A Prelude to the Polypill Concept
for Vascular Disease Prevention
Johnny K. Lokin, MD, FPNA
Stroke Services
Department of Neurology & Psychiatry
University of Santo Tomas Hospital
Overview
• 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
BURDEN OF CARDIOVASCULAR DISEASE
Others
9%
Injuries
9%
Cardiovascular
Disease
(Heart disease &
Stroke)
17 M or 30 %
DM - 2 %
Respiratory
Dse - 9 %
Cancer
13 %
Total Deaths 2005
58 million
Communicable dse,
Nutritional def
30 %
BURDEN OF CARDIOVASCULAR DISEASE
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
3,745 1,037
16,585
BURDEN 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
WHO. The Atlas of Heart Disease and Stroke 2004.
BURDEN OF STROKE
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
GLOBAL BURDEN OF STROKE
• 16 M first ever strokes
• 62 M stroke survivors
• 6 M deaths worldwide
• Most of the stroke
deaths (87%) occur in
developing countries
% of STROKE DEATHS
World Bank income group
High
Income
13%
Middle
Income
55%
Low income
32%
STROKE MORTALITY in ASIA, 2003
China
Japan
S Korea
India
Vietnam
Indonesia
Cambodia
Malaysia
Singapore
Thailand
Philippines
0
20
40
60
80
100
120
140
No per 100,000 population
MacKay J and Mensah G. Atlas of Heart Disease and Stroke. 2004. Geneva. WHO.
BURDEN OF STROKE
• Incidence stable or dropping in developed
countries
– Halving of number of smokers & possibly better control of
hypertension
Auckland 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 vs HEMARRHAGIC STROKE
Incidence
Hemorrhagic stroke
12%
88%
Ischemic stroke
Ischemic stroke makes up >80% of all strokes
American Heart Association Heart Disease and Stroke Statistics—2005 Update.
STROKE 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
Feigin V, et al. Lancet Neurology 2006;5:130-139
STROKE IN ASIA
• 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
Results : Stroke Prevalence
in the Philippines
N = 4753 adults (> 20 yrs old),
17 Regions, 79 provinces
Aug to Dec 2003
Philippines
2003
%
By Questionnaire
1.3 and 1.9
By History
1.4
Dans A. et al. Phil J Int Med; 43(3) : 103 -115
Slide courtesy of A. Roxas, MD
Results : Stroke Prevalence
in the Philippines (by Age)
7
6
6.4%
5
6.1%
4
3
2
3.0%
1.3%
1
0
20-29
30-39
40-49
50-59
60-69
70>
Dans A. et al. Phil J Int Med; 43(3) : 103 -115
Slide courtesy of A. Roxas, MD
TARGETS IN STROKE PREVENTION
STROKE RISK FACTORS
80 % of premature
heart disease, stroke
can be prevented
Managing the Patient at Risk – Multiple Risk
Factors Require Multiple Interventions
Modifiable risk factors
 Smoking
 Diet
 Sedentary lifestyle
 Alcohol/drug abuse
 Obesity
 CAD
 Atrial fibrillation
 Hypertension
 Diabetes
 Dyslipidemia
Goldstein LB, et al. Stroke. 2001;32:280-299.
Unmodifiable risk factors
 Age
 Male sex
 Race
 Family history of
stroke/TIA
 Prior stroke/TIA
CAD=coronary artery disease; TIA=transient
ischemic attack; CHD=coronary heart disease
Multiple CV Risk Management Results in
Dramatic Reductions in CVD
10%
Reduction
in BP
+
10%
Reduction
in TC
=
45%
Reduction
in 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 al
and Jackson et al
Emberson J et al. Eur Heart J. 2004;25:484-491. Jackson R et al. Lancet. 2005;365:434-441.
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=Anglo-Scandinavian Cardiac Outcomes Trial; CARDS=Collaborative AtoRvastatin Diabetes Study; VALUE=Valsartan Antihypertensive Long-term Use
Evaluation.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT): A
Study in Hypertensive Patients at Low to Moderate CV Risk
19,257 hypertensive patients with ≥3 CV
risk factors and no CHD
ASCOTBPLA
amlodipine-based regimen
N=9639
atenolol-based regimen
N=9618
10,305 hypertensive patients (≥3 CV risk
factors and no CHD) with total cholesterol
≤6.5 mmol/L (251 mg/dL)
ASCOT-LLA
atorvastatin 10 mg
N=5168
amlodipine-based atenolol-based
regimen
regimen
ASCOT-LLA
2x2
N=2584
N=2584
placebo
N=5137
amlodipine-based atenolol-based
regimen
regimen
N=2554
N=2583
Sever PS et al. Lancet. 2003;361:1149-1158.
