Post on 23-Jan-2021
Managing Dyslipidemia in ACS Patients
Lidwina Tarigan, Cardiologist –Interventionist
Bethesda Hospital Yogyakarta
Medicine Faculty UKDW
Burden of Cardiovascular Disease in Indonesia
https://www.who.int/nmh/countries/idn_en.pdf (WHO. Indonesia. NCD Country Profile 2018); J Epidemiol 2016;26(10):515-5212
ECG, Biomarkers
Symptom Relief
Cardiac
Catheterization
Revascularization
Secondary
Prevention
Lifestyle modification
Cardiac rehabilitation
Morrow DA, 2016 after Libby P. Sci Am. 2002;286:46-55.
Amsterdam EA, et al. J Am Coll Cardiol. 2014;64:e139–e228
ACS Management
3
Early HMG-CoA Reductase Inhibition
in ACS
4
• MIRACL:
– 16% ↓ CV events (Atorvastatin 80 vs placebo) at 16 weeks.
• A to Z:
– No statistically significant benefit (Simvastatin 40/80 vs Placebo/Simvastatin 20) at 24 months
– High Intensity Statin Atorvastatin better than plasebo Schwartz GG et al. JAMA 2001;285:1711-1718de Lemos JA et al. JAMA 2004;292:1307-1316
Post-PCI Trial Data
5
PROVE IT-TIMI 22 (Substudy)
• 2868 Patients with ACS who had
PCI just before enrollment.
• 22% reduction in major CV
events with atorvastatin 80mg
compared to pravastatin 40mg1
– LDL 56 (Atorva) vs 89 mg/dl (Prava)
at 30 days
• Intensity of statin therapy was
more important than the agent
used in lowering LDL-C2-3
• High Intensity statin vs Moderate
Intensity statin
LIPS
• Patients with average
cholesterol randomized after PCI
to fluvastatin 80 mg versus
placebo.
• At 4 years, 22% relative risk
reduction (5.3% absolute) in
major adverse cardiac events.
with fluvastatin 4
1. Gibson CM, et al. J Am Coll Cardiol 2009;54:2290–5. 2. Cannon CP, et al. N Engl J Med. 2004;350(15):1495.
3. Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411– 6. 4. Serruys PW, et al. JAMA. 2002;287(24):3215
6
Intensive vs. Moderate Lipid Lowering with Statin after ACS
LD
L-C
(m
g/d
L)
20
40
60
80
100
120
30 Days 4 Mos. 8 Mos. 16 Mos. Final
Pravastatin 40 mg
Atorvastatin 80 mg
P<0.001
Baseline
Cannon CP, et al. N Engl J Med. 2004;350:1495-1504.
PROVE-IT trial: 4,162 patients with an ACS < 10 days
Median LDL-C during the study
95 mg/dL
62 mg/dL
0 3 18 21 24 27 306 9 12 15
De
ath
or
Ma
jor
Ca
rdio
va
scu
lar
Eve
nt
(%)
Months of Follow-up
Pravastatin 40 mg(26.3%)
Atorvastatin 80 mg(22.4%)
HR 16%
P= 0.005
30
25
20
15
10
5
0
ACS = Acute coronary syndrome, LDL-C= Low-density lipoprotein cholesterol, PROVE-IT= Pravastatin or Atorvastatin
Evaluation and Infection Therapy, HR= Hazard Ratio
7
30 Days
90 Days
180 Days
End of Follow-up
PROVE IT-TIMI
Primary Endpoint Over Time
Atorvastatin 80mg Better
0.5 0.75 1.0 1.25 1.5
Pravastatin 40mg Better
*2-year event rates
RR Atorva 80 Prava 40
17% 1.9% 2.2%
18% 6.3% 7.7%
14% 12.2% 14.1%
16% 22.4%* 26.3%*
Cannon CP, et al. N Engl J Med. 2004;350:1495-1504
Ray K, et al. JACC 2005;46:1405–1410
PROVE-IT: atorvastatin 80 mg reduced the composite triple endpoint (death, MI, or rehospitalization for ACS) within 30 days of randomization
This benefit remained stable from 30 days onward
9
Meta-analysis of Intensive Statin
Therapy
Odds Reduction
-16%
-16%
-12%
+3%
-6%
-18%
Coronary Death or Any
Cardiovascular Event
Coronary Death or MI
Cardiovascular Death
Non-Cardiovascular Death
Total Mortality
Stroke
High-dose
statin better
High-dose
statin worse
0.5 1 2.5
Odds Ratio (95% CI)
Cannon CP et al. J Am Coll Cardiol. 2006;48:438-445.
