Statin role in primary

& secondary prevention:

Mailani Karina Akhmad, MD

Lipid Management with Statins:
Meta-analyses from CTT
Lancet 366: 2005 Overall Population
14 Trials: 90,056 patients with 5.1 years of FU
23% MI and coronary deaths and 12% mortality per 1 mmol/L decrease in LDL-C
Lancet 371: 2008 Diabetic Population
14 Trials: 6,956 DM with CVD compared to 11,703 without CVD
Similar 22% CHD, 21% CVA, 9% mortality in both groups
Lancet 376: 2010 High vs. Low Dose Statin
5 trials: 39,612 individuals with 5.1 years f/u
Further 15% reduction in CV risk for 0.51 mmol/L LDL reduction
Independent of baseline LDL-C
Lancet 380: 2012 Low-Risk Indivduals
27 trials in 174,149 patents
21% fewer CVD events per 1 mmol/L reduction
Similar proportional reduction in the low risk (<5% or 5 to 10% 5-year risk
Lancet 2005; 366:1358.
Kearney et al Lancet 2008; 371(9607):117
Baigent et al Lancet 2010; 376: 1670–81
Mahaylova et al Lancet; 380:581-590
2
CVD Primary Prevention
Statin Benefit Independent of Baseline Lipids:
Meta-analysis of 14 Trials
Cholesterol Treatment Trialists’ Collaboration
Groups Events (%)
Treatment Control Treatment Control
Total-C (mg/dL) (45,054) (45,002) better better
≤201 13.5 16.6 0.76
>201–251 13.9 17.4 0.79
>251 15.2 19.7 0.80
LDL-C (mg/dL)
≤135 13.4 16.7 0.76
>135–174 14.2 17.6 0.79
>174 15.8 20.4 0.81
HDL-C (mg/dL)
≤35 18.2 22.7 0.78
>35–43 14.3 18.2 0.79
>43 11.4 14.2 0.79
TG (mg/dL)
≤124 13.4 16.8 0.79
>124–177 13.8 18.0 0.78
>177 15.3 18.8 0.80
Overall 14.1 17.8 0.79
0.5 1.0 1.5
Relative risk
CHD death, MI, stroke, coronary revascularization

CTT Collaborators. Lancet. 2005;366:1267-78.

3
CVD Primary Prevention
Effect of Statins on CVD Event Rates

All-cause Mortality: 0.90 ( 0.87–0.93); median f/u: ~ 5.0 yrs.

Adapted from Cholesterol Treatment Trialists’ (CTT) Collaboration. Lancet. 2010;376(9753): 1670–1681.
4
CVD Primary Prevention
Statin Therapy in Primary Prevention
• Cardiovascular disease is a world-wide escalating problem, the number one
cause of death globally and expected to increase
• Hyperlipidemia and diabetes are increasing in prevalence world-wide and a
major contributor to cardiovascular disease
• Statin therapy has been shown to be effective in reducing cardiovascular events
in individuals with known CVD, diabetes with other CVD risk factors and in those
with multiple risk factors associated with a high future risk of CVD events
• Appreciating these facts has been reflected in more validated risk assessment
tools and new hyperlipidemia treatment guidelines throughout the world
• Under-recognition and under treatment of risk factors including hyperlipidemia is
common
• Statin therapy is one part of a multifactorial approach to managing risk factors
and preventing CVD. The total risk approach allows flexibility; if perfection cannot
be achieved with one risk factor, trying harder with others can still reduce risk

5
CVD Primary Prevention
Rationale For Lowering LDL-C with Statins
in Diabetes
• UKPDS: elevated LDL-C and HDL-C strongly associated new CHD
• STENO-2: CVD mortality reduction of 53% in diabetics is primarily (70%)
explained by lipid treatment (LDL-C of 83 mg/dL in vs. 126 mg/dl)

• Similar benefit with statin treatment in diabetics with or without CVD

• Heart Protection Study revealed similar relative risk reduction whether pre-
treatment LDL-C is high or low

