a maximum twice-daily dose of 25 mg.

Results: 

COPERNICUS randomized 2289 patients: 1133 received placebo and 1156 received carvedilol. Baseline characteristics were similar between groups with a mean age of 63 years, a mean LVEF 20%, and an ischemic etiology for heart failure in 67% of all patients randomized. Slightly more women were randomized to carvedilol, 25.8%, than to placebo, 20.1%. The trial was designed to study all-cause mortality as the primary end point and to continue until 900 patients met this end point. After 29 months, the data safety monitoring board stopped the trial early after a predefined stopping boundary was crossed with an excess mortality rate noted in the placebo arm. The data presented showed 190 deaths in the placebo arm compared with 130 deaths in patients randomized to carvedilol. These results are consistent with an absolute mortality reduction of 7.1% and an RR reduction of 35% (95% CI 19%-48%, P = .00014) with the use of carvedilol instead of standard therapy in the randomized cohort. Carvedilol therapy was also noted to be very well tolerated because more patients, 16% vs 13%, had withdrawn at 1 year because of a perceived adverse event in the placebo group than in the carvedilol group. A post-hoc analysis that subdivided the randomized cohort into three groups on the basis of the severity of their left ventricular dysfunction, the frequency of hospitalizations before randomization, the hospitalization status at the time of randomization, and the presence of fluid retention was unable to identify a group for which the use of carvedilol did not improve mortality.

Conclusions: 

Carvedilol therapy added to standard heart failure therapy including stable doses of ACE inhibitors and diuretics in patients with severe yet clinically compensated symptoms leads to a 35% reduction in mortality.

Interpretation: 

The COPERNICUS trial results now unequivocally support the use of β-blockers to reduce mortality risk in all clinically stable patients with mild, moderate, and severe heart failure symptoms and depressed left ventricular function. The excellent tolerability of carvedilol also needs to be highlighted and should allow for rapid translation of these results to the larger population. Although these data serve to expand the indication for β-blocker use, several populations such as asymptomatic patients with depressed left ventricular function, symptomatic patients with preserved left ventricular function, and the acutely decompensated NYHA class IV patient have heretofore been understudied and deserve further evaluation in controlled clinical trials. Ongoing clinical trials comparing different β-blocker agents should address unanswered questions regarding a differential effect of β-blockade by racial subgroup or by agent.

References 

Study: 

Transcoronary Ablation of Septal Hypertrophy (TASH) for Hypertrophic Obstructive Cardiomyopathy: Acute and Long-term Results in Patients with Provocable Outflow Obstruction

Background: 

TASH is a developing therapy in the treatment of hypertrophic obstructive cardiomyopathy (HOCM). Studies have demonstrated the safety and effectiveness at improving symptoms of a technique that induces areas of myocardial necrosis within the subaortic septum with use of selective intracoronary ethanol infusion. However, most of these data have been from patients with resting outflow obstruction. The use of TASH for patients with no resting outflow gradient but with inducible gradients has been less extensively evaluated.

This study evaluated the effect of TASH among patients with HOCM and clinical symptoms unresponsive to medical therapy who had significant outflow obstruction only after provocation. Outcomes were evaluated 7 months after TASH and included changes in resting and postextrasystolic gradient, left ventricular end-diastolic pressure (LVEDP), NYHA functional class, and peak oxygen consumption, among others.

Results: 

The study evaluated outcomes after treatment with TASH of 32 patients with resting outflow gradients <30 mm Hg but with >30 mm Hg gradient after provocation. The treatment, on average, was associated with a reduction in resting outflow gradient (13 mm Hg vs 6 mm Hg, P < .001), a reduction in postextrasystolic gradient (111 mm Hg vs 20 mm Hg, P < .001), and a decrease in LVEDP (19 mm Hg vs 13 mm Hg, P < .001). Patients had improvements in NYHA functional class (2.8 vs 1.5, P < .001), exercise capacity (74 vs 91 watts, P < .001), and peak oxygen consumption (14.5 vs 17.2 mL/kg/min, P = .009).

