A Prelude to the Polypill Concept for Vascular Disease Prevention Johnny K. Lokin, MD, FPNA Stroke...

A Prelude to the Polypill Concept for Vascular Disease

Prevention

A Prelude to the Polypill Concept for Vascular Disease

Prevention

Johnny K. Lokin, MD, FPNAStroke Services

Department of Neurology & Psychiatry

University of Santo Tomas Hospital

Johnny K. Lokin, MD, FPNAStroke Services

Department of Neurology & Psychiatry

University of Santo Tomas Hospital

OverviewOverview

• Prevalence and burden of stroke in Asia and worldwide

• Targets in stroke prevention with multiple interventions

• Patient Adherence

• Duo Pill

• Polypill Concept

• Conclusions

• Prevalence and burden of stroke in Asia and worldwide

• Targets in stroke prevention with multiple interventions

• Patient Adherence

• Duo Pill

• Polypill Concept

• Conclusions

Prevalence and burden of STROKE in Asia and

worldwide

Prevalence and burden of STROKE in Asia and

worldwide

BURDEN OF CARDIOVASCULAR DISEASE


Total Deaths 2005 58 million

Total Deaths 2005 58 million

Cardiovascular Disease

(Heart disease & Stroke)

17 M or 30 %

Cardiovascular Disease

(Heart disease & Stroke)

17 M or 30 %

Communicable dse, Nutritional def

30 %

Communicable dse, Nutritional def

30 %

Cancer 13 %

Cancer 13 %

Injuries 9 %

Injuries 9 %

Others 9 %

Others 9 %

Respiratory Dse - 9 %

Respiratory Dse - 9 %

DM - 2 %DM - 2 %

AFR AMR EUR SEAR WPR EMR WORLD

STROKE 307 454 1,480 1,070 1,926 218 5,455

Isch Heart Disease

333 967 2,433 1,972 964 523 7,181

HPN Heart Dse

54 131 175 138 285 91 874

ALL CVDS

985 1,979 5,042 3,797 3,7451,03

716,585



BURDEN OF STROKEBURDEN OF STROKE

• 15 million strokes worldwide every year

• Stroke is third leading cause of death in developed countries

– 5.5 million people die every year– 5 million people left disabled every year– Commonest cause of major disability in UK

• 60% of patients who suffer a stroke die or become dependent

• 15 million strokes worldwide every year

• Stroke is third leading cause of death in developed countries

– 5.5 million people die every year– 5 million people left disabled every year– Commonest cause of major disability in UK

• 60% of patients who suffer a stroke die or become dependent

WHO. The Atlas of Heart Disease and Stroke 2004.

Oxford Vascular Study• Population based study of 2,024 vascular

events in 91,106 people

• 918 (45%) cerebrovascular events– 618 strokes/ 300 TIAs

• 856 (42%) coronary vascular events– 159 STEMI / 316 NSTEMI

– 218 unstable angina / 163 sudden cardiac deaths

Oxford Vascular Study• Population based study of 2,024 vascular

events in 91,106 people

• 918 (45%) cerebrovascular events– 618 strokes/ 300 TIAs

• 856 (42%) coronary vascular events– 159 STEMI / 316 NSTEMI

– 218 unstable angina / 163 sudden cardiac deaths

Rothwell PM. Lancet 2005;366:1773-83


Middle Income55%

High Income13%

Low income32%

Middle Income55%

High Income13%

Low income32%

% of STROKE DEATHSWorld Bank income group

% of STROKE DEATHSWorld Bank income group

• 16 M first ever strokes• 62 M stroke survivors• 6 M deaths worldwide

• 16 M first ever strokes• 62 M stroke survivors• 6 M deaths worldwide

• Most of the stroke deaths (87%) occur in developing countries

• Most of the stroke deaths (87%) occur in developing countries

GLOBAL BURDEN OF STROKEGLOBAL BURDEN OF STROKE

0 20 40 60 80 100 120 140

Philippines

Thailand

Singapore

Malaysia

Cambodia

Indonesia

Vietnam

India

S Korea

Japan

China

No per 100,000 population

STROKE MORTALITY in ASIA, 2003 STROKE MORTALITY in ASIA, 2003

MacKay J and Mensah G. Atlas of Heart Disease and Stroke. 2004. Geneva. WHO.

• Incidence stable or dropping in developed countries– Halving of number of smokers & possibly better

control of hypertensionAuckland Regional Community Stroke Study. Stroke 2005

• But, overall incidence is increasing because of aging population

• Incidence stable or dropping in developed countries– Halving of number of smokers & possibly better

control of hypertensionAuckland Regional Community Stroke Study. Stroke 2005

• But, overall incidence is increasing because of aging population

WHO. The Atlas of Heart Disease and Stroke 2004.


Ischemic stroke makes up >80% of all strokesIschemic stroke makes up >80% of all strokes

Hemorrhagic strokeHemorrhagic stroke

88%

12%

ISCHEMIC vs HEMARRHAGIC STROKE

ISCHEMIC vs HEMARRHAGIC STROKE

American Heart Association Heart Disease and Stroke Statistics—2005 Update.

IncidenceIncidence

Ischemic strokeIschemic stroke

STROKE IN ASIASTROKE IN ASIA

• Intracerebral hemorrhage makes up 20–30% of all strokes in Asian populations– Chinese and Japanese studies in early 1980s

– Korean, Singaporean and Filipinos in late 1990’s and early 2K

• Intracerebral hemorrhage in 22% of Asians vs 11% Europeans in New Zealand

– Auckland Regional Community Stroke Study

• Intracerebral hemorrhage makes up 20–30% of all strokes in Asian populations– Chinese and Japanese studies in early 1980s

– Korean, Singaporean and Filipinos in late 1990’s and early 2K

• Intracerebral hemorrhage in 22% of Asians vs 11% Europeans in New Zealand

– Auckland Regional Community Stroke Study

Feigin V, et al. Lancet Neurology 2006;5:130-139

• More intracranial stenosis in Asian populations

– 40–50% TIA / stroke patients in China and Korea have intracranial stenosis (vs 8 to 11% North America)

– 7% of asymptomatic villagers in rural China

– 13% of people with hypertension, diabetes or hyperlipidemia in Hong Kong had middle cerebral artery stenosis

• More intracranial stenosis in Asian populations

– 40–50% TIA / stroke patients in China and Korea have intracranial stenosis (vs 8 to 11% North America)

– 7% of asymptomatic villagers in rural China

– 13% of people with hypertension, diabetes or hyperlipidemia in Hong Kong had middle cerebral artery stenosis

Wong KS, et al. Neurology 2007; 68:2031–2034; Wong KS, et al. Neurology 2007;68:2035-2038

STROKE IN ASIASTROKE IN ASIA

Philippines2003

%

By Questionnaire

1.3 and 1.9

By History 1.4

N = 4753 adults (> 20 yrs old),

17 Regions, 79 provincesAug to Dec 2003

Results : Stroke Prevalencein the Philippines

Results : Stroke Prevalencein the Philippines

Slide courtesy of A. Roxas, MDDans A. et al. Phil J Int Med; 43(3) : 103 -115

0

1

2

3

4

5

6

7

20-29 30-39 40-49 50-59 60-69 70>

1.3%1.3%

3.0%3.0%

6.4%6.4%

6.1%6.1%

Slide courtesy of A. Roxas, MD

Dans A. et al. Phil J Int Med; 43(3) : 103 -115

Results : Stroke Prevalencein the Philippines (by Age)Results : Stroke Prevalencein the Philippines (by Age)

TARGETS IN STROKE PREVENTIONTARGETS IN STROKE PREVENTION

STROKE RISK FACTORSSTROKE RISK FACTORS

80 % of premature heart disease, stroke

can be prevented

80 % of premature heart disease, stroke

can be prevented

Goldstein LB, et al. Stroke. 2001;32:280-299.

