P H Y S I C I A N S ' A C A D E M Y ...

P H Y S I C I A N S ’ A C A D E M Y F O R C A R D I O V A S C U L A R E D U C A T I O N

Presentation topicPractical challenges in optimalCV risk management

Slide lecture prepared and held by:Peter Lansberg, MDAcademic Medical Centre,Amsterdam, The Netherlands

June 26 -27, 2010Ho Chi Minh City, Vietnam

Asian Cardiovascular Master Class

The lessons learned in the 90ies

• (Most) Statins are Safe!

• 25 – 30 % risk reduction

• Benefit extends to – Patients with CAD

• Stable disease

• ACS

– Patients with CVD

– Patients with diabetes and/or multiple risk factors

• Majority of patients not adequately treated!– More patients need to be treated

– Patients are not treated aggressively enough

CHD Reduction in Secondary Prevention Trials

Study Statin Placebo/Comparator

Achieved LDL-C, mg/dL (mmol/L)

CHD event rate

(% patients)

Achieved LDL-C, mg/dL (mmol/L)

CHD event rate

(% patients)

4S 122 (3.2) 19.4 190 (4.9) 28.0

LIPID 112 (2.9) 12.3 150 (3.9) 15.9

CARE 98 (2.5) 10.2 135 (3.5) 13.2

HPS 89 (2.3) 8.7 128 (3.3) 11.8

TNT 77 (2.0) 6.7 101 (2.6) 8.3

Adapted from Law et al bmj.com 2003;326:1423

0 -10 20 -30 -40 -50 -60

10mg

-5 -15 -25 -35 -45 -55

20mg

10mg

20mg

80 mg

10mg

20mg

40mg

80mg

10mg

20mg

40mg

rosuvastatin

atorvastatin

simvastatin

pravastatin

40mg

LDL-C Reduction across separate studies

40mg

Cholesterol Goal Attainment in the Real World: The REALITY Asia Study

Asia REALITY StudyCurrent status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia In Asian countries and region:the Return on ExpenditureAchieved for Lipid Therapyin Asia (REALITY-Asia) study

Hyo-Soo Kima, Yangfeng Wub, Shing-Jong Linc, Chaicharn Deerochanawongd, Robaayah Zambaharie, Liancheng Zhaof, Qiaoyi Zhangg and Peter Yanh aSeoul National University Hospital, Seoul, South KoreabPeking University School of Public Health, Beijing, ChinacTaipei Veterans General Hospital, Taipei, Taiwan dRajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand eNational Heart Institute, Kuala Lumpur, Malaysia fFu Wai Hospital, Beijing, ChinagOutcomes Research, Reimbursement & Health Technology Assessment, Merck & Co., Inc., Whitehouse Station, New Jersey, USA hGleneagles Medical Centre, Singapore

Cholesterol Goal Attainment in the Real World: The REALITY Asia Study

LDL-C Goal Attainment by Risk and Country

Adapted from: Return on Expenditure Achieved for Lipid Therapy in Asia - REALITY-Asia study

Target lipid levels

Can J Cardiol Vol 25 No 10 October 2009

Percentage of patients achieving total cholesterol target (< 5.0 mmol/L)

Br J Cardiol 2007;14:280-5

Switch cohort Control cohort

(n=1,257) (n=4,792)Patients achieving cholesterol target (%)

At baseline 60 74

One-year 65 72post-index

Time to Death or First Major Cardiovascular Event

Br J Cardiol 2007;14:280-5

Time to Discontinuation of Statin Therapy

Br J Cardiol 2007;14:280-5

12

Crystalline vs amorphous atorvastatin

Atorvastatin amorphousAtorvastatin crystalline

Readily degradesMore Stable

The National Lipid AssociationStatin Safety Task Force Report

Review of the Literature

Review of the Literature

Review of Drug Interaction

Literature

Review of Drug Interaction

Literature

Meta-analysis of Randomized,Clinical Trials

Meta-analysis of Randomized,Clinical Trials

Analysis of Managed Care

Databases

Analysis of Managed Care

Databases

Analysis of FDA AERS Database

Analysis of FDA AERS Database

Review of Data from NDA

Submissions

Review of Data from NDA

Submissions

NLA Statin Safety Task ForceJM McKenney, Chairman

NLA Statin Safety Task ForceJM McKenney, Chairman

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

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

Independent Analysis by Subspecialist Panels• Muscle Panel (PD Thompson et al.)• Liver Panel (DE Cohen et al.)

