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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®.