Unmodifiable risk factors

Unmodifiable risk factors

Modifiable risk factorsModifiable risk factors

Smoking Diet Sedentary lifestyle Alcohol/drug abuse Obesity CAD Atrial fibrillation Hypertension Diabetes Dyslipidemia

Smoking Diet Sedentary lifestyle Alcohol/drug abuse Obesity CAD Atrial fibrillation Hypertension Diabetes Dyslipidemia

Age

Male sex

Race

Family history of stroke/TIA

Prior stroke/TIA

Age

Male sex

Race

Family history of stroke/TIA

Prior stroke/TIA

CAD=coronary artery disease; TIA=transient ischemic attack; CHD=coronary heart disease

Managing the Patient at Risk – Multiple Risk Factors Require Multiple

Interventions

Managing the Patient at Risk – Multiple Risk Factors Require Multiple

Interventions

Multiple CV Risk Management Results in Dramatic Reductions in CVD

Multiple CV Risk Management Results in Dramatic Reductions in CVD

10% 10% ReductionReduction

in BPin BP

10% Reductio

nin TC

+45% 45%

ReductionReductionin CVDin CVD

=

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

– J. Emberson et aland Jackson et al

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

– J. Emberson 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.

Clinical Evidence Supports Comprehensive Treatment of Multiple CV

Risk Factors

Clinical Evidence Supports Comprehensive Treatment of Multiple CV

Risk Factors

• ASCOT: supports a new standard of care in patients with hypertension and additional CV risk factors– Low to moderate risk patients with normal to mildly

elevated cholesterol levels

• Other studies in patients with multiple CV risk factors – VALUE: patients at high risk with hypertension

• Approximately 46% were on statin therapy

– CARDS: patients with diabetes• 84% were hypertensive• 67% receiving antihypertensive treatment

• ASCOT: supports a new standard of care in patients with hypertension and additional CV risk factors– Low to moderate risk patients with normal to mildly

elevated cholesterol levels

• Other studies in patients with multiple CV risk factors – VALUE: patients at high risk with hypertension

• Approximately 46% were on statin therapy

– CARDS: patients with diabetes• 84% were hypertensive• 67% receiving antihypertensive treatment

ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial; CARDS=Collaborative AtoRvastatin Diabetes Study; VALUE=Valsartan Antihypertensive ASCOT=Anglo-Scandinavian Cardiac Outcomes Trial; CARDS=Collaborative AtoRvastatin Diabetes Study; VALUE=Valsartan Antihypertensive Long-term Use Evaluation.Long-term Use Evaluation.

Sever PS et al, for the ASCOT Investigators. Sever PS et al, for the ASCOT Investigators. Lancet. Lancet. 2003;361:1149-1158. Julius et al. 2003;361:1149-1158. Julius et al. LancetLancet. 2004;363:2022-2031. Colhoun et al. . 2004;363:2022-2031. Colhoun et al. LancetLancet. . 2004;364:685-696. 2004;364:685-696.

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

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

amlodipine-based regimenN=9639

amlodipine-based regimenN=9639

atenolol-based regimenN=9618

atenolol-based regimenN=9618

ASCOT- BPLA

ASCOT- BPLA

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

cholesterol ≤6.5 mmol/L (251 mg/dL)

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

atorvastatin 10 mgN=5168

placeboN=5137placeboN=5137

ASCOT-LLAASCOT-LLA

amlodipine-based regimen

N=2584


N=2584

atenolol-based regimen

N=2584


N=2584


N=2554


N=2554


N=2583


N=2583

ASCOT-LLA 2x2

ASCOT-LLA 2x2

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

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to

Moderate CV Risk

The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A Study in Hypertensive Patients at Low to

Moderate CV Risk

*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, 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.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.

100

8481

62

5

10

2323

14

26

2633

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 Seen in Clinical Practice

(Hypertension Plus 3 Risk Factors for CHD*)

ASCOT-LLA: Patient Population Routinely Seen in Clinical Practice

(Hypertension Plus 3 Risk Factors for 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 practice

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 practice

ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to BP

Treatment

ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke When Atorvastatin Added to BP

Treatment

Atorvastatin 10 mg (n=5168)

Placebo (n=5137)

Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158.

Years0.0 0.5 1.0 1.5 2.0 2.5 3.0 5.03.5

HR=0.73 (0.56-0.96)

Trial stopped Trial stopped early early PP=.0236=.0236

Pro

port

ion

of

Even

ts (

%)

Pro

port

ion

of

Even

ts (

%)

00

11

22

33

ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention

ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD Prevention

End Point

Amlodipine

Perindopril + Statin

Atenolol

Thiazide + Placebo

Relative Risk

Reduction

Fatal CHD and nonfatal MI

4.8 9.2 48%

Fatal and nonfatal stroke 4.6 8.2 44%

Rates/1000 Patient-Rates/1000 Patient-YearsYears

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

ASCOT-BPLA and -LLA Combined: Insight Into Optimal CVD PreventionASCOT-BPLA and -LLA Combined:

Insight Into Optimal CVD Prevention

ASCOT-LLA Secondary End Point: Fatal and Non-Fatal Stroke

ASCOT-LLA Secondary End Point: Fatal and Non-Fatal Stroke

ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD

ASCOT-LLA Primary End Point: Nonfatal MI and Fatal CHD

ASCOT-LLA demonstrates that adding Lipitor® (atorvastatin calcium) to an effective BP regiman results in impressive CV event reductions.

ASCOT-LLA demonstrates that adding Lipitor® (atorvastatin calcium) to an effective BP regiman results in impressive CV event reductions.

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

What Are the Implications for Clinical Practice?What Are the Implications for Clinical Practice?

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

• Hypertensive patients frequently seen in clinical practice, emphasising need for comprehensive risk assessment

• Atorvastatin added to antihypertensive therapy results in significant benefits in low to moderate and high-risk patient populations

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

• Hypertensive patients frequently seen in clinical practice, emphasising need for comprehensive risk assessment

• Atorvastatin added to antihypertensive therapy results in significant benefits in low to moderate and high-risk patient populations

Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

RISK FACTORS% Contribution to Stroke


0

20

40

60

80

HPN Choles BMI Smoking PhysicalInactivity

AlcoholDiet

* Computed from risk factor prevalence & hazard size

DevelopedCountries

DevelopingRegions

HPN Choles BMI SmokingDietPhysicalInactivity

Alcohol

Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362: 271 - 280

European Stroke InitiativeEuropean Stroke Initiative

• Discourage smoking• Regular physical

exercise• Reduce weight (if

high BMI) • Low-salt, low-fat

diet rich in fruits, vegetables, fiber

• Discourage heavy alcohol use

• Discourage smoking• Regular physical

exercise• Reduce weight (if

high BMI) • Low-salt, low-fat

diet rich in fruits, vegetables, fiber

• Discourage heavy alcohol use

• Reduce blood pressure to <140/90 <135/80 if diabetic

• Initiate cholesterol-lowering therapy for high-risk patients

• Encourage strict control of glucose levels if diabetic

• Reduce blood pressure to <140/90 <135/80 if diabetic

• Initiate cholesterol-lowering therapy for high-risk patients

• Encourage strict control of glucose levels if diabetic

European Stroke Initiative Executive Committee and EUSI Writing Committee. Cerebrovasc Dis 2003;16:311-337.

