CV Risk Management 2016 Moscow, Russia David D. Waters, MD - PowerPoint PPT Presentation

Managing Lipids: Integrating Novel Insights with Gold Standard Therapies CV Risk Management 2016 Moscow, Russia David D. Waters, MD October 14, 2016

Relation Between the Proportional Reduction in MAJOR VASCULAR EVENTS and Mean Absolute LDL-C Reduction in 14 Statin Trials Cholesterol Treatment Trialist Collaborators, Lancet 2005;366:1267

LDL-C Reduction with Statins and CV Event Reduction Collins R et al , Lancet epub Sept 9, 2016

Reduction in CV Events with Statins in Subgroups Collins R et al , Lancet epub Sept 9, 2016

Figure 4 Event Reduction Is Independent of Baseline LDL-C Trend RR (CI) per 1 mmol/L reduction in LDL-C Events (% per annum) test Statin/more Control/less All trials combined <2 mmol/L 910 (4.1%) 1012 (4.6%) 0.78 (0.61 – 0.99) ≥2 to <2.5 mmol/L 1528 (3.6%) 1729 (4.2%) 0.77 (0.67 – 0.89) 0.77 (0.70 – 0.85)  2 ≥2.5 to <3.0 mmol/L 1866 (3.3%) 2225 (4.0%) 1 =1.08 ≥3 to <3.5 mmol/L 2007 (3.2%) 2454 (4.0%) 0.76 (0.70 – 0.82) (p=0.3) ≥3.5 mmol/L 4508 (3.0%) 5736 (3.9%) 0.80 (0.76 – 0.83) Total 10973 (3.2%) 13350 (4.0%) 0.78 (0.76 – 0.80) 99% or 95% CI Statin/more Control/less Cholesterol Treatment Trialists’ Collaboration, Lancet 2010;376:1670

Risk Reduction According to Baseline Risk Major vascular event Events (%/year) RR (CI) per 1 mmol/L Risk at baseline Statin Control Reduction in LDL-C Cholesterol Treatment Trialists ’ (CTT) Collaborators, Lancet 2012;380:581

CV Events Avoided Per 10,000 Patients Treated For 5 Years Collins R et al , Lancet epub Sept 9, 2016

CV Event Reduction with Statins… • is proportional to LDL-C reduction • applies to a broad population • is independent of baseline LDL-C • is independent of baseline risk

Reduction in CV Events Per Year of Statin Treatment Collins R et al , Lancet epub Sept 9, 2016

Effect of LDL-C Lowering With Statins on Cause-Specific Mortality Collins R et al , Lancet epub Sept 9, 2016

Effect of LDL-C Lowering With Statins on Cancer Incidence Collins R et al , Lancet epub Sept 9, 2016

HOPE-3: Baseline Characteristics 12,705 randomized Age (yrs) 66 Female 46% Blood Pressure (mmHg) 138/82 LDL-Cholesterol (mg/dL) 128 LDL-Cholesterol (mmol/L) 3.3 Elevated waist-to-hip ratio 87% hsCRP (g/L) median 2.0 Ethnicity White Caucasian 20% Latin American 28% Chinese 29% Other Asian 20% Black African 2%

CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure 0.10 HR (95% CI) = 0.75 (0.64-0.88 ) Cumulative Hazard Rates 0.08 P-value = 0.0004 0.06 Placebo 0.04 Rosuvastatin 0.02 0.0 0 1 2 3 4 5 6 7 Years Rosuva 6361 6241 6039 2122 Placebo 6344 6192 5970 2073 21

West of Scotland Study • 6,595 men aged 45-64 years with hypercholesterolemia and no evidence of previous MI were randomized to pravastatin 40 mg or placebo and followed for 4.9 years • mean LDL-C at baseline: 192 mg/dL (5.0 mmol/L) • 44% smokers, 16% hypertensives, 1% diabetics • primary endpoint: CHD death plus non-fatal MI • LDL-C reduced by 26% in pravastatin group • primary endpoint reduced by 31% (95% CI 17-43%, p <0.001) • trial completed in 1995 • in the original pravastatin and placebo groups, 28.6% and 24.3% at 1 year after the trial, and 38.7% and 35.2% at 5 years were taking statins Shepherd J et al, N Engl J Med 1995;333:1301-7

West of Scotland Study: 20-Year Follow-Up Mortality: (A) All Cause, (B) CV, (C) CHD, and (D) Non-CVD Ford I et al , Circulation 2016;133:1073-80

West of Scotland Study: 20-Year Follow-Up Cumulative hospitalizations for (A) CV disease, (B) MI, (C) heart failure, and (D) coronary revascularization Ford I et al , Circulation 2016;133:1073-80

Change in LDL-C with Rosuvastatin 20 mg (JUPITER) +50% 0 -50% 0 2,000 4,000 6,000 8,000 Number of Patients Boekholdt SM et al, J ACC 2014;64:485

JUPITER: LDL-C Reduction  CV Event Reduction Ridker PM et al, Eur Heart J 2016;37:1373-1379

Early Statin Discontinuation Is Associated with Increased Risk of MI and CHD Death Nielsen SF and Nordestgaard BG, Eur Heart J 2016;37:908-916

Predictors of Early Statin Discontinuation (<6 Months) Nielsen SF and Nordestgaard BG, Eur Heart J 2016;37:908-916

