What we’ll cover in today’s presentation

Microsoft PowerPoint - STH 19_PCU_Track 1_Session 5_Medtelligence_HTG_Bhattsyllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes.
3:10-4:10pm
New Approaches to the Clinical Management of Patients with or at High- risk of Cardiovascular Disease Events
SPEAKERS Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC
What we’ll cover in today’s presentation
• The new 2018 cholesterol guidelines • Residual ASCVD risk beyond statin monotherapy • Elevated triglycerides (TG) as a predictor of residual ASCVD risk • Recent CVOT results and their clinical implications • Prescription medications for ASCVD risk reduction, adjunctive to statin use
ACC Risk Calculator Plus to Assess Risk Category tools.acc.org/ascvd-risk-estimator-plus/#!/calculate/estimate
Use the calculator to Assess Risk Category
≥7.5% to <20% “Intermediate Risk”
≥20% “High Risk”
<5% “Low Risk”
5% to <7.5% “Borderline Risk”
Then use the new ACC/AHA Cholesterol guideline algorithms to guide management
• Estimates 10-year hard ASCVD (nonfatal MI, CHD death, stroke) for ages 40-79 and lifetime risk for ages 20-59
• Intended to promote patient-provider risk discussion, and best ways to reduce risk
• ≥7.5% identifies statin eligibility, but not an automatic prescription for a statin Also available: MESA 10-Year CHD Risk with
Coronary Artery Calcification* -iPhone and Android app
*mesa-nhlbi.org/MESACHDRisk/MesaRiskScore/RiskScore.aspx
Risk Category (%10-y ASCVD event risk)
Very High (20-30%)
+ other risk factor ASCVD plus • DM, • CKD OR • HeFH
**FH3 ASCVD “premature” (<55yrs/65yrs)
High (20-30%)
Prior ASCVD plus MetSynd5
(All plus MetSynd5) FH3 w/o ASCVD
4 Higher Risk = Lower NNT = More cost-effective 5 Termed “poorly controlled cardiometabolic milieu”, similar to the conventional definition of the Metabolic Syndrome (abbr. “MetSynd”): ↑TG, ↓HDL-C, DM2, central obesity, ↑glucose/insulin, etc. After Robinson JG. Rev Cardiovasc Med. 2018;19(S1):S1-S8
1 LDL-C goal <55 mg/dL 2 Mild to moderately CKD, eGFR 15-60 3 FH = Familial Hypercholesterolemia (heterozygous) After Jellinger PS, et al. Endocrine Pract. 2017;23(4):479-497.
AACE Lipid Guidelines JG Robinson, et al.
syllabi/Slides for this program are a supplement to the live CME session and are not intended for other purposes.
Age 0-19 y Lifestyle to prevent or reduce
ASCVD risk Diagnosis of Familial
Hypercholesterolemia → statin
encourage lifestyle to reduce ASCVD risk
Consider statin if family history premature ASCVD and LDL-C
≥160 mg/dL (≥4.1 mmol/L)
(1.8 to <4.9 mmol/L) without diabetes mellitus
10-year ASCVD risk percent begins risk discussion
≥7.5% to <20% “Intermediate Risk”
≥20% “High Risk”
Risk discussion: If risk estimate + risk
enhancers favor statin, initiate moderate- intensity statin to reduce LDL-C by
30% - 49% (Class I)
LDL-C ≥50% (Class I)
Risk discussion: Emphasize lifestyle
Risk discussion: If risk enhancers present then risk
discussion regarding moderate-intensity
5% to <7.5% “Borderline Risk”
If risk decision is uncertain: Consider measuring CAC in selected adults:
CAC = zero (lower risk; consider no statin, unless diabetes, family history of premature CHD, or cigarette smoking are present) CAC = 1-99 favors statin (especially after age 55)
CAC = 100+ and/or ≥75th percentile, initiate statin therapy
