11

Nama Nama :: Prof. Dr. dr H. Djanggan Sargowo SpPD,SpJP(K), FIHA, FACC, FCAPC, FESC, Prof. Dr. dr H. Djanggan Sargowo SpPD,SpJP(K), FIHA, FACC, FCAPC, FESC, FASCCFASCC

Tempat/Tgl lahirTempat/Tgl lahir :: Sragen, 21 September 1947Sragen, 21 September 1947

AlamatAlamat :: Wilis Indah E-10 Malang, Telp. 0341-552395 Wilis Indah E-10 Malang, Telp. 0341-552395Pendidikan :Pendidikan : 1.1. Lulus Dokter dari UGM, tahun 1974Lulus Dokter dari UGM, tahun 19742.2. Lulus Cardiologist dari Univ. Indonesia, tahun 1983Lulus Cardiologist dari Univ. Indonesia, tahun 19833.3. Lulus Internist dari Univ. Airlangga, tahun 1986Lulus Internist dari Univ. Airlangga, tahun 19864.4. Lulus Doktor, Univ. Airlangga, tahun 1996Lulus Doktor, Univ. Airlangga, tahun 19965.5. Advanced Cardiology Course, Univ. Hongkong, tahun 1984Advanced Cardiology Course, Univ. Hongkong, tahun 19846.6. Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 1996Senior Visiting Program, Institut Jantung Negara, Kualalumpur, 19967.7. Fellow American College of Cardiology (FACC), September 2006.Fellow American College of Cardiology (FACC), September 2006.8.8. Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 2007Fellow Collage Asia Pacific Society of Cardiology (FCAPC), Desember 20079.9. Fellow European Sociaty of Cardiology (FESC), 2008Fellow European Sociaty of Cardiology (FESC), 200810.10. Fellow Asean Collage of Cardiology (FASCC), 2008Fellow Asean Collage of Cardiology (FASCC), 2008

Jabatan :Jabatan :1.1. Direktur Program Pascasarjana Universitas BrawijayaDirektur Program Pascasarjana Universitas Brawijaya2.2. Ketua MKEK Ikatan Dokter Indonesia Cabang Malang RayaKetua MKEK Ikatan Dokter Indonesia Cabang Malang Raya3.3. Ketua PERKI Cabang Malang RayaKetua PERKI Cabang Malang Raya4.4. Anggota Kolegium Kardiovaskuler IndonesiaAnggota Kolegium Kardiovaskuler Indonesia

Curriculum VitaeCurriculum Vitae

22

NEW APPROACH FOR CV RISK NEW APPROACH FOR CV RISK MANAGEMENTMANAGEMENT

Djanggan SargowoDjanggan Sargowo

Hotel Tugu Malang, 21 Maret 2009Hotel Tugu Malang, 21 Maret 2009

33

CLINICAL BENEFITCLINICAL BENEFIT

PATHOPHYSIOLOGYPATHOPHYSIOLOGY

EPIDEMIOLOGYEPIDEMIOLOGY

44

CVD RISK FACTORSCVD RISK FACTORSHYPERTENSION*HYPERTENSION* Cigarette smokingCigarette smoking Obesity* (BMI Obesity* (BMI >>30 kg/m30 kg/m22)) Physical inactivityPhysical inactivity Dyslipidemia*Dyslipidemia* Diabetes mellitus*Diabetes mellitus* Microalbuminuria or estimated GFR <60 Microalbuminuria or estimated GFR <60

ml/minml/min Age (older than 55 for men, 65 for women)Age (older than 55 for men, 65 for women) Family history of premature CVD Family history of premature CVD (men under age 55 or women under age 65)(men under age 55 or women under age 65)

*Components of the metabolic syndrome.

55

EVOLUTION IN EVOLUTION IN UNDERSTANDING CVDUNDERSTANDING CVD

66

ATHEROTHROMBOSIS SIGNIFICANTLY ATHEROTHROMBOSIS SIGNIFICANTLY SHORTENS LIFESHORTENS LIFE

ATHEROTHROMBOSIS REDUCES LIFE EXPECTANCY BY APPROXIMATELY 8–12 YEARS IN PATIENTS AGED OVER 60 YEARS1

HealthyHealthyHistory of History of

cardiovascular cardiovascular diseasedisease

History History of AMIof AMI

History History of strokeof stroke

Average remaining life expectancy at age 60 (men)

02

46

8

10

12

14

16

1820

YE

AR

S -9.2 -9.2 yearsyears

-7.4 -7.4 yearsyears

-12 -12 yearsyears

Analysis of data from the Framingham Heart Study1. Peeters et al. Eur Heart J 2002; 23: 458– 466

77

CURRENT GUIDELINES RECOGNIZE CURRENT GUIDELINES RECOGNIZE IMPORTANCE OF TOTAL CV RISK IMPORTANCE OF TOTAL CV RISK

MANAGEMENTMANAGEMENTHypertensionHypertension ESH/ESC (2003)ESH/ESC (2003)

WHO/ISH (2003)WHO/ISH (2003)

JNC 7 (2003)JNC 7 (2003)

BHS IV (2005)BHS IV (2005)

CHEP (2006)CHEP (2006)

CV PreventionCV Prevention European Joint European Joint

Task Force (2003)Task Force (2003)

JBS 2 (2005)JBS 2 (2005)

