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Management of Ischemic Heart Disease and Lipids 2020
Benjamin M. Scirica, MD MPHSenior Investigator, TIMI Study Group
Cardiovascular Division, Brigham and Women’s HospitalAssociate Professor of Medicine, Harvard Medical School
Disclosures
• Financial Relationships over past 24 months
• Institutional research grant to Brigham and Women’s Hospital from AstraZeneca, Eisai, Merck, Novartis, NovoNordisk, and Pfizer. Consulting fees from AbbVie, Allergan, AstraZeneca, Boehringer Ingelheim, Eisai, Elsevier Practice Update Cardiology, Esperion, Lexicon, Medtronic, Merck, NovoNordisk, and equity in Health [at] Scale.
• I am amember of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from: Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., BRAHMS, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, The Medicines Company, Zora Biosciences
What is Ischemic Heart Disease
SIHD by Any Other Name…• Chronic stable angina• Stable angina pectoris• Stable ischemic heart disease• Stable coronary artery disease • Non-acute coronary syndrome
“… angina secondary to stable ischemic heart disease (SIHD) is the most common clinical presentation of cardiovascular disease encountered by general practitioners and cardiologists.”
Harrington R, et al. http://theheart.medscape.org/viewarticle/739504. Accessed: Feb 16, 2012.
Stable Ischemic Heart Disease (Old School)
But it’s just not that simple
Small Vessel Atherosclerosis and Microvascular Disease
Della Rocca and Pepine. EHJ. 2012 (Oct)
Pathobiological Contributors to IHD
Marzilli M et al. J Am Coll Cardiol. 2012;60:951-956.
INFLAMMATION
PLATELETS AND COAGULATION
VASOSPASM
MICROVASCULAR DYSFUNCTION
ENDOTHELIAL DYSFUNCTION
CRITICAL CORONARYSTENOSIS
MYOCARDIAL ISCHEMIA
Reduce Ischemia & Relieve Anginal Symptoms
Improve “Quality of Life”
Dual Goals for Management of Stable Ischemic Heart Disease (SIHD)
Prevent MI and Death (Disease Modification)
Improve “Quantity of Life”
Secondary Prevention Goals of Therapy in SIHD
• Antiplatelet Therapy– ASA 81 mg; ADP antagonist if recent ACS or stent
• ACEI / ARB (especially if DM, HF, EF <40%, HTN)
• Lipid Lowering
• Diabetes Rx with proven CV benefit (GLP1RA and SGLT2i)
• Smoking cessation
• Other Secondary Prevention Measures– BP control
– Weight management
– Physical exercise
– Influenza Vaccine
Reduce/stabilize atherosclerotic plaque → ACS/MI/SCD
Consider
initiating
low-dose
aspirin
and adding a
proton-pump
inhibitor
Consider
initiating
low-dose
aspirin
Initiate
low-
dose
aspirin
ASCVD DIABETESINCREASED BLEED RISK
AGE > 70 years
High
ASCVD
riskLow
ASCVD
risk
Do not
initiate
low-dose
aspirin
High
ASCVD
risk
High
ASCVD
risk
Do not
initiate
low-
dose
aspirin
Do not
initiate
low-dose
aspirin
PRIMARY PREVENTION
Low
ASCVD
risk
SECONDARY
PREVENTION
IMAGED VASCULAR DISEASE*
High
ASCVD
risk
Consider
initiating
low-dose
aspirin
*Evidence of atherosclerosis on CT scan or vascular ultrasound tests, or an elevated
coronary calcium score; ASCVD = atherosclerotic cardiovascular disease.
IMPROVE-IT vs CTT: CV Benefit Proportional to LDL-C for Both Ezetimibe and Statins
*Using CTT methods: LDL difference between groups using baseline LDL for Pts without blood samples. Endpoint of CV Death, MI,
stroke or revascularization >30days post Rand. Cox HR reported.
Cannon CP, et al. N Engl J Med. 2015;372(25):2387-97.
