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Curriculum Vitae

• Name : Prof. DR. Dr. Idrus Alwi SpPD, K-KV, FACC, FESC,
FAPSIC, FINASIM, FACP.
• Current Position : President of Indonesian Society of
Internal Medicine

• Medical Student : Faculty of Medicine University of Indonesia 1986


• Internist : Faculty of Medicine University of Indonesia 1996
• Cardiovascular Consultant : The Indonesian Society of Internal Medicine ,
2001
• PhD : Faculty of Medicine University of Indonesia, 2006
• FACC : American College of Cardiology, 2006
• FESC : European Society of Cardiology, 2008
• FAPSIC : Asia Pacific Society of Interventional Cardiology, 2009
• FINASIM : Indonesian Society of Internal Medicine, 2009
• FACP : American Colleague of Physician, 2013
• Advanced Course in Cardiology, Melbourne 1997
• Advanced Course on Echocardiography and Others Non Invasive
Cardiology, Melbourne 1997.
• Stem cell NOGA course, Cincinnatti, Ohio, 2009
• ASAN Interventional Cardiology Course, Seoul, 2011
Separating Facts from Myths:
Safety Concern of High Intensity Statins

Prof. Idrus Alwi MD, PhD, FINASIM, FACP, FACC, FESC, FAPSIC

Division of Cardiology, Department of Internal Medicine,


Faculty of Medicine , University of Indonesia,
Jakarta , Indonesia
Statins Have Revolutionised CVD Risk
Management
4S simva-
All drugs in class
WOSCOPS prava-
CARE prava- 20–50%
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
Relation Between the Proportional Reduction in
MAJOR VASCULAR EVENTS and Mean Absolute
LDL-C Reduction in 14 Statin Trials

Cholesterol Treatment Trialist Collaborators, Lancet 2005;366:1267


Figure 4
Event Reduction Is Independent of Baseline LDL-C

RR (CI) per 1 mmol/L reduction in LDL-C Trend


Events (% per annum)
test
Statin/more Control/less

All trials combined


<2 mmol/L 910 (4.1%) 1012 (4.6%) 0.78 (0.61–0.99)
≥2 to <2.5 mmol/L 1528 (3.6%) 1729 (4.2%) 0.77 (0.67–0.89)
≥2.5 to <3.0 mmol/L 1866 (3.3%) 2225 (4.0%) 0.77 (0.70 – 0.85) 21 =1.08
≥3 to <3.5 mmol/L 2007 (3.2%) 2454 (4.0%) 0.76 (0.70–0.82) (p=0.3)
≥3.5 mmol/L 4508 (3.0%) 5736 (3.9%) 0.80 (0.76–0.83)
Total 10973 (3.2%) 13350 (4.0%) 0.78 (0.76–0.80)

99% or
95% CI
Statin/more Control/less

Cholesterol Treatment Trialists’ Collaboration, Lancet 2010;376:1670


Risk Reduction According to Baseline Risk

Cholesterol Treatment Trialists' (CTT) Collaborators, Lancet 2012


Definition of Statin Intensity (ACC/AHA 2013)
Daily dose Simvastatin 10 mg
lowers LDL– Pravastatin 10–20 mg
Low C on
Lovastatin 20 mg
intensity average, by
<30% Fluvastatin 20–40 mg
Pitavastatin 1 mg

Moderate Atorvastatin 10 (20) mg


Daily dose
intensity Rosuvastatin (5) 10 mg
lowers LDL–
C on Simvastatin 20–40 mg
average, by Pravastatin 40 (80) mg
approx 30% Lovastatin 40 mg
to <50% Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
High intensity Pitavastatin 2–4 mg
Daily dose
lowers LDL– Atorvastatin (40)–80 mg
C on Rosuvastatin 20 (40) mg
average, by
approx
≥50%

Stone NJ, et al. Circulation 2013; doi:10.1161/01.cir.0000437738.63853.7a/-/DC1


New ACC/AHA Guideline: Who to Treat

Group 1 Group 2

Clinical ASCVD LDL-C ≥190 mg/dL


CHD, stroke, and
(~5 mmol/L)
peripheral arterial
disease, all of presumed
atherosclerotic origin

Group 3 Group 4

Diabetes mellitus ASCVD risk ≥7.5%

+ age of 40–75 years No diabetes


+ LDL-C 70–189 mg/dL + age of 40–75 years
(~1.8–5 mmol/L) + LDL-C 70–189 mg/dL
(~1.8–5 mmol/L)

* Subgroup analysis
Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print
New ACC/AHA Guideline:
Which Statin Trials Support Which Groups?

Group 1 Group 2
Trials: Trials:
TNT-Atorva Clinical ASCVD LDL-C ≥190 mg/dL None
IDEAL-Atorva CHD, stroke, and
(~5 mmol/L)
PROVE-IT-Atorva peripheral arterial
disease, all of presumed
SPARCL-Atorva atherosclerotic origin

Group 3 Group 4
Trials: Trials:
CARDS-Atorva Diabetes mellitus ASCVD risk ≥7.5% ASCOT LLA-Atorva
TNT*-Atorva HPS-Simva
HPS*-Simva + age of 40–75 years No diabetes JUPITER-Rosuva
+ LDL-C 70–189 mg/dL + age of 40–75 years
(~1.8–5 mmol/L) + LDL-C 70–189 mg/dL
(~1.8–5 mmol/L)

* Subgroup analysis
Stone NJ, et al. J Am Coll Cardiol 2013 Nov 7. Epub ahead of print
Statin Issue and Safety

• Erectile Dysfunction
• Haemorrhagic Stroke
• Myopathy
• New Onset Diabetes
• Dementia
Are the use of statin can cause
erectile dysfunction?

