Polypill,un nuovo estintore per
le fiamme delle malattie
cardiovascolari
GF Gensini
Napoli 14 aprile 2016
…the use of a combination (fixed-dose) pill could be considered
and evaluated in patients suffering from almost all cardiovascular
conditions…
Objectives:
To determine the
combination of
• drugs and
• vitamins, and
• their doses,
for use in a single daily pill to achieve a
large effect in preventing cardiovascular
disease with minimal adverse effects.. BMJ VOLUME 326 28 JUNE 2003 bmj.com
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke.
BMJ VOLUME 326 28 JUNE 2003 bmj.com
Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation).
BMJ VOLUME 326 28 JUNE 2003 bmj.com
The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.
BMJ VOLUME 326 28 JUNE 2003 bmj.com
Polypill,un nuovo estintore per le fiamme delle
malattie cardiovascolari
OLDER PEOPLE AND INDIVIDUALS IN
LOWER SOCIOECONOMICS GROUPS
HAD
HIGH LEVELS OF
INFLAMMATORY MARKERS?
Immunosenescence is a progressive modification
of the immune system that leads to greater
susceptibility to infections, neoplasias, and
autoimmune manifestations.
With aging, the level of type 1 and 2 cytokines increases in T
Lymphocytes.
The age-related dysregulation leads to the abnormal distribution of the
subtypes Th1 and Th2, with a consequent relative increase of the number
of Th2 lymphocytes compared with Th1.
Plasma levels of proinflammatory Th2 cytokines and
their soluble receptors are higher in aged than in
young subjects.
Clin Med Card FI
CRP
(mg/
l)
3
2
1
0
C Reactive Protein Levels by Age in “INCHIANTI” Study
(n=1020)
< 40 yrs
1.02 (0.1-28.6)
40- 50 yrs >80 yrs 50- 60 yrs 60- 70 yrs 70- 80 yrs
1.17 (0.1-70.8)
1.71 (0.3-35.4)
2.37 (0.1-110)
2.76 (0.1-147)
4.06 (0.1-97.2)
N=117 N=55
N=66
N=353
N=466
N=365
P<0.0001
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
PLEIOTROPIC EFFECTS OF STATINS
17,802 apparently healthy men and women with LDL-cholesterol levels <130 mg/dL (3.4 mmol per liter) and CRP levels >2.0 mg/L were randomly assigned to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of
the combined primary end point of myocardial infarction, stroke, arterial revascularization,
hospitalization for unstable angina, or death from cardiovascular causes
In this trial of apparently healthy persons without hyperlipidemia but with elevated CRP levels, rosuvastatin significantly reduced the incidence
of major cardiovascular events
C-reactive protein concentration and the vascular
benefits of statin therapy: an analysis of 20 536
patients in the Heart Protection Study 20 536 men and women aged 40–80 years at high risk of vascular events
were randomly assigned to simvastatin 40 mg daily versus matching placebo
for a mean of 5·0 years.
Overall, allocation to simvastatin resulted in a significant 24% (95% CI 19–
28) proportional reduction in the incidence of first major vascular event after
randomisation (2033 [19·8%] allocated simvastatin vs 2585 [25·2%] allocated
placebo).
There was no evidence that the proportional reduction in this endpoint, or
its components, varied with baseline CRP concentration (trend p=0·41).
Even in participants with baseline CRP concentration less than 1·25 mg/L,
major vascular events were significantly reduced by 29% (99% CI 12–43,
p<0·0001; 239 [14·1%] vs 329 [19·4%]).
There was clear evidence of benefit in those with both low LDL cholesterol and
low CRP (27% reduction, 99% CI 11–40, p<0·0001; 295 [15·6%] vs 400
[20·9%]).
Heart Protection Study Collaborative Group, Lancet 2011
Evidence from this large-scale
randomised trial does not lend
support to the hypothesis that
baseline CRP concentration
modifies the vascular benefits
of statin therapy materially.