ASCVD Risk Enhancers: • Family history of premature ASCVD • Persistently elevated LDL-C ≥160 mg/dL • Chronic kidney disease • Metabolic syndrome • Conditions specific to women (eg, preeclampsia, premature
menopause) • Inflammatory disease (especially rheumatoid arthritis, psoriasis, HIV) • Ethnicity (eg, South Asia ancestry)
Lipid/Biomarkers: • Persistently elevated triglycerides (≥175 mg/dL)
In selected individuals if measured: • hs-CRP ≥2.0 mg/L • Lp(a) levels >50 mg/dL or >125 nmol/L • Apo B ≥130 mg/dL • Ankle-brachial index (ABI) <0.9
Primary Prevention: Assess ASCVD Risk in Each Age Group
Emphasize Adherence to Health Lifestyle
LDL-C 190 mg/dL ( 4.9 mmol/L) No risk assessment; High-intensity statin
(Class I)
(Class I)
Diabetes mellitus and age 40-75 y Risk assessment to consider high-intensity statin
(Class IIa)
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Primary Prevention
Grundy SM et al. Circulation. 2018;Nov. 10 [Epub ahead of print]. Although high TG was noted as a CVD risk factor, treatment of HTG was covered only briefly and prescription omega-3 was not mentioned. (Published simultaneously with REDUCE-IT)
Initiation of moderate- or high-intensity
statin is reasonable (Class IIa)
Continuation of high- intensity statin is
reasonable (Class IIa)
tolerated, use moderate- intensity
and LDL-C ≥70 mg/dL
(Class I) If on maximal statin and
LDL-C ≥70 mg/dL
(≥1.8 mmol/L), adding
If PCSK9-I is considered,
add ezetimibe to maximal
statin before adding
PCSK9-I (Class I)
IF on clinically judged maximal LDL-C lowering therapy and LDL-C ≥70 mg/dL
(≥18 mmol/L), or non-HDL-C ≥100 mg/dL (≥2.6 mmol/L), adding PCSK9-I is reasonable
(Class IIa)
effective
2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Secondary Prevention
Grundy SM et al. Circulation. 2018;Nov. 10 [Epub ahead of print].
Age ≤75 y Age >75 y
Clinical ASCVD
Healthy Lifestyle
High-intensity or maximal statin (Class I)
HX of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm
Hx of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions
Despite ASCVD Benefit with Statin Monotherapy, Substantial Residual CV Risk Remains
14S Group. Lancet. 1994;344:1383-9. 2LIPID Study Group. N Engl J Med. 1998;339:1349-57. 3Sacks FM et al. N Engl J Med. 1996;335:1001-9. 4HPS Collaborative Group. Lancet. 2002;360:7-22. 5Shepherd J et al. N Engl J Med. 1995;333:1301-7. 6Downs JR et al. JAMA. 1998;279:1615-22. 7Ridker PM et al. N Engl J Med. 2008;359:2195-207.
0
10
20
30
40
JUPITER7N
1.4 0.8
On-treatment LDL-C (mg/dL) 117 112 97 93 140 115 55
4444 9014 4159 20,536 6595 6605 17,802
Residual CV risk may be due not only to other lipid measures that may not be controlled, but other risk factors at suboptimal control such as hypertension, diabetes, or smoking.
Elevated High Sensitivity C-Reactive Protein (hsCRP) Can Add to Risk Prediction by Elevated LDL-C and Traditional Risk Predictors
Ridker P et al. Circulation. 2003;108:2292-7.
Residual HTG Predicts Residual ASCVD Risk Despite LDL-C at Goal on Statin Monotherapy
Despite achieving LDL-C <70 mg/dL with a high-dose statin, patients with TG ≥150 mg/dL have a 41% higher risk of coronary events*
*Death, myocardial infarction, or recurrent acute coronary syndrome, PROVE-IT-TIMI 22 Miller M et al. J Am Coll Cardiol. 2008;51:724-30.
