Cottrell Memorial Lecture Has Reversing Atherosclerosis Become the New Gold Standard in the Treatment of Cardiovascular Disease? Stephen Nicholls MBBS PhD @SAHMRI_Heart
Disclosures Research support: AstraZeneca, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi- Regeneron and LipoScience Consulting and honoraria: AstraZeneca, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim
Atherosclerosis is a Chronic Disease
Coronary Angiography
Expanding World of Plaque Imaging Coronary Calcium Carotid IMT IVUS NIR Spectroscopy Coronary CT MR Angiography IVUS-VH OCT
To Study the Disease You Need to Image the Vessel Wall
Glagov s Coronary Remodeling Hypothesis Progression Compensatory expansion maintains constant lumen Expansion overcome: lumen narrows Normal vessel Minimal CAD Moderate CAD Severe CAD Adapted from Glagov et al. N Engl J Med. 1987;316:1371 1375.
Remodeling and Clinical Events 60 40 Unstable Stable p=0.001 20 0 Expansive Constrictive Schoenhagen Circulation 2000; 101:598-603
Regression with High Intensity Statins 0.0 LDL-C 1.8 mmol/l LDL-C 1.5 mmol/l Change Percent Atheroma Volume -0.5-1.0-0.99 P<0.001* P=0.17-1.22-1.5 Atorvastatin comparison between groups. * comparison from baseline P<0.001* Rosuvastatin Nicholls et al N Engl J Med 2011; 365:2078-87
Lowering CRP Associated With Slowing of Combined atorvastatin and pravastatin treatment groups Atheroma Progression -14-12 -10-8 -6-4 -2 0 2 4 6 Change in C Reactive Protein (mg/l) Nissen. N Engl J Med 2005;352(1):29-38 3.5 3 2.5 2 1.5 1 0.5 0-0.5-1 -1.5-2 -2.5 Change in Percent Atheroma Volume (%)
Changes in CRP Influence Degree of Regression with High Intensity Statins 0.0 Change PAV (%) -0.5-1.0 P=0.007-1.5 Decrease Increase Change CRP Puri. Circulation 2013;128(22):2395-403
LDL-C and Plaque Progression 2 CAMELOT Placebo REVERSAL Pravastatin Median Change Percent Atheroma Volume 1 0-1 ASTEROID Rosuvastatin SATURN Rosuvastatin REVERSAL Atorvastatin STRADIVARIUS Placebo SATURN Atorvastatin A-PLUS Placebo ILLUSTRATE Atorvastatin +Placebo -2 40 60 80 100 120 Nicholls et al N Engl J Med 2011; 365:2078-87 Mean LDL-C (mg/dl)
Plaque Progression When LDL-C <1.8 mmol/l Odds Ratio Baseline PAV Diabetes Change in SBP Change in HDL-C Change in APOB Baseline LDL-C Concomitant Statin Use Change in LDL-C Bayturan et al J Amer Coll Cardiol 2010 0 0.5 1.0 1.5 2.0 2.5 Favors Non-Progressors Favors Progressors
Discord Between LDL Particles and Cholesterol Normal Cholesterol Content Lower Cholesterol Content 2 mmol/l 2 mmol/l Cholesterol Triglycerides Cholesterol Balance Clin Cardiol 1999;22(6 Suppl):1121-27
Development of PCSK9 Inhibitory Monoclonal Antibodies
Regression with PCSK9 Inhibition Change in Percent Atheroma Volume (%) 0.2 0-0.2-0.4-0.6-0.8-1 0.05 P = NS LDL-C 2.3 mmol/l P < 0.0001 LDL-C 0.9 mmol/l -0.95 P <0.0001-1.2 Nicholls et al JAMA 2016; 316:2373-84 Statin monotherapy Statinevolocumab
Mean On-Treatment LDL-C vs. Change in PAV Change Percent Atheroma Volume (%) Locally Weighted Polynomial Regression (LOESS) Plot with 95% confidence limits On-Treatment LDL-C (mg/dl)
Benefit of Combination HDL Raising and LDL Lowering with Statins Change Atheroma Volume (mm 3 ) 2.5 0.0-2.5-5.0-7.5-10.0 LDL-C (mmol/l) % Change HDL-C <2.2 >7.5 Nicholls JAMA. 2007;297:499-508. <2.2 <7.5 P<0.001 for trend >2.2 >7.5 >2.2 <7.5