Conclusions: 

These data support previous observations from surgical interventions for HOCM suggesting that the absence of a resting outflow tract gradient does not preclude clinical benefit among patients with provocable dynamic outflow obstruction. The clinical improvements observed in this cohort are similar to those previously reported among patients with large resting gradients. Therefore a large outflow tract gradient at rest should not be a necessary precondition for therapy with TASH in patients with HOCM.

Interpretation: 

These data from a small cohort of patients at a single center are intriguing and suggest that the clinical benefit associated with septal alcohol ablation may extend to the population of symptomatic patients with HOCM who have small resting gradients but significant gradients on provocation. Ideally, these observations will be carried forward to a randomized clinical trial against medical therapy, the current standard of care for such patients, to rigorously evaluate the safety and efficacy of this promising procedure.

Study: 

Treatment of CHF with carvedilol in pediatric patients

Background: 

The current standard of care for the treatment of CHF among pediatric patients includes therapy with diuretics, ACE inhibitors, and digoxin. Despite best medical therapy, many patients still progress to end-stage CHF. β-Blockers have been shown to be of marked benefit in the treatment of adults with CHF,1 and they could potentially improve clinical outcomes among the pediatric population.2 The safety, efficacy and appropriate dosing of this class of drugs, however, has not been adequately studied in children.

Carvedilol is one of the β-blockers shown to be of clinical benefit in the treatment of CHF among adult patients. This pilot study was designed to evaluate the safety, tolerability, and pharmacokinetic response to carvedilol in a population of children with CHF. At baseline and monthly for 6 months, assessments were made of ejection fraction (EF), CHF symptoms (Modified Ross Score [MRS]),3 plasma renin activity (PRA), and N-terminal probrain natriuretic peptide (BNP). Pharmacokinetics were assessed by measuring plasma concentrations of carvedilol over the 12-hour period after the initial dose.

Results: 

Twelve pediatric patients (aged 2 months to 18 years) with CHF were treated with carvedilol in addition to standard care. After a test dose of 0.1 mg/kg, carvedilol was titrated at 10- to 14-day intervals to a target dose of 0.7 mg/kg/d. Over the 6-month study follow-up, on average, EF improved (30% vs 51%, P < .05), CHF symptoms improved (MRS 5 vs 2.6, P < .05), BNP concentrations decreased (670 vs 480 fmol/mL, P = .06), and PRA decreased (38 vs 14 μg/L/h, P < .05). Mean terminal elimination half-life of carvedilol in these 12 children was 2.5 hours, about 50% faster than reported in adults.4

Conclusions: 

This study suggests that children with CHF could benefit from treatment with carvedilol; this therapy appears to be safe with a gradual titration of dose. The rapid elimination half-life of carvedilol observed suggests that children likely need a different dosing regimen than adults. Further controlled studies with pediatric patients have to follow.

Interpretation: 

Children with cardiovascular disease represent a grossly understudied population of patients, and the current study is a step in the right direction toward systematic clinical trial assessment of promising therapies for pediatric patients. These preliminary data from a small, single-center pilot study are encouraging with regard to the potential safety and efficacy of carvedilol. The difference in pharmacokinetics between children and adults is intriguing. As the authors state, this trial paves the way for future adequately powered clinical trials to further assess carvedilol, and, in fact, these investigators have initiated such a multicenter trial.

References 

Packer et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med 1996;334:1349-55.

Shaddy et al. Beta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children: multi-institutional experience. J Heart Lung Transplant 1998;18:269-74.

Ross RD, et al. Grading the severity of congestive heart failure in infants. Pediatr Cardiol 1992;13:72-5.

Mc Tavish et al. Carvedilol: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy. Drugs 1993; 45:232-58.

