Issues & Safety on

Statin Usage
Dr. Pradana Tedjasukmana, SpJP
 Statins Have Revolutionised CVD Risk
Management
4S simva-
All drugs in class
WOSCOPS prava-
20–50%
CARE prava-
Relative Risk Reduction
LIPID prava-
AF/TEXCAPS lova- In primary and
secondary prevention
HPS simva-
PROSPER prava- In men and women
ASCOT atorva- 40–85 years of age
CARDS atorva- In diabetics,
TNT atorva- hypertensives, smokers
Lower LDL-C is better
National Lipid Association's Statin Safety
Task Force Review of Statin Safety

NLA
NLAStatin
StatinSafety
SafetyTask
TaskForce
Force

Analysis of
Review of Review Analysis of Review of Analysis
real-life use of
of
Review of the
Review of the DrugReview of
Interaction Review
of Randomized Analysis
FDA AERSof Review
Statin NDAof real-life use of
statins from
Literature Drug Interaction of Randomized FDA AERS Statin NDA statins Care
from
Literature Literature Clinical Trials Database Submissions Managed
Literature Clinical Trials Database Submissions Managed
Databases Care
Databases

Independent Analysis by Subspecialist Panels

Independent Analysis by Subspecialist Panels
• Muscle Panel • Renal Panel
• Muscle Panel
• Liver Panel • Neurology Panel
• Liver Panel

Final Conclusions and Recommendations

Final Conclusions and Recommendations
• Evidence-based
• Evidence-based
• Practical Treatment Guidelines
• Practical Treatment Guidelines

Am J Cardiol 2006; 97 (8, Suppl 1):S1-S98

Statin Safety in Perspective

Number needed to harm for 1 year to:

Cause a GI Bleed1 Cause a Fatal GI Bleed1

Aspirin 248 2066

Cause Severe Myositis2 Cause Fatal Myositis

100,000 1,000,000
Statins

Derry S, Loke YK. 2000

1

Thompson PD, et al. 2003

2
How about the safety and
issues in longterm use?

Are All statin the same?

 Statin Issue and Safety

• Cancer
• Erectile Dysfunction
• Haemorrhagic Stroke
• Myopathy
• Renal function
Are the use of statin can increase the risk of
CANCER?

7
8
Dale KM et al. JAMA 2006;295:74-80
Cancer Incidence

9
Dale KM et al. JAMA 2006;295:74-80
Cancer Death

10
Conclusion

Statins have a neutral effect on cancer and cancer

death risk in randomized controlled trials. We found
that no type of cancer was affected by statin use and no
subtype of statin affected the risk of cancer.

11
 Are the use of statin can cause erectile
dysfunction?

12
• Based on study conducted by Saltzman Erin A et al
(published in journal urology 2004) shows that
Atorvastatin improve erectile function in men with
hypercholesterolemia
• Atorvastatin mechanism to improve ED
– Atorvastatin have the ability to lowering plasma cholesterol
by blocking oxidize-LDL
– Atorvastatin have antioxidant effect
– Increase Nitric Oxide

13
14
15
Conclusion

There is no clear evidence that statin will cause ED,

however ED may be caused by hypercholesterolemia
(atherosclerosis).

Some of the study proves that by using statin in patient

with hypercholesterolemia will improves their erectile
function.

16
 Are the use of statin associate with
haemorrhagic stroke?

17
Statin Therapy Is Not Associated With Increased
Risk for Hemorrhagic Stroke
A recent meta-analysis demonstrated that statin therapy does not increase
risk of hemorrhagic stroke vs control

Trials Odds Ratios (95% Cl)

HPS
GREACE*
MIRACL
KLIS*
LIPID
CARE
4S
AFCAPS
OVERALL (95% Cl) HR 0.90 (0.65-1.22)
Heterogeneity P=.15

0.05 0.2 0.5 1.0 3.0 10.0

*Statin vs usual care. Favors statin Favors control

Adapted with permission from Amarenco P et al. Stroke. 2004;35:2902-2909.

LDL < 66 mg/dl
AHA/ASA 2008 Guideline
 Are all the statin have the same
musculoskeletal adverse events?

