The Most Potent Statin in ACS ;

Why It Matter Most ?

Andrianto, FIHA FASCC

Risk of death in patients with CHD :
Greatest early after an ACS.

Deaths/100 patients/month
25
Acute MI
20 Unstable angina
Stable angina
15

10

0 1 2 3 4 5 6
Time (months after hospital admission)

Braunwald (1996)
Men & Women With ACS :
At High Risk of Early Mortality

CCU=coronary care unit.

Adapted from Perers E et al. Int J Cardiol. 2005;103:120-127.

Bagaimana Proses
Terjadinya Penyakit ?
 Relationship Between on-Treatment LDL-C & CV Events Rates :
- Landmark Statin Trials
30

25
Lower is Better 4S - Placebo

Secondary
4S - Rx
Prevention
20

LIPID - Placebo
15
CARE - Placebo
LIPID - Rx Primary
CARE - Rx
10
HPS - Rx TNT – ATV10 HPS - Placebo Prevention
ROVE-IT - PRA WOSCOPS – Placebo
TNT – ATV80
PROVE-IT – ATV AFCAPS - Placebo
5 AFCAPS - Rx 6
WOSCOPS - Rx
ASCOT - Placebo
ASCOT - Rx

40 60 80 100 120 140 160 180 200

(1.0) (1.6) 2.1) (2.6) (3.1) (3.6) (4.1) (4.7) (5.2)

LDL-C achieved mg/dL (mmol/L)

1. Rosenson RS. Exp Opin Emerg Drugs 2004; 9 (2):269-279
2. LaRosa JC, et al. NEJM 2005; 352:1425-1435
CAD & Statins Trials :
Treatment Gap

Chest 2005;128:3641-3651
Pathophysiology of ACS
Potential pharmacological interventions

1. Downstream from thrombus

myocardial ischaemia/necrosis
(β-blockers, nitrates etc)

Fibrin 2. Activation of clotting

Fibrinogen clot cascade – thrombin
Thrombin (heparin/LMWH)
GP IIb/IIIa
receptor
3. Platelet adhesion/
activation/aggregation
(aspirin, clopidogrel,
Platelet
GP IIb/IIIa inhibitors)

4. Plaque rupture,
cholesterol content,
inflammation (hs-CRP)
(statins)
Lipid & Non-lipid (Pleiotropic) Effects Of Statins
Pathobiology of lipid and non-lipid mechanisms in ACS

Hypothesized non-lipid-related Lipid-related

(early/rapid effect) (slower/late effect)
Endothelial
dysfunction/activation
Statins

Liver
Hepatic
cholesterol
Inflammation/ Coagulation/ synthesis
immune activation Inhibitory platelet activation
Statins
Inhibitory

Plaque rupture/
thrombotic occlusion

Thrombus

Lipid core

Lipid-rich atherosclerotic
plaque
Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1425-1433.
Rationale for early statin therapy
 Gives constant reduction in risk
 May stabilise plaque maximum
 Other non-lipid-lowering effects
 Patient already in hospital
 Discharged on statin therapy
most effective when absolute
risk is highest
benefit when given early
eg anti-inflammatory, effects
on endothelial dysfunction
patient more likely to adhere to
therapy
underscores need for
continued statins
Very early initiation of Statin therapy

The earlier  The better

Acute Card Care. 2012 Mar;14(1):34-9.
 Meta-Analysis of Time-Related Benefits of Statin
Therapy in Pts With ACS Undergoing PCI :
Myocardial Infarction At 30 Days

Significant reduction of myocardial infarction in the statin group

Navarese EP, et al. Am J Cardiol 2014;113:1753-1764
Meta-Analysis of Time-Related Benefits of Statin Therapy
in Pts With ACS Undergoing PCI:
MACE At & Beyond 30 Days

Significant reduction of MACE in the statin group

Navarese EP, et al. Am J Cardiol 2014;113:1753-1764
What about more intensive lipid
lowering?

Lower LDL More Regression ?

Rosuvastatin Trials?
Evolution of Lipid Guidelines
The Need For More Stringent LDL-C Goals

Garber A, et al. Endocr Pract 2017;23:207-238

Intensity of Statin Therapy

High-Intensity Statin Moderate-Intensity Low-Intensity Statin

Therapy Stain Therapy Therapy

LDL–C ↓ ≥50% LDL–C ↓ 30% to <50% LDL–C ↓ <30%

Rosuvastatin 20 (40) Rosuvastatin (5) 10 mg Simvastatin 10 mg

Atorvastatin 10 (20) mg Pravastatin 10–20 mg
mg Simvastatin 20–40 mg‡ Lovastatin 20 mg
Atorvastatin (40†)–80 mg Pravastatin 40 (80) mg Fluvastatin 20–40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2–4 mg
Lifestyle modification remains a critical component of ASCVD risk reduction, both prior to and in
concert with the use of cholesterol lowering drug therapies.