Independent Analysis by Subspecialist Panels• Muscle Panel (PD Thompson et al.)• Liver Panel (DE Cohen et al.)

• Renal Panel (BK Kasiske et al.)• Neurology Panel (LM Brass et al.)

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

Transaminases and Liver Disease

measuring aminotransferases at baseline cannot adequately identify those who have underlying liver

disease

There is no sound rationale why statins should not be used in patients with chronic liver disease who

otherwise need statin therapy

Use of Atorvastatin or Pravastatin in Patients with NASH

• 5 patients with NASH 20 mg Prava for 6 months1

Normalization of liver enzymes in all patients Some improvement in hepatic inflammation and steatosis (liver

biopsies) 7 patients with NASH 20 mg Atorvastatin 21 months (± 2

months)2

Well tolerated No increase in liver enzymes Significant improvement of hepatic histology in some

patietns

1. Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174: 193-196.

2. Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120:A544.

Use of Simvastatin in Patients with Hepatitis C

• 219 patients with HCV – 17 were identified as using statin – Men with a mean age of 58.9 years. – All were taking simvastatin– Mean dose of 23 (±18 mg) /day– Five patients had a LFT = 1.5 x ULN

• statins are not associated with significant liver enzyme elevations in patients with HCV infection

Kimberly Gibson, PharmDa, and Joseph P. Rindone, PharmDb. Experience With Statin Use in Patients With Chronic Hepatitis C Infection Am J Cardiol 2005;96:1278 –1279

Transaminases and Liver Disease

• Dallas Heart Study1

– 79% of patients with hepatic steatosis normal LFT

• Patients with documented NASH2

– 36% normal LFT but signs of liver cirrhosis

1. Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. HEPATOLOGY 2004;40:1387-13952. Mofrad P et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values

HEPATOLOGY 2003;37:1286-1292.

*ALT >3 x ULN on 2 successive occasions

Statin Tolerability and Safety– Liver Effects

• Elevations in liver transaminaselevels are infrequent but recognised complication of treatment with statins*

• Before statin therapy:– Liver function tests recommended

– Caution in patients who consume excessive quantities of alcohol and/or have a historyof liver disease

– Contraindicated in patients with active liver disease

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

Some Definitions…

Reported Cases of Serious Rhabdomyolysis for Statins: AERS

Category All Statins Atorva Fluva Lova Prava Rosuva Simva Vytorin Ezet

US Spontaneous Serious

Rhabdomyolysis1362 348 56 45 75 103 760 2 68

Total Prescriptions

(Millions)383.9 209.5 16.3 16.7 46.0 7.61 87.74 0.80 15.2

Reporting Rate (Per Million

Prescriptions)3.55 1.66 3.50 2.65 1.63 12.88 8.64 2.00 4.53

Total AE Reports 10842 3713 517 251 965 2562 3072 35 920

Proportion Reporting Rate 0.13 0.09 0.11 0.18 0.08 0.04 0.25 0.06 0.07

Davidson MH et al. Am J Cardiol. 2006;97:32C-43C

There were only 73 reported cases of

fatal rhabdomyolysis associated with

484,273,000 prescriptions of statins

in the USA

In Summary…The Risk is Small!

FDA Warning March 2010

• No Simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone.

• No simvastatin >10 mg with gemfibrozil, cyclosporine, or danazol

• No simvastatin >20 mg with amiodarone or verapamil

• No simvastatin >40 mg with diltiazem

• Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products.

• caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products

The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients

not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/day) of a niacin-containing product. It

is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.

Atorvastatin 2003 and 2006 Safety Meta-analyses*

Newman et al, 2003 Analysis of 44 studies N = 9416 (atorvastatin patients) 10 mg-80 mg and placebo

Newman et al, 2006 Analysis of 49 studies N = 14,236 (atorvastatin & placebo patients) 10 mg, 80 mg, and placebo

American Journal of Cardiology

Newman C et al. Am J Cardiol. 2003;92:670-676; Newman C et al. Am J Cardiol. 2006;97:61-67.

Increased Patient Exposure to Atorvastatin 80 mg in Clinical Trials

10001000

30003000

5000500049254925

Pat

ien

t-ye

ars

Newman C et al. Am J Cardiol. 2006;97:61-67.