21
Some Definitions…
Myalgia:
Muscle symptoms reported by the patient

Myopathy:
Muscle symptoms with CK elevation >10x ULN

Rhabdomyolysis:
Widespread muscle injury with CK >10x ULN
and accompanying organ (renal) damage.
Myoglobinuria/emia feature
• Myalgia, myopathy and, rarely,
rhabdomyolysis have been reported in
patients treated with all statins

• Some Statin have more incidence than

the others
 Statin Safety in General Dose

R H A B D O M Y O L Y S IS
A E R S / m ill R x
20

15
P < 0 ,0 1
10

5 P < 0 ,0 0 1
P < 0 ,0 0 1
0
R o s u va s t a t in S im va s t a t in P ra va s t a t in A t o rva s t a t in

A ls e ik h - A li e t a l. P o s tm a r k e tin g S a f e ty o f R o s u v a s ta tin ; C ir c u la tio n ; M a y 2 3 , 2 0 0 5

Treating to New Targets: Safety

Event atorva 10 mg (n=5006) atorva 80 mg (n=4995)

Drug-related AEs 289 497

Discontinued for AEs 265 360

Myalgia 234 241

AST or ALT >3x ULN

9 60
consecutively

CK >3x ULN consecutively 0 0

No significant differences in any events

LaRosa JC, et al. N Eng J Med. 2005;352

Atorvastatin Musculoskeletal Adverse Event
across dose range TIME TO BENEFIT
in Atorvastatin Trials

Atorvastatin Atorvastatin Atorvastatin Atorvastatin

Placebo
10mg 20mg 40mg 80mg
n=1949
n=6343 n=242 n=186 n=2345

Myalgia 2% 3% 2% 3% 3%
Arthralgia 1% 2% 0% 3% 1%
Arthritis 1% 1% 2% 0% <1%
Joint disorder <1% <1% 0% 1% <1%
Myopathy* 0% 0% 0% 0% 0%

* In post-marketing surveillance, rare cases of myopathy and rhabdomyolysis have been reported with atorvastatin
and other statins

Newman CB, Palmer G, Silbershatz H, et al. Safety Of Atorvastatin Derived From Analysis of 44 Completed Trials In 9416 Patients. Am J
Cardiol.2003;92:670-676.
26
 How is renal safety among statins?

27
 Statin Renal Safety in General Dose

P R O T E IN U R IA R E N A L F A IL U R E
A E R S / m ill R x A E R S / m ill R x
3 20
2 ,5
15
2
1 ,5 10
1 P < 0 ,0 0 1
5 P < 0 ,0 0 1
0 ,5 P < 0 ,0 0 1 P < 0 ,0 0 1
P < 0 ,0 0 1 P < 0 ,0 0 1
0 0
R o s u va s t a tin S im va s t a tin P ra va s ta tin A to rva s t a tin R o s u va s ta tin S im va s ta tin P ra va s ta tin A to rva s ta tin

A ls e ik h - A li e t a l. P o s t m a r k e t in g S a f e ty o f R o s u v a s t a t in ; C ir c u la t io n ; M a y 2 3 , 2 0 0 5 A ls e ik h -A li e t a l. P o s tm a r k e tin g S a f e ty o f R o s u v a s ta tin ; C ir c u la tio n ; M a y 2 3 , 2 0 0 5

NKF KDOQI Recommendation of statin
in CKD patient
TIME TO BENEFIT
in Atorvastatin Trials

29
TIME TO BENEFIT
in Atorvastatin Trials

30
PLANET 1 & PLANET 2 TIME TO BENEFIT
in Atorvastatin Trials

• Results were presented on June 27, 2010 at the

European Renal Association-European Dialysis and
Transplant Association in Munich, Germany and have
not yet been published
• Authors stated
– “sort of dismembers the class effect”
– “if you are considering putting such a patient on a statin,
you should not put them on rosuvastatin”
– “it certainly would point any practicing nephrologist toward
using atorvastatin”

31
 TIME TO BENEFIT

PLANET I: Prospective EvaLuation

in Atorvastatin Trials

of ProteinuriA and ReNal Function

in DiabETic Patients With
Progressive Renal Disease
“Atorvastatin clearly has the advantage over
rosuvastatin”