Hypertension guidelines support the recognition of risk factors beyond Hypertension guidelines support the recognition of risk factors beyond hypertension in developing an appropriate treatment strategy for patients with hypertension in developing an appropriate treatment strategy for patients with

hypertensionhypertension

Hypertension guidelines support the recognition of risk factors beyond Hypertension guidelines support the recognition of risk factors beyond hypertension in developing an appropriate treatment strategy for patients with hypertension in developing an appropriate treatment strategy for patients with

hypertensionhypertension

De Backer G et al. De Backer G et al. Eur Heart JEur Heart J. 2003;24:1601-1610. World Health Organization.. 2003;24:1601-1610. World Health Organization. J Hypertens J Hypertens. 2003;21:1983-1992. Williams B et al. . 2003;21:1983-1992. Williams B et al. Hum Hum HypertensHypertens. 2004;18:139-185. 2003 European Society of Hypertension. . 2004;18:139-185. 2003 European Society of Hypertension. J Hypertens.J Hypertens. 2003;21:1011-1053. Grundy SM et al. 2003;21:1011-1053. Grundy SM et al. Circulation.Circulation. 2004;110: 227-239. Chobanian AV et al. 2004;110: 227-239. Chobanian AV et al. Hypertens.Hypertens. 2003;42:1206-1252. CHEP Recommendations for the management of Hypertension 2003;42:1206-1252. CHEP Recommendations for the management of Hypertension 2005. Available at www.hypertension.ca/recommendations_2005/ultrashortexecsummary2005.pdf. Accessed April 10, 2006. Joint British 2005. Available at www.hypertension.ca/recommendations_2005/ultrashortexecsummary2005.pdf. Accessed April 10, 2006. Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Available at: heart.bmjjournals.com. Accessed 14 March Societies’ guidelines on prevention of cardiovascular disease in clinical practice. Available at: heart.bmjjournals.com. Accessed 14 March 2006.2006.

88

ESH-ESC HYPERTENSION ESH-ESC HYPERTENSION GUIDELINESGUIDELINES

99

NoNo YesYes

1010

MULTIPLE CV RISK MANAGEMENT MULTIPLE CV RISK MANAGEMENT RESULTS RESULTS

IN DRAMATIC REDUCTIONS IN CVDIN DRAMATIC REDUCTIONS IN CVD10% 10%

ReductionReductionin BPin BP

10% Reduction

in TC+45% 45%

ReductionReductionin CVDin CVD

=

““Attention should be moved from knowing one’s BP and Attention should be moved from knowing one’s BP and cholesterol concentrations to knowing one’s absolute CV cholesterol concentrations to knowing one’s absolute CV risk and its determinants.”risk and its determinants.”

– J. Emberson et al– J. Emberson et aland Jackson et aland Jackson et al

Emberson J et al. Emberson J et al. Eur Heart J.Eur Heart J. 2004;25:484-491. Jackson R et al. 2004;25:484-491. Jackson R et al. Lancet. Lancet. 2005;365:434-441.2005;365:434-441.

1111Adapted from Pepine CJ. Am J Cardiol. 2001;88(suppl):5K-9K.

DEVELOPMENT AND PROGRESSION DEVELOPMENT AND PROGRESSION OF CVDOF CVD

Risk factorsRisk factorsRisk factorsRisk factors

Oxidative stressOxidative stress Oxidative stressOxidative stress

Functional alterationsFunctional alterationsFunctional alterationsFunctional alterations

Structural alterationsStructural alterationsStructural alterationsStructural alterations

Clinical sequelaeClinical sequelaeClinical sequelaeClinical sequelae

Endothelial functionEndothelial function EPCs EPCs

Endothelial functionEndothelial function EPCs EPCs

EPCs = endothelial progenitor cells

Genetic factorsGenetic factorsGenetic factorsGenetic factors

Age, gender, smoking, Age, gender, smoking, inactivity, obesity,inactivity, obesity,

cholesterol, BP, glucosecholesterol, BP, glucose

Age, gender, smoking, Age, gender, smoking, inactivity, obesity,inactivity, obesity,

cholesterol, BP, glucosecholesterol, BP, glucose

1212

TARGETING ATHEROSCLEROSIS-AN TARGETING ATHEROSCLEROSIS-AN EVIDANCE UPDATEEVIDANCE UPDATE

SUPPORTING : GLOBAL RISK REDUCTIONSUPPORTING : GLOBAL RISK REDUCTION

IntroductionIntroductionEndovascular ScienseEndovascular ScienseClinical CaveatsClinical Caveats

Atorvastatin 80 mg-18 monthsAtorvastatin 80 mg-18 monthsREVERSALREVERSAL

1313

PATHOPHYSIOLOGY : ADDITIVE PATHOPHYSIOLOGY : ADDITIVE EFFECT OF CHOLESTEROL AND EFFECT OF CHOLESTEROL AND

BP ON CHD RISKBP ON CHD RISK

1414

SOFT END POINTSOFT END POINT(Better surrogate (Better surrogate

outcome)outcome)

Hard end pointHard end point(Better Clinical Outcome)(Better Clinical Outcome)

Clinical EvidencesClinical EvidencesClinical EvidencesClinical Evidences

1616

NORVASKNORVASK®® (AMLODIPINE BESYLATE) EXTENSIVELY (AMLODIPINE BESYLATE) EXTENSIVELY STUDIED IN LARGE TRIALSSTUDIED IN LARGE TRIALS

Patients studied

Comparators

Trial duration

End points: CHD death and nonfatal MI

End points: CHD death and nonfatal MI

End point: CV events and plaque progressionEnd point: CV events

and plaque progression

End point:cardiac morbidity

and mortality

ALLHAT

High-risk hypertensive

(N=33,357)

Amlodipinebesylate,lisinopril,

chlorthalidone

6 years

VALUE

High-risk hypertensive

(N=15,245)

Amlodipinebesylate,valsartan

6 years

CAMELOT/NORMALISE

CHD patients(n=1991)

Amlodipinebesylate,enalapril, placebo

2 years

ASCOT-BPLAModerate-risk hypertensive

(N=19,342)

Amlodipinebesylateperindopril,atenolol

thiazide

Trial stopped

early

ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997; Julius et al, for the VALUE trial group. Lancet. 2004;363:2022-2031; Sever et al, for the ASCOT Investigators. J Hypertens. 2001;19:1139-1147; Nissen et al, for the CAMELOT Investigators. JAMA. 2004;292:2217-2226.