ASCOT-LLA: Patient Population Routinely
Seen in Clinical Practice
(Hypertension Plus 3 Risk Factors for CHD*)
100
Hypertension
Age 55 years
Male
Microalbuminuria/proteinuria
Smoker
Family history of early coronary disease
Type 2 diabetes
Certain ECG abnormalities
Left ventricular hypertrophy
Plasma TC/HDL-C ratio 6
Previous cerebrovascular events
Peripheral vascular disease
84
81
62
33
26
26
23
23
14
10
5
0
20
40
60
80
100
Patients with Risk Factor (%)
Two of the most common additional risk factors were male sex and
age ≥55 yearsrepresentative of patients frequently seen in practice
*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.
Please see prescribing information at the end of this slide presentation.
Proportion of Events (%)
ASCOT-LLA: 27% RRR in Fatal and Nonfatal Stroke
When Atorvastatin Added to BP Treatment
Atorvastatin 10 mg (n=5168)
Placebo (n=5137)
3
Trial stopped early
P=.0236
2
1
HR=0.73 (0.56-0.96)
0
0.0
0.5
1.0
1.5
2.0
2.5
Years
3.0
3.5
5.0
Sever PS et al for the ASCOT Investigators. Lancet. 2003;361:1149-1158.
ASCOT-BPLA and -LLA Combined:
Insight Into Optimal CVD Prevention
Rates/1000 Patient-Years
End Point
Amlodipine  Atenolol  Relative
Perindopril + Thiazide +
Risk
Statin
Placebo Reduction
Fatal CHD and nonfatal MI
4.8
9.2
48%
Fatal and nonfatal stroke
4.6
8.2
44%
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 Prevention
ASCOT-LLA Primary End Point: Nonfatal
MI and Fatal CHD
ASCOT-LLA Secondary End Point: Fatal
and Non-Fatal Stroke
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?
• 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.
RISK FACTORS
% Contribution to Stroke
80
60
Developed
Countries
Developing
Regions
40
20
0
HPN Choles BMI Smoking Diet Physical Alcohol
Inactivity
HPN Choles BMI
Smoking Diet Physical Alcohol
Inactivity
* Computed from risk factor prevalence & hazard size
Ezzati, M for the Comparative Risk Assessment Group Lancet 2003; 362: 271 - 280
European 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
•
Reduce blood pressure
to <140/90 <135/80 if
diabetic
•
Initiate cholesterollowering 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
• 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 dipyridamoleintolerant
Amarenco, et al. Australian Stroke Guidelines 2007
Antihypertensive therapies significantly
reduced risk of recurrent stroke
Relative risk reduction (%)
0
All
Diuretics
-10
Beta-blockers
ACEI
–7
–7
ACEI + Diuretic
-20
-30
–24*
–32†
-40
‡
-50
–45
ACEI=Angiotensin-converting enzyme inhibitors. *P=.005. †P=.01. ‡P<.00001.
Rashid P, et al. Stroke 2003;34:2741-2749.
Blood pressure lowering after Stroke
• Antihypertensive therapy should be started in all
patients with stroke or TIA unless contraindicated
Grade A, Level I evidence, Australian Stroke Guidelines 2007
• 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)
Dahlöf B et al. Lancet. 2005;366:895-906.
Lipid-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
Stroke should be considered a CHD risk equivalent
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.
ASCOT-LLA: fatal and nonfatal stroke
(secondary end point)
Sever PS et al. Lancet. 2003;361:1149-1158.
Lipid 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
CONCLUSIONS
• Modifiable risk factors should be managed
• Pharmacologic options include:
– Anti-thrombotic therapies
– Anti-hypertensive agents
– Statin therapy
Multiple Risk Factor
Intervention
Factors affecting ADHERENCE
No. of Additional Medications
Most Hypertensive Patients Need Multiple Medications for Effective
Management, Yet Adherence to Concomitant Antihypertensive and LipidLowering Therapy Decreases as Number of Medications Increases
0
58.8%
1
48.6%
2
42.0%
8
32.7%
9
28.3%
1
24.5%
0
0
10
20
30
40
Median PDC*
50
60
70
Incremental pill burden had greatest effect on adherence
in patients taking the fewest medications
*Calculated for first year of concomitant therapy with antihypertensive and lipid-lowering drugs. Patients adherent if PDC 80%
for both classes. PDC=proportion of days covered by antihypertensive and lipid-lowering drugs.