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
Effect of Beta-Blockers (metoprolol, bisoprolol) on
Circulating Levels of Inflammatory and Anti Inflammatory
Cytokines in Patients With Dilated Cardiomyopathy
Comparisons of
serum levels of IL-
10 (A), TNF-alpha
(B), sTNF-R1 (C)
and sTNF-R2 (D)
at baseline and 12
weeks after the
initiation of beta-
blocker therapy
in 32 patients with
DCM
Tomoaki Ohtsuka et al., JACC 2001
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
Relationships between inflammation, oxidative
stress, renin-angiotensin system, endothelial
dysfunction and atherosclerosis
. RA: Renin-angiotensin
Angiotensin (Ang) II-mediated effects on plaque
vulnerability and rupture
ACE-i enalapril ameliorated the oxidative vascular
injury by suppressing inflammatory mediators
Suarez-Martinez Adv Cardiovasc Dis 2014
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
HOMOCYSTEINE
UP-REGULATION OF THE EXPRESSION OF THE INFLAMMATORY MARKERS (IL-1 beta, TNF-alpha, MCP-1 AND IL-8) IN
EC, SMC AND MONOCYTES
COLLAGEN SYNTHESIS AND
PRO-COAGULANT ACTIVITY
CELL INJURY/DYSFUNCTION BY A MECHANISM INVOLVING
OXIDATIVE STRESS
OXIDATIVE STRESS
HOMOCYSTEINE
INFLAMMATION
VITAMINS
InCHIANTI Study Serum levels of Inflammatory Markers According to Circulating
Homocysteine
*(P values are adjusted for age, sex, creatinine and total energy intake)
Hcy <12.2 μmol/L Hcy 12.2-15.6 μmol/L Hcy >15.6 μmol/L
n=430 n=439 n=451
C-Reactive Protein (mg/L)
2.3 (2.0-2.8)
2.4 (2.1-2.8)
2.7 (2.1-3.2)
0
1.0
1.5
2.0
2.5
Gori et al., Am J Clin Nutr 2005
P=0.10 3.0
Zoungas et al., JACC 2006
Cardiovascular morbidity and mortality in the
Atherosclerosis and Folic Acid Supplementation Trial
(ASFAST) in chronic renal failure
315 patients with chronic
renal failure randomized
to 15 mg of folic acid or
placebo and followed for
3.6 years
Hcy plasma levels over the time, by treatment
Efficacy of Homocysteine-Lowering Therapy With Folic Acid in Stroke Prevention: A Meta-Analysis
Effect of folic acidupplementation on the risk of stroke in prespecified subgroups.
Stroke 2010;41;1205-1212
• Folic acid supplementation did not demonstrate a major effect in averting stroke. However, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, merit further investigation.
Homocysteine lowering interventions for preventing
cardiovascular events - A Cochrane meta-analysis
Study, year Intervention Control
Baseline End Follow-Up Baseline End Follow-Up
CHAOS-2, 2002 11.2 ± 6.9 9.7 ± 5.3 N.R. N.R.
FOLARDA, 2004 N.R. N.R. N.R. N.R.
GOES, 2003 12.0 ± 4.8 N.R. 12.2 ± 3.8 N.R.
HOPE-2, 2006 12.2 At 2 years: 9.2
At 5 years: 9.7
12.2 At 2 years: 13.2
At 5 years: 12.9
NORVIT, 2006 13.1 ± 5.0 9.5 ± 3.6 13.2 ± 5.2 13.2 ± 6.2
VISP, 2004 13.4 Decreased 2.0 at 1
month, 2.2 at 1
year, 2.3 at 2 years
13.4 Decreased 0.3 at
1 month
WAFACS, 2008 12.1 9.8 12.5 11.8
WENBIT, 2008 N.R. N.R. N.R. N.R.
Hcy concentrations in intervention studies
Marti-Carvajal et al., Cochrane 2009
Conclusion/Significance: Folic acid supplementation does not effect on the incidence of
major cardiovascular events, stroke, myocardial infarction or all cause mortality.
Socioeconomic and racial/ethnic differentials of CRP
levels: a systematic review of population-based studies Aydin Nazmi* and Cesar G Victora
BMC PUBLIC HEALTH 2007
C-REACTIVE PROTEIN
Socioeconomic and racial/ethnic differentials of CRP
levels: a systematic review of population-based studies Aydin Nazmi* and Cesar G Victora
BMC PUBLIC HEALTH 2007
Results: CRP levels were examined with respect to SOCIAL
ECONOMIC POSITION and race/ethnicity in 25 and
studies, respectively. Of 20 studies that were unadjusted or
adjusted for demographic variables, 19 found inverse
associations between CRP levels and SEP. Of 15
similar studies, 14 found differences between racial/ethnic
groups such that whites had the lowest while blacks,
Hispanics and South Asians had the highest CRP levels.
