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Clin. Cardiol. 23, 858–861 (2000)

Progress in Clinical Trials

ADVANCE (Additional Value of Nir Stent for Treatment of Long Coronary Lesions)

Presenter: Patrick W. Serruys, M.D., at the XXII European Society of Cardiology, Amsterdam, The Netherlands.

Background: A recent trend among cardiologists is to prefer stenting to dilatation alone when either may be appropriate.

Purpose: ADVANCE investigated whether using stents after balloon dilation for long (20–50 mm) coronary lesions provides additional benefit and reduces reocclusion rates.

Study population: A total of 288 patients who underwent balloon angioplasty of long coronary lesions, and who did not require initial bailout percutaneous coronary intervention (PCI) were enrolled. The patients were randomized to receive one or multiple long stents, or to have no further PCI.

Study design: A total of 40% of cases had 20–24 mm lesions and were treated with one stent; 36% with 25–30 mm lesions were treated with two stents. Another 19% and 5% had 31–40 mm, and 41–50 mm lesions, respectively. Both were treated with two stents.

Ultimately, 1, 2, 3, and 4 stents were used in 81, 11, 7, and 1% of cases, respectively.

Results: No significant differences were seen in the primary endpoints of cardiac death, acute myocardial infarction (MI), and coronary artery bypass graft (CABG) or target-lesion revascularization at nine months. The rates of event-free survival were 81% for stented patients and 86% for percutaneous transluminal coronary angioplasty (PTCA)-only patients. Restenosis (>50% lesion recurrence) occurred in 42% of 118 balloon-only patients, and 27% of 124 balloon plus stent patients.

The post-stent restenosis rate was significantly better at six months (when restenosis was defined as presence of a >50% target-site lesion by quantative coronary angiography), but the difference disappeared when the restenosis threshold was set at >60%.

Conclusions: The ADVANCE trial showed no additional value from the use of stents once PTCA has achieved good results.

Comment (Patrick Serruys, M.D.): How the general community of interventional cardiologists is going to interpret these results is a big question mark. One message of ADVANCE could be that stenting should remain provisional for long lesions. But the trial could be seen as a long-lesion green light to stenting enthusiasts.

APRICOT-2 (Antithrombotics in the Prevention of Reocclusion in Coronary Thrombolysis)

Presenter: Mark Brouwer, M.D., at the XXII Congress of the European Society of Cardiology, Amsterdam, The Netherlands.

Background: Previous trials of thrombolysis have shown reduced mortality in acute MI, but have indicated that patients treated with thrombolytic agents have higher reinfarction rates than those treated with placebo. The earlier APRICOT-1 study showed 25 and 30% one-year reocclusion rates for thrombolytic-treated post-MI patients receiving aspirin and Coumadin (warfarin sodium), respectively.

Purpose: The purpose of the trial was to investigate whether the addition of Coumadin to aspirin after successful thrombolytic therapy reduces clinical and angiographic reocclusion.

Study population: APRICOT-2 was a randomized, controlled trial of 308 post-MI patients with a mean age of 57 years.

Study design: All patients received thrombolytic therapy, aspirin (160 mg), and heparin. After angiography (<48 h post-thrombolysis) those with TIMI 3 flow were randomized to 80 mg aspirin and discontinuation of heparin, or to a combination of 80 mg of aspirin, Coumadin, and heparin until an INR of 2–3 was attained. Follow-up angiography was conducted at 3 months. The primary endpoint of reocclusion was defined as TIMI 2 flow at follow-up.

Results: Preliminary analysis (conducted among 269 patients) revealed that reocclusion occurred in 30% of patients receiving aspirin and in 18% of those receiving the aspirin/Couma-din combination (p = 0.02). Event-free survival (freedom from death, reinfarction, revascularization) was significantly greater (<0.01) (83 vs. 70%) in the aspirin/Coumadin group.

Major bleeding was infrequent (0% intracranial in both groups, 1% extracranial for the aspirin/Coumadin group). Minor bleeding occurred in 6% of the aspirin/Coumadin group compared with 3% of the group taking aspirin alone.

Conclusion: Long-term treatment with aspirin and moderate intensity Coumadin reduced angiographic and clinical reocclusion compared with aspirin alone. The observed benefits were achieved with an acceptable bleeding risk.