1388

167

3910

1780

4681

1996 2001 2004

Atv 10 mg Atv 80 mg

>121 million patient-years of exposure to atorvastatin in the real world>121 million patient-years of exposure to atorvastatin in the real world

Musculoskeletal Adverse Events With the 80-mg Dose

Reported AE

2006 Safety Analysis

PROVE IT* IDEAL* TNT*

Atv 10(n=7258

)

Atv 80(n=4798

)

Prav 40(n=206

3)

Atv 80(n=209

9)

Simva 20

(n=4449)

Atv 80(n=443

9)

Atv 10(n=500

6)

Atv 80(n=499

5)

Myalgia 2.9% 2.7% NR NR 1.1% 2.2% 4.7% 4.8%

Myopathy 0 0.02%† NR NR 0.25%† 0.14%† 0.06% 0.04%

Persistent CPK >10 x ULN

0 0.06% NR NR NR NR 0 0

Rhabdomyolysis

0 0 0 0 0.07% 0.05% 0.06% 0.04%NR, not reported

*Studies not included in 2006 safety meta-analysis†Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms)

NR, not reported

*Studies not included in 2006 safety meta-analysis†Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms)

Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al. JAMA. 2005;294:2437-2445.

Adverse and Serious Adverse Events in CARDS

No of events (% of patients with event)

122 (8.5%)Discontinued for AE

19 (1.1%)Associated SAE

13,238 (97%)Any adverse event

835 (29%)Serious AE

599 (23%)Associated AE

Atorvastatin 10mg

145 (10%)

20 (1.1%)

13,365 (98%)

920 (31%)

609 (25%)

PlaceboType of Event

Intensive vs Aggressive Lipid Lowering

• 190 NSTEMI patients randomized (PROBE)• Severe CAD – invasive intervention not possible• 12 monts follow up

– 146 pts Atorva 20 mg (up titrated ) <100 mg/dl • Average dosage 24.8 mg• LDL-c 94 mg/dl ± 5

– 144 pts Atorva 80 mg• LDL-C 62 mg/dl ± 5

• Event rate– Atorva 24.8 mg 39/146 (26.7%)– Atorva 80 mg 23/144 (16%)

HR: 0.56 (0.33-0.93) p=0.027

Colivicchi – ESC 2008

High Dose Statins after ACS

Lancet 2007;369:27

• Dept. of Cardiology Stoke on trent• September/October 2005

– Suspension of Atorvastatin due to costs• Audit patients with UA or MI

– December 2004 – February 2005• Atorvastatine 80 – 40 mg

– December 2005 – February 2006• Simvastatin 20 – 40 mg

Acute coronary syndrome event Cardiac readmissions Non cardiac readmissions Death

High Dose Statins after ACS

Rob Butler, James Wainwright . Lancet 2007;369:27

Incidence of Musculoskeletal Adverse Events Were Similar Across Dose Range

Atorvastatin

Pbo(n=1949

)

10 mg (n=634

3)20 mg

(n=242)40 mg

(n=186)80 mg(n=234

5)

Myalgia 2% 3% 2% 3% 3%

Myopathy 0 0 0 0 0

Persistent CPK >10 x ULN

0 0 0 0 1

Rhabdomyolysis 0 0 0 0 0

Data from 2003 safety meta-analysis involving 11,205 patients from 44 trials Data from 2003 safety meta-analysis involving 11,205 patients from 44 trials

Newman CB et al. Am J Cardiol. 2003;93:670-676.

Factors that Increase the Risk of Statin Induced Myopathy

Patient characteristics• Increasing age• Female gender• Renal insufficiency• Hepatic dysfunction• Hypothyroidism• Diet (i.e. grapefruit juice)

• Polypharmacy

Statin properties• High systemic exposure• Lipophilicity• High bioavailability• Limited protein binding• CYP 450 3A4 metabolism

Am J Cardiol 2006; 97 (8, Suppl 1):S1-88c

Number needed to treat for 1 year to:

Cause a GI Bleed1 Cause a Fatal GI Bleed1

Aspirin

Cause Severe Myositis2 Cause Fatal Myositis2

Statins

1Derry S, Loke YK. 20002Thompson PD, et al. 2003

Statin Safety in Perspective

248 2066

100,000 1,000,000