Antiplatelet Therapy after Stroke

Antiplatelet Therapy after Stroke

• Long-term antiplatelet therapy should be prescribed to all ischemic stroke or TIA patients who aren’t prescribed anti-coagulation therapy

Grade A, Level I evidence, Australian Stroke Guidelines 2007

• Low dose aspirin & dipyridamole

• Aspirin alone or clopidogrel alone if dipyridamole-intolerant

• Long-term antiplatelet therapy should be prescribed to all ischemic stroke or TIA patients who aren’t prescribed anti-coagulation therapy


• Low dose aspirin & dipyridamole

• Aspirin alone or clopidogrel alone if dipyridamole-intolerant

Amarenco, et al. Australian Stroke Guidelines 2007

Antihypertensive therapies significantly reduced risk of recurrent

stroke

Antihypertensive therapies significantly reduced risk of recurrent

stroke

Rashid P, et al. Stroke 2003;34:2741-2749.ACEI=Angiotensin-converting enzyme inhibitors. *P=.005. †P=.01. ‡P<.00001.

*

†

‡

–7–7

–45–45

–7–7

–32–32

–24–24

-50

-40

-30

-20

-10

0AllAll DiureticsDiuretics Beta-blockers Beta-blockers ACEIACEI ACEI + DiureticACEI + Diuretic

Rela

tive r

isk r

ed

ucti

on

(%

)R

ela

tive r

isk r

ed

ucti

on

(%

)

Blood pressure lowering after Stroke

Blood pressure lowering after Stroke

• Antihypertensive therapy should be started in all patients with stroke or TIA unless contraindicated


• In general aim for <140/90 mmHg; if diabetic, aim for <130/85 mmHg

• Most direct evidence for ACE inhibitor ( diuretic) Rashid et al. Stroke.2003;34:2741-8

• More recent evidence of benefit of angiotensin receptor blockers Schrader et al. Stroke 2005;36:1218

• Antihypertensive therapy should be started in all patients with stroke or TIA unless contraindicated


• In general aim for <140/90 mmHg; if diabetic, aim for <130/85 mmHg

• Most direct evidence for ACE inhibitor ( diuretic) Rashid et al. Stroke.2003;34:2741-8

• More recent evidence of benefit of angiotensin receptor blockers Schrader et al. Stroke 2005;36:1218

ASCOT-BPLA: fatal and nonfatal stroke (secondary end point)

ASCOT-BPLA: fatal and nonfatal stroke (secondary end point)

Dahlöf B et al. Lancet. 2005;366:895-906.

Lipid-lowering TherapyLipid-lowering Therapy

Goal• Patients without diabetes: low-density lipoprotein

cholesterol (LDL-C) <100 mg/dL (2.6 mmol/L)

• Patients with diabetes: Consider LDL-C goal of <70 mg/dL (1.8 mmol/L)

Treatment • If the patient is not at LDL-C goal, initiate intensive lifestyle changes

• Lipid-lowering therapy may be commenced at the same time as initiating the lifestyle changes

Goal• Patients without diabetes: low-density lipoprotein

cholesterol (LDL-C) <100 mg/dL (2.6 mmol/L)

• Patients with diabetes: Consider LDL-C goal of <70 mg/dL (1.8 mmol/L)

Treatment • If the patient is not at LDL-C goal, initiate intensive lifestyle changes

• Lipid-lowering therapy may be commenced at the same time as initiating the lifestyle changes

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497; Grundy SM et al. Circulation. 2004;110:227-239. The SPARCL Investigators. N Engl J Med 2006;355:549-559.

Stroke should be considered a CHD risk equivalentStroke should be considered a CHD risk equivalent

ASCOT-LLA: fatal and nonfatal stroke (secondary end point)

ASCOT-LLA: fatal and nonfatal stroke (secondary end point)

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

Lipid lowering following StrokeLipid lowering following Stroke

• Therapy with a statin should be used for all patients with ischemic stroke or TIA

Grade B, Level II, Australian Stroke Guidelines 2007

• Statins– Good safety profile Law & Rudnicka. Am J Cardiol 2006;97:S52-

60

– Well tolerated– Higher compliance if started in hospital

Sannosian, et al. Arch Neurol 2006;63:1081-3

• Therapy with a statin should be used for all patients with ischemic stroke or TIA

Grade B, Level II, Australian Stroke Guidelines 2007

• Statins– Good safety profile Law & Rudnicka. Am J Cardiol 2006;97:S52-

60

– Well tolerated– Higher compliance if started in hospital

Sannosian, et al. Arch Neurol 2006;63:1081-3

CONCLUSIONS CONCLUSIONS

• Modifiable risk factors should be managed

• Pharmacologic options include:

– Anti-thrombotic therapies

– Anti-hypertensive agents

– Statin therapy

• Modifiable risk factors should be managed

• Pharmacologic options include:

– Anti-thrombotic therapies

– Anti-hypertensive agents

– Statin therapy

Multiple Risk Factor Intervention

Factors affecting ADHERENCE


Factors affecting ADHERENCE

Most Hypertensive Patients Need Multiple Medications for Effective Management, Yet Adherence to Concomitant Antihypertensive and

Lipid-Lowering Therapy Decreases as Number of Medications Increases

Most Hypertensive Patients Need Multiple Medications for Effective Management, Yet Adherence to Concomitant Antihypertensive and

Lipid-Lowering Therapy Decreases as Number of Medications Increases

58.8%

48.6%

42.0%

32.7%

28.3%

24.5%

0 10 20 30 40 50 60 70

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

No.

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Median PDC*Median PDC*

1100

99

88

22

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Incremental pill burden had greatest effect on adherence

in patients taking the fewest medications

Incremental pill burden had greatest effect on adherence

in patients taking the fewest medications

Concurrently Starting 2 Medications Improved Adherence

Concurrently Starting 2 Medications Improved Adherence

0.80

0.90

1.00

1.10

1.20

1.30

1.40

1.50

1.60

1.70

1-30 Days1-30 Days 31-60 Days31-60 Days 61-90 Days†61-90 Days†

OR

for

Ad

here

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OR

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Time Between Start of Antihypertensive and Lipid-Lowering Therapies

Time Between Start of Antihypertensive and Lipid-Lowering Therapies

Retrospective cohort study in a large managed-care population (N=8406).Retrospective cohort study in a large managed-care population (N=8406).*Relative odds of being adherent with both antihypertensive and lipid-lowering therapy at any point in time. *Relative odds of being adherent with both antihypertensive and lipid-lowering therapy at any point in time. ††Reference group.Reference group.Chapman RH et al. Chapman RH et al. Arch Intern MedArch Intern Med. 2005;165:1147-1152.. 2005;165:1147-1152.

P<.001P<.001

Simplified Medication Regimen Improved Persistence

Simplified Medication Regimen Improved Persistence

Dezii CM. Dezii CM. Manag Care. Manag Care. 2000;9(suppl):S2-S6.2000;9(suppl):S2-S6.