10
Statin Potency - Guidelines
AHA/ACC Recommendations
High-intensity statins recommended to all patients with established ASCVD1-2
Higher doses more beneficial than lower doses in ACS3
EAS/ESC Recommendations
Type of statin used should reflect the LDL-C goal in a given patient.4
Prescribe statin to highest recommended/tolerated dose to reach goal.4
1. Stone NJ et al. Circulation. 2014;129:S1. 2. Joshan K et al. CMAJ 2008;178:576-84
3. Gibson CM et al. J Am Coll Cardiol 2009;54:2290–5 4. Capatano AL et al. Eur Heart J.
2016;37(39):2999-3058
11O’Gara et al. 2013 ACCF/AHA STEMI Guideline. JACC Vol.61.No.4.2013:e78-140
Among currently available statin, only high-dose atorvastatin (80 mg daily) has been shown to reduce
death and ischemic events among patients with ACS
STEMI= ST-Elevation Myocardial Infarction, ACS = Acute coronary syndrome
12O’Gara et al. 2013 ACCF/AHA STEMI Guideline. JACC Vol.61.No.4.2013:e78-140
2018 ACC/AHA Guidelines categorized patient in 4 management groups…
SecondaryASCVD
Prevention
Diabetes Mellitus in
Adults
Primary Prevention
Severe Hypercholes-
terolemia
• Clinical ASCVD consists of • ACS• history of MI• unstable angina or coronary other
arterial revascularization• stroke, transient ischemic attack
(TIA),• peripheral artery disease (PAD)
including aortic aneurysm• all of atherosclerotic origin
• ACS indicates acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; MI, myocardial infarction; and PCSK9-I, PCSK9inhibitor.
Grundy SM, et al. Circulation. 2018;000:e000-e000.
Grundy SM, et al. Circulation. 2018;000:e000-e000.
Secondary ASCVD Prevention
Grundy SM, et al. Circulation. 2018;000:e000-e000.
Secondary ASCVD Prevention
Secondary ASCVD
Prevention
Diabetes Mellitus in
Adults
Primary Prevention
Severe Hyercholest
erolemia
Grundy SM, et al. Circulation. 2018;000:e000-e000.
Percent reductions are estimates from data across large populations. Individual responses to statin therapy varied in the RCTs and should be expected to vary in clinical practice"
Grundy SM, et al. Circulation. 2018;000:e000-e000.
Adapted from: Grundy SM, et al. Circulation. 2018;000:e000-e000.
High-, Moderate-, and Low-Intensity Statin Therapy
LDL-C= Low-density lipoprotein cholesterol
LDL-C goals across risk categories
Mach F, et al. Eur Heart Journal 2019, 00,1-78
Adapted from: Mach F, et al. Eur Heart Journal 2019, 00,1-78
LDL-C= Low-density lipoprotein cholesterol, SCORE= Systematic Coronary Risk Estimation, T1DM= Type 1 diabetes mellitus, T2DM= Type 2 diabetes mellitus,
DM= Diabetes mellitus, TC= Total cholesterol, BP= Blood pressure, FH= Familial hypercholesterolemia, CKD= Chronic kidney disease, eGFR= estimated
glomerular filtration rate, ASCVD= Atherosclerotic cardiovascular disease
Acute coronary syndrome (ACS): key recommendations
• All ACS patients without contraindication or intolerance: high-dose statin as
early as possible, regardless of initial LDL-C (IA)
• Goals: LDL <1.4 mmol/L (<55 mg/dL) and ≥50% reduction from baseline
• Not achieving goals after 4−6 weeks’ max. statin: combination with
ezetimibe recommended (IB)
• Not achieving goals despite max. statin + ezetimibe: combination with
PCSK9 inhibitor recommended (IB)
• Presenting with ACS, LDL-C not at goal despite already taking max. statin +
ezetimibe: consider early PCSK9 inhibitor (IIa/C)
• Undergoing PCI for ACS or elective PCI: consider routine pre-treatment or
loading with high-dose statin (IIa/B)
Mach F, et al. Eur Heart Journal 2019, 00,1-78
ACS = Acute coronary syndrome, ESC= European Society of Cardiology, EAS= European Atherosclerosis
Society, LDL-C= Low-density lipoprotein cholesterol, LDL= Low-density lipoprotein, PCI= Percutaneous