IMPROVE-IT
Reduction in LDL Cholesterol (mmol/L)
Red
uc
tio
n in
Rate
of
Ma
jor
Va
sc
ula
r E
ve
nts
(%
)
-10
0
10
20
30
40
50
0 0.5 1.0 1.5 2.0
ALLHAT-LLT
GISSIALERT
LIPS
AFCAPS/TexCAPSASCOT-LLA
WOSCOPS
PosT CABGCAREHPS
4SCARDS
PROSPER
LIPID
Yasuyoshi Ouchi, et al. Circulation. 2019;140:992–
1003
EWTOPIA 75: Ezetimibe vs. Placebo in Primary Prevention Patients > 75 years old
Sudden cardiac death, MI, coronary
revascularization, or strokeLDL
PCSK9 Regulates LDL-R Expression
Shimada YJ, Cannon CP. Eur Heart J. 2015;36:2415–2424.
PCSK9
SecretionEndocytosis
LDL, LDL-R, and PCSK9
degradation
PCSK9/LDL-R
complex
LDL-C Reduction via PCSK9 Inhibition
Shimada YJ, Cannon CP. Eur Heart J. 2015;36:2415–2424.
LDL-R
recycling
X
Secretion
PCSK9PCSK9 inhibitor
Endocytosis
FOURIER: Effects of PCSK9i Evolocumab
27,564 high-risk, stable patients with established CV disease
Evolocumab
(median 30 mg/dl, IQR 19-46 mg/dl)
Placebo
59% reduction
P<0.00001
Absolute 56 mg/dl
HR 0.85 (0.79-0.92)
P<0.0001
HR 0.80 (0.73-0.88)
P<0.0001
CVD, MI, stroke
UA, cor revasc
CVD, MI, stroke
Sabatine MS et al. NEJM. 2017; 376: 1713-22.
14.6
9.9
12.6
7.9
0
5
10
15
KM
Ra
te (
%)
at
3 Y
ea
rs
ACC.18
19
Primary Efficacy Endpoint: MACE
ARR* 1.6%
*Based on cumulative incidence
MACE: CHD death,
non-fatal MI,
ischemic stroke, or
unstable angina requiring
hospitalization
HR 0.85(95% CI 0.78, 0.93)
P=0.0003
FOURIER – Lower CV Event Rates with Lower
LDL-C Levels*, Even Down to 20 mg/dL
*Relationship between the achieved LDL-cholesterol concentration at 4 weeks and the risk of CVD, MI, or stroke.
Giugliano RP, et al. Lancet. 2017 Aug 25. [Epub ahead of print]
0.06
0.08
0.1
0.12
0.14
0.16
0 0.5 1 1.5 2 2.5 3 3.5 4 4.5
Ad
juste
d e
ven
t ra
te (
pro
bab
ilit
y)
LDL cholesterol 4 weeks after randomization mmol/L)
p=0.0001 for the β coefficient
Inclisiran
Ray KK, et al. N Engl J Med. N Engl J Med 2020; 382:1507-1519
Inclisiran
• small interfering
RNA(siRNA)
targeting PCSK9 messenge
r RNA
• Dosed q 6 or 12 months
• Possible approval in 2020
• ?s about cost (less than
mAb)
Bempedoic Acid
• Inhibitor of ATP
citrate lyase in
cholesterol synthesis
pathway
• “upstream to HMG-
CoA reductase
• FDA Approved as
Nexletol
• Do not use with statin
Ray KK et al. N Engl J Med 2019;380;11
hs-CRPLDL Chol
REDUCE IT Targeting Triglycerides with Omega-3 FFACV Death, MI, Stroke, Coronary Revasc, Unstable Angina
Icosapent Ethyl
23.0%Placebo
28.3%
Years since Randomization
Pati
en
ts w
ith
an
Even
t (%
)
0 1 2 3 4 5
0
10
20
30
P=0.00000001
RRR = 24.8%
ARR = 4.8%
NNT = 21 (95% CI, 15–33)
Hazard Ratio, 0.75(95% CI, 0.68–0.83)
Bhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2018. Bhatt DL. AHA 2018, Chicago.
REDUCE IT Outcomes by baseline Trig level
https://doi.org/10.1016/j.jacc.2019.06.043
ACC/AHA Cholesterol
Guidelines 2018
Secondary Prevention
Very High-Risk* for ASCVD
Major ASCVD Events
Recent ACS (within the past 12 mo)
History of MI (other than recent ACS
event listed above)
History of ischemic stroke
Symptomatic peripheral arterial
disease (history of claudication with
ABI <0.85, or previous
revascularization or amputation)
High-Risk Conditions
Age ≥65 y
Heterozygous familial hypercholesterolemia
History of prior coronary artery bypass surgery or
percutaneous coronary intervention outside of the
major ASCVD event(s)
Diabetes mellitus
Hypertension
CKD (eGFR 15-59 mL/min/1.73 m2)
Current smoking
Persistently elevated LDL-C (LDL-C ≥100 mg/dL
despite maximally tolerated statin and ezetimibe
History of congestive HF
ACC/AHA Cholesterol
Guidelines 2018
Secondary Prevention
* Multiple ASCVD events or 1 major
event and multiple high risk conditions
Statin Safety and Statin-Associated Side Effects
Recommendations for Statin Safety and Statin-Associated Side Effects
COR LOE Recommendations
III: No
BenefitB-R
Coenzyme Q10 is not recommended for routine use in
patients treated with statins or for the treatment of
SAMS.