Conclusion: Increasing poverty and non-white race
was associated with elevated CRP levels among
adults. Most analyses in the literature are underestimating
the true effects of racial/ethnic and socioeconomic factors due
to adjustment for mediating factors.
The formulation which met our objectives
was:
• a statin (for example, atorvastatin (daily
dose 10 mg) or simvastatin (40 mg));
• three blood pressure lowering drugs
(for example, a thiazide, a beta-
blocker, and an ACE inhibitor), each at
half standard dose;
• folic acid (0.8 mg); and
• aspirin (75 mg). BMJ VOLUME 326 28 JUNE 2003 bmj.com
RR OF A FIRST MI ASSOCIATED WITH BASE-LINE PLASMA CONCENTRATIONS OF crp,
STRATIFIED ACCORDING TO A RANDOMIZED ASSIGNMENT TO ASPIRIN OR PLACEBO
0
1
2
3
4
5
1 2 3 4
PLACEBO
ASPI RI N
Quartile of Plasma CRP
Rel
ativ
e R
isk
of M
I
Ridker et al., NEngl J Med 1997
Figure 1.
Human platelets have a rich repertoire of dynamic functions that span thrombotic and
inflammatory pathways. Panel A: In response to agonists such as thrombin, adenosine
diphosphate (ADP), lipopolysaccharide (LPS), and other pathogens or toxins, platelets are
activated. Platelet activation results in numerous functional responses that include the
expression of surface ligands, homotypic and heterotypic binding, protein synthesis, the
release of pro-thrombotic and pro-inflammatory mediators, and signaling to leukocytes and
endothelial cells. These responses and interactions are discussed in the text. Panel B:
Immunocytochemistry (ICC) image demonstrating freshly isolated human platelets activated
with thrombin and adhering to fibrinogen. In this image, the green stain identifies actin
filaments, the red stain identifies fibrin strands (white arrowheads), and the magenta stain
identifies the binding of wheat germ agglutinin (WGA) to sialic acid residues within
platelets (white arrows). Panel C: The functional responses of activated platelets are pivotal
in acute thrombotic disorders, such as stroke. Illustrated here are activated platelets
interacting with and binding to monocytes and red blood cells (RBC) to form a thrombotic
occlusion within the vascular lumen.
Mohebali et al. Page 11
J Am Geriatr Soc. Author manuscript; available in PMC 2015 March 01.
NIH
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or M
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IH-P
A A
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or M
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scrip
t
Figure 1.
Human platelets have a rich repertoire of dynamic functions that span thrombotic and
inflammatory pathways. Panel A: In response to agonists such as thrombin, adenosine
diphosphate (ADP), lipopolysaccharide (LPS), and other pathogens or toxins, platelets are
activated. Platelet activation results in numerous functional responses that include the
expression of surface ligands, homotypic and heterotypic binding, protein synthesis, the
release of pro-thrombotic and pro-inflammatory mediators, and signaling to leukocytes and
endothelial cells. These responses and interactions are discussed in the text. Panel B:
Immunocytochemistry (ICC) image demonstrating freshly isolated human platelets activated
with thrombin and adhering to fibrinogen. In this image, the green stain identifies actin
filaments, the red stain identifies fibrin strands (white arrowheads), and the magenta stain
identifies the binding of wheat germ agglutinin (WGA) to sialic acid residues within
platelets (white arrows). Panel C: The functional responses of activated platelets are pivotal
in acute thrombotic disorders, such as stroke. Illustrated here are activated platelets
interacting with and binding to monocytes and red blood cells (RBC) to form a thrombotic
occlusion within the vascular lumen.
Mohebali et al. Page 11
J Am Geriatr Soc. Author manuscript; available in PMC 2015 March 01.
NIH
-PA
Auth
or M
an
uscrip
tN
IH-P
A A
uth
or M
an
uscrip
tN
IH-P
A A
uth
or M
anu
scrip
t
Figure 1.