Benner JS et al. ACC 2006. Abstract.
Concurrently Starting 2 Medications
Improved Adherence
1.70
OR for Adherence*
1.60
P<.001
1.50
1.40
1.30
1.20
1.10
1.00
0.90
0.80
1-30 Days
31-60 Days
61-90 Days†
Time Between Start of Antihypertensive and
Lipid-Lowering Therapies
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. †Reference group.
Chapman RH et al. Arch Intern Med. 2005;165:1147-1152.
Simplified Medication Regimen
Improved Persistence
Patients Adherent (%)
100
90
1-pill combination therapy
2-pill therapy
80
70
~20%
60
50
0
1
2
3
4
5
6
7
8
9
Months Since Initiation of Therapy
10
11
12
Dezii CM. Manag Care. 2000;9(suppl):S2-S6.
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
Adjusted Likelihood of Being
Adherent; AH and LL Rx
3
2.5
P<.001
†
P<.001
†
2
P<.001
†
1.5
P<.001
†
1
0.5
0
0
1
2
3.5
Number of Preexisting Rx Meds
6+
Reference
Group
*Preexisting is defined as the number of prescription medications a patient was taking in the year prior to initiating AH and LL
medications. †Comparisons were statistically significant vs a patient taking 6+ preexisting Rx medications.
Rx=prescription; meds=medications; AH=antihypertensive therapy; LL=lipid-lowering therapy.
Chapman RH et al. Arch Intern Med. 2005;165:1147-1152.
Please see prescribing information at the end of this slide presentation.
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
Multiple Risk Factor Intervention
Feasibility of Single-Pill combinations
“The
Duo Pill”
RISK FACTORS
% Contribution to Stroke
80
60
Developed
Countries
Developing
Regions
40
20
0
HPN Choles BMI Smoking Diet Physical Alcohol
Inactivity
HPN Choles BMI
Smoking Diet Physical Alcohol
Inactivity
* Computed from risk factor prevalence & hazard size
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
•
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. Lancet. 2003;361:1149-1158. Julius S et al for the VALUE trial group. Lancet.
2004;363:2022-2031. Blank R et al. J Clin Hypertens. 2005;7:264-273. Chapman RH et al. Arch Intern Med. 2005;165:1147-1152.
McCombs JS et al. Med Care. 1994;32:214-226. Bisognano J et al. Am J Hypertens. 2004;17:676-683. CADUET® [SmPC 5/10].
Please see prescribing information at the end of this slide presentation.
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
1:1
PK
PD
10/10
1:2
1:4
1:8
5/10
5/20
5/40
10/20
10/40
10/80
BE=bioequivalency; PK=pharmacokinetics; PD=pharmacodynamics.
Flack J, et al. Atheroscler Suppl. 2003;4:244. Flack J et al. J Hypertens. 2004;22(suppl 1):12S.
Preston RA, et al. Am J Hypertens. 2004;17:185A. Data on file. Pfizer Inc, New York, NY.
1:16
5/80
AVALON: Patients reaching goals for BP &
LDL-C at 8 and 28 weeks
80
%
70
68.8
67.5
65.1
67.3
60
50
45.5
40
28.6
30
20
10
0
Number of pts
828 wks
8.3
3.5
Plac
227189
AML
192 166
ATV
192 180
AML/ATV
200 171
Messerli, et al. J Clin Hypertens 2006;8:571-81
Treatment-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
AEs=adverse events.
Flack J et al. J Hypertens. 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
• ENVACAR® (amlodipine besylate/atorvastatin calcium) AEs
are similar in nature, frequency, and severity to those
reported with amlodipine and atorvastatin taken
separately
Adverse Event
Peripheral oedema
Headache
Dizziness
Rate of Discontinuations due to Adverse Events
Amlodipine
Atorvastatin
Amlodipine with
Only
Only
Atorvastatin
Placebo
Pooled Across Pooled Across
Pooled Across
(%,
Dose Range
Dose Range
Dose Range
n=111)
(%, n=221)
(%, n=443)
(%, n=885)
2.7
12.2
1.1
9.9
9.9
5.0
7.7
5.3
2.7
3.2
1.1
2.4
Results of RESPOND (N=1660), a multicentre, double-blind, randomised, placebo-controlled study designed to evaluate the BPand 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 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.
