international journal ofc ardiology · volume 201, supplement 1, december 2015 issn 0167-5273 a...

Volume 201, Supplement 1, December 2015 ISSN 0167-5273

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A polypill strategy for global secondary cardiovascular prevention: a worldwide reality

Guest EditorValentín Fuster

Editor-in-ChiefAndrew J.S. Coats

International Journal of

CARDIOLOGY

Affiliated with the International Society for Adult Congenital Heart Disease

Available online at www.sciencedirect.com

for online access via your library

Affiliated with the International Societyfor Adult Congenital Heart Disease


Guest Editor: Valentín Fuster

This supplement has been sponsored by Ferrer

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Vol. 201, Supplement 1

December 2015CONTENTS

Affi liated with the International Societyfor Adult Congenital Heart Disease

Cited in: Elsevier BIOBASE/Current Awareness in Biological Sciences; Current Contents (Life Sciences; Clinical Medicine); EMBASE / Excerpta Medica;Index Internacional de Cardiología; Index Medicus (MEDLINE); Sociedad Iberoamericana de Información Científi ca (SIIC); Research Information Systems.


Global burden of CVD: focus on secondary prevention of cardiovascular diseaseSameer Bansilal, José M. Castellano, Valentín Fuster S1

The cardiovascular polypill: clinical data and ongoing studiesJosé M. Castellano, Héctor Bueno, Valentín Fuster S8

The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular preventionJuan Tamargo, José M. Castellano, Valentín Fuster S15

International Journal of Cardiology 201 S1 (2015) S1–S7

The global cardiovascular disease pandemic, current status and future projections

Despite encouraging advances in our knowledge of the

prevention, diagnosis and treatment of atherothrombosis,

cardiovascular disease (CVD) remains a major cause of disability

and premature death throughout the world [1]. Globally an

estimated 16.7 million deaths in the year 2010 were attributed

to CVD; with projections showing a staggering 23.3 million

by 2030. CVD mortality rates are considered equivalent to the

combined number of deaths due to nutritional deficiencies,

infectious diseases, and maternal and perinatal conditions [2].

This massive growth of CVD during the last decade is mainly due

to the increasing incidence in low-and middle-income countries

(LMICs) [2]. In 2012, the Developed and Caucasus and Central

Asia regions had the highest CVD death rates in the world (>400

deaths per 100,000 population, in both genders). Lowest CVD

death rates were estimated for the Oceania region (85 deaths per

100,000 population, in both genders) [3] (Fig. 1).

CVDs (including coronary heart disease (CHD), stroke and

other CVD) cause more than 4 million deaths each year in the

53 countries of the World Health Organization (WHO) European

Region and over 1.9 million deaths in the European Union

(EU) countries [4]. Data from the Organisation for Economic

Co-operation and Development (OECD) show that in 2010,

coronary heart disease (CHD) alone was responsible for 13% of

all deaths in EU member states. However, mortality from CHD

varies considerably being generally higher in the countries of the

former communist bloc. Rates are also relatively high in Finland

and Malta, being several times higher than in France, Portugal,

the Netherlands and Spain. Rates are generally lower in the

southern countries, frequently considered to be a consequence

of the Mediterranean diet. In all countries, death rates for CHD

are higher for men than women in 2012 [4] (Fig. 2).

Since the mid-1990s, CHD mortality rates have declined

in most European countries. Declining tobacco consumption

contributed significantly to reducing mortality rates but

improvements in medical care have also played a part. A recent

study compared short-term outcomes in patients with acute

myocardial infarction (MI) in the United Kingdom (UK) and

Sweden. Unadjusted 30-day mortality was more than a third

higher in the UK (10.5% [95% CI: 10.4–10.6]) than in Sweden

(7.6% [95% CI: 7.4–7.7]) in 2004–2010. The authors suggest that

the difference is mostly due to the more rapid adoption of new

technologies and recommendations for practice in Sweden than

in the UK despite similar spending on acute MI in both countries

[5]. In the United States of America (USA), CHD alone caused

375,295 deaths. Each year an estimated 635,000 Americans have

a new coronary attack (defined as first hospitalized MI or CHD

death) [6].

K E Y W O R D S

Global cardiovascular disease

Secondary prevention

Therapeutic adherence

Accessibility to drugs

A B S T R A C T

Despite encouraging advances in prevention and treatment of atherothrombosis, cardiovascular

disease (CVD) remains a major cause of deaths and disability worldwide and will continue to grow

mainly due to the increase in incidence in low and middle income countries (LMIC). In Europe and the

United States of America (USA), coronary heart disease (CHD) mortality rates have decreased since the

mid-1990s due to improvements in acute care, however the prevalence of CHD is increasing largely in

part due to the overall aging of the population, increased prevalence of cardiovascular (CV) risk factors,

and improved survival of patients after a CV event. Data from clinical trials has consistently proven

the efficacy of pharmacologic interventions with aspirin, statins, and blood pressure (BP)-lowering

agents in reducing the risk of CV events and total mortality in the ever growing pool of patients in

secondary prevention. However, large gaps between indicated therapy and prescribed medication can

be observed worldwide, with very low rates of use of effective therapies in LMIC countries. Adherence

to medication is very poor in chronic patients, especially those treated with multiple pharmacologic

agents, and has been directly correlated to a greater incidence of recurrent CV events and increase in

direct and indirect healthcare costs. In this article, we review the global burden of CV disease, status of

secondary prevention therapy and major barriers for treatment adherence.