0
5
10
15
20
25
+41%
Classification of Fasting TG Levels (2011 AHA/2014 NLA)
Jacobson TA et al. J Clin Lipidol. 2014;8:473-88. American Heart Association (AHA) Scientific Statement. Miller M et al. Circulation. 2011;123:2292-333.
Fasting Triglycerides (mg/dL)
200–499 High
500 Very high
Miller M et al. Circulation. 2011;123:2292-333. Jacobson TA et al. J Clin Lipidol. 2014;8:473-88.
Prevalence (%) of Triglycerides 150 mg/dL
9,593 US adults aged >20 years (219.9 million projected) in the US National Health and Nutrition Examination Surveys 2007-2014 were studied. Fan W et al. J Clin Lipidol. 2018;Dec. 1 [Epub ahead of print].
56.9
12.3
44.6
0
20
40
60
Triglyceride Levels ≥150 mg/dL, U.S. Adults Age ≥20 years (Millions)
≥150 mg/dL
Patients with Elevated TG Often Have High Overall CVD Risk
p< 0.0001 (weighted) for comparing proportion of ACC/AHA Pooled Cohort 10-year ASCVD risk score categories among triglyceride levels. Fan W et al. J Clin Lipidol. 2018;Dec. 1 [Epub ahead of print].
58.1
<150 mg/dL 150–199 mg/dL 200–499 mg/dL 500 mg/dL
Triglycerides
≥7.5%
(NHANES 2007–2014)
Three Possible Mechanisms for High ASCVD Risk with HTG
• Elevated TG leads to smaller, denser LDL particles – Conversion of VLDL and IDL into smaller LDL-C increases atherogenic Apo B
• Triglyceride-rich lipoproteins (TGRL) may promote artery-wall inflammation – Conversion into saturated fatty acids increases foam cell formation, leukocyte
recruitment, macrophages, and inflammatory vascular cell adhesion molecule-1, MCP-1, IL-8, and others
– In HTG, TGRL can deliver more cholesterol per particle to macrophages than LDL • Non-lipid factors that may drive CVD risk
– Coagulation factors – Impairment of fibrinolysis – Pro-inflammatory factors – Endothelial dysfunction
Update on Cardiovascular Outcomes Trials (CVOTs)
Further LDL-C Lowering with Statin Adjuncts Further Reduce MACE (Recent CVOTs)
IMPROVE-IT1 FOURIER2 ODYSSEY Outcomes3
CI=confidence interval; Cor Revasc=coronary revascularization; EZ=ezetimibe; HR=hazard ratio; MACE=major adverse cardiovascular events; MI=myocardial infarction; NNT=number needed to treat; Simva=simvastatin; UA=unstable angina. 1. Cannon CP et al. N Engl J Med. 2015;372:2387-97. 2. Sabatine MS et al. N Engl J Med. 2017;376:1713-22. 3. Schwartz GG et al. N Engl J Med. 2018;379:2097-107.
Ev en
Negative* Fenofibrate CVOTs (As Statin Adjunct)
*Note that post hoc analysis for both studies found statistically significant benefit in the subgroup of patients with TG≥204 mg/dL & HDL-C ≤34 md/dL (Sacks FM et al. N Engl J Med. 2010;363:692-4). ACCORD Study Group et al. N Engl J Med. 2010;362:1563-74. Keech A et al. Lancet. 2005;366:1849-61.
Study CV Risk Profile Statin Use
Daily Inter-
CV risk factors
22 mg/d)
• P=0.32
(26%) Fenofibrate 154 mg/dL –30%
(at 1 yr)
• Nonfatal MI or
• P=0.16
Boden WE et al. N Engl J Med. 2011;365:2255-67
Time (years)
C um
ul at
iv e
Monotherapy Combination Therapy
N at risk Monotherapy
Combination Therapy 1696 1718
AIM-HIGH (–29% TG)
Years of Follow-up
5
10
15
20
14.5%
Placebo
Log-rank P=0.29 Risk ratio 0.96 (95% CI 0.90–1.03)
Effect of ERN / LRPT on Major Vascular Events
HPS2-THRIVE (–26% TG)
HPS2-THRIVE Collaborative Group. N Engl J Med. 2014;371:203-12.