100100

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Pati

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(%)

Pati

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dh

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(%)

Pati

en

ts A

dh

ere

nt

(%)

9090

8080

7070

6060

5050

0000 1111 2222 3333 4444 5555 6666 7777 8888 9999 10101010 11111111 12121212Months Since Initiation of TherapyMonths Since Initiation of TherapyMonths Since Initiation of TherapyMonths Since Initiation of Therapy

~20%~20%~20%~20%

1-pill combination therapy1-pill combination therapy1-pill combination therapy1-pill combination therapy

2-pill therapy2-pill therapy2-pill therapy2-pill therapy

Lower Pill Burden is Associated with Better Adherence to Antihypertensive and Lipid-

Lowering Therapy

Lower Pill Burden is Associated with Better Adherence to Antihypertensive and Lipid-

Lowering Therapy• As the number of preexisting* Rx meds increased, the

likelihood of adequately refilling AH and LL meds decreased• As the number of preexisting* Rx meds increased, the

likelihood of adequately refilling AH and LL meds decreased

Number of Preexisting Rx MedsNumber of Preexisting Rx Meds

PP<.00<.0011††

PP<.00<.0011††

PP<.00<.0011††

PP<.00<.0011††

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PP<.00<.0011†† PP<.00<.00

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*Preexisting is defined as the number of prescription medications a patient was taking in the year prior to *Preexisting is defined as the number of prescription medications a patient was taking in the year prior to initiating AH and LL medications. initiating AH and LL medications. ††Comparisons were statistically significant vs a patient taking 6+ preexisting Rx Comparisons were statistically significant vs a patient taking 6+ preexisting Rx medications.medications.Rx=prescription; meds=medications; AH=antihypertensive therapy; LL=lipid-lowering therapy. Rx=prescription; meds=medications; AH=antihypertensive therapy; LL=lipid-lowering therapy. Chapman RH et al. Chapman RH et al. Arch Intern MedArch Intern Med. 2005;165:1147-1152. . 2005;165:1147-1152. Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

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Is Poor Adherence an Essential CV Risk Factor?

Is Poor Adherence an Essential CV Risk Factor?

• Increasing pill burden decreases adherence

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

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

concurrently– Combination therapy reduces pill burden– Reduced pill burden improves adherence

• Nonadherence to medication increases CV risk

• Increasing pill burden decreases adherence

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

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

concurrently– Combination therapy reduces pill burden– Reduced pill burden improves adherence

• Nonadherence to medication increases CV risk


Feasibility of Single-Pill combinations

“The Duo Pill”


Feasibility of Single-Pill combinations

“The Duo Pill”



0

20

40

60

80

HPN Choles BMI Smoking PhysicalInactivity

AlcoholDiet

* Computed from risk factor prevalence & hazard size

DevelopedCountries

DevelopingRegions

HPN Choles BMI SmokingDietPhysicalInactivity

Alcohol

Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362: 271 - 280

ENVACAR® (amlodipine besylate/atorvastatin calcium): Optimizing CV Event Reduction by

Management of Total CV Risk

ENVACAR® (amlodipine besylate/atorvastatin calcium): Optimizing CV Event Reduction by

Management of Total CV Risk

ENVACAR• Benefits patients with hypertension plus additional

CV risk factors

• Provides in a single pill– Proven BP-lowering of amlodipine – Proven lipid-lowering and CV event reductions of atorvastatin– Proven safety and tolerability of both parent compounds

• Can be easily incorporated into current CV treatment strategies

• May improve adherence rates, resulting in– Better rates of goal attainment– Reduced risk of having a CV event– Improved cost–benefit ratio

ENVACAR• Benefits patients with hypertension plus additional

CV risk factors

• Provides in a single pill– Proven BP-lowering of amlodipine – Proven lipid-lowering and CV event reductions of atorvastatin– Proven safety and tolerability of both parent compounds

• Can be easily incorporated into current CV treatment strategies

• May improve adherence rates, resulting in– Better rates of goal attainment– Reduced risk of having a CV event– Improved cost–benefit ratio

Sever PS et al for the ASCOT Investigators. Sever PS et al for the ASCOT Investigators. Lancet. Lancet. 2003;361:1149-1158. Julius S et al for the VALUE trial group. 2003;361:1149-1158. Julius S et al for the VALUE trial group. LancetLancet. 2004;363:2022-2031. Blank R et al.. 2004;363:2022-2031. Blank R et al. J Clin Hypertens. J Clin Hypertens. 2005;7:264-273. Chapman RH et al. 2005;7:264-273. Chapman RH et al. Arch Intern Arch Intern MedMed. 2005;165:1147-1152. McCombs JS et al. . 2005;165:1147-1152. McCombs JS et al. Med CareMed Care. 1994;32:214-226. Bisognano J et al. . 1994;32:214-226. Bisognano J et al. Am J HypertensAm J Hypertens. . 2004;17:676-683. CADUET2004;17:676-683. CADUET®® [SmPC 5/10]. [SmPC 5/10]. Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

Sever PS et al for the ASCOT Investigators. Sever PS et al for the ASCOT Investigators. Lancet. Lancet. 2003;361:1149-1158. Julius S et al for the VALUE trial group. 2003;361:1149-1158. Julius S et al for the VALUE trial group. LancetLancet. 2004;363:2022-2031. Blank R et al.. 2004;363:2022-2031. Blank R et al. J Clin Hypertens. J Clin Hypertens. 2005;7:264-273. Chapman RH et al. 2005;7:264-273. Chapman RH et al. Arch Intern Arch Intern MedMed. 2005;165:1147-1152. McCombs JS et al. . 2005;165:1147-1152. McCombs JS et al. Med CareMed Care. 1994;32:214-226. Bisognano J et al. . 1994;32:214-226. Bisognano J et al. Am J HypertensAm J Hypertens. . 2004;17:676-683. CADUET2004;17:676-683. CADUET®® [SmPC 5/10]. [SmPC 5/10]. Please see prescribing information at the end of this slide presentation.Please see prescribing information at the end of this slide presentation.

ENVACAR® (amlodipine besylate/atorvastatin calcium) Clinical Trial Program: PK Studies, AVALON and

RESPOND

ENVACAR® (amlodipine besylate/atorvastatin calcium) Clinical Trial Program: PK Studies, AVALON and

RESPOND

• Pharmacokinetic studies– BE studies at 5/10 and 10/80 mg– PK drug interaction at 10/80 mg

• AVALON (N=847) and RESPOND (N=1660)– Pivotal, double-blind, registration studies– Full safety and efficacy across the dose range– Fully characterise the PD relationship

• Pharmacokinetic studies– BE studies at 5/10 and 10/80 mg– PK drug interaction at 10/80 mg

• AVALON (N=847) and RESPOND (N=1660)– Pivotal, double-blind, registration studies– Full safety and efficacy across the dose range– Fully characterise the PD relationship

5/10 5/20 5/40 5/80

10/10 10/20 10/40 10/80

1:1 1:2 1:4 1:8 1:16 1:1 1:2 1:4 1:8 1:16

PK

PD

BE=bioequivalency; PK=pharmacokinetics; PD=pharmacodynamics.BE=bioequivalency; PK=pharmacokinetics; PD=pharmacodynamics.Flack J, et al. Flack J, et al. Atheroscler SupplAtheroscler Suppl. 2003;4:244. Flack J et al. . 2003;4:244. Flack J et al. J HypertensJ Hypertens. 2004;22(suppl 1):12S. . 2004;22(suppl 1):12S. Preston RA, et al. Preston RA, et al. Am J Hypertens. Am J Hypertens. 2004;17:185A. Data on file. Pfizer Inc, New York, NY.2004;17:185A. Data on file. Pfizer Inc, New York, NY.