• IVUS in ASTEROID showed that treatment to a low LDL-C in the 60’s mg/dL on
statin therapy is associated with regression of plaque

• Intensive statin therapy demonstrated a further 15% reduction in CVD risk for
each 0.51 mmol/L LDL-C reduction

• Trials in DM without CVD: the strongest beneficial effects with low on-
treatment LDL-C: 68 mg/dL in CARDS, 85 mg/dL in ASCOTT
6
CVD Primary Prevention
Benefits of LDL-C Lowering in Diabetes

Primary event rate (%) Aggressive Aggressive Difference in

lipid-lowering lipid-lowering LDL-C
Treatment Control better worse P (mg/dL)
ASCOT-LLA 0.77
Diabetes, HTN 9.2 11.9 0.036 35†

CARDS 0.63
Diabetes, no CVD 5.8 9.0 0.001 46†

HPS 0.73
All diabetes 9.4 12.6 <0.0001 39†

0.67 39†
Diabetes, no CVD 9.3 13.5 0.0003

TNT 0.75
Diabetes, CHD 13.8 17.9 0.026 22*

0.5 0.7 0.9 1 1.7

*Atorvastatin 10 vs 80 mg/day
†Statin vs placebo Relative risk

HPS Collaborative Group. Lancet 2003. Shepherd J et al. Diabetes Care 2006.
Colhoun HM et al. Lancet 2004. Sever PS et al. Diabetes Care 2005.

7
CVD Primary Prevention
Correction of dyslipidemia in Diabetes would confer substantial
protection against cardiac & cerebrovascular events

↓20% RR
NNT = 19 (4.9 years)
NNT = 38 (4.3 years)
NNT, number needed to treat

39 mg/dL of LDL-C reduction

decreases:
CV events by 21%
Coronary events by 22%
Cerebrovascular events by
21%
CV mortality by 13%
The benefits are independent
from baseline LDL-C

Cholesterol Treatment Trialists’ (CTT) Collaborators, et al. Lancet 2008;371:117-125.

8
 Global primary prevention trials of statins
(including patients with diabetes)

CHD risk vs
Diabetic Lipid-altering drug
Trial Total (N) placebo in diabetic
patients (N) mg/d
patients, %
CARDS 2,838 2,838 Atorvastatin 10 -37 (p=0.001)

AFCAPS 155 6,605 Lovastatin 20-40‡ -44 (NS)

HPS 2,912 7,150 Simvastatin 40 -33 (p=0.0003)

-23 (p=0.036)
ASCOT 2,532 10,305 Atorvastatin 10 total CV events &
procedure
PROSPER 623 5,804 Pravastatin 40 +27 (NS)

1. Bays H, et al. Future Cardiol 2005;1:39-59. 2. Colhoun HM, et al. Lancet 2004;364:685-696. 3. Downs JR, et al. JAMA
1998;279:1615-1622. 4. HPS Collaborative Group. Lancet 2003; 361:2005-2016. 5. Sever PS, et al. Lancet 2003;361:1149-1158. 6.
Shepherd J, et al. Lancet 2002;360:1623-1630.

9
Atorvastatin global studies in patients with type II diabetes

Patient
Study Comparators
population
Atorvastatin 10 mg Key global study in
CARDS1 Diabetes diabetic patients
Placebo
Atorvastatin 10 mg
ASCOT-LLA2 Hypertension*
Placebo
Atorvastatin 10 mg
TNT3 Stable CHD* *Subanalysis
Atorvastatin 80 mg
available in
Atorvastatin 80 mg diabetic patient
PROVE IT4 ACS* subgroup
Pravastatin 40 mg
Atorvastatin 10–80 mg
GREACE5 CVD*
Usual care