Lipoprotein and PCSK9 Metabolism Bergeron N et al, Circulation 2015;132:1648

Lipoprotein Metabolism and PCSK9 Inhibition Bergeron N et al, Circulation 2015;132:1648

OSLER 1 and 2: LDL-C Levels Sabatine MS et al NEJM 2015;372:1500-9

OSLER 1 and 2: CV Events* * CV events were death, MI, UA requiring hospitalization, coronary revascularization, stroke, TIA, and hospitalization for heart failure Sabatine MS et al NEJM 2015;372:1500-9

ODYSSEY Long-Term Trial: LDL-C Levels Robinson JG et al, NEJM 2015;372:1489-99

ODYSSEY Long-Term Trial: CV Events CV Events Alirocumab Placebo P value (n=1550) (n=788) Death from CHD 4 (0.3%) 7 (0.9%) 0.26 Myocardial infarction 14 (0.9%) 18 (2.3%) 0.01 Ischemic stroke 9 (0.6%) 2 (0.3%) 0.35 Unstable angina (hospitalization) 0 1 (0.1%) 0.34 CHF (hospitalization) 9 (0.6%) 3 (0.4%) 0.76 Coronary revascularization 48 (3.1%) 24 (3.0%) 1.0 All CV events 72 (4.6%) 40 (5.1%) 0.68 Major CV events ( post hoc ) 27 (1.7%) 26 (3.3%) 0.02 Robinson JG et al, NEJM 2015;372:1489-99

Relation Between the Proportional Reduction in MAJOR VASCULAR EVENTS and Mean Absolute LDL-C Reduction in 14 Statin Trials and 2 PCSK9 Inhibitor Trials Cholesterol Treatment Trialist Collaborators, Lancet 2005;366:1267; Sabatine MS, et al., N Engl J Med 2015;DOI:10.1056/NEJMoa1500858; Robinson JG, et al., N Engl J Med 2015;DOI:10.1056/NEJMoa1501031

IMPROVE-IT: Simvastatin vs. simvastatin + ezetimibe in 18,144 high-risk patients with ACS Primary endpoint: cardiovascular death, MI, documented unstable angina requiring rehospitalization , coronary revascularization (≥30 days), or stroke 40 HR 0.936 (95% CI, 0.89 – 0.95) Simvastatin: 2742 events (34.7%) Mean LDL-C at 1 yr 69.9 mg/dL (≈1.8 mmol/L) p=0.016 Event Rate (%) (ITT analysis) NNT= 50 30 RRR=6.4% 20 Ezetimibe/simvastatin: 2572 events (32.7%) Mean LDL-C at 1 yr 53.2 mg/dL (≈1.4 mmol/L) 10 0 0 1 2 3 4 5 6 7 Time since randomization (years) Cannon CP, et al. New Engl J Med 2015; DOI: 10.1056/NEJMoa1410489. Published online June 3, 2015

IMPROVE-IT: Subgroup Analysis • 11% of subjects had missing data for the primary endpoint • No benefit in non-diabetics (73% of population) • No benefit in patients <75 years old (84% of population) • FDA Advisory Committee voted 10 to 5 against approval • FDA did not approve new indication • EMEA did approve new indication Subgroup Number HR 95% CI P Value Diabetics 4,933 0.86 0.78-0.94 0.001 Non Diabetics 13,202 0.98 0.91-1.04 0.49 Age ≥75 2,797 0.80 0.70-0.90 0.0003 Age <75 15,338 0.97 0.91-1.03 0.34 FDA Briefing Document, Endocrinologic and Metabolic Drugs Advisory Committee, December 14, 2015

LDL-C Reduction Versus CV Event Reduction: Statin Trials Plus IMPROVE-IT a) GISSI Preventione b) ALL-HAT LLT c) ALERT d) LIPS e) AFCAPS/TexCAPS f) CARE g) LIPID h) PROSPER i) ASCOT-LLA j) WOSCOPS k) Post CABG l) CARDS m) HPS n) 4S Cannon CP et al, N Engl J Med 2015;372:2387

Clinical Trials of Fibrates and Niacin in the Statin Era • FIELD Trial – No benefit of fenofibrate on cardiac death + MI in 9,765 patients with diabetes followed for 5 years • ACCORD Lipid Trial – No benefit of fenofibrate added to simvastatin on cardiac death, MI and stroke in 5,518 patients with diabetes followed for 4.7 years • AIM-HIGH – No benefit of niacin added to high-dose simvastatin in 3,414 patients with CAD followed for 3 years • HPS2-THRIVE – No benefit of niacin/laropiprant added to simvastatin in 25,673 high-risk patients followed for 3.9 years The Field Study Investigators, Lancet 2005;366:1849 The ACCORD Study Group. N Engl J Med 2010;362:1563 Boden WE et al, N Engl J Med 2011;365:2255 http://www.thrivestudy.org, accessed May 9, 2014 (Paper has not been published)

Recommendations for Nonstatin Drugs • “The panel could find no data supporting the routine use of nonstatin drugs added to statin therapy to further reduce ASCVD events” 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to reduce Atherosclerotic Cardiovascular Risk in Adults, p 45 • “Do not routinely offer fibrates for primary or secondary prevention of CVD” National Institute for Health and Care Excellence Lipid modification July 2014 http://www.nice.org.uk/Guidance/CG181 • “Combination therapy has been shown not to provide additional cardiovascular benefit above statin therapy alone and is not generally recommended” ADA. 8. Cardiovascular Disease and Risk Management. Diabetes Care 2015;38(suppl 1):S52