Cottrell Memorial Lecture. Has Reversing Atherosclerosis Become the New Gold Standard in the Treatment of Cardiovascular Disease?

Transcription

1 Cottrell Memorial Lecture Has Reversing Atherosclerosis Become the New Gold Standard in the Treatment of Cardiovascular Disease? Stephen Nicholls MBBS

2 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

3 Atherosclerosis is a Chronic Disease

4 Coronary Angiography

5 Expanding World of Plaque Imaging Coronary Calcium Carotid IMT IVUS NIR Spectroscopy Coronary CT MR Angiography IVUS-VH OCT

6 To Study the Disease You Need to Image the Vessel Wall

7 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:

8 Remodeling and Clinical Events Unstable Stable p= Expansive Constrictive Schoenhagen Circulation 2000; 101:

9 Regression with High Intensity Statins 0.0 LDL-C 1.8 mmol/l LDL-C 1.5 mmol/l Change Percent Atheroma Volume P<0.001* P= Atorvastatin comparison between groups. * comparison from baseline P<0.001* Rosuvastatin Nicholls et al N Engl J Med 2011; 365:

10 Lowering CRP Associated With Slowing of Combined atorvastatin and pravastatin treatment groups Atheroma Progression Change in C Reactive Protein (mg/l) Nissen. N Engl J Med 2005;352(1): Change in Percent Atheroma Volume (%)

11 Changes in CRP Influence Degree of Regression with High Intensity Statins 0.0 Change PAV (%) P= Decrease Increase Change CRP Puri. Circulation 2013;128(22):

12 LDL-C and Plaque Progression 2 CAMELOT Placebo REVERSAL Pravastatin Median Change Percent Atheroma Volume ASTEROID Rosuvastatin SATURN Rosuvastatin REVERSAL Atorvastatin STRADIVARIUS Placebo SATURN Atorvastatin A-PLUS Placebo ILLUSTRATE Atorvastatin +Placebo Nicholls et al N Engl J Med 2011; 365: Mean LDL-C (mg/dl)

13 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 Favors Non-Progressors Favors Progressors

14 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):

15 Development of PCSK9 Inhibitory Monoclonal Antibodies

16 Regression with PCSK9 Inhibition Change in Percent Atheroma Volume (%) P = NS LDL-C 2.3 mmol/l P < LDL-C 0.9 mmol/l P < Nicholls et al JAMA 2016; 316: Statin monotherapy Statinevolocumab

17 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)

18 Benefit of Combination HDL Raising and LDL Lowering with Statins Change Atheroma Volume (mm 3 ) LDL-C (mmol/l) % Change HDL-C <2.2 >7.5 Nicholls JAMA. 2007;297: <2.2 <7.5 P<0.001 for trend >2.2 >7.5 >2.2 <7.5

19 Variable Effects of HDL Infusions on Plaque Change in Atheroma Volume (mm 3 ) ETC CSL Delip HDL 2010 MDCO CER Nissen JAMA 2003; Tardif JAMA 2007; Waksman JACC 2010; Nicholls AHA 2016; Nicholls ACC 2017

20 Do Triglyceride Rich Lipoproteins Matter? non-hdl-c TG P<0.001 Change PAV (%) P<0.001 P<0.001 Change PAV (%) P< LDL <70 LDL >70 Puri Arterioscler Thromb Vasc Biol 2016 <100 > LDL <70 LDL >70 <200 >200

21 Residual Disease Progression in Diabetes Despite LDL C Lowering 1.5 Percent Atheroma Volume No DM LDL<80 Nicholls J Amer Coll Cardiol 2008;52: No DM LDL>80 DM LDL<80 DM LDL>80

22 Plaque Regression in Diabetes with High Intensity Statins and PCSK9 Inhibition 0.0 Change PAV (%) SATURN GLAGOV Stegman Diabetes Care 2014; 37: Nicholls et al JAMA 2016; 316:

23 Benefit of Changing the TG/HDL C Ratio in Patients with Type II Diabetes 0.8 Change PAV (%) P=0.02 for trend -0.4 T1 T2 T3 Nicholls et al J Amer Coll Cardiol Tertiles of % Change TG/HDL-C Ratio

24 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 Number of Achieved Targets

25 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

26 Relationship Between Disease Burden and Cardiovascular Events Death, myocardial infarction and coronary revascularization Survival Nicholls J Amer Coll Cardiol 2010 Q1 Q2 Q3 Q Days 600

27 Relationship Between Disease Progression and Cardiovascular Events Hazard Ratio for MACE 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 Annual Changes Percent Atheroma Volume