1. Colhoun H, et al. Lancet 2004;364:685-696

2. Sever PS, et al. Diabetes Care 2005;28:1151–1157
3. Shepherd J, et al. Diabetes Care 2006;29:1220–1226
4. Ahmed S, et al. Eur Heart J 2006;27:2323–2329
5. Athyros VG, et al. Angiology 2003;54:679–690
10
 CARDS: Type 2 diabetes outcomes trial
CARDS was a multicenter, randomized, double-blind study

Patient population
 Type 2 diabetes, no
clinically evident Atorvastatin 10 mg/day
CHD
 ≥1 other CHD risk
factor (smoking, n=2838
HTN, albuminuria,
retinopathy) Placebo
 LDL-C ≤160 mg/dL
 TG ≤600 mg/dL
 Aged 40–75 years 3.9-year median follow-up

 Primary endpoint: Time to first occurrence of a major CV event, defined as

acute CHD events (ie MI including silent MI, unstable angina, acute fatal CHD,
resuscitated cardiac arrest), coronary revascularization, or stroke

11
CARDS, Collaborative AtoRvastatin Diabetes Study Colhoun HM, et al. Lancet. 2004;364:685–696
 CARDS: Atorvastatin 10 mg reduced LDL-C by
40% VS Placebo in patients with type II diabetes

LDL-C (mmol/L) TC (mmol/L)

Average difference 40% Average difference 26%
(1.2 mmol/L, p<0.0001) (1.4 mmol/L, p<0.0001)
4 6

3
4
mmol/L

mmol/L
2

2
1

0 0
0 1 2 3 4 4.5 0 1 2 3 4 4.5
Years of Study Years of Study
Placebo Atorvastatin

Colhoun H, et al. Lancet 2004;364:685-696

12
 CARDS: Efficacy results in patients with
type 2 diabetes
 CARDS: Atorvastatin 10 mg provided a significant reduction in CV events in patients
with type 2 diabetes and ≥1 risk factor compared with placebo
Incidence of major CV events*
15 Placebo (n=1410); final LDL-C=121 mg/dL Fatal/non-
Stroke fatal MI
Atorvastatin 10 mg (n=1428); final LDL-C=82 mg/dL
Cumulative incidence (%)

10 37% 48% 42%

RRR RRR RRR
95% CI 95% CI 95% CI
0.17–0.52 0.31–0.89 0.39–0.86
(p=0.001) 1 (p=0.016) 2 (p=0.007) 3

5 ARR=3.2% ARR=1.3% ARR=1.9%

0 //
0.0 1.0 2.0 3.0 3.9
Time (years)
CARDS was stopped ~2 years early due to significant CV benefits with atorvastatin
Reprinted from The Lancet, 364, Colhoun HM, Betteridge DJ et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial, 685–96., Copyright (2004), with permission from Elsevier
1. Colhoun HM, et al. Lancet. 2004;364(9435):685–696; 2. Hitman GA, et al. Diabet Med. 2007;24(12):1313–1321;
13
*Primary endpoint 3. Lipitor Highlights of US Prescribing Information, 2013
 CARDS: Safety results in patients with
type 2 diabetes

Data from the CARDS study of 2,838 patients with type 2 diabetes
Atorvastatin 10 mg Placebo
%
(n=1428) (n=1410)
Withdrawals due to muscle-related AEs 0.5 0.6
Myopathy 0.1 0.1
Myalgia 4.3 5.1
≥1 ALT elevation >3 x ULN 1.2 1.0
≥1 AST elevation >3 x ULN 0.4 0.3
Rhabdomyolysis 0 0

14
ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal Colhoun HM et al. Lancet. 2004;364:685–696
CARDS: Beneficial effect of atorvastatin on eGFR,
most apparent in albuminuric diabetic patients
Mean change in eGFR from baseline

Colhoun HM et al. Am J Kidney Dis 2009;54:810-819.