3.58.3

28.6

45.5

65.167.5 68.8 67.3

0

10

20

30

40

50

60

70

80

Plac227189

Plac227189

AML192 166

AML192 166

ATV192 180

ATV192 180

AML/ATV200 171

AML/ATV200 171

%%

Messerli, et al. J Clin Hypertens 2006;8:571-81

AVALON: Patients reaching goals for BP & LDL-C at 8 and 28 weeks

AVALON: Patients reaching goals for BP & LDL-C at 8 and 28 weeks

Number of pts828 wks

Number of pts828 wks

Messerli, et al. J Clin Hypertens 2006;8:571-81

Nicola Westwood

7_Slide15_Ref11.1 - p576

Treatment-Emergent AEs in AVALON and RESPONDTreatment-Emergent AEs in AVALON and RESPOND

• Overall low rate of AEs observed in AVALON and RESPOND

• No unexpected differences regarding AEs observed with ENVACAR® (amlodipine besylate/ atorvastatin calcium) from those observed with parent compounds

• AEs observed in ENVACAR-treated patients were easily recognisable and attributable to amlodipine or atorvastatin

• Overall low rate of AEs observed in AVALON and RESPOND

• No unexpected differences regarding AEs observed with ENVACAR® (amlodipine besylate/ atorvastatin calcium) from those observed with parent compounds

• AEs observed in ENVACAR-treated patients were easily recognisable and attributable to amlodipine or atorvastatin

AEs=adverse events.AEs=adverse events.Flack J et al. Flack J et al. J HypertensJ Hypertens. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.

Side Effect Profile of Amlodipine and Atorvastatin in Combination Comparable to Amlodipine and

Atorvastatin Separately

Side Effect Profile of Amlodipine and Atorvastatin in Combination Comparable to Amlodipine and

Atorvastatin Separately

• ENVACAR® (amlodipine besylate/atorvastatin calcium) AEs are similar in nature, frequency, and severity to those reported with amlodipine and atorvastatin taken separately

• ENVACAR® (amlodipine besylate/atorvastatin calcium) AEs are similar in nature, frequency, and severity to those reported with amlodipine and atorvastatin taken separately

Rate of Discontinuations due to Adverse Events

Adverse Event

Placebo (%,

n=111)

Amlodipine Only

Pooled Across Dose Range (%, n=221)

Atorvastatin Only

Pooled Across Dose Range (%, n=443)

Amlodipine with

Atorvastatin Pooled Across Dose Range (%, n=885)

Peripheral oedema 2.7 12.2 1.1 9.9Headache 9.9 5.0 7.7 5.3Dizziness 2.7 3.2 1.1 2.4

Results of RESPOND (N=1660), a multicentre, double-blind, randomised, placebo-controlled study designed to Results of RESPOND (N=1660), a multicentre, double-blind, randomised, placebo-controlled study designed to evaluate the BP- and lipid-lowering efficacy and safety of amlodipine and atorvastatin coadministered in evaluate the BP- and lipid-lowering efficacy and safety of amlodipine and atorvastatin coadministered in patients with comorbid hypertension and dyslipidaemia. Patients were randomised to receive treatment for 8 patients with comorbid hypertension and dyslipidaemia. Patients were randomised to receive treatment for 8 weeks and received both amlodipine 5 mg or 10 mg once daily or matching placebo, and atorvastatin 10 mg, 20 weeks and received both amlodipine 5 mg or 10 mg once daily or matching placebo, and atorvastatin 10 mg, 20 mg, 40 mg, or 80 mg once daily or matching placebo.mg, 40 mg, or 80 mg once daily or matching placebo.CADUETCADUET®® [SmPC 5/10]. [SmPC 5/10].

Clinical Benefit of ENVACAR® (amlodipine besylate/atorvastatin calcium)

AVALON and RESPOND Conclusions

Clinical Benefit of ENVACAR® (amlodipine besylate/atorvastatin calcium)

AVALON and RESPOND Conclusions

AVALON• Amlodipine 5 mg and atorvastatin 10 mg more effective than

single agent in reaching NCEP ATP III and JNC VI goals, respectively • Simultaneous therapy safe and well tolerated in the treatment of

comorbid dyslipidaemia and hypertension

RESPOND• Across the dose range

– Effect of atorvastatin on LDL-C not modified by amlodipine– Effect of amlodipine on BP not modified by atorvastatin

• The combination was well tolerated– Rate of discontinuation similar to that with the parent compounds and

placebo

• The safety profile of the combination was consistent with that seen with the parent compounds administered separately

AVALON• Amlodipine 5 mg and atorvastatin 10 mg more effective than

single agent in reaching NCEP ATP III and JNC VI goals, respectively • Simultaneous therapy safe and well tolerated in the treatment of

comorbid dyslipidaemia and hypertension

RESPOND• Across the dose range

– Effect of atorvastatin on LDL-C not modified by amlodipine– Effect of amlodipine on BP not modified by atorvastatin

• The combination was well tolerated– Rate of discontinuation similar to that with the parent compounds and

placebo

• The safety profile of the combination was consistent with that seen with the parent compounds administered separately

Flack J et al. Flack J et al. J HypertensJ Hypertens. 2004;22(suppl 1):12S.. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.Data on file. Pfizer Inc, New York, NY.

• Modern treatment guidelines for HTN & dyslipidemia have introduced the concept of global CV risk

• Single-pill combinations of antihypertensive drugs and lipid-lowering agents increase adherence and the attainment of treatment goals

• For the same relative risk reduction, high-risk compared with low-risk patients experience larger absolute benefit

• Modern treatment guidelines for HTN & dyslipidemia have introduced the concept of global CV risk

• Single-pill combinations of antihypertensive drugs and lipid-lowering agents increase adherence and the attainment of treatment goals

• For the same relative risk reduction, high-risk compared with low-risk patients experience larger absolute benefit

CONCLUSIONSCONCLUSIONS

Can a Polypill prevent stroke? Can a Polypill prevent stroke?

CONCEPT OF POLYPILLCONCEPT OF POLYPILL

List the risk factors for stroke and cardiovascular diseases

Determine the medication/s (one or more) to treat each risk factor

Create a single tablet (for optimal patient compliance) containing various combination of medications to achieve maximal benefit with minimal side-effects

List the risk factors for stroke and cardiovascular diseases

Determine the medication/s (one or more) to treat each risk factor

Create a single tablet (for optimal patient compliance) containing various combination of medications to achieve maximal benefit with minimal side-effects

Randomised trials: drugs to lower 3 risk factors — LDL, BP & platelet function (with aspirin) ↓ the incidence of IHD and stroke

Randomised trials: drugs to lower 3 risk factors — LDL, BP & platelet function (with aspirin) ↓ the incidence of IHD and stroke

Risk FactorsRisk Factors

Optimal Dose of Aspirin for Prevention of Stroke

Optimal Dose of Aspirin for Prevention of Stroke

Treatment effect: p < 0.0001

Antithrombotic Trialists’ Collaboration:Br Med J 2002, 324:71-86

Meta-analysis of Aspirin(Stroke, MI, or Vascular death in high risk patients)Meta-analysis of Aspirin(Stroke, MI, or Vascular death in high risk patients)

99% confidence interval

Aspirin Dose Trials Antiplatelet(events/n)

Control(events/n)

Odds ratio (Cl)Antiplatelet:Control

Odds reduction

(SE)

High(500~1,500 mg)

34 1,621/11,215 1,930/11,236 19% (3)

Medium(160~325 mg)

19 1,526/13,240 1,963/13,273 26% (3)

Low(75~150 mg)

12 366/3,370 517/3,406 32% (6)

Extremely low(below 75 mg)

3 316/1,827 354/1,828 13% (8)