Human platelets have a rich repertoire of dynamic functions that span thrombotic and
inflammatory pathways. Panel A: In response to agonists such as thrombin, adenosine
diphosphate (ADP), lipopolysaccharide (LPS), and other pathogens or toxins, platelets are
activated. Platelet activation results in numerous functional responses that include the
expression of surface ligands, homotypic and heterotypic binding, protein synthesis, the
release of pro-thrombotic and pro-inflammatory mediators, and signaling to leukocytes and
endothelial cells. These responses and interactions are discussed in the text. Panel B:
Immunocytochemistry (ICC) image demonstrating freshly isolated human platelets activated
with thrombin and adhering to fibrinogen. In this image, the green stain identifies actin
filaments, the red stain identifies fibrin strands (white arrowheads), and the magenta stain
identifies the binding of wheat germ agglutinin (WGA) to sialic acid residues within
platelets (white arrows). Panel C: The functional responses of activated platelets are pivotal
in acute thrombotic disorders, such as stroke. Illustrated here are activated platelets
interacting with and binding to monocytes and red blood cells (RBC) to form a thrombotic
occlusion within the vascular lumen.
Mohebali et al. Page 11
J Am Geriatr Soc. Author manuscript; available in PMC 2015 March 01.
NIH
-PA
Au
tho
r Ma
nu
scrip
tN
IH-P
A A
uth
or M
an
uscrip
tN
IH-P
A A
uth
or M
an
uscrip
t
Figure 1.
Human platelets have a rich repertoire of dynamic functions that span thrombotic and
inflammatory pathways. Panel A: In response to agonists such as thrombin, adenosine
diphosphate (ADP), lipopolysaccharide (LPS), and other pathogens or toxins, platelets are
activated. Platelet activation results in numerous functional responses that include the
expression of surface ligands, homotypic and heterotypic binding, protein synthesis, the
release of pro-thrombotic and pro-inflammatory mediators, and signaling to leukocytes and
endothelial cells. These responses and interactions are discussed in the text. Panel B:
Immunocytochemistry (ICC) image demonstrating freshly isolated human platelets activated
with thrombin and adhering to fibrinogen. In this image, the green stain identifies actin
filaments, the red stain identifies fibrin strands (white arrowheads), and the magenta stain
identifies the binding of wheat germ agglutinin (WGA) to sialic acid residues within
platelets (white arrows). Panel C: The functional responses of activated platelets are pivotal
in acute thrombotic disorders, such as stroke. Illustrated here are activated platelets
interacting with and binding to monocytes and red blood cells (RBC) to form a thrombotic
occlusion within the vascular lumen.
Mohebali et al. Page 11
J Am Geriatr Soc. Author manuscript; available in PMC 2015 March 01.
NIH
-PA
Au
tho
r Ma
nu
scrip
tN
IH-P
A A
uth
or M
anu
scrip
tN
IH-P
A A
uth
or M
an
uscrip
t
Platelet activation
Activated platelets interacting
with and binding to monocytes
and red blood cells to form a
thrombotic occlusion within the
vascular lumen.
Donya Mohebali et al., Am J Geriatr Soc 2014
Figure 2.
Aging is associated with platelet hyperreactivity, leading to increased expression of platelet
surface ligands, exaggerated platelet and leukocyte aggregation, and enhanced release of
pro-thrombotic and pro-inflammatory mediators. These changes contribute to the increased
risk of adverse thrombo-inflammatory events in older adults and are discussed in the text.
Mohebali et al. Page 12
J Am Geriatr Soc. Author manuscript; available in PMC 2015 March 01.
NIH
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or M
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tN
IH-P
A A
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or M
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uscrip
t
Aging is associated with platelet hyperreactivity, leading
to increased expression of platelet surface ligands,
exaggerated platelet and leukocyte aggregation, and
enhanced release of pro-thrombotic and pro-
inflammatory mediators.
Donya Mohebali et al., Am J Geriatr Soc 2014
BMJ. 2003 Oct 4; 327(7418): 807.
“Polypill” to fight cardiovascular disease Patients before populations
EDITOR—Wald and Law's provocative paper and the accompanying editorial on the “Polypill” was disappointing in focusing only on the advantage to the population and ignoring the individual's views of the benefit he or she would wish to see from taking preventive drugs.
Conclusions
Combinations of statins, aspirin, and beta-blockers improve survival in
high risk patients with cardiovascular disease, although the addition of an
ACE inhibitor conferred no additional benefit despite the analysis being
adjusted for congestive cardiac failure.