Dr De Zeeuw
PLANET I: Design
353 Patients
• Type 1 or 2 diabetes
• Mild hypercholesterolemia
• Fasting LDL-C ≥90 mg/dL
• Moderate proteinuria
• Receiving ACE inhibitor and/or
ARB treatment for >3 months
PRIMARY END POINT:
• Change in urinary/creatinine ratio
from baseline to Week 52
TIME TO BENEFIT
in Atorvastatin Trials
Rosuvastatin 10 mg
Rosuvastatin 20 mg Rosuvastatin 40 mg
Atorvastatin 40 mg Atorvastatin 80 mg
Weeks 0 4 52
Period 1 Period 2
KEY SECONDARY END POINTS:
• Assessment of relationship between renal
effects and lipid parameters from baseline
to Weeks 26 and 52
• Change in GFR from baseline to Weeks 26
and 52
33
PLANET 1: Change in eGFR TIME TO BENEFIT
in Atorvastatin Trials

Week 26 Week 52
0
Change in eGFR (mL/min)

P=0.04 P=0.01
-1
-2
-3 -2.73 RSV 10/10
-4 -3.7 RSV 20/40
-5 ATV 40/80

-6 -5.46

-7
-8 -7.29

34
PLANET I: Summary of renal adverse events (%)

Rosuvastatin Rosuvastatin Atorvastatin

10 mg/day 40 mg/day 80 mg/day
Adverse event (n = 116) (n = 123) (n = 110) p
Any renal 7.8 9.8 4.5 NS
adverse event

Acute renal failure 0.0 4.1 0.9 <0.05

Serum creatinine 0.0 4.9 0.0 <0.01

doubling

Serum creatinine 0.0 7.3 0.9 <0.01

doubling or acute
renal failure

de Zeeuw D. 2010European Renal Association-European Dialysis and

Transplant Association Congress; June 27, 2010; Munich, Germany.
 PLANET II: Prospective TIME TO BENEFIT
in Atorvastatin Trials

EvaLuation of ProteinuriA and

ReNal Function in Non-DiabETic
Patients With Progressive Renal
Disease
The results dismember the “class effect of
statins ……

Dr De Zeeuw
PLANET II: Design
237 Patients
• Mild hypercholesterolemia
• Fasting LDL-C ≥90 mg/dL
• Moderate proteinuria
• Receiving ACE inhibitor and/or
ARB treatment for >3 months
PRIMARY END POINT:
• Change in urinary/creatinine ratio
from baseline to 52 weeks
TIME TO BENEFIT
in Atorvastatin Trials
Rosuvastatin 10 mg
Rosuvastatin 20 mg Rosuvastatin 40 mg
Atorvastatin 40 mg Atorvastatin 80 mg
Weeks 0 4 52
Period 1 Period 2
KEY SECONDARY END POINTS:
• Assessment of relationship between
renal effects and lipid parameters
from baseline to 26 and 52 weeks
• Change in GFR from baseline to 26
and 52 weeks
37
PLANET 2: Change in eGFR TIME TO BENEFIT
in Atorvastatin Trials

Week 26 Week 52
1.39 †
Change in eGFR (mL/min)

-1.61
-1.74
†
†

-2.71
†
-3.41 -3.30

* * *P0.03, †P=NS vs
baseline

38
 Conclusion from the Articles TIME TO BENEFIT
in Atorvastatin Trials

In diabetic and nondiabetic patients with proteinuria, using

optimal therapy, including ACE inhibitors and ARBs:

• Atorvastatin 80 mg/day significantly reduced proteinuria by about 20%.

• Rosuvastatin 10 or 40 mg/day had no effect on proteinuria.

• Rosuvastatin 40 mg/day was associated with a significant decline in

eGFR of about 8 mL/min per 1.73 m2 per year.

• Atorvastatin 80 mg/day had no effect on eGFR.

• Atorvastatin 80 mg/day has a clear advantage over rosuvastatin

40 mg/day in terms of renal protection and renal damage.

39
Overall Conclusions

• Despite lowering LDL-C, not all statin have the

same safety profile
• Several issues such as cancer, ED, and
haemorrhagic Stroke shows that all statins did
not associate with the event.
• In contrary, musculoskeletal and renal safety
differs among statin group
• NKF KDOQI with PLANET I and II Study set the
new perspective on renal safety among statins.
THANK YOU