SAGE Effects of Intensive Versus Moderate Lipid Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease

Effects of Intensive Versus Moderate Lipid-Lowering Therapy on Myocardial Ischemia in Older Patients With Coronary Heart Disease: Results of the Study Assessing Goals in the Elderly (SAGE) SAGE Trial Prakash Deedwania, MD; Peter H. Stone, MD; C. Noel Bairey Merz, MD; Juan Cosin-Aguilar, MD; Nevres Koylan, MD; Don Luo, PhD; Pamela Ouyang, MBBS; Ryszard Piotrowicz, MD; Karin Schenck-Gustafsson, MD, PhD; Philippe Sellier, MD; James H. Stein, MD; Peter L Thompson, MD; Dan Tzivoni, MD Published in Circulation February 13, 2007 Clinical Trial Results . org SAGE Trial: Background • Atherosclerosis is a progressive disease and therefore coronary artery disease (CAD) is most prevalent in older persons. • The risk of CAD events can reduced by lowering lowdensity lipoprotein cholesterol (LDL-C), for which statins are the preferred drug. • However, no studies to date have assessed intensive versus moderate statin therapy in older patients with stable coronary syndromes. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Background • The purpose of the SAGE study was to compare the effects of intensive versus moderate statin therapy on the reduction of myocardial ischemia, as assessed by ambulatory ECG, in older men and women with stable CAD. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Study Design 893 ambulatory CAD patients 65-85 years with ≥ 1 MI that lasted ≥ 3 minutes during 48- hour ambulatory ECG at screening Prospective. Randomized. Double-blind. Double-dummy. Multi-Center. International. Mean follow-up 12 months R Atorvastatin Pravastatin 80 mg/d n=377 40 mg/d n=374 3 and 12 mos. follow-up   Primary Efficacy Parameter: Absolute change from baseline in total duration of myocardial ischemia on 48-hour Holter Monitor Secondary Efficacy Parameters: (1) absolute change in total duration of ischemia from baseline to month 3; from baseline to month 3 and to month 12: (2) the % change in total duration of ischemia, (3) the absolute and % change in no. of ischemic episodes, (4) the % change in ischemic burden, (5) the proportion of patients who were totally free of ischemia, and (6) the % change in the levels of total cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), triglycerides, and apolipoprotein B. Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. Clinical Trial Results . org SAGE Trial: Baseline Characteristics Characteristic Age, y Weight**, kg Body Mass Index**, kg/m2 Cholesterol, mg/dL Total LDL HDL Triglycerides, mg/dl Atorvastatin (n= 446) 72.4 ± 5.1 77.4 ± 13.2 27.4 ± 4.0 225.8 ± 36.1 147.5 ± 30.1 45.5 ± 11.5 164.4 ± 71.5 Pravastatin (n= 445) 72.6 ± 5.2 75.1 ± 11.5 26.8 ± 3.5 221.9 ± 35.9 144.0 ± 31.5 46.4 ± 11.1 157.1 ± 78.0 Apolipoprotein B 100**, mg/dL Duration of ischemia, min No. of ischemia events Men (%) 143.6 ± 25.4 113.5 ± 122.0 3.9 ± 3.8 307 (68.8) 139.3 ± 26.3 124.3 ± 145.3 3.9 ± 3.8 312 (70.1) White (%) **Denotes statistical significance Clinical Trial Results . org 433 (97.1) 430 (96.6) Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Primary Efficacy Endpoint Mean total duration of myocardial ischemia over 48 hours Total duration of Myocardial Ischemia (min) 140 120 100 81.4 80 60 40 20 0 Atorvastatin 140 124.3 113.5 P<0.001 120 P<0.001 100 70.8 80 60 40 20 0 75.3 78.7 • The total duration of myocardial ischemia at month 12 was significantly reduced from baseline in both atorvastatin- and pravastatin-treated patients. • There was no significant difference between atorvastatin and pravastatin. Pravastatin (n=408) (n=396) Baseline Clinical Trial Results . org Month 3 Month 12 Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Secondary Efficacy and Lipid Parameters • There were no significant differences between atorvastatin and pravastatin for any of the secondary efficacy parameters at month 3 or month 12. • Compared with pravastatin 40 mg/d, atorvastatin 80 mg/d produced significantly greater decreases in total cholesterol, LDL-C, triglycerides, and apolipoprotein B at month 3 and at month 12 (all P<0.001). • Levels of HDL-C increased in both groups, with significantly larger increases in the pravastatin group at month 3 (p<0.001) and 12 (p=0.009) than in the atorvastatin group. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Lipid Parameters Least Squares Mean Percent Changes in Lipid Parameters from Baseline 20 LS mean percent change Total LDL Pravastatin 2.2 HDL 5.5 5.8 7.6 10 0 -10 -20 -30 -40 -50 -60 p<0.001 -56.3 -55.4 -40.9 -39.6 -21.9 -21.3 -32.1 -32.4 Atorvastatin Pravastatin Atorvastatin Atorvastatin Pravastatin p=0.009 Month 3 Month 12 p<0.001 Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Lipid Parameters Least Squares Mean Percent Changes in Lipid Parameters from Baseline LS mean percent change 20 10 0 -10 -20 -30 -40 -50 -60 -28.4 Triglycerides Atorvastatin Pravastatin -7 Apolipoprotein B 100 Atorvastatin Pravastatin -10.6 -26.3 -25.1 -24.5 p<0.001 -45.6 -44.8 Month 3 Month 12 p<0.001 Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: MACE and All-Cause Mortality 20% 10% Major Adverse Cardiovascular Events (MACE) Incidence (%) 8% All-Cause Mortality 11.2% 10% 6% 8.1% 4% 4.0% • There was a favorable trend for fewer atorvastatin patients to experience MACE than pravastatin patients (HR 0.71; 95% CI, 0.46, 1.09, p=0.114). • A significant 77% reduction in allcause mortality 2% 1.3% was observed with atorvastatin n =36 n =50 n =18 n =6 relative to 0% 0% Atorvastatin Pravastatin pravastatin (HR, Atorvastatin Pravastatin 40 mg/d 80 mg/d 40 mg/d 880 mg/d 0.33, 95% CI, 0.13, 0.83; p=0.014). Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. Clinical Trial Results . org SAGE Trial: Limitations • It is possible that reductions in ischemia did not differ significantly between the 2 treatment groups because ambulatory ischemia is not an adequately sensitive measure of change in cardiovascular event risk. • The study may have been underpowered to detect differences between the 2 treatment groups. • The number of events for the mortality analysis was small and was analyzed post-hoc. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Summary • After comparing the effects of intensive versus moderate statin therapy in older individuals, this study found that both regimens were equally effective in the reduction of the frequency and duration of myocardial ischemia. • Intensive atorvastatin therapy improved lipids and reduced all-cause death more effectively than did moderate pravastatin. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707. SAGE Trial: Summary • Also considering a trend toward reductions in MACE with atorvastatin versus pravastatin, these results support the concept that mechanisms of ischemic events, which are related to oxygen supply and demand, may differ from acute coronary events, which are related to plaque stability. • These findings, together with the greater cardiovascular risk in the elderly population, suggest that intensive statin therapy should be considered in the elderly population. Clinical Trial Results . org Deedwania et al. Circulation. 2007 Feb 13; 115: 700 - 707.