The underlying tenet of the polypill—that combination
therapy is better than monotherapy—may well be correct,
particularly with regard to secondary prevention of
cardiovascular disease.
Hippisley-Cox and Coupland’s paper goes some way in
providing data concerning the effects of combined
treatment in secondary prevention of coronary heart
disease.
Editorial
BMJ 2005;330;1035-1036
In terms of primary prevention, development and
testing of combination pills aimed at reducing
more than one risk factor seems entirely logical,
particularly in the context of assessment of global
cardiovascular risk.
Funding bodies and the NHS need to support
the necessary trials and cost effectiveness
studies to further examine the polypill strategy
in comparison with nonpharmacological
alternatives.
BMJ 2005;330;1035-1036
European Heart Journal (2006) 27, 1651–1656
European Heart Journal (2006) 27, 1651–1656
European Heart Journal (2006) 27, 1651–1656
Conclusions
Guidelines for the management of CVD stress the importance of
treating global risk, rather than individual risk, factors.
The use of multiple-target, fixed combination products, such
as atorvastatin/amlodipine and aspirin/pravastatin, which
concomitantly reduce multiple risk factors without increasing the
pill burden or the risk of adverse effects, has the potential to
improve CV risk factor management, thereby reducing the
incidence of CVD.
Discussions with regulatory bodies are required in order to
obtain some ‘balance’ between an overcautious registration
approach and the potentially large public health benefits that
would arise from affordable combinations of well-proven
therapies.
European Heart Journal (2006) 27, 1651–1656
The World Heart Federation recently announced that it
would support the development and evaluation of a polypill
consisting of aspirin, an ACE inhibitor, and a statin.
Two Indian drug manufacturers have already developed
four-drug combination pills (the fourth drug being a
beta-blocker) and will soon begin clinical trials.
Such trials will provide further information on the cost-
effectiveness, safety, and adherence profile of a
combination pill and should reveal whether the polypill is a
miracle or a mirage.
Without such evidence, advocacy for the polypill would
be a mere leap of faith.
The Polypill in the Prevention of Cardiovascular Diseases
by Eva Lonn, Jackie Bosch, Koon K. Teo, Prem Pais, Denis Xavier, and Salim Yusuf
Circulation Volume 122(20):2078-2088
November 16, 2010
Copyright © American Heart Association, Inc. All rights reserved.
Population attributable risk for myocardial infarction associated with 7 major modifiable risk factors overall and by region in the INTERHEART study.
Eva Lonn et al. Circulation. 2010;122:2078-2088
Copyright © American Heart Association, Inc. All rights reserved.
Mean changes in LDL cholesterol from baseline and their 95% confidence intervals in the TIPS trial in the 9 groups.33 The change in LDL cholesterol in the Poycap group was of slightly lesser
magnitude than in the simvastatin group.
Eva Lonn et al. Circulation. 2010;122:2078-2088
Copyright © American Heart Association, Inc. All rights reserved.
As indicates aspirin; S, simvastatin;
T, thiazide; At, atenolol; R, ramipril;
and P, Polycap.
Rates of discontinuation of study drug over 3 months by categories of reasons in the TIPS trial.
Eva Lonn et al. Circulation. 2010;122:2078-2088
Copyright © American Heart Association, Inc. All rights reserved.
However, the polypill should not be considered in
isolation but as an integral part of a
comprehensive CVD prevention strategy.
Such a 4-pronged approach could substantially
reduce CVD by 80% to 90% globally in a highly
cost-effective manner. Even if the uptake of these
measures is only 50% of an “ideal” target, a
substantial reduction in CVD by half globally is
possible within thenext 2 decades.
Eva Lonn et al. Circulation. 2010;122:2078-2088
Copyright © American Heart Association, Inc. All rights reserved.
J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 7 1 – 8 2
J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 7 1 – 8 2
J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 7 1 – 8 2
Compared with the 3 drugs (aspirin,
simvastatin, and ramipril) given separately,
the use of a polypill strategy significantly
increases self-reported and directly-
measured medication adherence for
secondary prevention following an acute MI.
J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 7 1 – 8 2
PERSPECTIVESR SPECTIVES
In secondary prevention following an acute MI,
• younger age,
• depression, and
• following a complex drug treatment
are associated with a lower medication adherence,
whereas adherence is increased in patients with
• Higher levels of insurance coverage and
• social support.
