Polypill,un nuovo estintore per le fiamme delle malattie ... · le fiamme delle malattie...

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).


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.


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


was:






half standard dose;



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.


was:






half standard dose;



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


was:






half standard dose;



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


was:






half standard dose;



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.


was:






half standard dose;



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.

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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.



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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

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


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.



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.



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.



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 ….


…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.


… 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.


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

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.


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

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.


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