© 2015 Elsevier Ireland Ltd. All rights reserved.

Global burden of CVD: focus on secondary prevention of cardiovascular disease

Sameer Bansilala,b, José M. Castellanoa,b,c, Valentín Fustera,b,*

a Mount Sinai Cardiovascular Institute, New York, USAb Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainc HM Hospitales, Hospital Universitario Montepríncipe, Madrid, Spain

* Corresponding author at: Mount Sinai Heart. One Gustave L. Levy Place,

Box 1030 New York City, NY 10029. Tel.: +1212.241.3852; fax: +1212.423.9488.

E-mail address: [email protected] (V. Fuster).

0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.

Contents lists available at ScienceDirect

International Journal of Cardiology

j our na l homepage: www.e lsev ie r.com/ loca te / i j card

S2 S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7

Several studies in Europe have demonstrated that due to

stabilisation of the incidence of MI and the case-fatality decrease,

the prevalence of CHD is increasing. Recurrent CVD events are

common in people who have already had a MI. Various studies

have found a recurrence rate of close to 50% for any CVD event

[7,8] or for subsequent revascularisation [9] in the year after an

MI, and up to 75% of patients have a recurrent event within 3 years

[8,10] (Fig. 3). A recent report from Denmark showed increasing

prevalence of CHD associated with a decline in mortality and

ageing of the population. The number of prevalent cases of

CHD in Denmark increased from 125,000 in 2000 to 150,000

in 2009 and the number of people having survived an acute MI

increased from 67,000 to 72,000. This study showed that about

3% of the Danish population has CHD [11]. A recent study sought

to characterise the incidence for first and recurrent acute MI in

England in 2010 by means of a population based national-linked

database study. Overall, the annual age-standardised event rate

of all acute MI (first and recurrent) per 100,000 was 174 (95%

CI: 173–176) in men and 73.7 (95% CI: 72.9–74.5) in women. Of

all the events that occurred: 83% were first acute MIs and 13%

were re-infarctions. One-third (32%) of all acute MIs were fatal,

with about two-thirds of deaths being sudden acute MI deaths.

Similar proportions of all events were first and recurrent acute MI

deaths (23% and 21%, respectively) [12]. In the USA, an estimated

300,000 have a recurrent attack [6]. In addition, 17.1% of acute MI

were followed by a readmission within 30 days in 2009. For 1.6%

of the index admissions the reason for readmission was a new

MI, while for 2.0% the reason was a scheduled revascularization,

for 2.3% it was heart failure or shock and the remaining 11.2%

of index admissions were readmitted for other conditions and

procedures [10].

As short-term survival in acute MI hospitalised patients

improves, it becomes more important to understand the

implications for longer-term prognosis, both with respect to

survival and the risk of recurrence [13]. Factors associated with

higher risk of recurrence include: older age, socioeconomic

status, no revascularization procedures, presence of co-

Less or equal to 200 CV deaths per 100,000population

201 to 400 CV deaths per 100,000 population More than 400 CV deaths per 100,000population

Fig. 1. CV death rates per 100,000 population (age-standardized rates), the World Health Organization 2012 [3].

35

49

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52

55

55

68

68

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84

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0 200 400 600 800 1000

France

Netherlands

Luxembourg

Portugal

Spain

Belgium

Liechtenstein

Greece

Denmark

Cyprus

Turkey

Switzerland

Italy

Slovenia

Norway

United Kingdom

European Union (28 countries)

Sweden

Germany

Poland

Ireland

Serbia

Austria

Finland

Bulgaria

Malta

Croa

Estonia

Romania

Czech Republic

Hungary

Slovakia

Latvia

Lithuania

Age-standardised rates per 100,00 popul

MALES

FEMALES

Fig. 2. Ischaemic heart disease mortality rates 2012 (or nearest year) from the

Eurostat Statistics Database [60].

S. Bansilal et al. / International Journal of Cardiology 201 S1 (2015) S1–S7 S3

morbidities, and lack of adherence to secondary prevention

medication [12]. Both clinical care and secondary prevention are

important in improving the long-term outcome of hospitalized

patients with acute MI.

Current status of secondary prevention, accessibility and adherence to cardiovascular drugs

According to a WHO report, effective reduction of CV mortality

should be based on three key points: surveillance (mapping

and monitoring the epidemic of CVDs), prevention (reducing

exposure to risk factors) and management (equitable health care

for people with CVD) [14] (Fig. 4).

Overwhelming data from clinical trials show that pharma-

cologic interventions with aspirin, statins, and BP (BP)-lowering

agents considerably reduce the risk of vascular events and total

mortality [15–17]. Current European Cardiovascular Prevention

Guidelines in patients with established coronary artery disease

recommend the use of antiplatelet therapy, lipid-lowering agents

when low-density lipoprotein (LDL) cholesterol ≥2.5 mmol/L,

a beta-blocker, and additional BP-lowering agents in the case

of a systolic BP ≥140 mm Hg, unless contraindicated [18,19].