Total 65 3,829/29,652 4,764/29,743 23% (2)

Antiplatelet better Antiplatelet worse

0 0.5 1.0 1.5 2.095% confidence interval

Create a PolypillCreate a Polypill

• Combine all necessary ingredients in a single daily pill

• Aim for maximal benefit with minimal adverse effects

• To simultaneously reduce cardiovascular risk factors regardless of pretreatment levels

• Combine all necessary ingredients in a single daily pill

• Aim for maximal benefit with minimal adverse effects

• To simultaneously reduce cardiovascular risk factors regardless of pretreatment levels

Multiplication benefits, not merely additive effect from each agent Multiplication benefits, not merely additive effect from each agent

Number of life years gained free from IHD or strokeNumber of life years gained free from IHD or stroke

Side-effects of PolypillSide-effects of Polypill

Overall side-effects of polypill: 8 to 15% of patients 1-2% will withdraw from drug

Fatal side effects < 1 in 10 000

Excess risk of non-fatal major bleed (transfusion required) with aspirin cf placebo (mainly gastric) of 1.2 per 1000 person years

CONSTITUENTS OF SECONDARY-PREVENTION POLYPILL

CONSTITUENTS OF SECONDARY-PREVENTION POLYPILL

Version of Polypill

Aspirin dose (mg)

Lisinopril dose (mg)

Simvastatin dose (mg)

Atenolol dose (mg)

Low-Dose 75 5 10 25

Medium-Dose 75 10 20 50

High-Dose 75 10 40 50

Version of Polypill

Aspirin dose (mg)

Lisinopril dose (mg)

Simvastatin dose (mg)

Hydrochlorothiazide (mg)

Low-Dose 75 5 10 12.5

Medium-Dose 75 10 20 12.5

High-Dose 75 10 40 12.5

CONSTITUENTS OF PRIMARY-PREVENTION POLYPILL

CONSTITUENTS OF PRIMARY-PREVENTION POLYPILL

REFERENCE: Wald NJ and Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419

Who should take polypill ?Who should take polypill ?

• Pre-existing disease: heart disease, stroke, peripheral arterial disease and diabetes mellitus

• Those without pre-existing disease: Age

• > 95% of deaths from IHD and stroke occur in people > 55 years old, regardless of their risk factors. A large proportion are in those never diagnosed with any risk factor

• ? everyone in this group should be treated

• Pre-existing disease: heart disease, stroke, peripheral arterial disease and diabetes mellitus

• Those without pre-existing disease: Age

• > 95% of deaths from IHD and stroke occur in people > 55 years old, regardless of their risk factors. A large proportion are in those never diagnosed with any risk factor

• ? everyone in this group should be treated

What is new, radical and unique about Polypill?

What is new, radical and unique about Polypill?

• Treatment of several risk factors simultaneously, regardless of level, and without screening for them

• Instead of targeting people at high risk, they suggest intervention for all at increased risk (regardless of risk level) ie everyone > 55 yrs and people at any age with existing cardiovascular disease

• Because of the high cardiovascular risk among those > 55 yrs they believe screening for risk factors among those > 55 yrs is not necessary

• Treatment of several risk factors simultaneously, regardless of level, and without screening for them

• Instead of targeting people at high risk, they suggest intervention for all at increased risk (regardless of risk level) ie everyone > 55 yrs and people at any age with existing cardiovascular disease

• Because of the high cardiovascular risk among those > 55 yrs they believe screening for risk factors among those > 55 yrs is not necessary

Issues of UncertaintyIssues of Uncertainty

• Will the pill be too big to swallow ?

• Problems with formulation eg should the pill include aspirin as this is the least tolerated component• If treatment is stopped due to aspirin side effects, the benefits of the other well tolerated components of the pill will be lost

• Hence should aspirin be prescribed separately ?

• Will there be additional side-effects from a pill with 6 components? Potential interaction between the different components in the pill ?

• Need for dosage titration ?

• Will the pill be too big to swallow ?

• Problems with formulation eg should the pill include aspirin as this is the least tolerated component• If treatment is stopped due to aspirin side effects, the benefits of the other well tolerated components of the pill will be lost

• Hence should aspirin be prescribed separately ?

• Will there be additional side-effects from a pill with 6 components? Potential interaction between the different components in the pill ?

• Need for dosage titration ?

• Dosing of pill ?

• Some components in pill may have od dosing, otherwise BID dosing ?

• Final cost ?

• 2 models: Polypill model versus the traditional model of health screening and appropriate treatment.

• What is the health benefit of the first versus the second in terms of reduction of cardiovascular complications, quality of life and patient motivation / compliance to medication ?

• Dosing of pill ?

• Some components in pill may have od dosing, otherwise BID dosing ?

• Final cost ?

• 2 models: Polypill model versus the traditional model of health screening and appropriate treatment.

• What is the health benefit of the first versus the second in terms of reduction of cardiovascular complications, quality of life and patient motivation / compliance to medication ?


• Purely speculative, never tested on patients• Strategy based on meta-analysis of a very large number of trials• Limitations of meta analysis• Publication biases which favour positive results• Selection bias and confounding are troublesome• Observational studies are included; high likelihood of spurious results• Trials involve single risk factor intervention• Potential users of polypill likely to be healthy/health conscious,• Unlike the participants in those trials who are likely to be less healthy

• Purely speculative, never tested on patients• Strategy based on meta-analysis of a very large number of trials• Limitations of meta analysis• Publication biases which favour positive results• Selection bias and confounding are troublesome• Observational studies are included; high likelihood of spurious results• Trials involve single risk factor intervention• Potential users of polypill likely to be healthy/health conscious,• Unlike the participants in those trials who are likely to be less healthy


• Empiric evidence is lacking for simultaneous intervention of several risk factors

• Over estimation of treatment benefit

• Likely benefit is less than speculated because the study compares treatment with no treatment, whereas many of the elderly with diseases are likely already to be on some treatment

• Empiric evidence is lacking for simultaneous intervention of several risk factors

• Over estimation of treatment benefit

• Likely benefit is less than speculated because the study compares treatment with no treatment, whereas many of the elderly with diseases are likely already to be on some treatment


CONCERNSCONCERNS

Issues not addressed

Diabetes mellitus SmokingHigh fat high cholesterol diet ExerciseObesity StressHealth promotion effortsPatient / caregiver education and encouragementSedentary life styleIndustries / food establishments: less salt & fat – canned / outside food

Many chronic disease are due to unhealthy life style Using pharmacologic means to treat these problems !

Issues not addressed

Diabetes mellitus SmokingHigh fat high cholesterol diet ExerciseObesity StressHealth promotion effortsPatient / caregiver education and encouragementSedentary life styleIndustries / food establishments: less salt & fat – canned / outside food

Many chronic disease are due to unhealthy life style Using pharmacologic means to treat these problems !

• One size fits all

• Some under treated, others over treated

• Medical treatment is individualized - each patient has a different disease profile.

• Proper monitoring and tailoring of treatment is essential

• Wrong message ‘quick fix’ with magic bullet

• Polypill – treating a population and not an individual !

• One size fits all

• Some under treated, others over treated

• Medical treatment is individualized - each patient has a different disease profile.

• Proper monitoring and tailoring of treatment is essential

• Wrong message ‘quick fix’ with magic bullet

• Polypill – treating a population and not an individual !

CONCERNSCONCERNS

Like 3-in-one coffee, brew our coffee, milk and sugar

Everything quick, treatment also !

Like 3-in-one coffee, brew our coffee, milk and sugar

Everything quick, treatment also !

