Clinical Trials in Coronary Artery Disease: VIVA ASSENT-2 InTime-II GISSI SCAT GUARDIAN ---------------------- VIVA VEGF in Ischemia for Vascular Angiogenesis Trial This is a phase 2 trial of the safety and effectiveness of vascular endothelial growth factor (VEGF) in patients with angina that has not responded to other treatments. VEGF has numerous effects, including angiogenesis, vasodilation and increased endothelial cell activity. Phase one studies have shown that VEGF by IV or injected into the heart is safe. Patients with unstable angina, recent MI or bypass, EF less than 25% or retinopathy were excluded. 178 angina patients took either placebo or one of two VEGF doses - 17ng/kg/minute or 50ng/kg/minute. Primary endpoint was exercise treadmill time at 60 days. Secondary endpoints included MUGA results at 60 days, angina class and quality of life (QOL) at 60 and 120 days, and exercise time at 120 days. At 60 days there were no significant differences in treadmill exercise times. There was no significant change in angina class at 60 days. Quality of life was measured by the Seattle Angina Questionnaire. At 60 days of follow-up, there was no significant quality of life difference between patients treated with placebo or VEGF. CONCLUSION: Treatment with VEGF was safe but this Phase 2 trial did not show any real difference between placebo and VEGF groups for exercise time, angina class or quality of life at 60 days of follow-up. ASSENT-2 Assessment of the Safety and Efficacy of a New Thrombolytic: TNK-tPA This trial tests the safety and effectiveness of TNK-tPA, a "clot-buster." Heart attack patients seen within 6 hours of pain onset were given one of 2 treatments: weight-based doses of TNK-tPA or accelerated doses of tPA. All patients were also treated with aspirin and heparin. The primary endpoint was all-cause death at 30 days. Secondary endpoints were rate of stroke, intracranial hemorrhage, bleeding complications, and overall effect. 16,950 patients were enrolled. All patients had acute MI pain, ST segment elevation, or new left bundle branch block. The rate of stroke was similar in the 2 groups. The combined endpoint of death or nonfatal stroke was similar. Mild to moderate bleeding was seen less in TNK-tPA-treated patients compared with tPA-treated subjects. CONCLUSION: Single-bolus TNK-tPA is equivalent to tPA in terms of 30-day mortality. Mild-to-moderate bleeding may be less likely in TNK-tPA-treated patients. InTime-II Lanoteplase (nPA) is a new genetically-engineered plasminogen activator with a long half-life, allowing for single dosing (bolus). Heart attack patients seen within 6 hours of pain onset received either nPA (120kU/kg) or tPA. The primary endpoint was all-cause death at 30 days. Secondary endpoints were new or worsened heart failure, intracranial hemorrhage, death or stroke. Patients were excluded if they were at increased risk for bleeding or were in cardiogenic shock. A total of 15,078 patients were enrolled. 30-day and 180-day mortality between the groups was similar. The 24-hour mortality was slightly better in nPA-treated patients. Among patients who died, intracranial hemorrhage was more frequent in nPA patients. Rate of stroke was similar. Overall bleeding complications were equal but mild complications happened more often in nPA patients. Secondary endpoints of urgent revascularization, severe heart failure, another heart attack or death were similar. CONCLUSION: Lanoteplase (nPA) is equally effective to tPA in reducing 30-day mortality. Overall survival of nPA-treated patients is similar despite a higher chance of intracranial bleeding. The benefits of single-bolus nPA over traditionally-dosed tPA include quicker treatment time and less chance of a dose mistake. This may be better for emergency room treatment. GISSI Prevention Study Gruppo Italiano Per Lo Studio Della Sopravvivenza Nell'Infarto Patients surviving acute heart attack (MI) are at increased risk for a second heart attack. It is being debated if diet and antioxidants help prevent these recurring MIs. This trial studied whether patients taking n-3 PUFA (Poly-Unsaturated FAt) supplements or vitamin E would do better than those on placebo. Also studied was whether the combination of both had more effect on MI prevention. Patients were given one of four treatments: 1) n-3 PUFA - 1 gram per day 2) vitamin E - 300mg per day 3) combination of n-3 PUFA (1 gm/day) and vitamin E (300mg/day) 4) placebo On average, patients were followed-up for 42 months. Patients enrolled had had a heart attack within the past 3 months but were otherwise healthy. Primary endpoint was combined total mortality, nonfatal heart attack or stroke. 