Managing Dyslipidemia in ACS Patients - WordPress.com...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

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

https://www.who.int/nmh/countries/idn_en.pdf

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.


Secondary ASCVD Prevention


Secondary ASCVD Prevention

Secondary ASCVD

Prevention

Diabetes Mellitus in

Adults

Primary Prevention

Severe Hyercholest

erolemia


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"


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


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


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


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%


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




• 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




• 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


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


Adapted from: Bodde MC, et al. Clinical Pharmacology & Therapeutics. 2018, 104(2):311-6



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


RADAR= Rosuvastatin and Atorvastatin in different Dosages And Reverse cholesterol

transport, hs-cTnI = High sensitivity troponin-I, LDL-C= Low-density lipoprotein cholesterol



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*



*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


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

Documents

Managing Dyslipidemia in ACS Patients - WordPress.com...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