15
But … are all high intensity
statins the same in renal
safety?

16
PLANET I and II investigated the effects of atorvastatin and
rosuvastatin on renal function
in patients with CKD with and without diabetes
PLANET I and II were multicenter, randomized, double-blind studies

Patient population 52 weeks follow-up

PLANET I
 Type I or II diabetes
Rosuvastatin 40 mg/day
PLANET II
 No diabetes PLANET I: n=325*
Both studies PLANET II: n=220*
Rosuvastatin 10 mg/day
 Moderate proteinurea1
 Hypercholesterolemia2 Atorvastatin 80 mg/day
 ACEis or ARBs for ≥3
months prior to screening

 Primary endpoint: Within-group change in urinary protein/creatinine ratio (UPCR) from

baseline to Week 52 or last on-treatment observation carried forward (Week 52 LOCF)

*Intention-to-treat (ITT) populations

1.Urinary protein/creatinine ratio 500–5,000 mg/g;
2.Fasting LDL-C ≥90 mg/dL (2.33 mmol/L);
ACEi, angiotensin converting enzyme inhibitor; De Zeeuw D, et al. Lancet 2015. http://dx.doi.org/10.1016/S2213-
17
ARB, angiotensin receptor blocker 8587(14)70246-3
 18
PLANET I: Effect of atorvastatin or rosuvastatin on
urinary protein/creatinine ratio
Rosuvastatin 10 mg
1.4 Rosuvastatin 40 mg
Atorvastatin 80 mg
UPCR (Baseline: on-treatment)
1.2

1.0 p=0.83
p=0.53
p=0.033
0.8

0.6
0
0 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 103 97 96 95 107
Rosuvastatin 40 mg 116 112 107 106 106 116
Atorvastatin 80 mg 102 96 91 88 82 102

Data are mean baseline: on-treatment ratios

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
LOCF, last observation carried forward; UPCR, urinary atorvastatin and rosuvastatin in patients with diabetes who
protein/creatinine ratio have progressive renal disease (PLANET I): a randomised clinical
18
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier
 19
PLANET I: Effect of atorvastatin or rosuvastatin on
estimated glomerular filtration rate
Rosuvastatin 10 mg
2 Rosuvastatin 40 mg
Atorvastatin 80 mg
(mL/min per 1.73 m2) 0

–2 p=0.21
Change in eGFR

–4

–6
p=0.0098
p=0.0002
–8

–10
0 4 8 14 26 39 52 LOCF
Number of patients Time (weeks)
Rosuvastatin 10 mg 107 106 104 103 99 95 95 107
Rosuvastatin 40 mg 116 115 112 111 109 104 109 116
Atorvastatin 80 mg 102 99 98 97 92 86 86 102

Data are mean changes from baseline

Error bars are 95% CIs. LOCF marks 52-week data accounting for all
patients in ITT population Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of
eGFR, estimated glomerular filtration rate; LOCF, last observation atorvastatin and rosuvastatin in patients with diabetes who
carried forward have progressive renal disease (PLANET I): a randomised clinical
19
p values are vs baseline trial, 181–190. Copyright (2015), with permission from Elsevier
 20

PLANET I: Reported adverse events

Rosuvastatin Rosuvastatin Atorvastatin
n (%)
10 mg (n=116) 40 mg (n=123) 80 mg (n=110)
Any adverse event 69 (59.5) 79 (64.2) 63 (57.3)

Any serious adverse event* 18 (15.5) 20 (16.3) 21 (19.1)

Any renal adverse event 9 (7.8) 12 (9.8) 5 (4.5)

Acute renal failure 0 5 (4.1) 1 (0.9)

Serum creatinine doubling 0 6 (4.9) 0

Serum creatinine doubling or
0 9 (7.3) 1 (0.9)
acute renal failure
Death 4 (3.4) 1 (0.8) 0

Statistical analysis of adverse events was not presented

One serious AE (2 episodes of cardiac failure in rosuvastatin 10 mg group) was considered related to study drug