Study: 

Ongoing Myocardial Necrosis Among Outpatients With Heart Failure: Implications of Elevated Troponin T and C-reactive Protein Concentrations

Background: 

Prior studies report elevated concentrations of cardiac troponin T/I in hospitalized patients with decompensated heart failure (HF). In a prospective, single-site cohort study, Duke physicians investigated whether elevated troponin T levels were associated with HF severity, etiology, and prognosis. Baseline data and blood samples were obtained from 136 stable HF outpatients with NYHA functional class 2, LVEF 35%, and no recent angina, MI, revascularization, or HF hospitalization. TnT was measured by the Elecsys TnT STAT (Roche) assay, and patient outcomes were assessed at 1.5 years.

Results: 

Twenty-four percent of HF patients had elevated concentrations of TnT 0.02 ng/mL, including 6 patients with levels exceeding the recommended MI cutoff value of 0.1 ng/mL. Elevated TnT concentrations were present in both ischemic and nonischemic HF patients and correlated with worse functional class, older age, and elevated serum creatinine (all P < .02). Elevated concentrations of TnT were associated with an increased risk of death or HF hospitalization (55% vs 22%, RR 2.4, P < .001) and death alone (33% vs 8%, RR 4.3, P = .02) compared with patients with TnT <0.02 ng/mL. After multivariable analysis, elevated TnT and NYHA functional class remained significant multivariable predictors of death or HF hospitalization.

Interpretation: 

Elevated TnT concentrations were associated with functional class, renal dysfunction, and adverse outcomes in a stable outpatient HF population. This provocative study highlights the growing awareness of ongoing myocardial necrosis and elevations of cardiac markers outside the spectrum of acute coronary syndromes. Future diagnostic and prognostic studies in heart failure should integrate troponin biochemical data with neurohormone levels, hemodynamic/clinical variables and treatment strategies.

Study: 

Early Statin Use in AMI Is Associated With a Reduced Hospital Mortality: Results of Maximal Individual Therapy in Acute Myocardial Infarction (MITRA)-2

Background: 

Long-term therapy with HmgCoA reductase inhibitors (“statins”) has been associated with improved long-term outcomes after acute coronary events among patients with elevated lipids. The early use of statins in the first few days after AMI has not been evaluated.

The MITRA registry includes 54 medical centers in Germany and was developed to provide quality control and to foster adherence to clinical guidelines in the treatment of acute MI among participating centers. MITRA-1 collected data from June 1994 to January 1997 and MITRA-2 included data from June 1998 to the present. This registry provided an opportunity to observe practice patterns among the participating centers and to correlate clinical outcomes of patients participating in the registry with differences in therapeutic interventions. Patients in the MITRA registry included all patients with an acute ST-elevation MI treated at participating centers. Lipid profiles were obtained on all patients on the day of admission and on the following workday. Statins were started on all patients within the first 3 days if low-density lipoprotein (LDL) cholesterol was above 100 mg/dL, in line with the German Society of Cardiology guidelines. If indicated but not started, physicians were required to document the reason statins were not used.

This study reported the rates of use of statins and other evidence-based therapies at hospital discharge after AMI and the clinical outcomes of patients in the registry as related to statin use and compared these observations with data from the MITRA-1 registry (1994-1997).

Results: 

Data from 2430 patients from MITRA-2 were presented and compared with data from 6067 patients in MITRA-1. No significant differences in baseline characteristics were observed between the 2 cohorts. In MITRA-2, 9% of AMI patients were taking statins at the time of presentation, and this number increased to 77% by hospital discharge. This represents a substantial increase in the frequency of statin use compared with MITRA-1 (0% and 15%, respectively). In MITRA-2, only 34% had a prior diagnosis of hypercholesterolemia, but 84% had a measured LDL cholesterol level >100 mg/dL. Significant increases were observed in the frequency of use in a number of other evidence-based therapies from MITRA-1 to MITRA-2, including reperfusion therapy, aspirin, β-blockers, and ACE inhibitors. In-hospital mortality significantly decreased from MITRA-1 to MITRA-2 (15.2% vs 13.0%, P < .01) (see Table I).

Table I.