1717

LIPITOR® (ATORVASTATIN CALCIUM) LIPITOR® (ATORVASTATIN CALCIUM) EXTENSIVELY STUDIED IN LARGE TRIALSEXTENSIVELY STUDIED IN LARGE TRIALS

Lipitor effectively reduces LDL-C Across a Broad Range of Patients

*80 mg is nota starting dose.RR=risk reduction.Nissen et al. JAMA. 2004;291:1071-1080; Cannon et al. N Engl J Med. 2004;350:1495-1504; LaRosa et al. N Engl J Med. 2005;352:1425-1435; Sever et al, for the ASCOT Investigators. Lancet. 2003;361:1149-1158; Colhoun et al. Lancet. 2004;364:685-696.

LDL-C level at randomisation

90mg/dL

10,305 patientswithout CHDin ASCOT-LLA

133mg/dL

2838 patientswith diabetes

in CARDS

77mg/dL

116mg/dL

Follow-upLDL-C level

10,001 patientswith CHD

in TNT

77mg/dL

<130mg/dL

654 patientswith CHD

in REVERSAL

79mg/dL

150mg/dL

4162 patientswith CHDin PROVE IT

62mg/dL

106mg/dL

10 mg10 mg 80 mg*80 mg*

• 36% RRRof nonfatal MIand fatal CHD• 27% RRR

of stroke

• 37% RRR of death and

major CV events• 48% RR

of stroke

Outcomes • 22% RR of major CV events

• 25% RR of stroke

Significantly impacted

atherosclerotic disease

progression; pravastatin

was associated with further

disease progression

• 16% RR ofmajor CV events

versuspravastatin

1818

HYPERTENSION INCREASES HYPERTENSION INCREASES ATHEROGENIC LIPOPROTEIN CONTENT ATHEROGENIC LIPOPROTEIN CONTENT

OF ARTERIAL VESSEL WALLSOF ARTERIAL VESSEL WALLS

Sposito AC. Eur Heart J Suppl. 2004;6(suppl G):G8-G12.

BP BPAtherogenicAtherogenic

VLDL, VLDL-R,VLDL, VLDL-R,IDL, LDLIDL, LDL

AtherogenicAtherogenicVLDL, VLDL-R,VLDL, VLDL-R,

IDL, LDLIDL, LDL

Intima- Enhanced – LP penetrationIntima- Enhanced – LP penetrationmedia media – LP retention – LP retentionIntima- Enhanced – LP penetrationIntima- Enhanced – LP penetrationmedia media – LP retention – LP retention

– Pressure-induced distension – Stretching – Pressure-induced distension – StretchingIntima-Intima-mediamedia

Pressure-drivenPressure-drivenconvectionconvection

LP = lipoprotein

1919Liao JK. Liao JK. Am J CardiolAm J Cardiol. 2005;96(suppl 1):24F-33F.. 2005;96(suppl 1):24F-33F.MMPs = matrix metalloproteinasesMMPs = matrix metalloproteinases

Platelet activationPlatelet activation

CoagulationCoagulation

Endothelial Endothelial progenitor cells progenitor cells

Effects on collagenEffects on collagen MMPsMMPs

ATAT11 receptor receptor VSMC proliferationVSMC proliferation

EndothelinEndothelin

MacrophagesMacrophages InflammationInflammation ImmunomodulationImmunomodulation

Endothelial functionEndothelial function

Reactive oxygen Reactive oxygen species species

NO bioactivityNO bioactivity

PLEIOTROPIC EFFECTS OF PLEIOTROPIC EFFECTS OF STATINSSTATINS

StatinsStatins

2020

PLEIOTROPIC EFFECTS OF BP-PLEIOTROPIC EFFECTS OF BP-LOWERING AGENTSLOWERING AGENTS

Lonn E et al. Lonn E et al. Eur Heart JEur Heart J Suppl.Suppl. 2003;5(suppl A):A43-A8. 2003;5(suppl A):A43-A8.Wassman S and Nickenig G. Wassman S and Nickenig G. Eur Heart J Suppl.Eur Heart J Suppl. 2004;6(suppl H):H3-H9. 2004;6(suppl H):H3-H9.

Mason RP et al. Mason RP et al. Arterioscler Thromb Vasc Biol.Arterioscler Thromb Vasc Biol. 2003;23:2155-63. 2003;23:2155-63.

ACEIs/ARBsACEIs/ARBs CCBsCCBs

FibrinolysisFibrinolysis

Platelet aggregationPlatelet aggregation

Mononuclear Mononuclear cell migration cell migration

Collagen matrix Collagen matrix formation formation

Endothelial functionEndothelial function

Oxidative stressOxidative stress InflammationInflammation

Plaque stabilityPlaque stability

Arterial Arterial compliancecompliance

NONO

MMP activityMMP activity

VSMC proliferationVSMC proliferation

Cholesterol Cholesterol depositiondepositionin membranein membrane

MMP = matrix metalloproteinaseMMP = matrix metalloproteinase

AHTNAHTNagentsagents

BothBoth

BP-BP-loweringloweringagentsagents

2121

APPROACHES TO CVD APPROACHES TO CVD PREVENTIONPREVENTION

Lipidmodification

Lifestyle intervention

BPlowering

Glucose lowering

OptimalOptimalCV riskCV risk

reductionreduction

2222

GEMINI: MORE THAN 55% OF GEMINI: MORE THAN 55% OF PATIENTS PATIENTS

ACHIEVED BOTH BP AND LDL-C ACHIEVED BOTH BP AND LDL-C GOALSGOALS

Patients(%)

0

10

30

50

70

90

LDL-C goal(NCEP ATP III)

BP goal(JNC VI)

Both LDL-Cand BP goals

82.1

65.557.7

Amlodipine/Atorvastatin Gemini Study N = 1220, 14 weeks with amlodipine/atorvastatin single-pill therapy

Expert Panel. NCEP ATP III. JAMA. 2001;285:2486-97.JNC VI. Arch Intern Med. 1997;157:2413-46.

