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

Cholesterol Treatment Trialists’ Collaboration, Lancet 2010;376:1670

Event Reduction Is Independent of Baseline LDL-C

All trials combined <2 mmol/L 910 (4.1%) 1012 (4.6%) ≥2 to <2.5 mmol/L 1528 (3.6%) 1729 (4.2%) ≥2.5 to <3.0 mmol/L 1866 (3.3%) 2225 (4.0%) ≥3 to <3.5 mmol/L 2007 (3.2%) 2454 (4.0%) ≥3.5 mmol/L 4508 (3.0%) 5736 (3.9%) Total 10973 (3.2%) 13350 (4.0%)

Events (% per annum) RR (CI) per 1 mmol/L reduction in LDL-C

Statin/more Control/less

0.78 (0.61–0.99) 0.77 (0.67–0.89) 0.77 (0.70 – 0.85) 2

1 =1.08

0.76 (0.70–0.82) (p=0.3) 0.80 (0.76–0.83) 0.78 (0.76–0.80)

Trend test 99% or 95% CI

Statin/more Control/less

Cholesterol Treatment Trialists’ (CTT) Collaborators, Lancet 2012;380:581

Risk Reduction According to Baseline Risk

RR (CI) per 1 mmol/L Reduction in LDL-C Major vascular event Risk at baseline Events (%/year) Statin Control

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

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 Latin American Chinese Other Asian Black African 20% 28% 29% 20% 2%

HOPE-3: Baseline Characteristics

12,705 randomized

CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure

Years

Cumulative Hazard Rates

0.0 0.02 0.04 0.06 0.08 0.10 1 2 3 4 5 6 7

Placebo Rosuvastatin

HR (95% CI) = 0.75 (0.64-0.88) P-value = 0.0004

6361 6241 6039 2122 6344 6192 5970 2073 Rosuva Placebo

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

• r 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

Boekholdt SM et al, JACC 2014;64:485 0 2,000 4,000 6,000 8,000

Number of Patients +50%

• 50%

Change in LDL-C with Rosuvastatin 20 mg (JUPITER)

Ridker PM et al, Eur Heart J 2016;37:1373-1379

JUPITER: LDL-C Reduction  CV Event Reduction

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

Sabatine MS et al NEJM 2015;372:1500-9

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

Robinson JG et al, NEJM 2015;372:1489-99

ODYSSEY Long-Term Trial: LDL-C Levels

CV Events Alirocumab (n=1550) Placebo (n=788) P value

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) 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

ODYSSEY Long-Term Trial: CV Events

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

Cannon CP, et al. New Engl J Med 2015; DOI: 10.1056/NEJMoa1410489. Published online June 3, 2015

Simvastatin: 2742 events (34.7%) Mean LDL-C at 1 yr 69.9 mg/dL (≈1.8 mmol/L) Ezetimibe/simvastatin: 2572 events (32.7%) Mean LDL-C at 1 yr 53.2 mg/dL (≈1.4 mmol/L)

HR 0.936 (95% CI, 0.89–0.95) p=0.016

NNT= 50

RRR=6.4% Event Rate (%) (ITT analysis) Time since randomization (years) 1 2 3 4 5 6 7 10 20 30 40

IMPROVE-IT: Subgroup Analysis

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

• 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

Cannon CP et al, N Engl J Med 2015;372:2387

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

LDL-C Reduction Versus CV Event Reduction: Statin Trials Plus IMPROVE-IT

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
• f 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

ACCELERATE Trial: Failure of Evacetrapib

• 12,092 high-risk coronary patients randomized to

evacetrapib or placebo

• primary endpoint was a composite of CV death, MI, stroke,

coronary revascularization or hospitalization for angina

• HDL-C higher in evacetrapib patients (104 vs 46 mg/dl,

130% difference)

• LDL lower in evacetrapib patients (55 vs 84 mg/dl, 37%

difference)

• primary endpoint: evacetrapib, 12.8%; placebo, 12.7%; HR =

1.01; 95% CI, 0.91-1.12

Better Lipids Levels Do Not Necessarily Translate to Fewer CV Events!

Unpublished data presented at ACC, April, 2016

ACCELERATE Trial: Failure of Evacetrapib

• 12,092 high-risk coronary patients randomized to

evacetrapib or placebo

Unpublished data presented at ACC, April, 2016

20 40 60 80 100 120

LDL-C mg/dl HDL-C mg/dl CV events %

Placebo Evacetrapib

LDL-C Lowering Drugs And CV Event Reduction

Silverman MG et al, JAMA 2016;316:1289-97

Conclusions

• CV event reduction with statins is proportional

to LDL-C lowering – lower is better

• statins have a proven long-term safety record
• PCSK9 inhibitors probably reduce CV events
• ezetimibe produces a small reduction in CV

events and is not cost-effective (NNT/yr = 350)

• CETP inhibitors reduce LDL-C but not events

David.Waters@ucsf.edu