Variable Effects of HDL Infusions on Plaque Change in Atheroma Volume (mm 3 ) 0-5 -10-15 ETC-216 2003 CSL-111 2007 Delip HDL 2010 MDCO-216 2016 CER-001 2017 Nissen JAMA 2003; Tardif JAMA 2007; Waksman JACC 2010; Nicholls AHA 2016; Nicholls ACC 2017
Do Triglyceride Rich Lipoproteins Matter? non-hdl-c TG 1.0 1.5 P<0.001 Change PAV (%) 0.5 0.0-0.5 P<0.001 P<0.001 Change PAV (%) 1.0 0.5 0.0-0.5 P<0.001-1.0 LDL <70 LDL >70 Puri Arterioscler Thromb Vasc Biol 2016 <100 >100-1.0 LDL <70 LDL >70 <200 >200
Residual Disease Progression in Diabetes Despite LDL C Lowering 1.5 Percent Atheroma Volume 1.0 0.5 0.0-0.5 No DM LDL<80 Nicholls J Amer Coll Cardiol 2008;52:255-62 No DM LDL>80 DM LDL<80 DM LDL>80
Plaque Regression in Diabetes with High Intensity Statins and PCSK9 Inhibition 0.0 Change PAV (%) -0.2-0.4-0.6-0.8-1.0 SATURN GLAGOV Stegman Diabetes Care 2014; 37:3114-20. Nicholls et al JAMA 2016; 316:2373-84
Benefit of Changing the TG/HDL C Ratio in Patients with Type II Diabetes 0.8 Change PAV (%) 0.4 0.0 P=0.02 for trend -0.4 T1 T2 T3 Nicholls et al J Amer Coll Cardiol. 2011 Tertiles of % Change TG/HDL-C Ratio
Benefit of Multiple Risk Factor Intervention in Type 2 Diabetes HbA1c <7%, LDL-C <2.5 mmol/l, TG <1.7 mmol/l, SBP <130 mmghg, CRP <2.0 mg/l 10 Change Total Atheroma Volume (mm 3 ) 5-5 P<0.001 for trend Kataoka Eur J Prev Card 2012-10 0 1-2 3 4 5 Number of Achieved Targets
Is It Really a 1% Reduction in Plaque? Total Plaque PAV 40.1% Plaque PAV 13.3% Normal Vessel PAV 26.7% Modifiable Plaque PAV 7.9% Non Modifiable Plaque PAV 5.4% As the total modifiable pool has at most a PAV 7.9%, reducing PAV by 1% represents at least a 12.6% reduction in modifiable plaque in 18 months Puri Eur Heart J Cardiovasc Imag 2014;15(4):380-8
Relationship Between Disease Burden and Cardiovascular Events Death, myocardial infarction and coronary revascularization Survival 1.0 0.9 0.8 0.7 0.6 Nicholls J Amer Coll Cardiol 2010 Q1 Q2 Q3 Q4 0 200 400 Days 600
Relationship Between Disease Progression and Cardiovascular Events Hazard Ratio for MACE 1.3 1.2 1.1 1.0 0.9 Q1 Q2 Q3 Q4 Baseline PAV Difference in change in PAV between those with and without a CV event is approximately 0.55% Nicholls J Amer Coll Cardiol 2010 0.8-4 -2 0 2 4 Annual Changes Percent Atheroma Volume
Benefit of Evolocumab on Plaque and 0.5 Cardiovascular Outcomes GLAGOV FOURIER Change PAV (%) 0.0-0.5 +0.05 P=NS P<0.001-1.0 Placebo Evolocumab Nicholls JAMA 2016. Sabatine NEJM 2017. -0.95 P<0.0001
Plaque Composition and Burden Predict Risk of Events 20 Present P<0.0001 Percent MACE Rate 15 10 5 Absent P<0.0001 P<0.0001 P<0.0001 P<0.0001 Stone N Engl J Med 2010 0 TCFA MLA<4mm 2 PB>70% PB>70% TCFA PB>70% MLA<4mm 2 TCFA
Statin Induced Plaque Composition Changes Percent Change 30 20 10-10 -20-30 Puri Eur Heart J Cardiovasc Imag 2014;15(4):380-8 0-11.9% P<0.001-20.8% P<0.001 +25% P=0.002 +1.5% P=0.84 Fibrous Fibro-fatty Calcium Necrotic Core * P values compared with baseline
Factors Associated with Change in Necrotic Core Volume in Statin-Treated Patients Parameter r P Value HDL-C -0.27 0.03 CRP 0.25 0.03 Puri et al. Eur Heart J Cardiovasc Imag. 2014;15(4):380-8.