The American Heart Association and the American College of

Cardiology Foundation (AHA/ACCF) Guidelines promote the

standard use of cholesterol-and BP-lowering agents, regardless

of the initial levels of LDL cholesterol or BP in patients with

established vascular disease [20,21].

In clinical practice, a substantial proportion of CHD patients

should be treated with aspirin, a statin, and BP-lowering agents

as a result of tailored and/or step-up therapy. However, large

gaps between indicated therapy and prescribed medication can

be observed worldwide, with very low rates of use of effective

therapies in LMICs countries [22,23]. In the secondary prevention

setting in high-income countries, around 60% of patients

are prescribed anti-platelet therapy, 50% beta-blockers, 40%

angiotensin converting enzyme inhibitor (ACEI) or angiotensin-

receptor blocker (ARB) and almost 70% statins [23]. An analysis

of data from the Antiplatelet Treatment Observational Registry

(APTOR) in 14 European countries showed that only 43% of

patients who had an acute coronary syndrome (ACS) event

between 2007-2009 were receiving optimal secondary prevention

(defined as use of aspirin and clopidogrel as well as three or

more of the following post-discharge medications: statins,

beta-blockers, ARB/ACEI, exercise or diet) at baseline and 1-year

post-discharge. There was considerable variation by country in

prescription of optimal therapy with highest rates reported for

Austria/Hungary and lowest rates for the Czech Republic [24]

(Fig. 5). The results of a prospective epidemiological registry

conducted in Europe showed that the overall use of combination

therapy with aspirin, statin, and ≥1 BP-lowering agent increased

substantially from 9% in 1996 to 66% in 2009. Except for CHD,

the trend to use combination therapy addressed to different risk

factors increases very slowly and that means that there are still

a high proportion of high risk patients not achieving a complete

protection [25]. In the USA, Muntner et al. estimated that among

patients with a history of CV disease, only 44.5% received aspirin,

87.8% received antihypertensive medication, and 64.6% received

statins [26]. The WHO study on Prevention of Recurrences of

Myocardial Infarction and StrokE (WHO-PREMISE) study found

that in some LMICs fewer than 40% of acute MI patients received

ACEIs, and only 20% received statins [27]. The Prospective Urban

Rural Epidemiological (PURE) study of individuals from rural and

urban communities in countries at various stages of economic

development aged 35–70 years confirmed that adherence

with drugs for secondary prevention in patients with CVD was

generally low and worst in the low income countries; with over

80% receiving none of the effective drug treatments in South Asia

[23].

Another fact that might affect the therapy of patients with

CVD is the accessibility to medication, which is highly different

among the different regions and countries of the world. In

the EU, although there are differences between countries in

relationship to healthcare systems the availability of drugs

is very high compared to the LMICs. Cameron et al. assessed

the availability of a basket of 15 medicines in the public and

private sectors of 36 LMICs. Overall, generic medicines were

not adequately available in both the public and private sectors

(median availability of 38% and 64%, respectively) [29]. An

analysis performed by Commonwealth Fund survey revealed

that in the USA, particularly the relatively young and healthy,

are more likely to use prescription drugs than are the residents

of Australia, Canada, Germany, the Netherlands, New Zealand,

and the UK, but they also experience more financial barriers

in accessing medications and spend more out-of-pocket for

prescriptions. In the USA, there are also larger income-related

inequities in pharmaceutical use [28].

Low adherence: prevalence, causes and burden of disease of

non-adherence

On the other hand, adherence to prescribed medication – the

extent to which patients take their medications as prescribed –

Women

Men

Years since first AMI0 1 2 3 4 5 6 7

Cum

ulat

ive

inci

denc

e

0

0.

05

0.

1

0.

15

Fig. 3. Risk of a second acute myocardial infarction (AMI) over 7 years among

30-day survivors of first acute MI by gender, 2004 to 2010, England [13].

Fig. 4. Vision on how to address cardiovascular disease (CVD): World Health

Organization 2011 [1].


is generally poor for all diseases but especially poor for chronic

conditions requiring long-term drug treatment such as CVD

[29,30]. A systematic review of studies in adherence among

patients with CVD showed that overall adherence was 57% over

a median of 24 months [31]. In a systematic review and meta-

analysis of 44 unique prospective studies (cohort, nested case–

control, or clinical trial) comprising 1,978,919 non-overlapping

participants at high CV risk, showed that 60% of included

participants had good adherence (adherence ≥80%) to CV

medications [32].

WHO has categorized potential barriers for medication

non-adherence into five groups, including patient, condition,

treatment, socioeconomic, and health system related factors

[33,34]. The most common barriers for medication non-

adherence have been the focus of numerous investigations of

adherence [35,36]. The cross-sectional Phase 1 of the FOCUS

(Fixed-Dose Combination Drug for Secondary Cardiovascular

Prevention) study showed that the risk of being non-adherent

was associated with younger age, depression, being on a complex

medication regimen, poorer health insurance coverage, and a

lower level of social support [37]. The concern about medication

side effects and patient’s lack of confidence in the benefit of

treatment all play a role in the lack of adherence. Poor provider-

patient relationship and difficulties accessing physicians or

pharmacies are, among other, relevant socioeconomic factors

[38]. Choudhry et al. conducted a retrospective study in a

cohort of lower income post-MI retired patients in the USA.