III: No
BenefitC-LD
In patients treated with statins, routine measurements
of creatine kinase and transaminase levels are not
useful.
What if we did full lipid therapy intensification for goal < 70 mg/dl?
A theoretical approach
ALI 75 = alirocumab 75 mg; ALI 150 = alirocumab 150 mg; EZE = ezetimibe; HIS = high-intensity statin; MIS = moderate- to low-intensity statin.
Cannon CP, Khan I, et al. JAMA Cardiol. 2017 Aug 2. [Epub ahead of print]
0%
1%
1%
2%
2%
3%
3%
4%
4%
5%
5%
0 20 40 60 80 100 120 140 160
Before Treatment Intensification
HIS + EZE (1%)
MIS + EZE (1%)
HIS Only (14%)
MIS Only (37%)
EZE Only (1%)
No Statin or EZE (46%)
% P
ati
en
ts in
1 m
g/d
L r
an
ges
LDL-C (mg/dL)
0 20 40 60 80 100
After Treatment Intensification
HIS + EZE + ALI 150 (2%)
HIS + EZE + ALI 75 (12%)
HIS + EZE (17%)
MIS + EZE (1%)
HIS Only (25%)
MIS Only (43%)
LDL-C (mg/dL)
LDL-C Levels for Optimal CV Risk Reduction: What We Know Now
High is bad
Average is not good
Lower is better
Even lower is even
better
Lowest is best
Conclusions on Lipids• 2018 ACC/AHA guidelines – still several years behind data
• Recommend statins for 4 groups
• Then add non-statins if LDL > 70 mg/dl for secondary prevention
• Ezetimibe, alirocumab, evolocumab, and icosapent ethyl have shown:
• Non-statin agents are effective in lowering LDL AND at reducing cardiovascular events
• Achieving lower LDL levels (< 55 mg/dL) is safe and can significantly reduce the risk of CV events in very high risk ASCVD
The Eternal Question in SIHD
“To cath, or not to cath, that is the question:Whether 'tis nobler in the mind to suffer
The slings and arrows of outrageous fortune,
Or to take Arms against a Sea of troubles,
And by opposing end them: to die, to sleep;
No more; and by a sleep, to say we end
The heart-ache, and the thousand natural shocks
That Flesh is heir to?”
Primary Endpoint:CV death, MI, hosp for UA, heart failure or resuscitated cardiac arrest
Qualifying Stress Test: Core Lab Interpretation
Baseline Coronary Anatomy by Cardiac CTA
Risk Factor ManagementBaseline vs last visit
No between group differences Inv v. Con
Clinical Outcomes
Effect on Quality of Life
• Invasive strategy had larger improvements in disease-specific health status (including angina symptoms, physical function, and disease-specific quality of life) than conservative strategy.
• modest differences favoring the invasive strategy in the overall trial population reflected differences that were confined to par participants who had had angina within the 4 weeks before randomization, with minimal, if any, benefit among those who had been asymptomatic at randomization.
• The magnitude of the difference was largest among participants who had entered the trial with daily or weekly angina.
Thus, provided there is strict adherence to guideline-based medical therapy, patients with stable ischemic heart disease who fit the profile of those in ISCHEMIA and do not have unacceptable levels of angina can be treated with an initial conservative strategy. However, an invasive strategy, which more effectively relieves symptoms of angina (especially in patients with frequent episodes), is a reasonable approach at any point in time for symptom relief.
Summary of “Disease Altering” Interventions in SIHD
• Greatest evidence for life prolonging or MI-reducing therapy is with optimal medical therapy
• Revascularization is very good for reducing angina and minimizing need for recurrent coronary interventions
• But, except in small, high risk populations immediate revascularization does not prolong life or reduce risk of future MI