Comments (Mark Brouwer, M.D.): Future research should investigate combining aspirin with other anticoagulants such as direct thrombin inhibitors, low molecular weight heparins, or factor Xa inhibitors.

COHORT (data from the Swedish National Register of Cardiac Intensive Care)

Presenter: Lars Wallentin, M.D., at the European Society of Cardiology, Amsterdam, The Netherlands.

Background: The COHORT registry is derived from the Swedish National Register of Cardiac Intensive Care. The registry contains information about all patients admitted to cardiac intensive care units in Sweden between 1995–1998 and includes data on 100 variables known to affect patient survival.

Purpose: The focus for analysis was the impact on one-year mortality, in "real-life" conditions, of early initiation of statins (started in-hospital) and early revascularization (within the first 14 days) in survivors of acute myocardial infarction (AMI).

Study population: A total of 22,683 patients (age (80 years) with a first diagnosed AMI who survived at least 40 days and were treated with statins or revascularization were enrolled.

Data highlights: COHORT data showed a wide range in Swedish hospitals (7–60%) in the portion of post-AMI patients treated with statins. Revascularization within 40 days of an AMI varied between 20–35% in hospitals equipped for these procedures.

Patients receiving statins tended to be younger, had fewer signs of congestive heart failure (CHF), and took fewer CHF medications. They also had more prior MI and treatment for angina pectoris. Revascularized patients tended to be younger, had lower rates of diabetes, less treatment for CHF, took more angina medications, and had more prior infarcts.

Results: There was an overall one-year mortality relative risk reduction of 34% for statin therapy alone, a relative risk reduction 46% for revascularization within 14 days of the MI, and a 64% relative risk reduction for the combination.

Conclusion: The COHORT study showed early statin treatment and early revascularization to have a significant impact on survival after AMI, both alone and in combination. There was an additive impact of the two treatment strategies within the first 14 days of AMI. Treatment was in addition to aspirin, beta blockers, and ACE-inhibitors.

COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival)

Presenter: Milton Packer, M.D., at the XXII Congress of the European Society of Cardiology, Amsterdam, The Netherlands.

Background: Only about 5–15% of severe heart failure patients receive beta blockers. While data are abundant regarding use of angiotensin-converting enzyme (ACE) inhibitors in all classes of heart failure, most large-scale beta-blocker trials have focused only on class II or III heart failure.

Purpose: COPERNICUS investigated treatment of patients with advanced heart failure who were receiving carvedilol, a beta blocker with alpha-blocking properties.

Study population: This international, double-blind placebo-controlled trial evaluated 2,389 patients in 334 centers with severe congestive heart failure. Participants had either ischemic or nonischemic cardiomyopathy with ejection fractions <25%, and symptoms at rest or with minimal exertion persisting for 2 months or longer.

Study design/methodology: Patients were randomized to placebo or carvedilol (74% were titrated to 25 mg b.i.d. after 12 weeks) plus conventional treatment and treated for up to 29 months. Conventional therapy consisted of diuretics and ACE inhibitors, and usually digitalis. The primary endpoint was all-cause mortality.

Results: Most patients tolerated the target dose (25 mg b.i.d.). All-cause mortality was 18.5% (190/1,133) in the placebo group and 11.4% (130/1,156) in the carvedilol group (p = 0.00014, p = 0.0014 adjusted), a 35% risk reduction. The benefit was consistent across all subgroups (age, gender, ejection fraction > or <20%, ischemic/nonischemic) despite placebo effects of up to 25% in some subgroups.

Conclusion: Treatment with carvedilol produced significant reductions in all-cause mortality, with benefits consistent across all subgroups.

Comment (Milton Packer, M.D.): For all severity classes of heart failure, treatment needs to include an ACE inhibitor, a beta blocker, a diuretic, and possibly digitalis. Treating 1,000 patients for 3 years with carvedilol will save 200 lives.

GUSTO-IV ASC (Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes)

Presenter: Maarten Simoons, M.D., at the XXII Congress of the European Society of Cardiology, Amsterdam, The Netherlands.