CONCERNSCONCERNS

ExerciseExercise

Inactivity ↑ incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases,

resulting in ~ 250 000 premature deaths a year !

Low level of aerobic fitness shown to be an independent and more powerful predictor of fatal cardiovascular event than other conventional risk

factors

Inactivity ↑ incidence of at least 17 unhealthy conditions, almost all of which are chronic diseases,

resulting in ~ 250 000 premature deaths a year !

Low level of aerobic fitness shown to be an independent and more powerful predictor of fatal cardiovascular event than other conventional risk

factors

Let us not overlook…….Let us not overlook…….

Idea of Polypill is good……….Idea of Polypill is good……….

• Reinforces importance of aggressive multifactorial intervention to reduce cardiovascular risk

• For health promotion to be effective major paradigm shifts are needed, supported by good public education and health campaigns

• These efforts go beyond the physician’s office and hospital pharmacy

• Reinforces importance of aggressive multifactorial intervention to reduce cardiovascular risk

• For health promotion to be effective major paradigm shifts are needed, supported by good public education and health campaigns

• These efforts go beyond the physician’s office and hospital pharmacy

To advocates of the Polypill……To advocates of the Polypill……

Add in “User instructions”

………..take this medication daily, followed by or preceded by more than 30 minutes of moderate-to-vigorous exercise, in combination with a low-fat, low-cholesterol diet, weight management, and cessation of cigarette smoking

Add in “User instructions”

………..take this medication daily, followed by or preceded by more than 30 minutes of moderate-to-vigorous exercise, in combination with a low-fat, low-cholesterol diet, weight management, and cessation of cigarette smoking

SALAMAT PO !SALAMAT PO !

Overall CV Risk Managementis Key to Reducing Risk of CV Events

Overall CV Risk Managementis Key to Reducing Risk of CV Events

• Current evidence suggests that treatment of a single CV risk factor is suboptimal

• Reduction of overall CV risk decreases CV events greater than single risk factor reduction

• Current guidelines recognise the importance of total CV risk management

• Overall CV risk management is the ultimate goal in order to maximise CV event reduction

• Current evidence suggests that treatment of a single CV risk factor is suboptimal

• Reduction of overall CV risk decreases CV events greater than single risk factor reduction

• Current guidelines recognise the importance of total CV risk management

• Overall CV risk management is the ultimate goal in order to maximise CV event reduction

AVALON: Most Frequently Reported Treatment-Emergent AEs

AVALON: Most Frequently Reported Treatment-Emergent AEs

[Number (%) of Patients]COSTAR Preferred Term

Amlodipine 5 mg qd + Atorvastatin 10

mg qd(N=207)

Atorvastatin10 mg qd (N=200)

Amlodipine5 mg qd (N=201)

Placebo(N=239)

Respiratory tract infection 15 (7.2) 12 (6.0) 17 (8.5) 17 (7.1)

Headache 14 (6.8) 20 (10.0) 14 (7.0)24

(10.0)

Peripheral oedema 11 (5.3) 1 (0.5) 11 (5.5) 5 (2.1)

Myalgia 10 (4.8) 5 (2.5) 5 (2.5) 5 (2.1)

Accidental injury 8 (3.9) 5 (2.5) 3 (1.5) 6 (2.5)

Asthenia 7 (3.4) 8 (4.0) 6 (3.0) 11 (4.6)

Sinusitis 6 (2.9) 2 (1.0) 2 (1.0) 2 (0.8)

Pain 5 (2.4) 4 (2.0) 5 (2.5) 5 (2.1)

Flatulence 5 (2.4) 6 (3.0) 3 (1.5) 6 (2.5)

qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms.qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms.

Data on file. Pfizer Inc, New York, NY. Data on file. Pfizer Inc, New York, NY.

RESPOND: Most Frequently Reported Treatment-Emergent AEs

RESPOND: Most Frequently Reported Treatment-Emergent AEs

[Number (%) of Patients]

COSTAR Preferred Term

Amlodipine + Atorvastatin (any

dose)(N=885)

Atorvastatin(any dose)

(N=443)

Amlodipine(any dose)

(N=221)

Placebo(N=111)

Peripheral oedema 88 (9.9) 5 (1.1) 27 (12.2) 3 (2.7)

Headache 47 (5.3) 34 (7.7) 11 (5.0) 11 (9.9)

Respiratory tract infection 43 (4.9) 17 (3.8) 7 (3.2) 5 (4.5)

Abdominal pain 20 (2.3) 10 (2.3) 2 (0.9) 0 (0.0)

Asthenia 19 (2.1) 8 (1.8) 4 (1.8) 3 (2.7)

Constipation 15 (1.7) 2 (0.5) 3 (1.4) 1 (0.9)

Rash 15 (1.7) 3 (0.7) 1 (0.5) 1 (0.9)

Myalgia 14 (1.6) 8 (1.8) 3 (1.4) 2 (1.8)

qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms.qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms.

Data on file. Pfizer Inc, New York, NY. Data on file. Pfizer Inc, New York, NY.

AVALON and RESPOND: Deaths and Serious Adverse Events

AVALON and RESPOND: Deaths and Serious Adverse Events

• A total of 8 deaths occurred in patients treated with either ENVACAR® (amlodipine besylate/atorvastatin calcium) or amlodipine + atorvastatin– None of these deaths were consider by the

investigator to be related to study medication

• There were 208 cases reporting 292 serious AEs in patients treated with either ENVACAR or amlodipine + atorvastatin– Most common serious AEs were cardiac disorders (46

cases), neoplasms (23 cases), and gastrointestinal disorders (20 cases)

• A total of 8 deaths occurred in patients treated with either ENVACAR® (amlodipine besylate/atorvastatin calcium) or amlodipine + atorvastatin– None of these deaths were consider by the

investigator to be related to study medication

• There were 208 cases reporting 292 serious AEs in patients treated with either ENVACAR or amlodipine + atorvastatin– Most common serious AEs were cardiac disorders (46

cases), neoplasms (23 cases), and gastrointestinal disorders (20 cases)

Data on file. Pfizer Inc, New York, NY. 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.

• The relationship between BP and cardiovascular risk is continuous, consistent and independent of other risk factors

• The ↑ the BP, the ↑ the risk – the risk of stroke increases progressively with increasing BP

• BP control contributes to the prevention of stroke as well as prevention & reduction of other target organ (heart, kidneys) damage

• Antihypt tx a/w ↓ risk of stroke and cardiovascular diseases

• It remains unsettled whether specific classes of antihypt drugs offer special protection against stroke in addition to their BP lowering effects

• The relationship between BP and cardiovascular risk is continuous, consistent and independent of other risk factors

• The ↑ the BP, the ↑ the risk – the risk of stroke increases progressively with increasing BP

• BP control contributes to the prevention of stroke as well as prevention & reduction of other target organ (heart, kidneys) damage

• Antihypt tx a/w ↓ risk of stroke and cardiovascular diseases

• It remains unsettled whether specific classes of antihypt drugs offer special protection against stroke in addition to their BP lowering effects

HYPERTENSIONHYPERTENSION

• Epidemiological and numerous prospective studies show a positive relationship between blood homocysteine levels and stroke risk

• B vitamins (folate, B6 and B12) ↓ homocysteine level

• Insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in patients with elevated homocysteine levels

• Use of folic acid and B vitamins in patients with known elevated homocysteine levels may be useful given their safety and low cost

• Epidemiological and numerous prospective studies show a positive relationship between blood homocysteine levels and stroke risk