Aung T et al. JAMA Cardiol. 2018;3:225-34. Bhatt DL et al. N Engl J Med. 2019;380:11-22.
Study (Year) EPA/DHA Dose (mg/d) EPA / DHA Source
DOIT (2010) 1150 / 800 Dietary supplement
AREDS-2 (2014) 650 / 350 Dietary supplement
SU.FOL.OM3 (2010) 400 / 200 Dietary supplement
JELIS (2007) 1800 / 0 Pure EPA Rx
Alpha Omega (2010) 226 / 150 Margarine with dietary supplement
OMEGA (2010) 460 / 380 Rx EPA/DHA
R&P (2013) 500 / 500 Rx EPA/DHA
GISSI-HF (2008) 850 / 950 Rx EPA/DHA
ORIGIN (2012) 465 / 375 Rx EPA/DHA
GISSI-P (1999) 850 / 1700 Rx EPA/DHA
VITAL (2018) 465 / 375 Rx EPA/DHA
ASCEND (2018) 465 / 375 Rx EPA/DHA
REDUCE-IT (2018) 4000 / 0 Rx EPA 2.0
Source Favors
Stroke Ischemic Hemorrhagic Underclassified/Other Any
Revascularization Coronary Noncoronary Any
Any major vascular event
0 0.5
Lack of Apparent Effect of OM-3 on ASCVD May be Due to Low Doses, Use of Dietary Supplements, or Lack of HTG Subjects
1.5
Fish Oil Dietary Supplements Are Widely Used
• Estimated global market for omega-3 products was $31 billion in 2015
• In a large UK prospective study, 31% of adults reported taking fish oils
• Estimates suggest 7.8% of US population (19 million people) take fish oil supplements
• Benefits claimed on the heart, brain, weight, vision, inflammation, skin, pregnancy and early life, liver fat, depression, childhood behavior, mental decline, allergies, bones…
1. US Food and Drug Administration. www.fda.gov/Food/DietarySupplements/default.htm. Updated April 4, 2016. Accessed Nov. 4, 2018. 2. Hilleman D and Smer A. Manag Care. 2016;25:46-52. 3. Mason RP and Sherratt SCR. Biochem Biophys Res Commun. 2017;483:425-9. 4. Albert BB et al. Sci Rep. 2015;5:7928. 5. Kleiner AC et al. J Sci Food Agric. 2015;95:1260-7. 6. Ritter JC et al. J Sci Food Agric. 2013:93:1935-9. 7. Jackowski SA et al. J Nutr Sci. 2015;4:e30. 8. Rundblad A et al. Br J Nutr. 2017;117:1291-8. 9. European Medicines Agency, 2018: 712678.
FDA Product Classification1 Food
Often difficult to achieve high doses likely needed for efficacy
Often have high saturated fat content
Omega-3 content often overstated
Tend to contain relatively high amounts of oxidized lipids which may increase CV risk
Can contain PCBs and dioxins at harmful levels
Dietary Supplement Fish Oil: Not Useful for ASCVD Prevention
Use for Treatment of Disease Not Recommended Ability to reduce ASCVD Not demonstrated
JELIS: Rx EPA Reduced Major Coronary Events* in Hypercholesterolemic Patients on Statins, and HTG Subgroup†
No. at Risk
Control
EPA
0 1 4 5 Years 9319 8931 8671 8433 8192 7958 9326 8929 8658 8389 8153 7924
C um
ul at
iv e
In ci
de nc
e of
M aj
↓
–19%
N=18,645 Japanese pts with TC ≥251 mg/dL prior to baseline statin Rx. Baseline TG=153 mg/dL. Statin up-titrated to 20 mg pravastatin or 10 mg simvastatin for LDL-C control. *Primary endpoint: Sudden cardiac death, fatal and non-fatal MI, unstable angina pectoris, angioplasty, stenting, or coronary artery bypass graft. Yokoyama M et al. Lancet. 2007;369:1090-8.