Background: The PRISM/PRISM, PURSUIT, and PARAGON trials, each with a different GP IIb/IIIa blocker, showed modest benefits in unstable angina. In many trials (total 9,000 patients) with abciximab in percutaneous coronary interventions, death and MI reductions have been uniformly substantial (about 50%).

Purpose: This trial investigated abciximab use among patients with acute coronary syndromes (ACS) not undergoing early revascularizations, and addressed whether the drug should be administered at 24 or 48 h. It evaluated the combination of this GPIIb\IIIa inhibitor with low-molecular weight heparin (LMWH) and assessed the prognostic value of troponin measurements.

Study population: GUSTO-IV included 7,800 patients who had non-ST elevation ACS. The average age was 65 years, and 38% of the population was female (higher than in other abciximab trials).

Study design: All patients received aspirin and unfractionated heparin (UH) or LMWH (dalteparin); 2,598 were randomized to placebo. Another 2,590 were randomized to abciximab (bolus of 0.25 mg/kg, followed by an infusion of 0.125 µg/kg/min to a maximum of 10 µg/kg/min) at 12 h, and another 2,612 at 48 h.

Results: Early revascularization was required in only in 1.6% of patients at 48 h, and the rate of death or MI in the placebo arm was 1.5%. There were no advantages with either active treatment regimen. Rates of death and MI, were 1.9% and 2.2%, respectively, at 48 h. No differences were found between treatment groups at 7 days. For death or MI at 30 days, the primary endpoint, rates were 8.0% for placebo, and 8.2 and 9.1% for 24- and 48-h abciximab. Events were similar for UH and LMWH. Troponin findings were also inconclusive. Major and minor bleeding were higher for patients receiving abciximab than for those receiving placebo.

Conclusion: Treatment with the GP IIb/IIIa blocker abciximab for 24 or 48 h in addition to aspirin and unfractionated or low-molecular weight heparin without early intervention does not reduce death or MI in patients with ACS.

Comment (Maarten Simoons, M.D.): Abciximab shows no advantage in patients with ACS, though it remains indicated in patients undergoing percutaneous interventions with or without a stent.

NICE-3 (National Investigators Collaborating on Enoxaparin)

Presenter: James J. Ferguson, M.D., at the XXII European Society of Cardiology, Amsterdam, the Netherlands.

Background: In treatment of acute coronary syndromes (ACS) and percutaneous coronary interventions (PCIs), low-molecular weight heparins (LMWHs) are easier to administer, and do not require the laboratory monitoring and frequent dose adjustments associated with unfractionated heparin (UH). Still, LMWHs are not widely used because of uncertainty about the safety of combining LMWHs with GPIIb/IIIa inhibitors, and uncertainty about giving LMWHs to patients who may be sent for cardiac catheterization.

Purpose: NICE-3 aimed to determine whether LMWH and GPIIb/IIIa inhibitor combination is safe in patients with ACS.

Study population: This 46-center study included 661 patients (mean age 62.9 years, 66% male) with unprovoked or rest angina presenting within 24 h, and documented ischemic coronary artery disease. Close to 64% were hypertensive, 30% diabetic, 30.7% had prior PCI, 20.9% prior coronary artery bypass graft (CABG), and 36.2% had prior MI.

Methodology: All patients received aspirin (162–325 mg/day) and open-label enoxaparin (1 mg/kg2). Most (616 patients) received one of three commercially available GPIIb/IIIa inhibitors at standard dosages. Additional therapies were at the discretion of the treating physician. The LMWH/GPIIb/IIIa inhibitor combination was continued among patients sent for catheterization with no UH. If the delay from treatment with enoxaparin to catheterization laboratory arrival was >8 h, 0.3 mg/kg of enoxaparin was administered intravenously. The primary endpoint was non-CABG major bleeding rates assessed in-hospital and at 14-day and 30-day follow-up.

Results: Analysis revealed a non-CABG major bleeding rate of 1.9%. At 30-day follow-up, death occurred in 1.3%, MI in 4.4%, and 5.3% needed urgent revascularization.

Conclusion: The combination of LMWH and GPIIb/IIIa inhibitor in ACS patients is safe. Non-CABG major bleeding rates were similar to those found in studies using UH.

Comment (Dr. Ferguson): The transition to the catheterization lab can be made carefully, but confidently, without the use of unfractionated heparin.