Results showed that only 38.6% of patients receiving a statin

after discharge were fully adherent [39]. Finally, Akincigil et al.

examined the duration of CV treatment within 24 months after

a MI. 7% of patients receiving ACEI prescription discontinued

treatment within 1 month, 22% at 6 months, 32% at 1 year and

50% at 2 years [40]. Finally, suboptimal medication adherence

is associated with racial/ethnic minority groups. Ens et al.

literature review examining factors contributing non-adherence

to CV medications in South Asian´s (India and Pakistan) showed

that medication side-effects, cost, forgetfulness and higher

frequency of dosing contributed to non-adherence. South Asian

immigrants also faced language barriers, which contributed to

non-adherence [41].

Many studies have evaluated the effect of adherence with

prescribed medications on outcomes in patients with existing

CVD who need secondary prevention therapy [42–44]. These

studies show that good adherence (generally defined as >80%

adherence) to the combined therapy with aspirin, ACEI, beta-

blockers and statins is associated with improved outcomes

(reduction in CV events, all-cause mortality or CVD mortality,

and reduced medical or pharmacy costs) [42–44]. So, in the

previously cited systematic review and meta-analysis conducted

by Chowduhry et al. of participants at high CV risk (≥18 years

old), risk estimates of CVD (defined as any fatal or non-fatal

CHD, stroke or sudden cardiac death) and/or all-cause mortality

(defined as mortality from any cause) outcomes were reported.

Overall, 60% (95% CI: 52–68%) of included participants had good

adherence (adherence ≥80%) to CV medications. The relative

risk reduction (RRR) of any CV disease in the adherent patients

was of a 20% when compared to patients with poor adherence

(RR 0.80 [95% CI: 0.77–0.84]) Corresponding RRR in all-cause

mortality was of a 38% in good vs. poor adherers (RR 0.62

[95% CI: 0.57–0.67]. These associations remained consistent

across subgroups representing different study characteristics.

According to these results, a considerable proportion of all CVD

events (approximately a 9% in Europe) could be attributed to

poor adherence to vascular medications alone [32]. In the USA,

Newby et al analyzed the use of evidence based therapies during

the period from 1995 to 2002 for patients with documented CHD

in the Duke Databank for Cardiovascular Disease. They showed

that consistent use of CV medication in patients with CHD was

asso ciated with statistically significant lower adjusted mortality

[45].

The burden of acute coronary syndromes (ACS) to healthcare

services in five European countries (UK, France, Germany, Italy

and Spain) was determined including medications prescribed,

intervention rates and hospital utilisation as well as health

outcomes during the first year following a diagnosis of ACS. All

costs were reported in 2004 Euros. Overall, the major contributors

to total costs were hospital stay and revascularisation procedures.

The total cost of ACS was estimated to be €1.9 billion in the UK,

€1.3 billion in France, €3.3 billion in Germany, €3.1 billion in

Italy and €1.0 billion in Spain. The cost per ACS patient ranged

from €7,009 in the UK to €12,086 in Italy [46]. The results of a

systematic review studying the impact of medication adherence

on CHD costs and outcomes found that the annual cost of

treating an adherent compared to a non-adherent patient was

significantly different ($4,040 versus $4,940 respectively, p<0.01)

[47]. A systematic review concluded that the overall costs of care

are lower in patients who are adherent to secondary prevention,

although medication costs are higher in adherent patients than

those who do not take their prescribed medications [47]. Finally,

out-of-pocket payments for the treatment of CV diseases lead to

significant costs for households in LMICs. Up to 71% of patients

who had an acute stroke were found to face catastrophic health

expenditure in China, and 37% of them fell below the poverty

line (1 USD per day) after paying for healthcare bills [48].

This evidence shows the potential of strategies that increase

adherence to cut direct healthcare costs.

Strategies to improve adherence to medications: an integrated approach

Different disease specific, patient, provider and health

system barriers have already been identified as key players to

be addressed in order to increase adherence across populations

[38,49]. Measures to enhance adherence to help maximize the

potentials of effective cardiac therapies in the clinical setting

are urgently required. This is reflected in the ESC Cardiovascular

prevention Guidelines, where adherence assessment in

secondary prevention is a Class 1A recommendation stating

that physicians must assess adherence to medication, and

identify reasons for non-adherence in order to tailor further

interventions to fulfill the individual needs of the patient or

person at risk [19].

38%41%

34%

25%

63%

28%

71%

46%

0%

10%

20%

30%

40%

50%

60%

70%

80%

Spai

n

UK

Fran

ce

Czec

h R

epub

lic

Ger

man

y

Gre

ece

Nor

dic

Aus

tria

-Hun

gary

Belg

ium

-Net

herl

ands

Paen

ts (%

)

Fig. 5. Use of optimal therapy by country cluster after hospital discharge [24].


Patient-targeted strategies

Strategies to address therapy-related barriers to medication

adherence in patients with CV disease have primarily focused

on reducing the complexity of the prescribed medical regimen.