No. of patients Control 475 444 432 414 400 392 EPA 482 455 443 427 413 403
0 1 2 3 4 5 Years
C um
ul at
iv e
in ci
de nc
e of
m aj
5.0
4.0
3.0
2.0
1.0
0
HR and P-value adjusted for age, gender, smoking, diabetes, and HTN † Pre-specified. Saito Y et al. Atherosclerosis. 2008;200:135-40.
Participants • Men and women ≥45 years of age • Established CHD or at high risk
for CHD (diabetes + ≥1 risk factor) • Atherogenic dyslipidemia – All patients required to be on stable
statin therapy for at least 4 weeks – LDL-C >40 mg/dL and ≤100 mg/dL
prior to randomization into the study • Fasting triglyceride level 135499 mg/dL
Study duration ≈ 4–6 years
Primary Endpoint Prevention of 1st major CV event (MACE); defined as:
• CV death • Nonfatal MI • Nonfatal stroke • Coronary revascularization • Unstable angina requiring
hospitalization
REDUCE-IT: Reduction of CV Events with Icosapent Ethyl – Intervention Trial
• Randomized, double-blind, parallel-group design • Secondary outcome measures: Incidence of additional CV events, lipid and lipoprotein levels,
subgroup analyses such as patients with diabetes, etc. • International trial; first patient dosed in December 2011 • All potential endpoint events adjudicated by blinded Clinical Endpoint Committee • 10% of enrolled pts had TGs of 135150 mg/dL
Pure EPA 4 g/day + Stable Statin Therapy
Placebo + Stable Statin Therapy
Biomarker (mg/dL)*
Placebo (N=4090) Median
Baseline Year 1 Baseline Year 1
Absolute Change from
Apo B 82.0 80.0 83.0 89.0 -8.0 -9.7 <0.0001
EPA (μg/mL) 26.1 144.0 26.1 23.3
REDUCE-IT: Effects on Biomarkers from Baseline to Year 1
*Apo B was measured at year 2.
Bhatt DL et al. N Engl J Med. 2019;380:11-22.
REDUCE-IT Primary Endpoint: CV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0% Placebo
10
20
30
RRR=24.8% ARR=4.8% NNT=21 (95% CI 15–33)
Hazard Ratio 0.75 (95% CI 0.68–0.83)
ARR=absolute risk reduction; CI=confidence interval; Revasc=revascularization; RRR=relative risk reduction. Bhatt DL et al. N Engl J Med. 2019;380:11-22. Bhatt DL. AHA 2018, Chicago.
20.0%
16.2%
Hazard Ratio 0.74 (95% CI 0.65–0.83)
RRR=26.5% ARR=3.6% NNT=28 (95% CI 20–47)
P=0.0000006
10
20
30
Bhatt DL et al. N Engl J Med. 2019;380:11-22. Bhatt DL. AHA 2018, Chicago.
Total Mortality 0.87 (0.74–1.02) 0.09
Endpoint
Fatal or Nonfatal Myocardial Infarction
Urgent or Emergency Revascularization
310/4090 (7.6%)
Placebo n/N (%)
901/4090 (22.0%)
606/4090 (14.8%)
507/4090 (12.4%)
355/4090 (8.7%)
321/4090 (7.8%)
213/4090 (5.2%)
157/4090 (3.8%)
134/4090 (3.3%)
690/4090 (16.9%)
274/4089 (6.7%)
0.4 1.0
RRR=relative risk reduction
23%
28%
32%
20%
35%
31%
25%
26%
25%
13%
Bhatt DL. AHA 2018, Chicago. Bhatt DL et al. N Engl J Med. 2019;380:11-22.