28 Benefit of Evolocumab on Plaque and 0.5 Cardiovascular Outcomes GLAGOV FOURIER Change PAV (%) P=NS P< Placebo Evolocumab Nicholls JAMA Sabatine NEJM P<0.0001

29 Plaque Composition and Burden Predict Risk of Events 20 Present P< Percent MACE Rate Absent P< P< P< P< Stone N Engl J Med TCFA MLA<4mm 2 PB>70% PB>70% TCFA PB>70% MLA<4mm 2 TCFA

30 Statin Induced Plaque Composition Changes Percent Change Puri Eur Heart J Cardiovasc Imag 2014;15(4): % P< % P< % P= % P=0.84 Fibrous Fibro-fatty Calcium Necrotic Core * P values compared with baseline

31 Factors Associated with Change in Necrotic Core Volume in Statin-Treated Patients Parameter r P Value HDL-C CRP Puri et al. Eur Heart J Cardiovasc Imag. 2014;15(4):380-8.

32 LDL-C and OCT Vulnerable Plaque Features < > P= P= P= Kataoka Athero 2015;242(2):490-5 Lipid Plaques (%) Lipid Arc ( o ) Cap Thickness (μm)

33 Cholesterol Crystals and OCT Features of Plaque Vulnerability Fibrous Cap Thickness (um) Microchannels (%) Plaque Rupture (%) 150 P= P< % 20 P= % um 84.1 um % % 0 0 cholesterol crystal (-) cholesterol crystal (+) 0 Kataoka, Nicholls et al. J Amer Coll Cardiol. 2015;65:630-2.

34 High Dose Statins and OCT Plaque Features Fibrous Cap Thickness (um) Prevalence of Microchannels (%) P= um 112 um % P= % Low-dose statin High-dose statin Kataoka, Nicholls et al. Am J Cardiol. 2014;114:

35 Lower Plaque Lipid Content on NIRS in Statin-Treated Patients 400 P= LCBI P= Andrews. ACC Mean LCBI Statin Max LCBI No Statin

36 Calcified Lesions are Less Likely to Progress or Regress 50 P=0.008 Percent Subjects P= Progressors Regressors Ca <Median Nicholls et al. J Am Coll Cardiol. 2007;49: Ca >Median

37 Spotty Calcification and Plaque 0.5 Progression Change PAV (%) P= No Spotty Ca Spotty Ca Kataoka, Nicholls et al. J Am Coll Cardiol. 2012;59:

38 Spotty Calcium and OCT Measures of Plaque Vulnerability Fibrous Cap Thickness (um) Prevalence of Plaque Rupture (%) um P= um P= % % No calcium Spotty calcium Kataoka et al. Cardiovasc Diag Ther. 2014;4:460-9.

39 Modifiability of High Risk Plaques High plaque burden, spotty calcification, positive remodeling 2 Change PAV (%) 1 0 P= No Statin Statin Kataoka Eur Heart J CV Imag 2014;15:

40 Plaque Erosion Versus Rupture Libby. Eur Heart J 2015; 10:191-6

41 Increasing Attention of Plaque Erosion on OCT in ACS Patients Percent Rupture Erosion Nodule Other Jia et al. J Amer Coll Cardiol 2013;62:

42 Women With Heart Attacks are More Likely to Demonstrate Plaque Erosion Elsewhere 15 Percent Male Kataoka et al. Circ Cardiovasc Imag 2016 Rupture Female Erosion

43 Can We Non invasively Monitor Disease? Coronary Calcium Carotid IMT Coronary CTA MRI

44 Molecular Imaging Can We Assess Plaque Activity? FDG-PET Macrophage Iron Thrombotic Activity Angiogenesis VCAM-1 Metalloproteinases Apoptosis

45 Sodium Fluoride Plaque Imaging IVUS VH Angio CT -PET Joshi N et al Lancet 2013

46 Plaque Burden Plaque Composition and Function Imaging Risk Prediction Evaluate Therapies Change Clinical Practice Improved Clinical Outcome

47 Does a High Calcium Score Influence Management? Parameter Risk Ratio (95% CI) Initiation of Therapy Lipid Lowering Therapy 1.53 ( ) BP Lowering Therapy 1.55 ( ) Aspirin 1.32 ( ) Continuation of Therapy Lipid Lowering Therapy 1.10 ( ) BP Lowering Therapy 1.05 ( ) Aspirin 1.14 ( ) Nasir Circ Cardiovasc Qual Outcomes 2010

48 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

49 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?

50 Acknowledgements to research teams at Cleveland Clinic and SAHMRI