No episodes of acute renal failure were considered related to study drug

Reprinted from The Lancet, 3, de Zeeuw D, et al, Renal effects of atorvastatin and
rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a
randomised clinical trial, 181–190. Copyright (2015), with permission from 20
Elsevier
 PLANET I: Conclusions

 In people with proteinuria with diabetes (PLANET I) or without diabetes

(PLANET II):
 Atorvastatin 80 mg reduced proteinuria; rosuvastatin 10 or 40 mg had
no effect
 Atorvastatin 80 mg had no effect on eGFR; rosuvastatin 10 or 40 mg
reduced eGFR
 Doubling of serum creatinine and acute renal failure were more
common with rosuvastatin
 Results suggest that atorvastatin and rosuvastatin have different
renal profiles

 According to the authors, atorvastatin seems to have more

renoprotective effects for the studied CKD population

De Zeeuw D, et al. Lancet 2015.http://dx.doi.org/10.1016/S2213-8587(14)70246-3

21
Han E, et al. Endocrinol Metab 2017;32:274-280
Background
• Hyperglycemia and dyslipidemia is an important risk factor for renal
function loss
• When DM and Dyslipidemia co-occur  risk of CKD is synergistically
increased

Research Study shown that statins have the potential to protect kidney via
anti-inflammatory and anti-proliferative pathway

How about the effect of statin in Diabetic Asian Patient on

kidney function in clinical practice?
1. Han E, et al. Endocrinol Metab 2017;32:274-280
2. Campese VM, Park J. Kindney Int 2007;71:1215-1222
 Methods

Patient Population Baseline: End of Study:

• FBG, HbA1C • FBG, HbA1C
• Lipid profile (TC, LDL-C, • Lipid profile (TC, LDL-C,
• Aged ≥ 20 years HDL-C, Triglyceride) HDL-C, Triglyceride)
• Diabetes Mellitus • eGFR • eGFR
• Naïve and started
moderate-intensity
statin
Atorvastatin 10 – 20 mg/day
484 patients
Rosuvastatin 5 – 10 mg/day
Primary Endpoint

• Change in eGFR
• Rapid renal decline - 12 months
>3% reduction in eGFR
Clinical Parameter at baseline: eGFR : estimated GFR; FBG : fasting Blood Glucose;
• Age, sex, height, weight TC : Total Cholesterol; DM : Diabetes Mellitus; HTN
• Duration of DM : Hypertension
• History of HTN and cardiac
disease
• Statin treatment information Han E, et al. Endocrinol Metab 2017;32:274-280
Han E, et al. Endocrinol Metab 2017;32:274-280
Han E, et al. Endocrinol Metab 2017;32:274-280
 Primary Endpoint : Change in eGFR
eGFR Reduction
eGFR Change
Atorvastatin Rosuvastatin
81 0
80,3
80 -0,5
79 78,7*
-1
mL/min/1.73m2

79,1
78
-1,5
77
-1,6
76 -2
*
76,1**
75 -2,5
74
-3
Baseline 12 months -3
-3,5 **
* p = 0.012
** p = 0.01
Atorvastatin Rosuvastatin

• Among all patients, eGFR was slightly decreased from 79.8 to 77.7 mL/min/1.73m 2 (P<0.001)
• There was a greater reduction of eGFR in rosuvastatin-treated group compared to
atorvastatin
Han E, et al. Endocrinol Metab 2017;32:274-280
Renal Function Decline
Renal Function Decline
60,00% P = 0.029

48,700%
50,00%

36,800%
40,00%

30,00%

20,00%

10,00%

,00%
Atorvastatin Rosuvastatin

• More individuals receiving rosuvastatin treatment experienced rapid renal function

decline than those receiving atorvastatin treatment.
• After adjusting confounding factors : compared with atorvastatin, rosuvastatin
treatment increased risk for rapid renal function loss by approximately 60%
(OR, 1.60; 95% CI, 1.06 to 2.42) Han E, et al. Endocrinol Metab 2017;32:274-280
 Other Parameters

The proportion of individuals who achieved an LDL-C response (>30% reduction) was similar
between the statin groups (52% and 59.6% for atorvastatin and
rosuvastatin, respectively, P=0.115) Han E, et al. Endocrinol Metab 2017;32:274-280
Discussion

• There is increasing evidence that statin have reno-protective effect.