Most Frequent Treatment Emergent Adverse Events: ≥5% in Either Treatment Group and Significantly Different
Preferred Term Icosapent Ethyl
Diarrhea 367 (9.0%) 453 (11.1%) 0.002
Peripheral edema 267 (6.5%) 203 (5.0%) 0.002
Constipation 221 (5.4%) 149 (3.6%) <0.001
Atrial fibrillation 215 (5.3%) 159 (3.9%) 0.003
Anemia 191 (4.7%) 236 (5.8%) 0.03
REDUCE-IT: Adverse Events of Interest: Serious Bleeding and AFib
Icosapent Ethyl (N=4089)
Bleeding related disorders 111 (2.7%) 85 (2.1%) 0.06
Gastrointestinal bleeding 62 (1.5%) 47 (1.1%) 0.15
Central nervous system bleeding 14 (0.3%) 10 (0.2%) 0.42
Other bleeding 41 (1.0%) 30 (0.7%) 0.19 • No fatal bleeding events in either group • Adjudicated hemorrhagic stroke - no significant difference between treatments (13 icosapent ethyl vs 10 placebo; P=0.55)
Positively Adjudicated Hospitalization for Atrial Fibrillation/Flutter
127 (3.1%) 84 (2.1%) 0.004
Limitations
• Few patients on ezetimibe though results were consistent with or without
• Concomitant PCSK9 inhibitors prohibited, but no reason to think they are not additive
• LDL-C increased in both arms, 5 mg/dL more in placebo arm - Cannot tell if this greater ↑LDL-C was due to mineral oil placebo, but - Would not account for 25% RRR, and - JELIS saw 19% RRR in open label design, no placebo/mineral oil, and - Consistent benefit w/ EPA vs placebo with LDL-C vs no LDL-C
• Mechanism of EPA benefit uncertain, might not be TG-related - Consistent reduction across triglyceride range (135–499 mg/dL) - Similar benefit by 1-year triglycerides < or > 150 mg/dL
• Cost-effectiveness unknown, though with NNT of 21, likely cost-effective
REDUCE-IT Summary
Compared with placebo, icosapent ethyl (EPA) 4 g/day significantly reduced important CV events by 25%, including:
• 20% reduction in death due to cardiovascular causes • 31% reduction in heart attack • 28% reduction in stroke
Low rate of adverse effects, including: • Small but significant increase in atrial fibrillation/flutter • Non-statistically significant increase in serious bleeding
Consistent efficacy across multiple subgroups • Including baseline triglycerides from 135–499 mg/dL • Including secondary and primary prevention cohorts
Mechanism-Based Statin-Adjunct Therapy for ASCVD Prevention
Why Did EPA Significantly Reduce CVD Events When Other OM-3s Did Not? • REDUCE-IT & JELIS: Highest doses among all OM-3 CVOTs1
• EPA: ≥96% pure single-molecule agent • EPA hepatic VLDL-TG synthesis and/or secretion & enhances TG clearance • EPA appears to improve ASCVD risk factors beyond TG-lowering2
LDL oxidation CV-related inflammatory parameters Platelet aggregation Cholesterol crystal formation Cell-membranes stability Endothelial function HDL function
1. Aung T et al. JAMA Cardiol. 2018;3:225-34. 2. Mason RP. Curr Atheroscler Rep. 2019;21:2. Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46. Dunbar RL et al. Lipids Health Dis. 2015:14:98. Ridker PM et al. N Engl J Med. 2008;359:2195-207. Bohula EA et al. Circulation. 2015;132:1224-33. Mason RP et al. J Cardiovasc Pharmacol. 2016;68:33-40. Sherratt SCR, Mason RP. Chem Phys Lipids. 2018; 212:73-9. Mason RP et al. Biochim Biophys Acta. 2016;1858:3131-40. Mason RP, Jacob RF. Biochim Biophys Acta. 2015;1848:502-9. Mason RP et al. Biomed Pharmacother. 2018;103:1231-7. Tanaka N et al. Atherosclerosis. 2014;237:577-83. Tanaka N et al. Circ J. 2018;82:596-601. Sherratt SCR, Mason RP. Biochem Biophys Res Comm. 2018;496:335-8.