Polypharmacy is a potentially modifiable and important

component of adherence to medical therapy for patients with

chronic conditions. Different ad-hoc tools such as electronic

medication aid caps have been developed to be delivered

directly to the patient to enhance use of CV medications as

prescribed. In addition, technology based strategies such as

cutting edge-technology in pill bottles which communicate with

a health-coach [50] are being studied at this time. As a matter

of fact, the Randomized Evaluation to Measure Improvements

in Non-adherence from Low-Cost Devices (REMIND) trial is

currently evaluating the impact on medication adherence of

three different pill-box devices [51]. Data showing the efficiency

of these approaches is still lacking. Another novel strategy that

attempts to address the adherence issue is the use of a CV polypill

as evidence suggests that reducing dosage demands is the most

effective single approach to enhancing medication adherence

[19]. Including the key medications necessary to reduce CV

risk into a single, once daily dose pill improves treatment

adherence, and could reduce CV events, hospitalizations and

therefore lower costs [52,53]. The Heart Outcomes Prevention

Evaluation (HOPE-4) trial [34] and the Secondary prevention of

CardiovascUlaR disease in the Elderly (SECURE) trial are large

CV outcomes-based randomized controlled trials testing the

polypill concept.

Provider-targeted strategies

Strategies aimed at improving patient´s knowledge towards

CV disease and use of medication as prescribed have increasingly

focused on the role of highly labor intensive multidisciplinary

care teams. These programs involve, between others, strategies

such as individual counseling, medication education, pharmacy

post-discharge programs and visiting nurse or nurse-practitioner

based services. Berben et al. evaluated which strategies CV nurses

and allied health professional utilize to enhance medication

adherence. Results showed that educational interventions were

the most frequently used tools. As a matter of fact, participants

reported using a higher proportion of educational/cognitive

interventions (36%) than counseling/behavioral (32%) or psycho-

logical/effective interventions (23%). Reading materials about

CV care was the most used adherence-enhancing specific

intervention, with 66% of respondents using it frequently. Only

the half of the participants (48%) reported that they frequently

trained patients on how to properly take their medications as

prescribed during their inpatient recovery [54]. Nieuwkerk et al.

examined the effect of nurse-led counseling program regarding

CV risk on adherence to statins. Patients taking statins for either

primary or secondary prevention of CV disease were randomized

to routine care or to the intervention arm. The intervention

consisted of nurse-led individualized counseling regarding CV

risk and subsequent regular visits to assess the degree of control

of dyslipidemia and other CV risk factors. At the completion of

the trial, self-reported adherence to statins was significantly

higher in the intervention arm as compared to those who

received routine care (100% vs. 95%; p<0.05) [55]. The addition

of a clinical pharmacist to monitor patients with CVD can lead

to an improvement in CVD patients in many areas, including

patient improvement of adherence medications and preventing

potential drug-related problems. Hohmann et al evaluated the

adherence to hospital discharge medication in patients with

ischemic stroke before and after implementing a program

provided by a clinical pharmacist. In the intervention group, the

clinical pharmacist listed the medication at discharge and gave

detailed information for all medication changes during hospital

stay. Significant differences between the control group and

intervention group were established with regard to adherence to

both antithrombotic medications (83.8% control group vs. 91.9%

intervention group, p=0.033) and to statin therapy (69.8% control

group vs. 87.7% intervention group; p<0.001) [56]. None of these

studies mentioned before reported economic outcomes.

Health system-targeted strategies

Medication non-adherence is increasingly recognized to

be associated with socioeconomic adversity. Factors such as

poverty and in particular food insufficiency and hunger [57],

and unstable housing [58] have been associated with medication

non-adherence in other chronic conditions such as human

immunodeficiency virus and acquired immune deficiency

syndrome (HIV/AIDS). In relation to CVD, low socioeconomic

status has been found to be associated with low adherence in a

number of different environments. Pharmacy benefit programs

have a direct influence on adherence to medicines. Higher copays

and restricted benefits lead to a reduction in use of medicines

as prescribed. The Rand study performed in the USA found

that doubling copays for commonly used drug classes reduced

adherence by 25% to 45% [57].

Strategies may be more effective if they: 1) are designed

for specific groups; 2) take into account behavioral patterns;

and 3) are based on evidence-based specific tools or programs.

Multifaced strategies simultaneously directed at patients,

physicians/practices, and healthcare or social systems targeting

physician prescribing behavior as well as interventions to

reduce social, financial and treatment-related barriers to enable

patients to adhere to prescribed therapy have been found to be

most effective in low income groups. Moreover, complex multi-

factorial strategies, addressing different barriers have been

mostly assessed without previous evaluation of their individual

components [59]. Individual interventions such as simplifying

dosage regimens and fixed combination pills appear to be the

most effective tool. The European Guidelines on CVD prevention

recommend all the physicians to reduce dosage demands of their

patients to the lowest feasible level and additionally, to provide

clear advice regarding the benefits and possible adverse effects

of the medication as well as of the duration and timing of dosing.

It is recommended to consider patients’ habits and preferences

and to ask patients in a non-judgmental way how the medication

works for them, discussing possible reasons for non-adherence

(e.g. side effects, worries). After the assessment of adherence it

is important to implement repetitive monitoring and feedback,

offering multisession or combined behavioral interventions

in the case of persistent non-adherence through physicians

assistants and/or trained nurses [19].