MUSTIC (Multisite Stimulation in Cardiomyopathy)

Presenter: Jean Claude Daubert, M.D., at the XXII Congress of the European Society of Cardiology, Amsterdam, The Netherlands.

Background: Recent noncontrolled pilot studies have suggested that biventricular cardiac pacing helps restore ventricular synchrony in patients with congestive heart failure (CHF), resulting in significant improvements in their well being.

Objective: MUSTIC assessed the clinical efficacy and safety of permanent biventricular (BiV) pacing in patients with severe heart failure.

Patient population: MUSTIC participants (n = 131) had severe heart failure (New York Heart Association class III) under optimal medical treatment due to chronic left ventricular systolic dysfunction of idiopathic or ischemic origin and major electrical ventricular dyssynchronization (QRS >150 ms).

Methodology: Group 1: 67 patients with no conventional indications for pacemaker therapy were randomized to 3 months of either BiV pacing or inactive pacing followed by a 3-month cross-over period. Group 2: 64 patients with chronic atrial fibrillation and slow ventricular rate were randomized to BiV VVIR pacing versus standard single site-RV VVIR pacing, with cross-over.

The primary endpoint was exercise tolerance assessed via a 6-min walk test.

Results: Group 1: With BiV, exercise tolerance was enhanced by 23% (399, 100 meters vs. 326, 134 meters, p<0.0001). Peak V02 was significantly enhanced, and quality of life (QOL) was significantly improved. Group 2: Among 48 randomized patients, BiV pacing produced a slight but significant improvement in exercise tolerance (374, 108 meters vs. 342, 103 meters, p<0.05). Peak V02 increased significantly, but QOL, hospitalizations and mortality were similar. After cross-over, 87% preferred BiV.

Conclusion: MUSTIC validates this novel resynchronization therapy concept in patients with severe heart failure and major intraventricular conduction delay. Overall long-term impact needs to be assessed.

LIMIT (Limitation of Myocardial Injury Following Thrombolysis in Acute Myocardial Infarction)

Presenter: K. Baran, M.D., at the XXII Congress of the European Society of Cardiology, Amsterdam, The Netherlands.

Background: Despite restoration of apparently normal epicardial flow following reperfusion therapy, there may be progression of myocardial injury through adhesion of activated leukocytes to the endothelium and subsequent release of mediators of inflammation.

Blockage of the CD18 receptor may prevent such adhesion and attenuate inflammatory response.

Objective: LIMIT assessed the safety and efficacy of single-dose administration of rhuMAb CD18, a novel antibody fragment [F(ab')2], following thrombolysis in acute MI.

Patient population: Patients (n = 391, mean age 58 years) had ST-segment elevation MI by standard criteria (2 or more leads, symptoms persisting for ¾12 hours). Patients with cardiogenic shock and prior coronary surgery were excluded. A third of those enrolled were female and about 15% had prior MI.

Methodology: Patients were randomized 1:1:1 to study drug (2 mg/kg or 0.5 mg/kg) or placebo and then full dose tPA. Coronary angiography was performed 90 min after tPA administration. GPIIb/IIIa inhibitors or PCIs were given/performed as required. The primary endpoint was corrected TIMI frame counts and TIMI flow grade. (Corrected TIMI frame counts <40 are considered similar to TIMI grade 3 flow and close to normal range.)

Results: Corrected TIMI frame counts were similar for all three groups (compared with placebo, p = 0.2 for 0.5 mg/kg and p = 1.0 for 2.0 mg/kg). Sixty-six percent of patients in the placebo arm achieved TIMI 3 flow (somewhat higher than expected). A nonsignificantly smaller percentage achieved TIMI 3 flow with active treatment. There were no differences between active treatment and controls in TIMI 2 flow, in >70% resolution of ST-segment elevation, or in reduction of infarct size.

Conclusion: RhuMAB CD18, in conjunction with thrombolysis, had no effect on coronary flow, infarct size, or ECG ST-segment resolution.

Comment (Dr. Baran): There may be non-CD18-dependent leukocyte binding and transmigration in acute myocardial infarction, or leukocytes may not be key to ischemia-reperfusion injury in human AMI.

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