Effective Treatment Options With Add-on or Combination Therapy Christie Ballantyne (USA)
Effective treatment options with add-on or combination therapy Christie M. Ballantyne, MD Center for Cardiovascular Disease Prevention Methodist DeBakey Heart & Vascular Center Baylor College of Medicine Houston, Texas
Disclosures Dr. Ballantyne consults with and speaks for biotechnological as well as pharmaceutical companies that develop drugs that influence lipoprotein metabolism and / or inflammation to prevent CVD
Key Issues/Controversies 1. What is the optimal LDL-C,non HDL-C or apo B target for our patients? 2. What do we do when a patient has elevated levels of atherogenic lipoproteins after statin therapy?
What Is Desirable Cholesterol? Cholesterol Levels Among Different Human Populations Hazda Inuit!Kung Pygmy San Adult American Huntergatherer humans 50 70 90 110 130 150 170 190 210 Mean total cholesterol, mg/dl Adapted from O Keefe JH Jr et al. J Am Coll Cardiol. 2004;43:2142 2146.
Relative Risk for Incident CHD 3.0 2.5 2.0 1.5 1.0 0.5 What is the Optimal LDL-C? ARIC Men 3.0 2.5 2.0 1.5 1.0 0.5 Women 0.0 LDL-C Quintiles mmol/l mg/dl (median) 1 2 3 4 5 3.10 3.55 4.04 120 137 156 2.45 95 4.78 185 0.0 1 2 3 4 5 2.93 3.40 3.94 113 131 152 2.27 88 Adjusted for age and race, 12-year follow-up; N=12,339 4.84 187 Sharrett AR et al. Circulation 2001;104:1108-1113.
Associations with LDL-C Ference BA. Presented at ACC.12, Chicago, 26 March 2012.
Associations with CHD Ference BA. Presented at ACC.12, Chicago, 26 March 2012.
Linear Effect on CHD (per unit lower LDL-C) Ference BA. Presented at ACC.12, Chicago, 26 March 2012.
Of 15 variants that alter HDL-C, 6 also affect MI risk
Proportional reduction in vascular event rate (95% CI) CTT meta analysis: Proportional reduction in MAJOR VASCULAR EVENTS versus absolute LDL-C reduction 30% 25% TNT Statin vs. control (21 trials) 20% More vs. Less (5 trials) IDEAL 15% 10% A to Z PROVE-IT 22% (20%-24%) risk reduction per mmol/l P<0.0001 5% SEARCH 0% 0.0 0.5 1.0 Mean LDL cholesterol difference between treatment groups (mmol/l) CTT Collaboration, Lancet 2010
LDL-C and Disease Progression - IVUS Median Change Percent Atheroma Volume
Comparative Clinical Benefit Prolonged exposure to lower LDL-C beginning early in life associated with 3-fold greater clinical benefit for each unit lower LDL-C than treatment with a statin started later in life May explain much of residual risk of coronary events in persons treated with a statin started later in life Ference BA. Presented at ACC.12, Chicago, 26 March 2012.
Combination Therapy to Reduce LDL-C Statin + bile acid binding resin Statin + ezetimibe Statin + niacin Statin + fibrate
Which of the following combinations have shown CV event reduction in RCT? Statin + bile acid binding resin Statin + ezetimibe Statin + niacin Statin + fibrate
EXPLORER: Lipid and CRP Results Change from baseline to week 6, % 20 10 0-10 -20-30 -40-50 -60-70 -80 LDL-C HDL-C CRP 9 11-57 -70 * *p <.001-29 -46 * rosuvastatin 40 mg rosuvastatin 40 mg + ezetimibe 10 mg Ballantyne CM et al. Am J Cardiol 2007;99:673 680.
Randomization Eze + Rosuva vs Rosuva Uptitration (the ACTE Study) Study Design LDL-C not at goal * Stratum I Rosuva 5 mg + Eze 10 mg (n=99) Rosuvastatin 5 mg Rosuvastatin 10 mg (n=98) Stratum II Rosuvastatin 10 mg Run-in Screening Rosuva 10 mg + Eze 10 mg Rosuvastatin 20 mg (n=122) (n=121) - 6-5 - 1 0 6 Week * LDL-C target < 100 mg/dl for moderately high or high risk subjects without atherosclerotic vascular disease (AVD), < 70 mg/dl for high risk subjects with AVD Bays et al. Am J Cardiol 2011; 108: 523-30
% change from baseline Rosuva 5 mg and 10 mg + Ezetimibe vs Rosuva 10 mg and 20 mg (Pooled data) % change from baseline * * * * p < 0.001 Bays et al. Am J Cardiol 2011; 108: 523-30
% patients attaining specified LDL-C target Attainment of pre-specified LDL-C targets after 6 weeks of therapy LDL-C < 100 mg/dl Patients w/o AVD LDL-C < 70 mg/dl Patients w/ AVD * * * * p < 0.001 n=219 n=217 n=98 n=96 n=121 n=121 Across Strata Stratum I Stratum II Bays et al. Am J Cardiol 2011; 108: 523-30
Percentage of Patients With First Event Rossebø et al. N Engl J Med 2008; 359 SEAS 2nd EP: Ischemic CV Events (ICE) 30 Intention to Treat Population 20 Hazard ratio: 0.78, p=0.024 Placebo 10 EZ/Simva 10/40 mg 0 0 1 2 3 Years in Study 4 5 No. at risk EZ/Simva 10/40 mg Placebo 917 898 867 838 823 788 769 729 76 76