Conclusion

It is clear that the current CVD pandemic calls for a revision

of the way we implement healthcare worldwide, as well as new

simple, efficacious and efficient strategies to contain the growth

of the disease worldwide.

The scenario in LMIC is especially worrisome, as many regions

suffer what has been called the double burden of disease (that

is, developing regions where communicable diseases are highly

prevalent are also suffering the health toll from chronic, non-

communicable diseases). In high income countries the higher

survival rate after a CV event, the aging of the population and

the increase in prevalence of CV risk factors has increased the


cost of treating CVD to a degree that will not be sustainable even

in the wealthiest economies. Even in high income European

countries where medication accessibility is guaranteed the

efficacy of proven treatments is severely hampered due to

poor adherence rates to pharmacologic therapy (consistently

shown to be about 45–60% in secondary prevention). Hence,

interventions toward improving adherence rates could have a far

greater impact on public health than any individual treatment.

Barriers to medication adherence might be surpassed through

programs delivered through the healthcare system, through

multidisciplinary care teams or directly by the patient by

reducing the dosage demands which could include the intake

of CV polypills. Hence, from a public health perspective, it is of

highest importance implement existing and innovative strategies

to achieve adequate adherence to secondary CV prevention

medication in order to ensure efficacy of treatment.

Conflict of Interest Statement

Nothing to declare.

References

[1] Writing C, Smith SC, Jr., Collins A, Ferrari R, Holmes DR, Jr., Logstrup S, McGhie

DV, Ralston J, Sacco RL, Stam H, Taubert K, Wood DA and Zoghbi WA. Our time:

a call to save preventable death from cardiovascular disease (heart disease

and stroke). Glob Heart. 2012;7:297-305.

[2] Organization WH and UNAIDS. Prevention of cardiovascular disease: World

Health Organization; 2007.

[3] WHO. WHO. Data and statistics.

[4] Nichols M, Townsend N, Scarborough P and Rayner M. Cardiovascular disease

in Europe: epidemiological update. Eur Heart J. 2013;34:3028-34.

[5] Chung SC, Gedeborg R, Nicholas O, James S, Jeppsson A, Wolfe C, Heuschmann

P, Wallentin L, Deanfield J, Timmis A, Jernberg T and Hemingway H. Acute

myocardial infarction: a comparison of short-term survival in national out-

come registries in Sweden and the UK. Lancet. 2014;383:1305-12.

[6] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de

Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela

BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB,

McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K,

Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ,

Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW,

Turner MB, American Heart Association Statistics C and Stroke Statistics S.

Heart disease and stroke statistics--2015 update: a report from the American

Heart Association. Circulation. 2015;131:e29-322.

[7] Tuppin P, Neumann A, Danchin N, Weill A, Ricordeau P, de Peretti C and

Allemand H. Combined secondary prevention after hospitalization for myo-

cardial infarction in France: analysis from a large administrative database.

Arch Cardiovasc Dis. 2009;102:279-92.

[8] Andres E, Cordero A, Magan P, Alegria E, Leon M, Luengo E, Botaya RM, Garcia

Ortiz L and Casasnovas JA. Long-term mortality and hospital readmission after

acute myocardial infarction: an eight-year follow-up study. Rev Esp Cardiol

(Engl Ed). 2012;65:414-20.

[9] Bischoff B, Silber S, Richartz BM, Pieper L, Klotsche J, Wittchen HU and Study-

Group D. Inadequate medical treatment of patients with coronary artery dis-

ease by primary care physicians in Germany. Clin Res Cardiol. 2006;95:405-12.

[10] Stranges E, Barrett M, Wier LM and Andrews RM. Readmissions for heart

attack, 2009. 2012.

[11] Koch MB, Davidsen M, Andersen LV, Juel K and Jensen GB. Increasing preva-

lence despite decreasing incidence of ischaemic heart disease and myocardial

infarction. A national register based perspective in Denmark, 1980-2009. Eur

J Prev Cardiol. 2015;22:189-95.

[12] Smolina K, Wright FL, Rayner M and Goldacre MJ. Incidence and 30-day case

fatality for acute myocardial infarction in England in 2010: national-linked

database study. Eur J Public Health. 2012;22:848-53.

[13] Smolina K, Wright FL, Rayner M and Goldacre MJ. Long-term survival and

recurrence after acute myocardial infarction in England, 2004 to 2010. Circ

Cardiovasc Qual Outcomes. 2012;5:532-40.

[14] Alwan A. Global status report on noncommunicable diseases 2010: World


[15] Law M, Morris J and Wald N. Use of blood pressure lowering drugs in the pre-

vention of cardiovascular disease: meta-analysis of 147 randomised trials in

the context of expectations from prospective epidemiological studies. Bmj.

2009;338.

[16] Antithrombotic Trialists C, Baigent C, Blackwell L, Collins R, Emberson

J, Godwin J, Peto R, Buring J, Hennekens C, Kearney P, Meade T, Patrono C,

Roncaglioni MC and Zanchetti A. Aspirin in the primary and secondary pre-

vention of vascular disease: collaborative meta analysis of individual partici-

pant data from randomised trials. Lancet. 2009;373:1849-60.

[17] Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland

LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J and Collins R.

Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-

analysis of data from 170,000 participants in 26 randomised trials. Lancet.

2010;376:1670-81.