		MITRA-1 (6/94-1/97) (n = 6067) (%)	MITRA-2 (from 6/98) (n = 2430) (%)	Statistical significance
	Statins	15	77	P < .01
	Reperfusion therapy	57.8	68.1	P < .01
	Thrombolysis	49.6	49.2
	Primary PTCA	8.3	18.9
	Aspirin	93.5	96.6
	β-Blocker	52.7	76.3	P < .01
	ACE inhibitor	50.5	70.9	P < .01
	In-hospital mortality	15.2	13	P < .01
	Nonfatal major adverse cardiovascular events	16.9	14.1	P < .01
	Reinfarction	3	2.3	NS
	Postinfarction angina	13.4	11.4	P = .07
	Stroke	0.7	0.5	NS

PTCA, Percutaneous transluminal coronary angioplasty; NS, not significant.

Conclusions: 

The use of statin therapy can be increased in clinical practice in up to 75% of all patients. This early and frequent use of statins and a high frequency of reperfusion and medical therapy were associated with a low hospital mortality (nonrandomized).

Interpretation: 

In light of other results reported at these meetings from the COHORT Swedish registry suggesting the life-saving benefit of early statin use in the treatment of AMI, the MITRA-2 finding of such a high frequency of use is all the more encouraging.

On a broader scale, compared with the MITRA-1 observations, the current data suggest the MITRA investigators have been remarkably successful at their principal objective, which is to foster the application of evidence-based medicine among the participating centers. There is little doubt that the improved clinical outcomes reported from MITRA-1 to MITRA-2, including an impressive 2% absolute reduction in in-hospital mortality, are the dividends of a successful quality improvement registry.

Study: 

Effect of Orlistat on Coronary Heart Disease Risk in Obese Patients with Hypertension and/or Hyperlipidemia

Background: 

Obesity is a risk factor for coronary artery diseases and is associated with multiple additional cardiac risk factors, including type 2 diabetes, hypertension, and dyslipidemia. Compared with diet management in randomized clinical trials, obese and overweight patients treated with diet plus orlistat, an intestinal lipase inhibitor, achieved significantly greater weight loss and greater improvements in several cardiovascular risk factors.1-4 However, these studies have generally excluded patients at intermediate to high cardiovascular risk.

The current randomized, double-blind, placebo-controlled study was designed to assess the effect of treatment with orlistat compared with placebo among patients with at least one concomitant cardiovascular risk factor treated predominantly at primary care centers in Sweden. The primary end point of the study was change in body weight after 1 year of study-drug treatment, with changes in blood pressure, serum lipids, fasting plasma glucose, and hemoglobin A1c assessed as secondary efficacy parameters.

Results: 

The study randomized 376 patients with body-mass index (BMI) 28 to 38 kg/m2 to orlistat (n = 190) or placebo (n = 186). Among randomized patients, 75% had hypertension, 40% had hyperlipidemia, and 26% had type 2 diabetes. Clinical characteristics were balanced between the treatment groups. After 1 year of study drug treatment, hypertensive patients assigned to the orlistat arm achieved a greater percent weight loss (6.3% vs 4.7%, P < .05) and had greater reductions in LDL cholesterol (7.1% vs 0.0%, P < .05) and fasting plasma glucose (4.3% vs 0.3%, P < .05). Among hypercholesterolemic patients, there was no difference in weight loss at 1 year, but assignment to orlistat was associated with greater reductions in LDL cholesterol (11.5% vs 6%). Orlistat was well tolerated among this high-risk population.

Conclusion: 

Orlistat plus diet was associated with greater improvements in cardiovascular risk profiles compared with diet alone. Orlistat may be beneficial as an adjunctive treatment for multifactorial risk reduction among overweight and obese patients with concomitant cardiovascular risk.

Interpretation: 

Orlistat appears to be a well-tolerated, safe, and effective adjunct to diet for weight loss among patients at risk for cardiovascular events. The favorable modification of selected cardiovascular risk factors suggests that this therapy could potentially decrease cardiovascular risk and therefore have a favorable impact on important long-term clinical outcomes. This hypothesis should be tested in a prospective clinical trial.