Blank R et al. J Clin Hypertens. 2005;7:264-73.

2323

ASCOT STUDY DESIGNASCOT STUDY DESIGN

Sever PS, et al. Lancet. 2003;361:1149-1158.

19,257 hypertensive patients with ≥3 CV risk factors and no CHD

amlodipine-based regimenn=9639

atenolol regimenn=9618

ASCOT- ASCOT- BPLABPLA

10,305 hypertensive patients (≥3 CV risk factors and no CHD) with total cholesterol

≤6.5 mmol/L (251 mg/dL)

atorvastatin 10 mgn=5168

placebon=5137

ASCOT-LLAASCOT-LLA

amlodipine-based regimenn=2584

atenolol-based regimenn=2584

amlodipine-based regimenn=2554

atenolol-based regimenn=2583

ASCOT-LLA ASCOT-LLA 2x22x2

2424

PATIENT INCLUSION PATIENT INCLUSION CRITERIACRITERIA

Screening and baseline BP

160/100 mm Hg untreated

140/90 mm Hg following treatment with 1

or more drugs

Age 40-79 years

No previous MI or current clinical CHD

3 or more CV risk factors

2525

2626*These risk factors were used as inclusion criteria for the study.*These risk factors were used as inclusion criteria for the study.The ASCOT Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=56. Accessed: April 6, 2006. Data on file. Pfizer Inc, New York, NY.The ASCOT Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=56. Accessed: April 6, 2006. Data on file. Pfizer Inc, New York, NY.Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

10084

8162

510

2323

14

2626

33

0 20 40 60 80 100

HypertensionAge 55 years

MaleMicroalbuminuria/proteinuria

SmokerFamily history of early coronary disease

Type 2 diabetesCertain ECG abnormalitiesLeft ventricular hypertrophyPlasma TC/HDL-C ratio 6

Previous cerebrovascular eventsPeripheral vascular disease

Patients with Risk Factor (%)

ASCOT-LLA: PATIENT POPULATION ROUTINELY ASCOT-LLA: PATIENT POPULATION ROUTINELY SEEN IN CLINICAL PRACTICE SEEN IN CLINICAL PRACTICE

(HYPERTENSION PLUS (HYPERTENSION PLUS 3 RISK FACTORS FOR 3 RISK FACTORS FOR CHD*)CHD*)

Two of the most common additional risk factors were male sex and Two of the most common additional risk factors were male sex and age age ≥55 years≥55 yearsrepresentative of patients frequently seen in practicerepresentative of patients frequently seen in practiceTwo of the most common additional risk factors were male sex and Two of the most common additional risk factors were male sex and age age ≥55 years≥55 yearsrepresentative of patients frequently seen in practicerepresentative of patients frequently seen in practice

2727

ASCOT-BPLA : AMLODIPINE-BASED ASCOT-BPLA : AMLODIPINE-BASED THERAPY WAS ASSOCIATED WITH THERAPY WAS ASSOCIATED WITH BETTER BP CONTROL COMPARED BETTER BP CONTROL COMPARED WITH ATENOLOL-BASED THERAPYWITH ATENOLOL-BASED THERAPY

SB

P (

mm

Hg

)

120120

140140

160160

180180

Years

0.50.5 11 1.51.5 22 2.52.5 33 3.53.5 44 4.54.5 55 5.55.5

Atenolol Atenolol bendroflumethiazide bendroflumethiazide

Amlodipine Amlodipine perindopril perindopril

137.7137.7

136.1136.1

Last Last visitvisit

Mean difference 2.7Mean difference 2.7PP<.0001<.0001

Dahlöf B et al for the ASCOT Investigators. Dahlöf B et al for the ASCOT Investigators. LancetLancet. 2005;366:895-906.. 2005;366:895-906.

00

2828

REDUCTIONS OBSERVED IN MOST REDUCTIONS OBSERVED IN MOST PRIMARY, SECONDARY, AND TERTIARY END PRIMARY, SECONDARY, AND TERTIARY END

POINTS IN ASCOT-BPLAPOINTS IN ASCOT-BPLA

Amlodipine perindopril better Atenolol bendroflumethiazide better0.50 0.70 1.00 1.45

Primary Nonfatal MI (incl silent) + fatal CHD

SecondaryNonfatal MI (exc. silent) + fatal CHDTotal coronary end pointTotal CV events and proceduresAll-cause mortalityCV mortalityFatal and nonfatal strokeFatal and nonfatal heart failure

Tertiary Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment

Post hoc Primary end point + coronary revasc procsCV death + MI + stroke

2.00

Unadjusted Hazard Ratio (95% CI)0.90 (0.79-1.02)

0.87 (0.76-1.00)0.87 (0.79-0.96)0.84 (0.78-0.90)0.89 (0.81-0.99)0.76 (0.65-0.90)0.77 (0.66-0.89)0.84 (0.66-1.05)

1.27 (0.80-2.00)0.68 (0.51-0.92)0.98 (0.81-1.19)0.65 (0.52-0.81)1.07 (0.62-1.85)0.70 (0.63-.078)0.85 (0.75-0.97)

0.86 (0.77-0.96)0.84 (0.76-0.92)

Dahlöf B et al for the ASCOT Investigators. Dahlöf B et al for the ASCOT Investigators. LancetLancet. 2005;366:895-906. . 2005;366:895-906. Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

130

140

150

160

170

0 1 2 3

Atorvastatin Placebo

0 1 2 3

LD

L-C

(m

g/d

L)

LD

L-C

(m

g/d

L)

SB

P (

mm

Hg

)S

BP

(m

m H

g)

ASCOT-LLA: SBP AND LDL-C ASCOT-LLA: SBP AND LDL-C CHANGESCHANGES

YearsYears

1.2 mmol/L 1.2 mmol/L (46 mg/dL)(46 mg/dL)

1.0 mmol/L1.0 mmol/L(38.7 mg/dL)(38.7 mg/dL)

150150

7575

125125

100100

00

Final mean BP: Atorvastatin 138/80 mm Hg Placebo 138/80 mm Hg

Adapted from Sever PS et al for the ASCOT Investigators. Adapted from Sever PS et al for the ASCOT Investigators. Lancet. Lancet. 2003;361:1149-1158. Available at 2003;361:1149-1158. Available at https://www.ascotstudy.org. Accessed April 12, 2006.https://www.ascotstudy.org. Accessed April 12, 2006.