CADUET® [SmPC 5/10].
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
Flack J et al. J Hypertens. 2004;22(suppl 1):12S. Data on file. Pfizer Inc, New York, NY.
CONCLUSIONS
•
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
Can a Polypill prevent stroke?
CONCEPT 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 minima
side-effects
Risk Factors
Randomised trials: drugs to lower 3 risk factors
— LDL, BP & platelet function (with aspirin) ↓ the
incidence of IHD and stroke
Optimal Dose of Aspirin for
Prevention of Stroke
Meta-analysis of Aspirin
(Stroke, MI, or Vascular death in high risk patients)
Antiplatelet
(events/n)
Control
(events/n)
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)
3
316/1,827
354/1,828
13% (8)
65
3,829/29,652
4,764/29,743
23% (2)
Extremely low
(below 75 mg)
Total
99% confidence interval
95% confidence interval
Odds ratio (Cl)
Antiplatelet:Control
Odds
reduction
(SE)
Trials
Aspirin Dose
0
0.5
Antiplatelet better
1.0
1.5 2.0
Antiplatelet worse
Treatment effect: p < 0.0001
Antithrombotic Trialists’ Collaboration:Br Med J 2002, 324:71-86
Create 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
Multiplication benefits, not merely
additive effect from each agent
Number of life years gained free from IHD or stroke
Side-effects of Polypill
Excess risk of non-fatal major bleed (transfusion required) with
aspirin cf placebo (mainly gastric) of 1.2 per 1000 person years
Overall side-effects of polypill: 8 to 15% of patients
1-2% will withdraw from drug
Fatal side effects < 1 in 10 000
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
CONSTITUENTS OF PRIMARY-PREVENTION
POLYPILL
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
REFERENCE: Wald NJ and Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;
326:1419
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
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
Issues 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 ?
Issues of Uncertainty
• 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 ?
Issues of Uncertainty
• 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
Issues of Uncertainty
• 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
CONCERNS
Issues not addressed
Diabetes mellitus
High fat high cholesterol diet
Obesity
Health promotion efforts
Patient / caregiver education
and encouragement
Sedentary life style
Industries / food establishments:
less salt & fat – canned / outside food
Smoking
Exercise
Stress
Many chronic disease are due to unhealthy life style
Using pharmacologic means to treat these problems !
CONCERNS
• 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
individual !
and not an
CONCERNS
Like 3-in-one coffee, brew our coffee, milk and
sugar
Everything quick, treatment also !
Exercise
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…….
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
To advocates of the Polypill……
Add in “User instructions”
SALAMAT PO !
………..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
Overall CV Risk Management
is 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
AVALON: Most Frequently Reported TreatmentEmergent AEs
[Number (%) of Patients]
COSTAR Preferred Term
Amlodipine 5 mg qd +
Atorvastatin 10 mg qd
(N=207)
Atorvastatin
10 mg qd
(N=200)
Amlodipine
5 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.
Data on file. Pfizer Inc, New York, NY.
RESPOND: Most Frequently Reported
Treatment-Emergent AEs
[Number (%) of Patients]
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)
COSTAR Preferred Term
qd=once daily; COSTAR=Coding symbols for thesaurus of adverse reaction terms.
Data on file. Pfizer Inc, New York, NY.
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)
Data on file. Pfizer Inc, New York, NY.
Please see prescribing information at the end of this slide presentation.
HYPERTENSION
• 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
Homocysteine
• 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
Aspirin
• 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
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)
Efficacy
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
Side-effect profile
Half standard dose
Thiazides
Calcium blockers
Beta blockers
ACE Inhibitor
ARB
Standard dose
2%
9.9% (p<0.001)
1.6%
8.3% (p<0.001)
5.5%
7.5% (p=0.04)
3.9%
3.9%
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)
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
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
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
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
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.
The Asia Pacific Cohort Studies Collaboration (352 033
patients):-
a 25% ↑ in ischemic stroke rates for every 1-mmol/L (38.7mg/dL) ↑ in
total 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
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
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%
But….problem of compliance