LDL-C and OCT Vulnerable Plaque Features <50 50-70 70-100 >100 250 P=0.01 200 150 P=0.001 100 P=0.01 50 0 Kataoka Athero 2015;242(2):490-5 Lipid Plaques (%) Lipid Arc ( o ) Cap Thickness (μm)
Cholesterol Crystals and OCT Features of Plaque Vulnerability Fibrous Cap Thickness (um) Microchannels (%) Plaque Rupture (%) 150 P=0.003 50 P<0.001 46.1% 20 P=0.01 17.9% 100 50 106.9 um 84.1 um 40 30 20 10 19.4% 15 10 5 9.4% 0 0 cholesterol crystal (-) cholesterol crystal (+) 0 Kataoka, Nicholls et al. J Amer Coll Cardiol. 2015;65:630-2.
High Dose Statins and OCT Plaque Features Fibrous Cap Thickness (um) Prevalence of Microchannels (%) 150 100 P=0.03 91 um 112 um 80 60 67% P=0.01 46% 40 50 20 0 0 Low-dose statin High-dose statin Kataoka, Nicholls et al. Am J Cardiol. 2014;114:549-54.
Lower Plaque Lipid Content on NIRS in Statin-Treated Patients 400 P=0.0005 300 LCBI 200 100 P=0.0003 0 Andrews. ACC. 2016. Mean LCBI Statin Max LCBI No Statin
Calcified Lesions are Less Likely to Progress or Regress 50 P=0.008 Percent Subjects 40 30 20 10 P=0.01 0 Progressors Regressors Ca <Median Nicholls et al. J Am Coll Cardiol. 2007;49:263-70. Ca >Median
Spotty Calcification and Plaque 0.5 Progression Change PAV (%) 0.4 0.3 0.2 0.1 P=0.002 0.0 No Spotty Ca Spotty Ca Kataoka, Nicholls et al. J Am Coll Cardiol. 2012;59:1592-7.
Spotty Calcium and OCT Measures of Plaque Vulnerability Fibrous Cap Thickness (um) Prevalence of Plaque Rupture (%) 150 100 112.5 um P=0.002 89.0 um 25 20 15 P=0.06 20.7% 50 10 9.3% 5 0 0 No calcium Spotty calcium Kataoka et al. Cardiovasc Diag Ther. 2014;4:460-9.
Modifiability of High Risk Plaques High plaque burden, spotty calcification, positive remodeling 2 Change PAV (%) 1 0 P=0.01-1 No Statin Statin Kataoka Eur Heart J CV Imag 2014;15:1035-41
Plaque Erosion Versus Rupture Libby. Eur Heart J 2015; 10:191-6
Increasing Attention of Plaque Erosion on OCT in ACS Patients 50 40 Percent 30 20 10 0 Rupture Erosion Nodule Other Jia et al. J Amer Coll Cardiol 2013;62:1748-58
Women With Heart Attacks are More Likely to Demonstrate Plaque Erosion Elsewhere 15 Percent 10 5 0 Male Kataoka et al. Circ Cardiovasc Imag 2016 Rupture Female Erosion
Can We Non invasively Monitor Disease? Coronary Calcium Carotid IMT Coronary CTA MRI
Molecular Imaging Can We Assess Plaque Activity? FDG-PET Macrophage Iron Thrombotic Activity Angiogenesis VCAM-1 Metalloproteinases Apoptosis
Sodium Fluoride Plaque Imaging IVUS VH Angio CT -PET Joshi N et al Lancet 2013
Plaque Burden Plaque Composition and Function Imaging Risk Prediction Evaluate Therapies Change Clinical Practice Improved Clinical Outcome
Does a High Calcium Score Influence Management? Parameter Risk Ratio (95% CI) Initiation of Therapy Lipid Lowering Therapy 1.53 (1.08 2.15) BP Lowering Therapy 1.55 (1.10 2.17) Aspirin 1.32 (1.03 1.69) Continuation of Therapy Lipid Lowering Therapy 1.10 (1.01 1.20) BP Lowering Therapy 1.05 (1.02 1.08) Aspirin 1.14 (1.04 1.25) Nasir Circ Cardiovasc Qual Outcomes 2010
CAUGHT-CAD Individuals with a family history of CAD who do not qualify for statin therapy Calcium Score Calcium Score 0 No statin Calcium Score >0 Statin Plaque Volume
Can We Modify The Residual Risk? Fibrotic Plaque Lipid Rich Necrotic Core Age Gender Family History Comorbidities Arrhythmias Pump Failure Lipids Blood Pressure Glucose Inflammation Thrombosis Other Targets Have existing therapies raised the bar to the point beyond which we can no longer observe incremental benefits?
Acknowledgements to research teams at Cleveland Clinic and SAHMRI