[18] Graham I, Atar D, Borch-Johnsen K, Boysen G, Burell G, Cifkova R, Dallongeville

J, De Backer G, Ebrahim S, Gjelsvik B, Herrmann-Lingen C, Hoes A, Humphries

S, Knapton M, Perk J, Priori SG, Pyorala K, Reiner Z, Ruilope L, Sans-Menendez

S, Op Reimer WS, Weissberg P, Wood D, Yarnell J, Zamorano JL, Walma E,

Fitzgerald T, Cooney MT, Dudina A, Vahanian A, Camm J, De Caterina R, Dean

V, Dickstein K, Funck-Brentano C, Filippatos G, Hellemans I, Kristensen SD,

McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Altiner

A, Bonora E, Durrington PN, Fagard R, Giampaoli S, Hemingway H, Hakansson

J, Kjeldsen SE, Larsen m L, Mancia G, Manolis AJ, Orth-Gomer K, Pedersen T,

Rayner M, Ryden L, Sammut M, Schneiderman N, Stalenhoef AF, Tokgozoglu

L, Wiklund O, Zampelas A, European Society of C, European Association for

Cardiovascular P, Rehabilitation, Council on Cardiovascular N, European

Association for Study of D, International Diabetes Federation E, European

Stroke I, Society of Behavioural M, European Society of H, Europe W, European

Heart N and European Atherosclerosis S. European guidelines on cardiovas-

cular disease prevention in clinical practice: full text. Fourth Joint Task Force

of the European Society of Cardiology and other societies on cardiovascular

disease prevention in clinical practice (constituted by representatives of nine

societies and by invited experts). Eur J Cardiovasc Prev Rehabil. 2007;14 Suppl

2:S1-113.

[19] Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren M, Albus C,

Benlian P, Boysen G and Cifkova R. European Guidelines on cardiovascular dis-

ease prevention in clinical practice (version 2012). European heart journal.

2012;33:1635-1701.

[20] Stone N, Robinson J, Lichtenstein A, Goff Jr D, Lloyd-Jones D, Smith Jr S,

Blum C and Schwartz J. ACC/AHA Cholesterol Guideline Panel. Treatment

of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in

adults: synopsis of the 2013 American College of Cardiology/American Heart

Association cholesterol guideline. Ann Intern Med. 2014;160:339-43.

[21] Smith SC, Jr., Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA,

Gibbons RJ, Grundy SM, Hiratzka LF, Jones DW, Lloyd-Jones DM, Minissian

M, Mosca L, Peterson ED, Sacco RL, Spertus J, Stein JH, Taubert KA, World

Heart F and the Preventive Cardiovascular Nurses A. AHA/ACCF Secondary

Prevention and Risk Reduction Therapy for Patients with Coronary and

other Atherosclerotic Vascular Disease: 2011 update: a guideline from the

American Heart Association and American College of Cardiology Foundation.

Circulation. 2011;124:2458-73.

[22] Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U and Group

ES. Cardiovascular prevention guidelines in daily practice: a comparison

of EUROASPIRE I, II, and III surveys in eight European countries. Lancet.

2009;373:929-40.

[23] Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi

R, Iqbal R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-

Jaramillo P, Oguz A, Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren

A, Teo KK and Prospective Urban Rural Epidemiology Study I. Use of second-

ary prevention drugs for cardiovascular disease in the community in high-

income, middle-income, and low-income countries (the PURE Study): a

prospective epidemiological survey. Lancet. 2011;378:1231-43.

[24] Zeymer U, Berkenboom G, Coufal Z, Belger M, Sartral M, Norrbacka K, Bakhai A

and investigators A. Predictors, cost, and outcomes of patients with acute cor-

onary syndrome who receive optimal secondary prevention therapy: results

from the antiplatelet treatment observational registries (APTOR). Int J Cardiol.

2013;170:239-45.

[25] Lafeber M, Grobbee DE, Spiering W, van der Graaf Y, Bots ML, Visseren FL and

Group SS. The combined use of aspirin, a statin, and blood pressure-lowering

agents (polypill components) in clinical practice in patients with vascular dis-

eases or type 2 diabetes mellitus. Eur J Prev Cardiol. 2013;20:771-8.

[26] Muntner P, Mann D, Wildman RP, Shimbo D, Fuster V and Woodward M.

Projected impact of polypill use among US adults: medication use, cardiovascu-

lar risk reduction, and side effects. American heart journal. 2011;161:719-725.

[27] Mendis S, Abegunde D, Yusuf S, Ebrahim S, Shaper G, Ghannem H and Shengelia

B. WHO study on Prevention of REcurrences of Myocardial Infarction and

StrokE (WHO PREMISE). Bull World Health Organ. 2005;83:820-9.

[28] Accessibility PD. Issues in International Health Policy. 2010.

[29] Haynes RB, McKibbon KA and Kanani R. Systematic review of randomised tri-

als of interventions to assist patients to follow prescriptions for medications.

Lancet. 1996;348:383-6.

[30] O’Flaherty M, Buchan I and Capewell S. Contributions of treatment and life-

style to declining CVD mortality: why have CVD mortality rates declined so

much since the 1960s? Heart. 2013;99:159-62.