EPA and DHA Have Differing Effects on Cellular Membranes
*Time-averaged location = the time-averaged electron density distribution (distance, Å, vs electrons/Å3) associated with the membrane lipid bilayer. Sherratt SCR, Mason RP. Chem Phys Lipids. 2018;212:73-9. Mason RP et al. Biophys J. 1989;55:769-78.
EPA increased membrane hydrocarbon core electron density over a broad area, indicating an average membrane orientation for EPA with its long axis parallel to the membrane.
*
EPA (4 g) + Statin
Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46. Dunbar RL et al. Lipids Health Dis. 2015:14:98. Ridker PM et al. N Engl J Med. 2008;359:2195-207. Bohula EA et al. Circulation. 2015;132:1224-33. Pradhan AD et al. Circulation. 2018;138:141-9.
Ezetimibe
PCSK9i + Statin
CANTOS: Reducing Inflammation “Alone” (Anti IL1-beta mAb, marker hsCRP) Reduces CV Events
CANTOS: Primary Cardiovascular Endpoint (MACE)
Stable CAD (post MI) Residual Inflammatory Risk
(hsCRP ≥2mg/L)
2011–2017 1490 Primary Events
All pts on statins Placebo SC q 3 months Canakinumab 150/300 SC q 3 months
0.25
0.20
0.15
0.10
0.05
0.00
Follow-up years
HR 0.85 (0.76-0.96) P=0.007
• 39% reduction in hsCRP • No change in LDL-C • 15% reduction in MACE
Further LDL-C Lowering with PCSK9i Reduces MACE Events Despite No Effect on hsCRP
FOURIER1 ODYSSEY Outcomes2
CI=confidence interval; Cor Revasc=coronary revascularization; HR=hazard ratio; MACE=major adverse cardiovascular events; MI=myocardial infarction; UA=unstable angina. 1. Sabatine MS et al. N Engl J Med. 2017;376:1713-22. 2. Schwartz GG et al. N Engl J Med. 2018;379:2097-107.
14.5%
12.5%
MARINE studied 229 patients with very high TG levels ≥500 mg/dL. ANCHOR studied 702 patients with well-controlled LDL-C and residually high TG levels 200–500 mg/dL. Bays HE et al. Am J Cardiovasc Drugs. 2013;13:37-46.
EPA Treatment Lowers Levels of Inflammatory and Oxidative Markers
-27.4
-67.9
-2.7
-33.2
-80
-60
-40
-20
Median placebo-adjusted change (%)
4 g/day
2 g/day
Additive hsCRP reduction with IPE + Statin MARINE + ANCHOR Pooled (N=931)
hsCRP decrease with EPA is enhanced with intensive statin use
-13.6
-36
-6.6
Markers of Inflammation Lp-PLA2 hsCRP Ox-LDL
hsCRP in REDUCE-IT
Biomarker Visit Median
Log hsCRP (mg/L)
Baseline 0.8 0.8
Year 2 0.6 -21.8 <0.0001 1.0 0.0 0.9203
Supplement to: Bhatt DL et al. N Engl J Med. 2019;380:11-22.
Statin Therapy Adjuncts Proven to Reduce ASCVD
*Major inclusion criteria for each trial. ACS=acute coronary syndrome; ASCVD=atherosclerotic cardiovascular disease. After Orringer C. Oral Discussion of REDUCE-IT presentation; AHA 2018, Chicago.
Acute coronary syndrome within 10 days*
+ Ezetimibe + Eicosapentaenoic Acid+ Alirocumab or Evolocumab
Intense Statin Therapy
Stable ASCVD + additional risk factors; or ACS within 1-12 months*
↑Pro-atherogenic factor Cholesterol Inflammation Thrombosis Triglycerides Lp(a)
Biomarker LDL-C >100 mg/dL
Lp(a) >50 mg/dL
pemafibrate?) Lp(a) ASO
Randomized Trial Evidence
ASO=antisense oligonucleotide. After Ridker PM. J Am Coll Cardiol. 2018;72:3320-31.