Last Last visitvisit

ASCOT-LLA: SUMMARY OF ALL ASCOT-LLA: SUMMARY OF ALL END POINTSEND POINTS

Hazard Ratio0.64 (0.50-0.83)

0.79 (0.69-0.90)0.71 (0.59-0.86)0.62 (0.47-0.81)0.87 (0.71-1.06)0.90 (0.66-1.23)0.73 (0.56-0.96)1.13 (0.73-1.78)

0.82 (0.40-1.66)0.87 (0.49-1.57)0.59 (0.38-0.90)1.02 (0.66-1.57)1.15 (0.91-1.44)1.29 (0.76-2.19)

0.5 1.0 1.5Atorvastatin better Placebo better

Primary End PointsNonfatal MI (incl silent) + fatal CHD

Secondary End PointsTotal CV events and proceduresTotal coronary eventsNonfatal MI (excl silent) + fatal CHDAll-cause mortalityCV mortalityFatal and nonfatal strokeFatal and nonfatal heart failure

Tertiary End PointsSilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseDevelopment of diabetes mellitusDevelopment of renal impairment

Risk Ratio

Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158.Please see prescribing information at the end of this slide presentation.

ASCOT-BPLA AND -LLA COMBINED: ASCOT-BPLA AND -LLA COMBINED:

INSIGHT INTO OPTIMAL CVD INSIGHT INTO OPTIMAL CVD PREVENTION PREVENTION

End PointEnd Point

Amlodipine Amlodipine Perindopril + Perindopril +

StatinStatin

Atenolol Atenolol Thiazide + Thiazide + PlaceboPlacebo

Relative Relative Risk Risk

ReductionReduction

Fatal CHD and nonfatal MIFatal CHD and nonfatal MI 4.84.8 9.29.2 48%48%

Fatal and nonfatal strokeFatal and nonfatal stroke 4.64.6 8.28.2 44%44%

Rates/1000 Patient-YearsRates/1000 Patient-Years

The ASCOT Study Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=86#52. Accessed: June 30, 2006.

ASCOT-LLA 2X2 ANALYSISASCOT-LLA 2X2 ANALYSISLDL-C reduction BP reduction

LDL-C & BP reduction comparable between amlodipine base regimen vs atenolol base regimen

ASCOT-LLA 2X2 ANALYSIS: THE SPECIFIC ASCOT-LLA 2X2 ANALYSIS: THE SPECIFIC COMBINATION OF COMBINATION OF

AN AMLODIPINE-BASED REGIMEN AND AN AMLODIPINE-BASED REGIMEN AND ATORVASTATIN DELIVERED AN EVEN GREATER ATORVASTATIN DELIVERED AN EVEN GREATER

RELATIVE RISK REDUCTIONRELATIVE RISK REDUCTION

The most common adverse events seen in ASCOT were diarrhoea, dizziness, dyspepsia, dyspnoea, erectile dysfunction, fatigue, headache, muscle cramps, myalgia, nausea, pain in limb and peripheral oedema. Important Safety InformationCADUET® is indicated for prevention of cardiovascular events in hypertensive patients, with three concomitant cardiovascular risk factors, normal to mildly elevated cholesterol levels, without clinically evident coronary heart disease where combined use of amlodipine and a low dose of atorvastatin is considered appropriate, in accordance with current treatment guidelines.CADUET® is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases; in women who are pregnant or may become pregnant and/or nursing; in patients with hypersensitivity to any component of this medication. Patient should promptly report muscle pain, tenderness, or weakness to their physician.In clinical trials, the most common adverse events were dizziness, headache, abdominal pain/nausea (amlodipine-specific adverse events: palpitations, flushing, oedema/peripheral oedema, and fatigue; atorvastatin-specific events: insomnia, hypothesia, paresthesia, dyspepsia, diarrhoea, constipation, flatulence, pruritus, rash, arthralgia, myalgia, back pain, chest pain, asthenia, hepatic enzyme elevations, ALT, AST, CPK increased levels). Additional specific safety information from the local label should be inserted. Sever PS, et al. Eur Heart J. 2006;27:2982-2988.

16%

0

1

2

3

4

0 0.5 1 1.5 2 2.5 3 3.5

Atenolol-based regimen+ atorvastatin

Cu

mu

lativ

e in

cid

en

ce (

%)

Time (years)

Atenolol-based regimen+ placebo

HR=0.84 (0.60-1.17)P<0.30

0

1

2

3

4

0 0.5 1 1.5 2 2.5 3 3.5

53%

Amlodipine-based regimen+ atorvastatin

Cu

mu

lativ

e in

cid

en

ce (

%)

Time (years)

Amlodipine-based regimen+ placebo

HR=0.47 (0.32-0.69)P<0.001

NOT SIGNIFICANT

3434

ASCOT CONCLUSIONS ASCOT CONCLUSIONS Patient population common in clinical practice Patient population common in clinical practice

− Hypertensive patients with ≥3 additional CV risk factorsHypertensive patients with ≥3 additional CV risk factors− Low-to-moderate riskLow-to-moderate risk

ASCOT-BPLAASCOT-BPLA: Amlodipine-based treatment compared with atenolol-: Amlodipine-based treatment compared with atenolol-based treatment resulted inbased treatment resulted in− Significant benefits in all-cause mortalitySignificant benefits in all-cause mortality