In patients following an acute MI, a polypill strategy
significantly increases adherence to medication.
TRANSLATIONAL OUTLOOK: Although this is a
short-term study, long-term evaluation of the polypill
strategy is necessary for a confirmation of adherence
and clinical endpoints. J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 7 1 – 8 2
J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 8 3 – 5
Pooled public procurement by the health systems of LMICs
(Low- and Middle- Income Countries) of quality-assured,
generically produced, price-controlled polypills will
improve their availability and affordability, especially when
distributed at no cost or low cost at public health care facilities.
This is already happening for
human immunodeficiency virus/acquired
immunodeficiency syndrome,
tuberculosis, and
malaria.
…the World Health Organization and LMICs must now accord
the same status to the provision of lifesaving CVD drugs .
Along with multisectoral policies that act at the population level
to prevent the acquisition or augmentation of CVD risk factors
(“poly-policy”),
the polypill can help us reach the “25x25” goal. J A C C 6 4 , NO . 2 0 , 2 0 1 4 : 2 0 8 3 – 5
…our study suggests that a three-in-one polypill (aspirin,
atorvastatin and ramipril) that improves adherence and
outcomes in patients with existing CV disease would have a
positive public health impact in the UK especially in the
context of inadequacies in physician prescribing and patient
adherence.
It could therefore become the mainstay of secondary
cardiovascular prevention for patients in whom such
triple therapy is suitable.
Future research is needed from long-term RCTs to confirm
whether this approach offers advantages over multiple
monotherapy in preventing CV events in patients who have
experienced an MI.
The polypill strategy is increasingly being recognized as a
part of a solution for improving global CVD prevention…
...to have different polypill
versions made available as an affordable and attractive health
service strategy for both high-income and lower middle–
income countries.
However, barriers to the implementation of the polypill strategy
include the manufacture of the polypill as a viable business for
pharmaceutical companies, despite its huge public health
potential and having supportive legislation and policy changes.
As such, the amalgamation of evidence
from international trials combined with further research in
cost effectiveness and acceptability of the strategy in different
contexts will determine the feasibility and policy significance
of the polypill strategy in improving CVD prevention worldwide.
Authors' conclusions Compared with placebo, single drug active component, or usual
care, the effects of fixed-dose combination therapy on all-cause
mortality or CVD events are uncertain; only few trials report
these outcomes and the included trials were primarily
designed to observe changes in CVD risk factor levels
rather than clinical events.
Reductions in blood pressure and lipid parameters are generally
lower than those previously projected, though substantial
heterogeneity of results exists.
Fixed-dose combination
therapy is associated with modest increases in adverse events
compared with placebo, single drug active component, or usual
care but may be associated with improved adherence to a
multidrug regimen. Ongoing trials of fixed-dose combination
therapy will likely inform key outcomes.
CONCLUSIONS
In conclusion, this study indicated that a potentially huge
number of stroke patients in China require preventive
therapy
and would be eligible for a combination treatment or a
polypill.
….
A combination of an antihypertensive,
a statin, and an antiplatelet agent is indicated for 53.9% of
stroke patients, estimated to be 6.4 million patients
nationwide.
Further research is needed to identify the most cost-effective
fixed-dose combination options for polypill products in China
and to evaluate the necessity of a public health policy with
resource support to promote polypill use in the secondary
prevention of stroke in China.
International Journal of Cardiology 201 S1 (2015) S8–S14
…Wald and Law claimed that a polypill containing
six components and administered to each
individual older than 55 years, irrespectively of
their risk factors status, would reduce the
incidence of cardiovascular disease by more than
80%.
This “vaccination approach” found strong
opposition among the scientific community ….
International Journal of Cardiology 201 S1 (2015) S8–S14
…There is no definitive proof of the efficacy,
safety, or cost-effectiveness of this approach,
although its feasibility has been shown in
several pilot studies. Overall, the studies
show that the use of a CV polypill significantly
increases treatment adherence.
…the results of new studies, some currently
underway, are required to confirm that the
polypill can play a role in the primary
prevention of coronary disease.
International Journal of Cardiology 201 S1 (2015) S8–S14
… the Fuster-CNIC-Ferrer polypill was
developed as a response
to the current challenging global scenario of
CVD.