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• 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

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13
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Statins (+/-) sildenafil may improve ED compared with placebo (+/- sildenafil)
Cui Y, J sex Med 2014;11:1367-1375
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.

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Are the use of statin associate
with haemorrhagic stroke?

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Role of lipids in Cerebrovascular
disease
• There are a strong association between
total and LDL cholesterol with ischemic
stroke risk, especially for atherosclerotic
subtype
• Conversely there is an increased risk of
intracerebral hemorrhage at the low end of
spectrum of total and LDL cholesterol level

Curr Treat Options Med 2016;18:27


LDL < 66 mg/dl
AHA/ASA 2008 Guideline
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.


Active statin therapy was not associated with significant increase in
Intra Cerebral Hemorrhage.
Stroke 2012;43:2149-2156
Statins and Intracerebral Hemorrhage

Curr Treat Options Med 2016;18:27


Are all the statin have the same
musculoskeletal adverse events?

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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

RHABDOMYOLYSIS
AERS/ mill Rx
20

15
P<0,01
10

5 P<0,001
P<0,001
0
Rosuvastatin Simvastatin Pravastatin Atorvastatin

Alseikh-Ali et al. Postmarketing Safety of Rosuvastatin; Circulation; May 23, 2005


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

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.
Statins & New onset diabetes?

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http://www.fda.gov/ForConsumers/
ConsumerUpdates/ucm293330.htm

new onset diabetes &


memory loss is class
effect of all Statins
Are statins really diabetogenic?

 Statin therapy significantly reduces CV events among


individuals with and without a history of diabetes.1,2
 Intensive statin therapy has been shown to further reduce
CV events1,3
 A recent meta-analysis demonstrated that statin therapy is
associated with an excess risk of developing diabetes4
 Findings from three large trials comparing intensive to
moderate dose statin therapy have suggested an excess
risk of incident diabetes among those on intensive
regimens5,6
1. Cholesterol Treatment Trialists’ (CTT) Collaboration, et al. Lancet 2010;376:1670-1681. 2. Kearney PM et al.
Lancet 2008;371:117-125. 3. Cannon CP et al. JACC 2006;48:438-445. 4. Sattar N et al. Lancet 2010;375:735-742. 5.
Search Collaborative Group. Lancet 2010;376:1658-1669. 6. Waters DD et al. JACC 2011;57:1535-1545.
New Onset Diabetes with Statin ?

• Statin therapy was associated with a 9% increased risk for incident diabetes, but
this does not show CAUSAL RELATIONSHIP
• This is retrospective data and did not consider number of Diabetes risk factors (such
as BMI, HbA1c, family history, lipid level, BP, etc) for both Statin & Placebo groups.
• Statins might be preferentially used in patients at higher risk of diabetes, thus NOD
might happen in those patients who already have risk factors of developing Diabetes,
not exclusively because of Statin usage itself
Statin use is associated with a modest increase in risk (~10 – 12%) for new onset
od T2DM, compared with placebo or usual care

Endocrinol Metab Clon N Am 2016;45(1):87-100


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• Intensive dosage of statin therapy seems to increase diabetes risk beyond that
of moderate dosage statin therapy
• Excess risk for diabetes with statin use is most clearly evident in those with major
risk factors for diabetes
• The CV benefits of statin therapy outweighth the potential risk for diabetes
development
Endocrinol Metab Clon N Am 2016;45(1):87-100
ADA GUIDELINES 2015

Diabetes Care 2015;38:Suppl 1


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Statins & Dementia?

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Is Statin cause Memory Loss?
Is Statin cause Memory Loss?

Wanamaker BL, Sweiger KJ, Blumenthal RS, et al. Clin Cardiol.2015;38(4):243-250


Swiger KJ, Manalac RJ,
Blumenthal RS, et al. Mayo
Clin
Proc.2013:88(11):1213-
1221
Swiger KJ, Manalac RJ, Blumenthal RS, et al. Mayo Clin Proc.2013:88(11):1213-1221
http://www.fda.gov/ForConsu
mers/ConsumerUpdates/uc
m293330.htm

Reports of Memory Loss


The reports about memory loss, forgetfulness and
confusion span all statin products and all age groups. Egan
says these experiences are rare but that those affected often report feeling
“fuzzy” or unfocused in their thinking.
In general, the symptoms were not serious and were reversible within a few
weeks after the patient stopped using the statin. Some people affected in this
way had been taking the medicine for a day; others had been taking it for years.
What should patients do if they fear that statin use could be
clouding their thinking? “Talk to your health care professional,”
Egan says. “Don’t stop taking the medication; the
consequences to your heart could be far greater.”
Sparks DL et al. Acta Neurol Scand 2006;1149 (suppl 185): 3-7
Alzheimer Disease Assessment Scale Cognitive data
from all evaluable individuals (n ¼ 63). Mean SE for screen and quarterly visits.

Sparks DL et al. Acta Neurol Scand 2006;1149 (suppl 185): 3-7


Summary
 Meta-analysis of statin trials suggests that CV benefits
outweigh the risk of NOD & memory loss
 While statin therapy is associated with a slightly increased
risk of development of diabetes, the risk is low in absolute
terms and also very low when compared with the statin-
induced reduction in coronary events in people with
diabetes
 On the basis of this evidence, the use of statins in patients
with moderate or high CV risk or with existing CVD should
not change
Thank You
For Your Kind Attention