References 

Sjöström L, Rissanen A, Andersen T, et al. Randomised placebocontrolled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998;352:167-72.

Davidson MH, Hauptman J, DiGirolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat. JAMA 1999;281:235-42.

Rössner S, Sjöström L, Noack R, et al. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. Obes Res 2000;8:49-61.

Hauptman J, Lucas C, Boldrin M, et al. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 2000;9:160-7.

Study: 

Clinical and Economic Analysis of Platelet GP IIb/IIIa Reopro Versus Integrilin Therapy During Elective Percutaneous Coronary Interventions (PRICE) Trial

Presenter: 

Dr Frank Aguirre, Prairie Cardiovascular Consultants, St Louis, Mo

Background: 

Three intravenous GP IIb/IIIa antagonists have undergone large-scale, randomized phase III clinical trials in percutaneous coronary intervention (PCI). Abciximab (c7E3 Fab, ReoPro, Centocor, Malvern, Pa, and Eli Lilly, Indianapolis, Ind), the first agent to be approved by the Food and Drug Administration, is a human-murine chimeric monoclonal Fab antibody fragment that binds with high affinity to the GP IIb/IIIa receptor. Eptifibatide (Integrilin, COR Therapeutics, South San Francisco, Calif, and Schering-Plough, Kenilworth, NJ) is a cyclic heptapeptide based on the Lys-Gly-Asp (KGD) amino acid sequence. This agent is a highly specific, competitive blocker of the GP IIb/IIIa complex. Finally, tirofiban (Aggrastat, Merck, Whitehouse Station, NJ) is a tyrosine-derived, nonpeptide mimetic inhibitor of GP IIb/IIIa that also specifically and competitively binds to the GP IIb/IIIa receptor in a rapidly reversible fashion.

A series of randomized, multicenter, parallel group, placebo-controlled clinical trials define our understanding of the benefits and risks of intravenous GPIIb/IIIa blockade as adjunctive therapy to elective PCI. These studies uniformly demonstrate that adjunctive GP IIb/IIIa inhibition during PCI reduces acute ischemic complications and that the effect is sustained at 30 days and 6 months. To date, however, GP IIb/IIIa receptor blockers have not been compared with each other in randomized clinical trials.

Results: 

The PRICE investigators reported the results of a small, prospective, randomized, double-blind pilot study of 320 patients undergoing percutaneous coronary intervention (89% received stents) between April 1999 and January 2000. Patients were randomized to receive abciximab (n = 163) (bolus dose of 0.25 mg/kg and 12-hour infusion at 0.125 μg/kg/min) or eptifibatide (n = 157) (bolus dose 180 μg/kg followed by an infusion at 2 μg/kg/min for 18 to 24 hours). Patients with AMI within 48 hours or with unstable angina with electrocardiographic changes within 12 hours before the intervention were excluded from the trial, as were patients with old saphenous vein graft lesions.

The primary end point of the study, total in-hospital costs based on an intention-to-treat analysis and assuming similar clinical outcomes between the GP IIb/IIIa inhibitors, was significantly lower for the eptifibatide-treated patients, $7758 versus $8829, P = .0002. The difference in cost was accounted for entirely by the reduced pharmacy costs of eptifibatide compared with abciximab, $524 and $1575, respectively (P < .00001). Clinical outcomes were similar in both groups, the composite of death, MI, and need for urgent revascularization occurring in 4.5% of the eptifibatide-treated patients and in 4.9% of those treated with abciximab. Mean platelet inhibition, measured with the Accumetrics bedside platelet aggregometer was 83% and 93% at drug discontinuation for abciximab- and eptifibatide-treated patients, respectively.

Interpretation: 

When used at doses similar to those tested in the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial (180 μg/kg bolus followed by a 2 μg/kg/min infusion), and in patients undergoing non-urgent percutaneous coronary intervention, predominantly with stent implantation, eptifibatide was associated with lower in-hospital costs with no apparent differences in clinical outcomes. Further studies, including long-term follow-up, will be required to confirm these findings.