Prior ASCVD Event or High-Risk 1o Prevention: On Aggressive Statin MonoRx
Residual Risk Factors
REDUCE-IT?
Reported Ongoing REDUCE-IT* STRENGTH* PROMINENT*
Agent Dose
N 8,179 Estimated 13,000 Estimated 10,000
Age ≥45 years ≥18 years ≥18 years
Risk Profile CVD (70%) or ↑CVD risk (30%)
CVD (50%) or ↑CVD risk (50%)
T2DM only CVD (2/3) or
↑CVD risk (1/3)
Follow-up 4–6 years (planned) 3–5 years (planned) 5 years (planned)
Statin Use 100% (at LDL-C goal) 100% (at LDL-C goal) Moderate- / high-intensity or LDL <70 mg/dL
Primary Endpoint Expanded MACE Expanded MACE Expanded MACE
Entry TG Entry HDL-C
135–499 mg/dL N/A
200–499 mg/dL ≤40 mg/dL
*Locations: International sites; Statistics: Powered for 15% RRR. REDUCE-IT: Bhatt DL et al. N Engl J Med. 2019;380:11-22. STRENGTH: NCT02104817. PROMINENT: NCT03071692.
Summary and Conclusions
• 2018 ACC/AHA cholesterol guidelines increased focus on statin-adjunct LDL-C lowering for preventing ASCVD events, but did not mention prescription omega- 3 (nor REDUCE-IT, reported same day as guideline release)
• Despite significant benefits of statins and other LDL-C lowering therapies, high residual risk remains in patients with HTG, even with very good LDL-C control
• Evidence for ASCVD benefit with “TG-lowering Treatment” has been lacking, including with fenofibrate, niacin, and low-dose EPA+DHA
Summary and Conclusions, cont.
• REDUCE-IT showed significant ASCVD reduction with 4 g/day EPA added to statin therapy in high-risk patients with mildmoderate TG elevations
• REDUCE-IT results suggest that mechanisms of ASCVD benefits may go beyond TG-lowering to include anti-inflammatory, anti-thrombotic, and other effects
• State-of-the-art ASCVD prevention now requires addressing risk factors beyond LDL-C
Mario: 45 y/o male comes for an office visit
Medical History: • Type 2 diabetes mellitus for 4 years • BMI 28 kg/m² • Hypertension • Dyslipidemia
Family History: • Mother: T2DM • Father: T2DM, CVA
Physical exam: • Height: 55 • Weight: 170 lb; BMI 28.3 kg/m2
• Waist circumference: 36 • Blood pressure: 145/88 mm Hg • Pulse: 84 bpm
Mario, cont.
The reason for the visit: Management of DM & prevention of further CKD & ASCVD
Current medications: • Saxagliptin 5 mg QD • Aspirin 81 mg QD • HCTZ 25 mg QD • Pravastatin 20 mg QD
Mario, cont.
Lab tests: • HbA1c 7.8% • Fasting glucose 137 mg/dL • Creatinine 1.5 mg/dL; GFR 55 mL/min • BUN 26 mg/dL • Urinary albumin 100 mcg/min • Uric acid 7.8 mg/dL • GGT 91 U/l, AST 71 U/l, ALT 55 U/l
Lipid profile (on 20 mg Pravastatin): • Total cholesterol 199 mg/dL • Triglycerides 285 mg/dL • LDL-C 108 mg/dL • HDL-C 34 mg/dL • Non-HDL-C 165 mg/dL • Lipoprotein(a) 36 mg/dL
Question 2: What is your estimate of Mario’s ASCVD Risk score?
1. <5% (Low Risk) 2. 5% to <7.5% (Borderline Risk) 3. ≥7.5% to <20% (Intermediate Risk) 4. ≥20% (High Risk)
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