coronary intervention, PCSK9= Proprotein convertase subtilisin/kexin type 9
19
ARMYDA-ACS trial: Study design (NSTE-ACS)
Patti et al, JACC Vol. 49, No. 12, 2007: 1272–8
ARMYDA-ACS= Atorvastatin for Reduction of MYocardial Damage During Angioplasty - Acute Coronary Syndromes, CK-MB= Creatine kinase MB, CRP= C-reactive protein, MI= Myocardial infarction, NSTE-ACS= Non–ST-segment elevation acute coronary syndrome, PCI= percutaneous coronary intervention, TVR= Target vessel revascularization, MACE= Major adverse cardiac event, PCI= Percutaneous coronary intervention
ARMYDA-ACS trialComposite primary end-point (30-day death, MI, TVR)
2020
0
5
10
15
2088% RISK REDUCTION OF MACE
Atorvastatin Placebo
Per
cen
tage
of
pat
ien
ts
5
17
p=0.01
Patti et al, JACC Vol. 49, No. 12, 2007: 1272–8
ARMYDA-ACS= Atorvastatin for Reduction of MYocardial Damage During Angioplasty - Acute Coronary Syndromes, MI= Myocardial infarction,
TVR= Target vessel revascularization, MACE= Major adverse cardiovascular events
ARMYDA-ACS trial
21
Patti et al, JACC Vol. 49, No. 12, 2007: 1272–8
0123456789
1011121314151617
Death Myocardial Infarction Target VeselRevascularization
Total MACE
0%
5%
0%
5%
0%
15%
2%
17%
Nu
mb
er o
f P
atie
nts
(%
)Individual and Combined Outcome Measures of the Primary End Point
at 30 Days in the Atorvastatin and Placebo Groups
Atorvastatin (n=86) Placebo (n=85)
* p=0.04** p=0.01
* **
ARMYDA-ACS= Atorvastatin for Reduction of MYocardial Damage During Angioplasty - Acute Coronary Syndromes, MACE= Major adverse cardiovascular events
REVERSAL Trial
-0.4
2.7
-1
0
1
2
3
4
Atorvastatin Pravastatin
Change in atheroma volume p=0.02 for change between atorvastatin vs pravastatin
Change in % obstruction volume p=0.0002 for change between atorvastatin vs
pravastatin
0.2
1.6
0
1
1
2
2
Atorvastatin Pravastatin
Nissen SE et al. JAMA. 2004;291:1071-1080
Ref: Nissen S et al. JAMA 2006; 295
REVERSAL STUDY
Atorvastatin 80 mg reduce atheroma
volume and increase lumen area
(from 7.7 mm2 to 9.8 mm2)
In REVERSAL, atorvastatin 80 mg slowed progression
of atherosclerosis at 18 months
Percent Reduction in CRP p<0.001
-36.4%
-5.2%
-45%
-35%
-25%
-15%
-5%
Atorvastatin Pravastatin
Result in Plaque Regression
23Ref: Nissen S et al. JAMA 2006; 295
Ref: Nissen SE, et.al. JAMA 2004; 291
REVERSAL STUDY
Atorvastatin reduce atheroma
volume and increase lumen area
(from 7.7 mm2 to 9.8 mm2)
ASTEROID STUDY
Rosuvastatin reduce atheroma
volume BUT ALSO reduce lumen
area
(from 6.19 mm2 to 5.96 mm2)
In REVERSAL, atorvastatin 80 mg slowed progression
of atherosclerosis at 18 months
24
Efficacy Evaluation of High-Dose Atorvastatin Pretreatment in Patients with Acute Coronary Syndrome: A Meta-Analysis of
Randomized Controlled Trials
• Seventeen RCTs including 10,072 patients were retrieved.
• High-dose atorvastatin showed greater benefits in reducing the incidence of
short-term MACEs (OR 0.72; 95% CI: 0.56 to 0.94; P=0.01) among ACS patients after PCI
Ma Y, et al. Med Sci Monit 2018; 24: 9354-63
25
Efficacy Evaluation of High-Dose Atorvastatin Pretreatment in Patients with Acute Coronary Syndrome: A Meta-Analysis of
Randomized Controlled Trials
Ma Y, et al. Med Sci Monit 2018; 24: 9354-63
• High-dose atorvastatin showed greater benefits in reducing
hs-CRP level (SMD –1.59; 95% CI: –2.38 to –0.80; P<0.0001) among ACS patients after PCI
26
Efficacy Evaluation of High-Dose Atorvastatin Pretreatment in Patients with Acute Coronary Syndrome: A Meta-Analysis of
Randomized Controlled Trials
Ma Y, et al. Med Sci Monit 2018; 24: 9354-63
• High-dose atorvastatin therapy also was not associated with alanine
aminotransferase (ALT) elevation (OR 1.95; 95% CI: 0.95 to 4.03; P=0.07).