ASCOT-LLA:ASCOT-LLA: Atorvastatin added to a hypertensive regimen results in Atorvastatin added to a hypertensive regimen results in significant reductions significant reductions − Nonfatal MI and fatal CHD (36% RRR)Nonfatal MI and fatal CHD (36% RRR)− Nonfatal MI (45% RRR)Nonfatal MI (45% RRR)− Stroke (27% RRR)Stroke (27% RRR)

ASCOT-BPLA and ASCOT-LLA combinedASCOT-BPLA and ASCOT-LLA combined: Significant reductions with : Significant reductions with amlodipine-based therapy + statin compared with atenolol-based therapy amlodipine-based therapy + statin compared with atenolol-based therapy + placebo+ placebo− Cummulative reduction in CV events (%53% RRR)Cummulative reduction in CV events (%53% RRR)− Nonfatal MI and fatal CHD (48% RRR)Nonfatal MI and fatal CHD (48% RRR)− Fatal and nonfatal stroke (44% RRR)Fatal and nonfatal stroke (44% RRR)

Lipid-lowering benefits seen in patients with normal to mildly elevated Lipid-lowering benefits seen in patients with normal to mildly elevated cholesterol levelscholesterol levels

Sever PS et al for the ASCOT Investigators. Sever PS et al for the ASCOT Investigators. Lancet.Lancet. 2003;361:1149-1158. Dahlöf et al, for the ASCOT Investigators. 2003;361:1149-1158. Dahlöf et al, for the ASCOT Investigators. Lancet. Lancet. 2005;366:895-906. Sever PS et al, for the ASCOT Investigators. 2005;366:895-906. Sever PS et al, for the ASCOT Investigators. J HypertensJ Hypertens. 2001;19:1139-1147. Data on file. Pfizer Inc, New . 2001;19:1139-1147. Data on file. Pfizer Inc, New York, NY. York, NY. The ASCOT Study Investigators. Available at: http://www.ascotstudy.org/get_doc.php?id=86#52. Accessed: June 30, 2006.

3535

WHAT ARE THE IMPLICATIONS WHAT ARE THE IMPLICATIONS FOR CLINICAL PRACTICE ?FOR CLINICAL PRACTICE ?

Assessment of overall CV risk critical to Assessment of overall CV risk critical to maximizing CV event reductionmaximizing CV event reduction

Hypertensive patients frequently seen in clinical Hypertensive patients frequently seen in clinical practice, emphasizing need for comprehensive practice, emphasizing need for comprehensive risk assessmentrisk assessment

Atorvastatin added to antihypertensive (especially Atorvastatin added to antihypertensive (especially Amlodipine) therapy results in significant benefits Amlodipine) therapy results in significant benefits in low to moderate and high-risk patient in low to moderate and high-risk patient populationspopulations

3636

ASCOT-BPLA demonstrated greater benefits of CCB ± ACEI vs -blocker ± diuretic in lowering BP and preventing CVD

Improved BP control with amlodipine ± perindopril may explain some, but not all, of the benefit

ASCOT-LLA extended benefit of lipid lowering to hypertensive patients

Survival curves separated almost immediately, with significant difference at 90 days

Dahlöf B et al. Lancet. 2005;366:895-906.Sever PS et al. Lancet. 2003;361:1149-58.

ASCOT supports use of newer BP drugs and statins, especially in patients with complicated hypertension

Treatment should depend on global assessment of risk, not on individual risk factors

ASCOT: CLINICAL IMPLICATIONSASCOT: CLINICAL IMPLICATIONS

3737

SUMMARY: OPTIMIZING SUMMARY: OPTIMIZING OUTCOMES IN PATIENTS WITH OUTCOMES IN PATIENTS WITH

MULTIPLE CVD RISKSMULTIPLE CVD RISKS

Improved clinical outcomeImproved clinical outcome

Multifactorial risk reductionMultifactorial risk reduction

Traditional Traditional risk factorsrisk factors

EmergingEmergingbiomarkersbiomarkers

ClinicalClinicaltrialstrials

CV RISK MANAGEMENT CV RISK MANAGEMENT PROBLEMPROBLEM

CV RISK MANAGEMENT CV RISK MANAGEMENT PROBLEMPROBLEM

3939

MOST HYPERTENSIVE PATIENTS NEED MULTIPLE MEDICATIONS FOR MOST HYPERTENSIVE PATIENTS NEED MULTIPLE MEDICATIONS FOR EFFECTIVE MANAGEMENT, YET ADHERENCE TO CONCOMITANT EFFECTIVE MANAGEMENT, YET ADHERENCE TO CONCOMITANT

ANTIHYPERTENSIVE AND LIPID-LOWERING THERAPY DECREASES AS ANTIHYPERTENSIVE AND LIPID-LOWERING THERAPY DECREASES AS NUMBER OF MEDICATIONS INCREASESNUMBER OF MEDICATIONS INCREASES

58.8%

48.6%

42.0%

32.7%

28.3%

24.5%

0 10 20 30 40 50 60 70

*Calculated for first year of concomitant therapy with antihypertensive and lipid-lowering drugs. Patients adherent if PDC *Calculated for first year of concomitant therapy with antihypertensive and lipid-lowering drugs. Patients adherent if PDC 80% for 80% for both classes. PDC=proportion of days covered by antihypertensive and lipid-lowering drugs.both classes. PDC=proportion of days covered by antihypertensive and lipid-lowering drugs.Benner JS et al. ACC 2006. Abstract.Benner JS et al. ACC 2006. Abstract.