However renal outcome according to statin potency is more
controversial.
• Regarding statin types and renal funtion, atorvastatin seems to be
more beneficial than rosuvastatin
• Although differences between mechanism in kidney function remains
unknown, previous study demonstrated
• greater decrease in serum uric acid level with artorvastatin than with
rosuvastatin treatment
• Increased endothelial function and renal blood flow on atorvastatin

Han E, et al. Endocrinol Metab 2017;32:274-280

Lipid Management Recommendation

O’Gara et al. 2013 ACCF/AHA STEMI Guideline. JACC Vol.61.No.4.2013:e78-140

O’Gara et al. 2013 ACCF/AHA STEMI Guideline. JACC Vol.61.No.4.2013:e78-140
Lipid Management Recommendation
•Treatment with statins in
patients with stabilized after
ACS (include STEMI) lower
the risk of CHD, death,
recurrent MI, stroke, and
coronary revascularization
•Only High-Dose Atorvastatin
has been shown to reduce
death and ischemic events
amongst patients with ACS
•Statin therapy after ACS is
beneficial even in patients
with baseline LDL<70 mg/dL
O’Gara et al. 2013 ACCF/AHA STEMI
Guideline. JACC Vol.61.No.4.2013:e78-140
PROVE-IT TIMI 22: Atorvastatin for reduction of
CV risk in patients with ACS
Study design highlights
Patient population: Double-blind period

 Enrolled at 349 sites in

eight countries Atorvastatin 80 mg/d
 Men and women, 4162
aged ≥18 years patients
 Hospitalized for an ACS in the
preceding 10 days Pravastatin 40 mg/d
 Total-C ≤240 mg/dL or total-C
≤200 mg/dL if receiving lipid- Mean 2-year follow-up
lowering therapy (925 primary events)

Primary endpoint:
 Time to the first occurrence of a
major CV event

Cannon CP, et al. N Engl J Med 2004;350:1495–1504

 PROVE-IT: Atorvastatin reduces CV risk in
patients
with ACS
 PROVE-IT: atorvastatin 80 mg reduced the risk of death or a major CV event by 16%
(p=0.005) compared with pravastatin 40 mg in patients with ACS

Incidence of death or major CV events*

30
16%
Death or major CV event (%)

25 RRR
95% CI,
20 5 to 26%
(p=0.005)
ARR 3.9%
15 NNT 26
over 2 years
10
Pravastatin 40 mg (n=2063). Median LDL-C 95 mg/dL
5 Atorvastatin 80 mg (n=2099). Median LDL-C 62 mg/dL

0
0 0.5 1.0 1.5 2.0 2.5
Time (years) Cannon CP, et al. N Engl J Med 2004;350:1495–1504
*Major CV events: MI, unstable From New England Journal of Medicine, Cannon CP, et al. Intensive versus
angina requiring hospitalization, Moderate Lipid Lowering with Statins after Acute Coronary Syndromes, 350, 1495–1504.
revascularization, and stroke Copyright ©(2004) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society
PROVE-IT: Benefit of atorvastatin over pravastatin
was evident at 30 days
• 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

5
ARR 1.2% NNT=83 over 30 days
28%
Death, MI, or rehospitalization

4 RRR
for ACS (%)

HR 0.72
3 95% CI,
0.52 to 0.99
(p=0.046)
2

1 Pravastatin 40 mg (n=2063). Mean LDL-C at 30 days=88 mg/dL

Atorvastatin 80 mg (n=2099). Mean LDL-C at 30 days=60 mg/dL

0
0 5 10 15 20 25 30
Time (days following randomization)
Ray K, et al. JACC 2005;46:1405–1410
Reprinted from Journal of the American College of Cardiology, Volume 46, Ray K, et al. Early and Late Benefits of High-Dose Atorvastatin
in Patients With Acute Coronary Syndromes, 1405–1410. Copyright (2005), with permission from Elsevier
 580 pts excluded for:
- 451 statin therapy
ARMYDA-ACS trial: Study design
- 41 emergency angiography
- 43 LVEF <30%
- 30 contraindications to statins 20 pts excluded for indication to:
- 15 severe renal failure - medical therapy (N=8)
- bypass surgery (N=12)