Statins/doses that were not tested in randomized controlled trials (RCTs) reviewed are listed in italics
†Evidence from 1 RCT only: down-titration if unable to tolerate atorvastatin 80 mg in IDEAL
‡Initiation of or titration to simvastatin 80 mg not recommended by the FDA due to the increased risk of myopathy,
including rhabdomyolysis.
Stone NJ, et al. J Am Coll Cardiol. 2013: doi:10.1016/j.jacc.2013.11.002. Available at:
http://content.onlinejacc.org/article.aspx?articleid=1770217. Accessed November 13, 2013.
 The Relationship Between Achieved LDL-C Level
and Change in Percent Atheroma Volume
(Stronger LDL-C Reduction is Directly Related To Plaque Regression)

1.0
Change in Percent Atheroma Volume, %

0.5

-0.5

-1.0

-1.5
10 20 30 40 50 60 70 80 90 100 110

On- Treatment LDL-C, mg/dL

Nicholls SJ, et al. JAMA. doi:10.1001/jama.2016.16951

 Relationship Between LDL-C Levels and Change
in Percent Atheroma Volume for Several IVUS Trials

1.8
REVERSAL
CAMELOT pravastatin
Change in Percent Atheroma

placebo
1.2

ACTIVATE
placebo
Volume

0.6 REVERSAL
atorvastatin A-Plus
ILLUSTRATE
placebo Progression
Torcetrapib ILLUSTRATE
0 Placebo
Regression
-0.6
ASTEROID
rosuvastatin
-1.2
50 60 70 80 90 100 110 120
Mean LDL-C (mg/dL)

Nissen SE et al. JAMA 2006

 In ACS...
How to treat ?
High Dose of Rosuvastatin ?
Lipid-Modifying Efficacy and Safety :
Rosuvastatin vs Atorvastatin in ACS

Pitt B et al. Am J Cardiol 2012; 109:1239-46

Rosuvastatin 40mg Reduces LDL-C :
More than Atorvastatin 80mg in ACS

Pitt B et al. Am J Cardiol 2012; 109:1239-46

Rosuvastatin 20 and 40 mg Increases HDL-C more than
Atorvastatin 80 mg in ACS

Pitt B et al. Am J Cardiol 2012; 109:1239-46

Preloading of Rosuvastatin
before PCI in ACS
 MACE of High Loading Dose Statin:
Rosuvastatin vs Control before PCI in ACS patients

Yun KH et al. Int J Cardiol. 2011;146:68-72.

Change in LDL-C Change in hs CRP

Yun KH et al. Int J Cardiol. 2011;146:68-72.

 Take Home Messages

• Early and intensive statin treatment in patients

with ACS improved clinical outcomes .

• High doses of rosuvastatin were more effective

than other statins not only in reducing LDL-C
but also reducing inflammatory markers, plaque
stabilization and more pronounce plaque
regression.
Example of Regression of Atherosclerosis
in a Patient in the Trial

Baseline Follow up
Comparison of Lipid-Modifying Efficacy of
Rosuvastatin Versus Atorvastatin in
Patients With ACS

(LUNAR Study)
Limiting Under treatment of lipids in ACS With Rosuvastatin

Am J Cardiol 2012;109:1239 –1246

 Lipid-Modifying Efficacy :
Rosuvastatin vs Atorvastatin in ACS

Lablanche JM. Arch Cardiovasc Dis 2010;103:160-169

- Compared the efficacy of RSV20 and RSV40 with ATV80
in patients with ACS

- Prospective, multicenter, randomized, open-label, 3-arm,

parallel-group trial.

Inclusion Criteria:
1. ACS patients with in 48 hrs of ischemia
- STEMI pts with intervention with in 12 hrs of
symptoms (TLT or PCI)
- NSTEMI/UA with conservative management
- LDL-C >70 mg/dl, fasting TG < 500 mg/dl with in
72 hrs of symptom onset
 Baseline
characteristics
of randomized
patients
(n = 825)
* p <0.05; † p < 0.01; ‡ p < 0.001 versus atorvastatin 80 mg/day.
Mean percent change from baseline by weeks 2, 6, and 12 in
low-density lipoprotein cholesterol (LDL-C)
Mean percent change from baseline by weeks 2, 6, and 12 in
(high-density lipoprotein cholesterol (HDL-C)..
Conclusion: LUNAR study

RSV 40 more effectively decreased LDL-C , increased

HDL-C and improved other blood lipid parameters when
compared to RSV20 And ATV80 in patients with ACS
Adverse Events and Drug Continuation:
Asteroid Trial
Why Rosuvastatin Has A Highest Potency vs
Other Statins:
More Binding Sites & Stronger Binder to HMG-CoA
Reductase

Istvan Eva S, Sciencemag 2001

Rosuvastatin is a Hydrophilic Statin and Not
Metabolized by CYP3A4
Less Prone To Drug Interactions & Rhabdomyolysis

Ramosevac AC, et Al. Acta Pharm 2013

Possible Pharmacokinetic Interaction of Atorvastatin and Clopidogrel
Among PCI Treated Patients:
Switching Atorvastatin to non CYP3A4-metabolized statin (Rosuvastatin)
Significantly decrease platelet reactivity and the prevalence of HPR*

*HPR = High Platelet Reactivity

Park Y, et al. European Heart Journal 2012
 Effects of Withdrawal of Statin After AMI

starters = did not receive before AMI but started after; users = before and continuing after AMI
Non-users =not receiving before or after AMI; stoppers = stopped statin after AMI.
Daskalopoulou S, et al. European Heart Journal (2008) 29, 2083–2091