No

. of

Ad

dit

ion

al M

edic

atio

ns

No

. of

Ad

dit

ion

al M

edic

atio

ns

Median PDC*Median PDC*

1100

99

88

22

11

00

Incremental pill burden had greatest effect on adherence Incremental pill burden had greatest effect on adherence in patients taking the fewest medicationsin patients taking the fewest medications

Incremental pill burden had greatest effect on adherence Incremental pill burden had greatest effect on adherence in patients taking the fewest medicationsin patients taking the fewest medications

4040

INCREASES IN OUT-OF-POCKET COSTS ARE INCREASES IN OUT-OF-POCKET COSTS ARE ASSOCIATED ASSOCIATED

WITH DECREASED ADHERENCE RATESWITH DECREASED ADHERENCE RATESDoubling copayments is associated with significant reductions in Doubling copayments is associated with significant reductions in

medication use across several widely prescribed therapeutic classesmedication use across several widely prescribed therapeutic classesDoubling copayments is associated with significant reductions in Doubling copayments is associated with significant reductions in

medication use across several widely prescribed therapeutic classesmedication use across several widely prescribed therapeutic classes

0 10 20 30 40 50

Antihistamines

NSAIDs

Antidiabetics

Antiasthmatics

Antiulcerants

Antihyperlipidaemics

Antihypertensives

Antidepressants

Reduction In Days Supplied When Copayments Double (%)Reduction In Days Supplied When Copayments Double (%)

NSAIDs=nonsteroidal anti-inflammatory drugs.NSAIDs=nonsteroidal anti-inflammatory drugs.Retrospective study of pharmacy claims data and health plan benefit data from 30 employers and 52 health Retrospective study of pharmacy claims data and health plan benefit data from 30 employers and 52 health plans, 1997-2000. N=528,969 members aged 18-64 years. plans, 1997-2000. N=528,969 members aged 18-64 years. Goldman DP et al. Goldman DP et al. JAMAJAMA. 2004;291:2344-2350. . 2004;291:2344-2350.

4141

MEDICATION ADHERENCE MEDICATION ADHERENCE DECLINES WHENDECLINES WHEN

A SECOND DRUG IS A SECOND DRUG IS PRESCRIBEDPRESCRIBED

Study description: retrospective claims analysis using data from managed care organizations (PharMetrics Integrated Outcomes Database). 5341 patients receiving AHT and LLT had their MPR (medication possession ratio) assessed at 2-month intervals to determine adherence.Schwartz JS, et al. J Am Coll Cardiol. 2003: 41: 526A.

Pa

tie

nts

wit

h M

PR

8

0 (

%)

AHT

LLT

Both80

70

60

50

40

30

20

10

Month 1-2 Month 3-4 Month 5-6 Month 7-8 Month 9-10

P=0.05 vs both

4242

MANY PATIENTS ARE NONADHERENT TO MANY PATIENTS ARE NONADHERENT TO AHT AND LLTAHT AND LLT

Study description: retrospective cohort study of 8406 patients from a managed care population. Synchronised start: LLT and AHT initiated within 90 days of each other. Adherence: PDC by a given drug class in each time interval. Index date: date when concomitant therapy (ie, second drug) was initiated.

Chapman RH, et al. Arch Intern Med. 2005.

Nonadherent (PDC <80%)

Adherent to LLT (PDC ≥80%) and nonadherent to AHT (PDC <80%)

Time since the index date (months)

Pat

ien

ts (

%)

100

90

80

70

60

50

40

30

20

10

03 6 9 12 15 18 21 24 27 30 33 36

36% of patients remained adherent to both AHT and LLT after 1 year

Adherent to AHT (PDC ≥80%) and nonadherent to LLT (PDC <80%)

Adherent to LLT and AHT (PDC ≥80%)

4343

+NorvaskNorvask®®

(amlodipine besylate)(amlodipine besylate)LipitorLipitor®®

(atorvastatin calcium)(atorvastatin calcium)

Potential Solution To Prevent CV Events Potential Solution To Prevent CV Events

Not Just Lowering BP but alsoNot Just Lowering BP but also

REDUCE Cardiovascular Risk REDUCE Cardiovascular Risk

4444

Stable plagueUnstable plaque

Inflammation

Repair

4545

UNSTABLE CORONARY ARTERY UNSTABLE CORONARY ARTERY DISEASE (II) DISEASE (II)

Thrombus forms and extends into the lumen

Adventitia

Thrombus

Lipid core

4646

Weissberg, 1999

Inflammation Repair

Stable plagueUnstable plaque

- STATINS- ACEI / AIIRA- CCB

4747

CARPE: CADUETCARPE: CADUET® (AMLODIPINE BESYLATE/ATORVASTATIN CALCIUM) ® (AMLODIPINE BESYLATE/ATORVASTATIN CALCIUM) THERAPY RESULTS IN MORE PATIENTS ACHIEVING ADHERENCE THERAPY RESULTS IN MORE PATIENTS ACHIEVING ADHERENCE

COMPARED TO CONCOMITANT CCB AND STATIN THERAPIESCOMPARED TO CONCOMITANT CCB AND STATIN THERAPIES

67.7%

49.9%40.4% 37.4%

46.9%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

CADUET Atorvastatin +Amlodipine

Amlodipine + OtherStatin

Other CCB +Atorvastatin

Other CCB + OtherStatin

All comparison cohorts significantly lower than CADUET, P <.0001

Unadjusted Proportion of Patients Achieving AdherenceUnadjusted Proportion of Patients Achieving Adherence

Per

cen

tag

e o

f P

atie

nts

wit

h P

DC

P

erce

nta

ge

of

Pat

ien

ts w

ith

PD

C ≥

80%

≥80%

CARPE Research Investigators. Presented at 2006 American Society of Hypertension, May 19, 2006. New York, NY.

4848

Are you hungry or

sleepy ????

Sciences

Are you hungry or

sleepy ????