85% were men, average age was 59, 15% were diabetics, and 14% had an ejection fraction of less than 40%. However, few were on beta-blockers or ACE inhibitors. There was a 10% risk reduction in patients getting n-3 PUFA compared with the control group. Risk reduction in vitamin E patients was only 5% compared with controls, which was not significant. Compared to controls, patients taking n-3 PUFA had a 45% reduced risk of death, vitamin E patients 35% and the combined group 25%. CONCLUSION: There was a 1.6% absolute reduction in cardiac death and sudden death at 3.5 years in patients taking one gram per day of n-3 polyunsaturated fatty acids, starting 3 months after a heart attack. No extra benefits came from combining n-3 PUFA with vitamin E. Vitamin E had no impact on the combined endpoint. SCAT The Simvastatin/Enalapril Coronary Atherosclerosis Trial SCAT tested the safety and effectiveness of these 2 drugs in patients with coronary artery disease (CAD). Caths were done to measure the effects of statins and ACE inhibitors on disease (CAD) progression. 460 patients with CAD took either simvastatin (Zocor), enalapril (Vasotec), both, or placebo. Patients were assigned a treatment and doses were titrated from 10mg to 40mg daily for Zocor and 2.5mg to 10mg twice daily for Vasotec. The average patient age was 61 years old and 89% were men. 85% of patients were also taking aspirin. Another cath was done after 4 years of follow-up. The primary endpoints were change in average heart diameter, minimal lumen diameter, and maximum percent blockage. HDL ("good" cholesterol) increased by 8% in the Zocor group and 3% in placebo patients. LDL decreased by 31% in Zocor patients and increased by 4% in the placebo group. Triglycerides decreased by 10% for Zocor patients and increased by 9% for the placebo group. There were no changes in lipid profiles between the Vasotec and placebo groups. CONCLUSION: Zocor slowed CAD progression compared to placebo. Vasotec had no effect on CAD progression. Zocor reduced need for angioplasty. Vasotec decreased rate of death, heart attack and stroke compared with placebo. Statins do help patients with CAD. ACE inhibitors are useful in heart attack survivors - 70% of the study group had a history of prior heart attack. GUARDIAN The Guard During Ischemia Against Necrosis Trial This was a phase 2-3 trial. This is the first large-scale study testing the safety and effectiveness of cariporide, a selective inhibitor of Na/H exchange. --- TECHNICAL ---During episodes of ischemia, there is an increased concentration of intracellular hydrogen ions. This leads to activation of the Na/H ion exchanger that pumps out H+ and pumps in Na. The elevated sodium level activates the Na/Ca exchanger that increases intracellular calcium, resulting in cellular swelling, malfunction and death. During episodes of reperfusion, the high intracellular hydrogen levels are washed out, again activating the Na/H exchange system. This leads to increased levels of intracellular sodium and calcium, resulting in cell death. Cariporide may slow the initial increase in intracellular sodium, protecting heart cells from stress. --- END TECHNICAL --- 11,590 patients enrolled from 43 countries. Patients had unstable angina (UA) or non-Q-wave heart attack (NQWMI), or were undergoing high-risk angioplasty or bypass surgery. Average patient age was 64, 70% were men, 16% had CHF and 32% had diabetes. Patients received either a 2-7 day course of placebo or one of three doses of cariporide (20mg, 80mg or 120mg) by IV every 8 hours. Primary endpoint was death or heart attack at 36 days. CONCLUSION: The hope was to prevent the calcium accumulation in heart cells that occurs with ischemia and reperfusion, thus preventing cell death. However, at all 3 doses, there was no difference between placebo and cariporide groups in death or MI. In the high-dose cariporide group there was a lower rate of heart attack for those having high-risk bypass or angioplasty.