30 days
Atorvastatin 80 mg
12 hrs pre-angio;
further 40 mg
Randomization (N=191)

PCI
2 hrs before
atorvastatin
N=96 N=86
771 pts with atorvast Primary
NSTE-ACS Coronary combined
sent to angiography end point:
early coronary PCI
Placebo placebo 30-day
angiography 12 hrs pre-angio; N=85 death, MI, T
(<48 hours) further VR
Jan ’05 - Dec ‘06 dose 2 hrs
before
N=95
1st blood sample 2nd and 3rd
blood samples
(pre-PCI)
(8 and 24 hrs
Primary end point:
Incidence of major adverse cardiac events post-PCI)
(MACE: death, MI, TVR) from the
procedure up to 30 days
CK-MB, troponin-I, myoglobin, CRP
 ARMYDA-ACS trial
Composite primary end-point (30-day death, MI, TVR)

88% Risk Reduction of MACE

% 20 17

15 P=0.01

Atorvastatin
10
Placebo

5 5

MACE = Major Acute Cardiovascular Events 38

 ARMYDA-ACS
Individual and Combined Outcome Measures
of the Primary End Point at 30 days
21
14/85
% 18 13/85 (17%)
(15%)
15 P=0.01
P=0.04
12
9
4/86 4/86
6 (5%) (5%)
1/85
3 (2%)

0
Death MI TVR MACE
Composite
Primary End Point
Atorvastatin Placebo
39
 REVERSAL
Study Design

Patient Population: Double-Blind Period

• Men and women with a
history of CHD Atorvastatin 80 mg/day
• Angiographic criteria: 654
•≥20% reduction in lumen patients
diameter in ≥1 coronary
artery lesion Pravastatin 40 mg/day
•≤50% reduction in lumen 18-Month Follow-up with IVUS
diameter of the left main
(BART at 3 months)
coronary artery
•≥1 coronary artery with
≤50% stenosis Primary End Point:
• Percent change in total plaque volume

Nissen SE et al. JAMA. 2004;291:1071-1080.

 REVERSAL Trial
Change in atheroma Change in percent
volume obstruction volume
p=0.02 for change between atorvastatin p=0.0002 for change between atorvastatin vs
4 vs pravastatin 2 pravastatin

1.6
3 2.7
2

2
1
1

1
0 0.2
-0.4
-1 0
Atorvastatin Pravastatin Atorvastatin Pravastatin

AHA 2003, Orlando, FL

 REVERSAL Trial
Percent Reduction in CRP
p<0.001

-5%
-5.2%

-15%

-25%

-35%
-36.4%

-45%
Atorvastatin Pravastatin
CRP (mg/L)
Pravastatin Atorvastatin
Baseline 3.0 2.8
18 Months 2.9 1.8 AHA 2003, Orlando, FL
 Result in Plaque Regression

REVERSAL STUDY
Atorvastatin reduce atheroma
volume and increase lumen area
(from 7.7 mm2 to 9.8 mm2)

Ref: Nissen SE, et.al. JAMA 2004; 291

In REVERSAL, atorvastatin 80 mg slowed progression

of atherosclerosis at 18 months

Ref: Nissen S et al. JAMA 2006; 295

 REVERSAL vs ASTEROID
Differentiation REVERSAL ASTEROID

Patient
Characteristic
• Baseline LDL-C 150.2 mg/dL 130.4 mg/dL
• History of DM 20% 13.2%