• B vitamins (folate, B6 and B12) ↓ homocysteine level

• Insufficient data to recommend a specific treatment approach that would reduce the risk of first stroke in patients with elevated homocysteine levels

• Use of folic acid and B vitamins in patients with known elevated homocysteine levels may be useful given their safety and low cost

Homocysteine Homocysteine

• Low dose aspirin (50-125 mg/day) = high dose (160-1500 mg/day)

• Hence trials of low dose aspirin • More than 6 months

• 15 trials• Healthy people (4 trials) and those with cardiovascular disease

• Low dose aspirin (50-125 mg/day) = high dose (160-1500 mg/day)

• Hence trials of low dose aspirin • More than 6 months

• 15 trials• Healthy people (4 trials) and those with cardiovascular disease

Aspirin Aspirin

Law MR, Wald NJ, Morris JK, Jordan R. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003;326:1427-31

BP – 5 main categories of drugs(thiazides, beta blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium blockers) produce similar ↓ of BP

Within each dose category, BP ↓ remarkably similar for different categories of drugs

No category was more effective than another; any differences between the drugs was small

BP ↓ with half standard dose were ~ 20% less than those with standard dose

(eg standard daily dose - atenolol 50 mg, norvasc 5 mg, lisinopril 10 mg)


BP – 5 main categories of drugs(thiazides, beta blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium blockers) produce similar ↓ of BP

Within each dose category, BP ↓ remarkably similar for different categories of drugs

No category was more effective than another; any differences between the drugs was small

BP ↓ with half standard dose were ~ 20% less than those with standard dose

(eg standard daily dose - atenolol 50 mg, norvasc 5 mg, lisinopril 10 mg)

Combination of 3 drugs from different categories have greater efficacy and fewer side effects compared to using a single drug or using 2 drugs (of different categories)

i.e. better BP ↓ effect with 3 drugs

Combination of 3 drugs from different categories have greater efficacy and fewer side effects compared to using a single drug or using 2 drugs (of different categories)

i.e. better BP ↓ effect with 3 drugs

EfficacyEfficacy

Half standard dose Standard dose

Thiazides 2% 9.9% (p<0.001)Calcium blockers 1.6% 8.3% (p<0.001)Beta blockers 5.5% 7.5% (p=0.04)ACE Inhibitor 3.9% 3.9%ARB no excess of symptoms cf placebo

ACE Inhibitor - cough the only S/E – no variation with dose

Prevalence of adverse effects with combination therapy was less than additive !(No potentiation of S/E from combination therapy)

Half standard dose Standard dose

Thiazides 2% 9.9% (p<0.001)Calcium blockers 1.6% 8.3% (p<0.001)Beta blockers 5.5% 7.5% (p=0.04)ACE Inhibitor 3.9% 3.9%ARB no excess of symptoms cf placebo

ACE Inhibitor - cough the only S/E – no variation with dose

Prevalence of adverse effects with combination therapy was less than additive !(No potentiation of S/E from combination therapy)

Side-effect profileSide-effect profile


From the average BP of 150/90 mmHg in people who have stroke, BP ↓ (20 mmHg systolic and 11 mm Hg diastolic) with 3 drugs in combination at half standard dose ↓ the incidence of IHD events by 46% and stroke by 63%


From the average BP of 150/90 mmHg in people who have stroke, BP ↓ (20 mmHg systolic and 11 mm Hg diastolic) with 3 drugs in combination at half standard dose ↓ the incidence of IHD events by 46% and stroke by 63%

Epidemiological studies initially found no consistent association between cholesterol levels and overall stroke rates but were likely confounded by the inclusion of hemorrhagic as well as ischemic stroke


Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–0

Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study. Stroke 1980;11:14–21.

Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinoren OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:2535–40.

Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989;320:904–0

Kagan A, Popper JS, Rhoads GG. Factors related to stroke incidence in Hawaii Japanese men. The Honolulu Heart Study. Stroke 1980;11:14–21.

Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinoren OP. Different risk factors for different stroke subtypes: association of blood pressure, cholesterol, and antioxidants. Stroke 1999;30:2535–40.


3 prospective studies in men subsequently showed increases in ischemic stroke rates at higher levels of total cholesterol, particularly for levels above 240 to 270 mg/dL


3 prospective studies in men subsequently showed increases in ischemic stroke rates at higher levels of total cholesterol, particularly for levels above 240 to 270 mg/dL

The Asia Pacific Cohort Studies Collaboration (352 033 patients):-

a 25% ↑ in ischemic stroke rates for every 1-mmol/L (38.7-mg/dL) ↑ intotal cholesterol

Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M; Asia Pacific Cohort Studies Collaboration. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol 2003;32:563–72

The Asia Pacific Cohort Studies Collaboration (352 033 patients):-

a 25% ↑ in ischemic stroke rates for every 1-mmol/L (38.7-mg/dL) ↑ intotal cholesterol

Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, MacMahon S, Woodward M; Asia Pacific Cohort Studies Collaboration. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J Epidemiol 2003;32:563–72

The US Women’s Pooling Project (24 343 women):-

a 25% ↑ risk of fatal ischemic stroke for each 1-mmol/L ↑ in total cholesterol in women 30 to 54 years of age

Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality in the Women’s Pooling Project. Stroke 2002;33:1863–8

The US Women’s Pooling Project (24 343 women):-

a 25% ↑ risk of fatal ischemic stroke for each 1-mmol/L ↑ in total cholesterol in women 30 to 54 years of age

Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality in the Women’s Pooling Project. Stroke 2002;33:1863–8

Eurostroke project (22 183 subjects, 34% female):-

a trend toward ↑ risk with 6% more cases of cerebral infarction for every 1-mmol/L ↑ in total cholesterol

Bots ML, Elwood PC, Nikitin Y, Salonen JT, Freire de Concalves A, Inzitari D, Sivenius J, Benetou V, Tuomilehto J, Koudstaal PJ, Grobbee DE. Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health. 2002;56(suppl 1):i19–i24

Eurostroke project (22 183 subjects, 34% female):-

a trend toward ↑ risk with 6% more cases of cerebral infarction for every 1-mmol/L ↑ in total cholesterol

Bots ML, Elwood PC, Nikitin Y, Salonen JT, Freire de Concalves A, Inzitari D, Sivenius J, Benetou V, Tuomilehto J, Koudstaal PJ, Grobbee DE. Total and HDL cholesterol and risk of stroke. EUROSTROKE: a collaborative study among research centres in Europe. J Epidemiol Community Health. 2002;56(suppl 1):i19–i24

LDL – Statins drug of choice

Statins can lower LDL by an average of 1.8 mmol/L which reduces the risk of IHD events by about 60% and stroke by 17%

Law MR et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7

LDL – Statins drug of choice

Statins can lower LDL by an average of 1.8 mmol/L which reduces the risk of IHD events by about 60% and stroke by 17%

Law MR et al. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003;326:1423-7

Stroke 2004;35:2902-9

Each 10% ↓ in LDL was estimated to ↓ the risk of all strokes by about 15.6% (95% CI, 6.7 to 23.6)

Stroke 2004;35:2902-9

Each 10% ↓ in LDL was estimated to ↓ the risk of all strokes by about 15.6% (95% CI, 6.7 to 23.6)

IHD reduced by 32%

Stroke reduced by 16%

IHD reduced by 32%

Stroke reduced by 16%

But….problem of complianceBut….problem of compliance

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A Prelude to the Polypill Concept for Vascular Disease Prevention Johnny K. Lokin, MD, FPNA Stroke...

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