Sciences

4949

CARPE STUDY: SINGLE-PILL CADUETCARPE STUDY: SINGLE-PILL CADUET® ® (AMLODIPINE BESYLATE/ATORVASTATIN (AMLODIPINE BESYLATE/ATORVASTATIN

CALCIUM) CALCIUM) IMPROVES ADHERENCE COMPARED TO IMPROVES ADHERENCE COMPARED TO 2-PILL COMBINATION THERAPIES2-PILL COMBINATION THERAPIES

0 0.5 1 1.5 2 2.5 3 3.5

CADUET vs Amlo + Atorva

CADUET vs Amlo + Other Statin

CADUET vs Other CCB + Atorva

CADUET vs Other CCB + Other Statin

CADUET is less likely to achieve adherence CADUET is more likely to achieve adherence

1.95 (1.80-2.13)**

2.05 (1.89-2.24)**

Multivariate Odds Ratios of Achieving PDC ≥80% (95% Confidence Interval)

3.10 (2.85-3.38)**

2.84 (2.61-3.10)**

**P<.0001

CARPE Research Investigators. Presented at 2006 American Society of Hypertension, May 19, 2006. New York, NY.

5050

IMPLICATIONS OF IMPLICATIONS OF CARPECARPE

In this insured population, In this insured population, CADUETCADUET®® ( (amlodipine amlodipine besylate/atorvastatin calcium) may bring besylate/atorvastatin calcium) may bring substantial substantial improvements to adherenceimprovements to adherence compared to existing single-agent combination compared to existing single-agent combination therapies in multiple risk-factor treatment settingstherapies in multiple risk-factor treatment settings

CADUET may result in a greater likelihood of CADUET may result in a greater likelihood of achieving adherence than Norvaskachieving adherence than Norvask®® + Lipitor + Lipitor®®

CADUET is particularly valuable for treating CADUET is particularly valuable for treating patients who need to follow simple drug regimenspatients who need to follow simple drug regimens

CARPE Research Investigators. Presented at 2006 American Society of Hypertension, May 19, 2006. New York, NY.Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

5151

IMPROVED OUTCOMES ACHIEVED IMPROVED OUTCOMES ACHIEVED IN CLINICAL IN CLINICAL

TRIALS WITH HIGHER ADHERENCETRIALS WITH HIGHER ADHERENCE

-32% -31%

-37%-37%

-46%

-37%

-50

-40

-30

-20

-10

0

Entire cohort 75%-100% adherent

CV DeathCV Death

Coronary Coronary Death or Death or

Nonfatal MINonfatal MIRevascularisation Revascularisation

ProceduresProcedures

The West of Scotland Coronary Prevention Study Group. The West of Scotland Coronary Prevention Study Group. Eur Heart JEur Heart J. 1997;18:1718-1724.. 1997;18:1718-1724.

Per

cen

t E

ven

t R

edu

ctio

nP

erce

nt

Eve

nt

Red

uct

ion

5252

IS POOR ADHERENCE AN IS POOR ADHERENCE AN ESSENTIAL CV RISK FACTOR?ESSENTIAL CV RISK FACTOR?

Increasing pill burden decreases adherenceIncreasing pill burden decreases adherence

In clinical trials, worse outcomes were attained when In clinical trials, worse outcomes were attained when adherence was loweradherence was lower

Patients need to adhere to their medications in order to Patients need to adhere to their medications in order to effectively treat their CV risk factorseffectively treat their CV risk factors− Improved adherence when starting 2 medications Improved adherence when starting 2 medications

concurrentlyconcurrently

− Combination therapy reduces pill burdenCombination therapy reduces pill burden

− Reduced pill burden improves adherenceReduced pill burden improves adherence

Nonadherence to medication increases CV riskNonadherence to medication increases CV risk

5353

““Adherence is ‘the sixth vital sign,’ as Adherence is ‘the sixth vital sign,’ as important as respiration, heart rate, important as respiration, heart rate, temperature, blood pressure, and temperature, blood pressure, and

pain.”pain.”

Take control with CADUET®.

—Dr. Edward C. Rosenow III, Mayo Clinic of Medicine

Important Safety InformationCADUET® is indicated for prevention of cardiovascular events in hypertensive patients, with three concomitant

cardiovascular risk factors, normal to mildly elevated cholesterol levels, without clinically evident coronary heart disease where combined use of amlodipine and a low dose of atorvastatin is considered appropriate, in accordance with current

treatment guidelines.CADUET® is contraindicated in patients with active liver disease or unexplained persistent elevations of serum

transaminases; in women who are pregnant or may become pregnant and/or nursing; in patients with hypersensitivity to any component of this medication. Patient should promptly report muscle pain, tenderness, or weakness to their physician.In clinical trials, the most common adverse events were dizziness, headache, abdominal pain/nausea (amlodipine-specific

adverse events: palpitations, flushing, oedema/peripheral oedema, and fatigue; atorvastatin-specific events: insomnia, hypothesia, paresthesia, dyspepsia, diarrhoea, constipation, flatulence, pruritus, rash, arthralgia, myalgia, back pain, chest pain, asthenia, hepatic enzyme elevations, ALT, AST, CPK increased levels). Additional specific safety information from

the local label should be inserted. Sever PS, et al. Eur Heart J. 2006;27:2982-2988.

CONCLUSIONCONCLUSIONCONCLUSIONCONCLUSION

5555

Optimal management of CV risk may involve the use of single-pill combination therapies to improve adherence

and to simultaneously target multiple risk factors

Optimal management of CV risk may involve the use of single-pill combination therapies to improve adherence

and to simultaneously target multiple risk factors

CVD: leading cause of death worldwide

CVD: leading cause of death worldwideHypertension is highly prevalentHypertension is highly prevalent

Most patients with hypertensionhave additional CV risk factors:

and are at increased risk of CVD and CV events

Most patients with hypertensionhave additional CV risk factors:

and are at increased risk of CVD and CV events

Single CV risk factor treatment has suboptimal

therapeutic benefit

Single CV risk factor treatment has suboptimal

therapeutic benefit

Caduet has Caduet has better surrogate and better surrogate and

clinical outcomeclinical outcome

5656

Thank YouThank You

Take control with CADUET®.