CLINICAL OUTCOME Vs SURROGATE MARKER Statin Real Experience Dr. Mostafa Sherif Senior Medical Manager Pfizer Egypt & Sudan
Objective Difference between Clinical outcome and surrogate marker Proper Clinical Evaluation for Trials used in management of CV Risk Factors
Burden of Hyper Cholesterolemia In terms of global mortality, elevated cholesterol is the sixth leading risk factor for death after hypertension, tobacco use, hyperglycemia, physical inactivity, and being overweight or obese. One-third of all ischemic heart disease globally is attributable to elevated cholesterol levels, resulting in an estimated 2.6 million deaths annually
Cardiovascular Risk Modifiable risk factors as: Hypertension Diabetes Dyslipidemia Smoking
Introduction to Atherosclerosis Dyslipidemia
Development of Atherosclerotic Plaque Plaque rupture Monocyte LDL-C Adhesion molecule Macrophage Oxidized LDL-C CRP Foam cell Smooth muscle cells
Morbidity Related to Atherosclerotic Lesion Brain Ischemic stroke Heart Coronary Heart Disease - Ischemic Heart and Angina - Myocardial Infarction - Acute Coronary Syndrome Kidney Chronic Kidney Disease & End-stage renal disease
Introduction to Dyslipidemia treatment Statins are the most commonly prescribed agents used to lower LDL-C, and there is a large body of data showing their clinical benefit in reducing the incidence of CV events. Early Clinical Trials on dyslipidemia were addressing the benefit of LDL Lowering Following this the benefit of LDL reduction on Cardiovascular morbidity and mortality was the main concern for RELIABALE Clinical Trials
Rationale on Dyslipidemia treatment Clinical Trials Dyslipidemia Lead to LDL Lead to Cardiovascular Disease Designing a Clinical trial Treatment of Dyslipidemia Lead to LDL Lowering Lead to Preventing Cardiovascular Disease Clinical trial from treatment till cardiovascular events Disadvantage of Clinical outcome trials: - Time consuming - Cost CLINICAL OUTCOME TRIAL
Rationale on Dyslipidemia treatment Clinical Trials Dyslipidemia Lead to LDL Lead to Cardiovascular Disease Designing a Clinical trial Treatment of Dyslipidemia LDL Lowering Assuming that the same outcome will be reached by the same LDL level Clinical trial from treatment till LDL reduction SURROGATE Marker (No Clinical outcome) Definition: Biomarker intended to substitute for a clinical end point
LDL-C IS IT A VALID SURROGATE MARKER?
Cumulative incidence (%) Cumulative incidence (%) A Tale OF TWO TRIALS With Equivalent LDL-C Reductions, Only LIPITOR Achieved Significant Event Reduction WEGYLIP6012019 MIRACL 1 A to Z 2 LDL-C Difference Between Arms 20 15 (63 mg/dl) Placebo -16% in CV Events 20 15 (62 mg/dl) No difference in CV Events in the First 4 Months and after two years of follow up 10 10 Placebo 5 LIPITOR 80 mg 5 0 P=0.048 0 4 8 12 16 0 Simvastatin 80 mg P=0.14 0 1 2 3 4 Weeks Months Primary composite end points. Non fatal acute MI, resuscitated cardiac arrest, worsening angina requiring rehospitalization Nissen SE. High-Dose Statins in Acute Coronary Syndromes Not Just Lipid Levels.JAMA 2004;292:1365-1367.
Patients experiencing hospitalization for HF (%) Despite the same % of LDL Reduction Only Lipitor Provide CV benefit in CHD Pt. TNT (HF Sub Analysis) CORONA LDL-C Difference Between Arms (77 mg/dl) (76 mg/dl) 20 15 41% RRR 10 5 0 0 1 2 3 4 5 6 Years No Significant difference in CV Events Patients with a history of HF Atorvastatin 10 mg (n=404) Atorvastatin 80 mg (n=377)
DO YOU STILL THINK LDL IS A RELIABLE SURROGATE FOR CV CLINICAL OUTCOME?
IS THIS REFLECTED ON GUIDELINES
Number of RCTs contributing to guidelines ACC/AHA 2013 Guideline recommendations based on RCT evidence 14 12 11 12 10 8 8 6 4 2 5 4 2 1 0 Atorvastatin Pravastatin Simvastatin Rosuvastatin Fluvastatin Lovastatin Non-statin
EVIDENCE Behind each statement in the guidelines Trials: TNT IDEAL PROVE-IT SPARCL Group 1 Clinical ASCVD CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin Group 2 LDL-C 190 mg/dl (~5 mmol/l) Trials: None Trials: CARDS TNT Group 3 Diabetes mellitus + age of 40 75 years + LDL-C 70 189 mg/dl (1.8 4.9 mmol/l) Group 4 ASCVD risk 7.5% No diabetes + age of 40 75 years + LDL-C 70 189 mg/dl (1.8 4.9 mmol/l) Trials: ASCOT- LLA JUPITER ASCVD, atherosclerotic cardiovascular disease CHD, coronary heart disease LDL-C, low-density lipoprotein-cholesterol 17 Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print
NICE 2014 Guidelines CVD has significant cost implications and was estimated to cost the NHS in England almost 6,940 million in 2003, rising to 7,880 million in 2010.
NICE 2014 Guidelines
WHAT ABOUT FDA INDICATION?
Lipitor Local Product Document
TAKE HOME MESSAGE The underlying goal of Cost effectiveness research is to allow clinicians and policymakers to make more rational decisions regarding clinical care and resource allocation in long term economic analysis. Decision in CV risk burden prevention should be based on clinical outcome if available
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