A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease
RADAR Study
Background
• Serum cardiac troponin is a specific marker of myocardial injury and is the cornerstone in the diagnosis and acute management of myocardial infarction
• High-sensitivity assays (hs-cTnI), which are up to 100 times more sensitive compared with the first-generation assays, permits the accurate determination of very low levels of circulating cardiac troponin
• Serum troponin within the normal range is an emerging predictor of cardiovascular mortality
• Differences between LDL-C-lowering effects between statins are well known but variances in pleiotropic effects are less clear. However, there are differences in pharmacokinetics and pharmacodynamics between statins
Study Objective : To determine how rapidly high sensitivity troponin-I (hs-cTnI) levels are lowered by statin therapy in patients with stable cardiovascular disease.
Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
RADAR= Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport, hs-cTnI = High sensitivity troponin-I
A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease
RADAR Study
• Patients were randomized to atorvastatin 20mg/day (n=39) or rosuvastatin
10mg/day (n=39)
• Up-titrated done at 6-week intervals to 80mg of atorvastatin or 40mg of
rosuvastatin.
• Hs-cTnI concentrations were measured at baseline and at 6 and 18 weeks of follow-up
Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
Adapted from: Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
RADAR= Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport, hs-cTnI = High sensitivity troponin-I
A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease
RADAR Study
Effect of Statin Therapy on The Total Group
• Statin induced effect on
hs-cTnI was evident as
early as after 6 weeks.
• During statin therapy,
serum hs-cTnI levels
decreased rapidly within
weeks of treatment,
suggesting an effect
beyond long-term
atherosclerosis
regression
• Decrease in Hs-cTnI was
independent of
decreases of LDL-c
concentrations.
• This novel finding
suggests a rapid benefit of
statin treatment on
Adapted from: Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
RADAR= Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol
transport, hs-cTnI = High sensitivity troponin-I, LDL-C= Low-density lipoprotein cholesterol
Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
A Rapid (Differential) Effect of Rosuvastatin and Atorvastatin on High-Sensitivity Cardiac Troponin-I in Subjects With Stable Cardiovascular Disease
RADAR Study
*P=0.053, **P=0.071, ***P=0.001
• Statin-induced effects on hs-cTnIwere evident as early as after 6 weeks.
• hs-cTnI levels were lowered by 21.8% with atorvastatin and by 4.1% with rosuvastatin (P=0.001 and P= 0.133, respectively) at week 18
• This effect was more pronounced with atorvastatin than with rosuvastatin*
Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
RADAR= Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol transport, hs-cTnI = High sensitivity troponin-I
*patients used atorvastatin 20mg/day and rosuvastatin 10mg.day
initially. Dosage were up-titrated at 6-week interval to 80 mg of atorvastatin and 40mg of rosuvastatin
Adapted from: Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6
Atorvastatin: Proven safety profile
across the dose range
Adverse events, %Atorvastatin 10 mg
(n=7,258)Atorvastatin 80 mg
(n=4,798)Placebo
(n=2,180)
Withdrawals due to treatment-related adverse events
2.4 1.8 1.2
Serious treatment-related nonfatal adverse events
0.2 0.5 4.2
Musculoskeletal 2.3 2.7 1.2
Treatment-related myalgia 1.4 1.5 0.7
Persistent ALT or AST >3 × ULN* 0.1 0.6 0.2
Persistent CPK >10 × ULN* 0 0.06 0
Rhabdomyolysis 0 0 0
Albuminuria 0.1 0.04 0
Hematuria 0.3 0.3 0.1
Data from a pooled analysis involving 14,236 patients from 49 trials
ALT, alanine transaminase; AST, aspartate transaminase; CPK, creatinine phosphokinase; ULN, upper limit of normal
*Based on the number of patients with laboratory measurements
Newman C, et al. Am J Cardiol 2006;97;61–67
Algorithm for
treatment of muscle
symptoms during
statin treatment
Conclusion
• Indonesia face a high burden of cardiovascular disease. This burden is attributable to major modifiable risk factors such as dyslipidemia
• Current international guidelines recommend the use of high intensity statin in the management of high-risk patient groups such as those with ACS
• Atorvastatin is proven to be effective and tolerable in the management of dyslipidemia in high risk patients