It is a three component polypill,
comprising aspirin, a statin and an ACE
inhibitor, designed for secondary prevention
in patients who have already suffered a CV
event.
International Journal of Cardiology 201 S1 (2015) S8–S14
This has led to regulatory approval of the Fuster-
CNICFerrer
CV Polypill in more than 20 countries to date and its
commercialization in 8 countries in Mexico, Central
America,
South America and Europe under the brands of
Trinomia. and
Sincronium..
The results of various trials under way (SECURE,
TIPS-3, and
HOPE-4) designed to show actual reductions in
morbimortality will provide the ultimate evidence for
the global implementation of this cardiovascular
prevention strategy. International Journal of Cardiology 201 S1 (2015) S8–S14
International Journal of Cardiology 201 S1 (2015) S15–S22
International Journal of Cardiology 201 S1 (2015) S15–S22
In stark contrast to the simple concept of the
cardiovascular polypill itself (including three active
principles in one pill) the pharmacological
development of such a strategy has proven to
be extremely complex from a formulation point of
view.
The Fuster-CNIC-Ferrer CV Polypill has made the
leap from this conceptual debate to clinical
reality and has become first in class to achieve
bioequivalence of all components, which in turn
has led to widespread approval by regulatory
agencies.
International Journal of Cardiology 201 S1 (2015) S15–S22
polypill version 1 : aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg,
atenolol 50 mg;
polypill version 2 :aspirin 75mg, simvastatin 40mg, lisinopril 10mg,
hydrochlorothiazide 12.5 mg.
International Journal of Cardiology 205 (2016) 147–156
International Journal of Cardiology 205 (2016) 147–156
International Journal of Cardiology 205 (2016) 147–156
Conclusion
…polypill-based care in patients at high risk of CVD
improved adherence and risk factor levels across
a wide range of patient groups.
There was little evidence of net benefit for those
already well treated but there is likely to be a
significant net benefit for those undertreated. Since
most CVD patients globally do not take these
medications at present, this strategy could contribute
significantly to the WHO goal of reducing CVD by
25% by 2025.
International Journal of Cardiology 205 (2016) 147–156
Conclusion
…The studies clearly demonstrated the effectivenessof the polypill in the
reduction of CVRFs, as well as its low cost and acceptability by patients
and doctors.
…the lack of evidence on outcomes has prevented and will, most likely,
prevent its future approval by the FDA or its acceptance by the WHO to be
added in the list of essential medicines for NCDs, although polypills with
different drug combinations have been approved for secondary
prevention in over 20 countries.
When approved by the FDA or WHO, it should be used primarily for
secondary prevention or for primary prevention in high risk individuals
such as older individuals ≥55 years old with concomitant major CVRFs.
Its use for primary prevention in low risk individuals should be
very limited or discouraged all together.
four component polypill consisting of 20 mg
simvastatin, 2.5 mg amlodipine,
25 mg losartan and 12.5 mg
hydrochlorothiazide
Eur J Epidemiol 2016
This was estimated on the basis of a 50 % uptake and a
previously published 83 % treatment adherence.
The total years of life gained without a first MI or
stroke in a mature programme is 990,000 each year in
the UK.
If the cost of the Polypill Prevention Programme were £1
per person per day, the total cost would be £4.76 bn
and, given the savings (at 2014 prices) of £2.65 bn
arising from the disease prevented, there would be a net
cost of £2.11 bn representing a net cost per year of life
gained without a first MI or stroke of £2120 (2692
euros). The results are robust to sensitivity analyses.
A national Polypill Prevention Programme would have a
substantial effect in preventing MIs and strokes and be
cost-effective.
Ideal System
Treat:
• the right patient
• with the right drugs
• at the right dose
• at the right time every time!
…Wald and Law claimed that a polypill containing six
components and administered to each individual older
than 55 years, irrespectively of their risk factors status,
would reduce the incidence of cardiovascular disease by
more than 80%.
This “vaccination approach” found strong opposition
among the scientific community because of the unknown
consequences of medicalizing an entire population, the
costs of potential adverse reactions, psychological
effects in a healthy population, as well as the possibility
of promoting unhealthy lifestyle habits. Without suitable
clinical studies demonstrating its efficacy, this
strategy is unlikely to gain the acceptance of health
care professionals and regulating authorities.
International Journal of Cardiology 201 S1 (2015) S8–S14