Drug Pravastatin Single arm no

Comparison 40mg comparator
 Result in Plaque Regression

REVERSAL STUDY
Atorvastatin 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
Ref: Nissen SE, et.al. JAMA 2004; 291

ASTEROID STUDY
Rosuvastatin reduce atheroma
volume BUT ALSO reduce lumen
area
(from 6.19 mm2 to 5.96 mm2)
Ref: Nissen S et al. JAMA 2006; 295
 ESTABLISH: Study Design (Japan
Population)

Atorvastatin 20 mg
Screening visit* 70 Patients Open label period
Usual care
(cholesterol absorption inhibitor initiated if
LDL-C > 150 mg/dL)

Patient Population Composite Primary End Point

ACS patients with significant To examine early aggressive

stenosis on initial coronary lipid lowering with atorvastatin
angiography and received PCI VS usual care in reducing in
plaque volume by stabilizing
vulnerable plaques
Okazaki S, et al. Circulation 2004; 110: 1061-1068.
*after PCI, IVUS performed
 ESTABLISH
IVUS Analysis: Atorvastatin

Before

After 6
months

Plaque volume 84.1 mm³ to 60.9 mm³

Lumen area 10.0 mm² to 10.5 mm²
Okazaki et al.Circulation. 2004;110:1061-1068.) Plaque area 8.6 mm² to 6.4 mm²
 ESTABLISH
IVUS Analysis: Control

Before

After 6
months

Plaque volume 94.88 mm³ to 99.4 mm³

Lumen area 6.2 mm² to 3.9 mm²
Plaque area 7.66 mm² to 9.0 mm²
Okazaki et al.Circulation. 2004;110:1061-1068.)
Early initiation and long-term continuation of LDL-C lowering
therapy with atorvastatin could be useful for reducing
plaque vulnerability in patients with CAD (1)

Hirayama et al. Circ J 2009; 73: 718 – 725

Early initiation and long-term continuation of LDL-C lowering
therapy with atorvastatin could be useful for reducing
plaque vulnerability in patients with CAD (2)

Standard yellow-color grading.

The plaques were graded on a
6-point scale:
0, not yellow at all;
1, pale yellow;
2, yellow;
3, deep yellow;
4, bright yellow;
5, ruptured plaque.

Hirayama et al. Circ J 2009; 73: 718 – 725

Early initiation and long-term continuation of LDL-C lowering
therapy with atorvastatin could be useful for reducing
plaque vulnerability in patients with CAD (3)

Changes in atheroma volume of

intravascular ultrasound (IVUS)
analysis segments.

Representative angioscopic & IVUS images of a yellow plaque and a 20-

mm IVUS analysis segment at the 3 time points (baseline, week 28 and
week 80) Hirayama et al. Circ J 2009; 73: 718 – 725
 Jangan lupa ibu nitip statin ya nak….

Terima Kasih
53
67 yo woman
BP 106/60 BMI: 20 kg/m2
History of HTN, No
diabetes, No smoking
USG carotid showed +/-
30% stenosis bilaterally
Lipid panel
TC 194 TG 38 HDL 78 LDL
108

54
35 yo
Non smoker, no diabetes
Exercise 4 days a week
Consume a heart-healthy
diet
Family history (+) father
had MI at 40
BP 130/80
Lipid panel : TC 225, TG
100, HDL 45, LDL 160
mg/dL
FBG 92 mfg/dL

55
30 yo
Untreated LDL 260, HDL
51, TG 102 mg/dL
Father died suddenly at
age 38, fathers brother
had MI at age 32, both
smokers
Social smokers
BP 110/60 BMI 21 kg/m2
Cardiovascular exam is
normal

56
45 yo
10 years history of type 2
DM
Non smoker
Family history of DM
BP 130/80
Lipid Panel
TC 203 TG 350 LDL 95 HDL
38 mg/dL
HbA1C 7.5%

57