Lunchsympo3 2. Ball B Lunch Sympo-prof. Idrus Alwi- Hopecardis_separating Facts From Myths.pdf

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 WOSCOPS

simvaprava-

CARE LIPID AF/TEXCAPS

pravapravalova-

HPS PROSPER ASCOT

simvapravaatorva-

CARDS TNT

atorvaatorva-

All drugs in class 20–50% Relative Risk Reduction In primary and secondary prevention In men and women 40–85 years of age In diabetics, 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 Events (% per annum) Statin/more

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

Trend test

Control/less

All trials combined <2 mmol/L 910 (4.1%) 1012 (4.6%) ≥2 to <2.5 mmol/L 1528 (3.6%) 1729 (4.2%) ≥2.5 to <3.0 mmol/L 1866 (3.3%) 2225 (4.0%) ≥3 to <3.5 mmol/L 2007 (3.2%) 2454 (4.0%) ≥3.5 mmol/L 4508 (3.0%) 5736 (3.9%) Total 10973 (3.2%) 13350 (4.0%)

0.78 (0.61–0.99) 0.77 (0.67–0.89) 0.77 (0.70 – 0.85) 21 =1.08 0.76 (0.70–0.82) (p=0.3) 0.80 (0.76–0.83) 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) Low intensity

Moderate intensity

Daily dose lowers LDL– C on average, by <30%

Daily dose lowers LDL– C on average, by approx 30% to <50%

High intensity Daily dose lowers LDL– C on average, by approx ≥50%

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

Simvastatin 10 mg Pravastatin 10–20 mg Lovastatin 20 mg Fluvastatin 20–40 mg Pitavastatin 1 mg

Atorvastatin 10 (20) mg Rosuvastatin (5) 10 mg Simvastatin 20–40 mg Pravastatin 40 (80) mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg bid Pitavastatin 2–4 mg

Atorvastatin (40)–80 mg Rosuvastatin 20 (40) mg

New ACC/AHA Guideline: Who to Treat Group 1

Group 2

Clinical ASCVD

LDL-C ≥190 mg/dL (~5 mmol/L)

CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin

Group 3

Group 4

Diabetes mellitus

ASCVD risk ≥7.5%

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

No diabetes + age of 40–75 years + 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

Trials: TNT-Atorva IDEAL-Atorva PROVE-IT-Atorva SPARCL-Atorva

Trials: CARDS-Atorva TNT*-Atorva HPS*-Simva

Clinical ASCVD CHD, stroke, and peripheral arterial disease, all of presumed atherosclerotic origin

Group 2 LDL-C ≥190 mg/dL (~5 mmol/L)

Group 3

Group 4

Diabetes mellitus

ASCVD risk ≥7.5%

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

No diabetes + age of 40–75 years + LDL-C 70–189 mg/dL (~1.8–5 mmol/L)

* Subgroup analysis

Trials: None

Trials: ASCOT LLA-Atorva HPS-Simva JUPITER-Rosuva

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?

11

• 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 12

13

14

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. 16

Are the use of statin associate with haemorrhagic stroke?

17

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) Heterogeneity

HR 0.90 (0.65-1.22) P=.15

0.05

*Statin vs usual care.

0.2

0.5

Favors statin

1.0

3.0

Favors control

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

10.0

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?

24

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 consecutively

9

60

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

Placebo n=1949

Atorvastatin 10mg n=6343

Atorvastatin Atorvastatin Atorvastatin 20mg 80mg 40mg n=242 n=2345 n=186

Myalgia

2%

3%

2%

3%

3%

Arthralgia

1%

2%

0%

3%

1%

Arthritis

1%

1%

2%

0%

<1%

<1%

<1%

0%

1%

<1%

0%

0%

0%

0%

0%

Joint disorder Myopathy*

* 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?

30

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 34

• 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

36

Statins & Dementia?

37

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):12131221

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 statininduced 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

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