Holme I et al. Am J Cardiol 2010;105:1802 1808 SEAS: Incidence of ischemic events by baseline AS severity % 30 25 20 15 HR=0.54 p=0.004 HR=0.63 p=0.033 HR=1.10 p=0.80 Placebo Simv+Eze 10 5 0 <2.8 2.8-3.3 >3.3 Aortic jet velocity m/sec
Proportional Reduction in Event Rate (SE) Holme I et al. Am J Cardiol 2010;105:1802 1808 ICE Reduction by LDL-C Lowering: SEAS vs CTT SEAS T1 SEAS T2 SEAS T3 Reduction in LDL-C (mmol/l)
SHARP: Randomization structure Randomized (9438) eze/simva 4193 simvastatin 1054 placebo 4191 + 457 886 re-randomized + 429 eze/simva 4650 4.9 years placebo 4620 Main analyses of safety and efficacy SHARP investigators Lancet 2011; 377:2181-92
Proportion suffering event (%) SHARP: Major Atherosclerotic Events 25 20 15 10 Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0021 Placebo Simv/Eze 5 0 0 1 2 3 4 5 Years of follow-up SHARP investigators Lancet 2011; 377:2181-92
Proportional reduction in atherosclerotic event rate (95% CI) Relation between proportional reduction in incidence of major coronary events and absolute LDL-C reduction at 1 year 30% Statin vs control (21 trials) 25% 20% 15% 10% 5% More vs Less (5 trials) SHARP 17% risk reduction SHARP 33 mg/dl 0% 0 10 20 30 40 Mean LDL cholesterol difference between treatment groups (mg/dl) SHARP investigators Lancet 2011; 377:2181-92
SHARP: Major Atherosclerotic Events by Renal Status Simv/Eze (n=4650) Placebo (n=4620) Risk ratio & 95% CI Non-dialysis (n=6247) 296 (9.5%) 373 (11.9%) Dialysis (n=3023) 230 (15.0%) 246 (16.5%) Major Atherosclerotic Event 526 (11.3%) 619 (13.4%) 16.6% SE 5.4 reduction (p=0.0021) No significant heterogeneity between non-dialysis and dialysis patients (p=0.25) 0.6 0.8 Simv/Eze better 1.0 1.2 1.4 Placebo better SHARP investigators Lancet 2011; 377:2181-92
Net compliance and LDL reduction differed between non-dialysis and dialysis patients egfr LDL-lowering drug use Mean LDL difference (mg/dl) eze/ simva placebo Absolute difference eze/ simva placebo Absolute difference Not on dialysis 73% 8% 65% -43-6 37 Dialysis 65% 11% 54% -29-6 23 All patients 71% 9% 61% -39-6 33 C. Baigent, WCC 2012
Proportional reduction in vascular event rate (95% CI) 0 5 10 15 20 25 30 CTT: Effect on major vascular/atherosclerotic events by trial-midpoint LDL-C reduction Statin vs control More vs less (21 trials) (5 trials) Not on dialysis (22% MAE risk reduction) SHARP (17% MAE risk reduction) Dialysis (10% MAE risk reduction) 0 10 20 30 40 Mean LDL cholesterol difference between treatment groups (mmol/l) C. Baigent, WCC 2012
IMPROVE-IT Design Patients stabilized post-acs 10 days LDL-C 125 mg/dl (or 100 mg/dl if prior statin) Double-blind ASA + Standard Medical Therapy N~18,000 Simvastatin 40 mg* Ezetimibe/ Simvastatin 10/40 mg* Follow-up visit day 30, every 4 months *up titrated to 80 mg if LDL-C >79 Duration: Minimum 2 1/2 year follow-up (5250 events) Primary Endpoint: CV Death, MI, Hospital Admission for UA, Revascularization (>30 days after randomization), or Stroke Cannon, C Am Heart J 2008;156:826-32
Conclusions Population studies and genetics suggest that the lower the LDL-C, the less CHD. Thus far, genes associated with LDL-C levels are routinely associated with CHD, whereas this is more complex with HDL-C The optimal LDL-C for all patients with CAD appears to be <70 mg/dl in regards to progression of CHD and clinical events Achievement of LDL-C <70 mg/dl will require 50% reduction of LDL-C in most patients LDL-C <70 mg/dl can be safely achieved in the majority of CAD patients if highly effective agents are used
Conclusions Clinical trials with ezetimibe and statins versus placebo show reduction in CHD expected by the reduction in LDL-C with good safety Ongoing trials will examine if the addition of ezetimibe or niacin leads to further CHD reduction At the current time, therapy should begin with statin and one should use a high efficacy statin at dose with around 50% expected LDL-C reduction before adding a second agent if tolerated In patients who cannot tolerate higher dose statins or any statins, then other therapies in combination can be used to lower LDL-C to target
ESC Congress 2012 Munich, Germany 25 29 August 2012 SATELLITE SYMPOSIUM SPONSORED BY MSD Tuesday, 28 August 2012 Clinical Considerations and Practical Approaches to Managing Patients With Dyslipidemia CO-CHAIRS: John Deanfield (UK) John J. P. Kastelein (Netherlands)