[31] Naderi SH, Bestwick JP and Wald DS. Adherence to drugs that prevent

cardiovascular disease: meta-analysis on 376,162 patients. Am J Med.

2012;125:882-7 e1.


[32] Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, Stricker B,

Mendis S, Hofman A, Mant J and Franco OH. Adherence to cardiovascular

therapy: a meta-analysis of prevalence and clinical consequences. Eur Heart J.

2013;34:2940-8.

[33] Sabaté E. Adherence to long-term therapies: evidence for action: World


[34] Castellano JM, Sanz G, Fernandez Ortiz A, Garrido E, Bansilal S and Fuster V. A

polypill strategy to improve global secondary cardiovascular prevention: from

concept to reality. J Am Coll Cardiol. 2014;64:613-21.

[35] Perreault S, Blais L, Lamarre D, Dragomir A, Berbiche D, Lalonde L, Laurier

C, St-Maurice F and Collin J. Persistence and determinants of statin therapy

among middle-aged patients for primary and secondary prevention. Br J Clin

Pharmacol. 2005;59:564-73.

[36] Kassab Y, Hassan Y, Abd Aziz N, Ismail O and AbdulRazzaq H. Patients’ adher-

ence to secondary prevention pharmacotherapy after acute coronary syn-

dromes. Int J Clin Pharm. 2013;35:275-80.

[37] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L,

Guzman L, Linares JC, Garcia F, D’Aniello F, Arnaiz JA, Varea S, Martinez F,

Lorenzatti A, Imaz I, Sanchez-Gomez LM, Roncaglioni MC, Baviera M, Smith

SC, Jr., Taubert K, Pocock S, Brotons C, Farkouh ME and Fuster V. A polypill

strategy to improve adherence: results from the FOCUS project. J Am Coll

Cardiol. 2014;64:2071-82.

[38] Osterberg L and Blaschke T. Adherence to medication. N Engl J Med.

2005;353:487-97.

[39] Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC and Shrank WH. Trends

in adherence to secondary prevention medications in elderly post-myocardial

infarction patients. Pharmacoepidem Dr S. 2008;17:1189-1196.

[40] Akincigil A, Bowblis JR, Levin C, Jan S, Patel M and Crystal S. Long-term adher-

ence to evidence based secondary prevention therapies after acute myocar-

dial infarction. J Gen Intern Med. 2008;23:115-121.

[41] Ens TA, Seneviratne CC, Jones C, Green TL and King-Shier KM. South Asians’

cardiac medication adherence. Eur J Cardiovasc Nurs. 2014;13:357-68.

[42] Ho PM, Magid DJ, Shetterly SM, Olson KL, Maddox TM, Peterson PN, Masoudi

FA and Rumsfeld JS. Medication nonadherence is associated with a broad

range of adverse outcomes in patients with coronary artery disease. American

heart journal. 2008;155:772-779.

[43] Dagenais GR, Pogue J, Fox K, Simoons ML and Yusuf S. Angiotensin-converting-

enzyme inhibitors in stable vascular disease without left ventricular systolic

dysfunction or heart failure: a combined analysis of three trials. The Lancet.

2006;368:581-588.

[44] Mukherjee D, Fang J, Chetcuti S, Moscucci M, Kline-Rogers E and Eagle KA.

Impact of combination evidence-based medical therapy on mortality in

patients with acute coronary syndromes. Circulation. 2004;109:745-749.

[45] Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER,

Muhlbaier LH and Califf RM. Long-term adherence to evidence-based secondary

prevention therapies in coronary artery disease. Circulation. 2006;113:203-12.

[46] Taylor MJ, Scuffham PA, McCollam PL and Newby DE. Acute coronary syn-

dromes in Europe: 1-year costs and outcomes. Current Medical Research and

Opinion®. 2007;23:495-503.

[47] Bitton A, Choudhry NK, Matlin OS, Swanton K and Shrank WH. The impact

of medication adherence on coronary artery disease costs and outcomes: a

systematic review. Am J Med. 2013;126:357 e7-357 e27.

[48] Heeley E, Anderson CS, Huang Y, Jan S, Li Y, Liu M, Sun J, Xu E, Wu Y, Yang

Q, Zhang J, Zhang S, Wang J and China QI. Role of health insurance in avert-

ing economic hardship in families after acute stroke in China. Stroke.

2009;40:2149-56.

[49] Marcum ZA, Sevick MA and Handler SM. Medication nonadherence: a diag-

nosable and treatable medical condition. JAMA. 2013;309:2105-6.

[50] Mwaka AD, Wabinga HR and Mayanja-Kizza H. Mind the gaps: a qualitative

study of perceptions of healthcare professionals on challenges and proposed

remedies for cervical cancer help-seeking in post conflict northern Uganda.

BMC family practice. 2013;14:193.

[51] Choudhry NK, Krumme AA, Ercole PM, Girdish C, Isaman DL, Matlin OS,

Brennan TA, Shrank WH and Franklin JM. Rationale and design of the

Randomized Evaluation to Measure Improvements in Non-adherence from

Low-Cost Devices (REMIND) trial. Contemporary clinical trials. 2015;43:53-59.

[52] Castellano JM, Sanz G and Fuster V. Evolution of the polypill concept and

ongoing clinical trials. Canadian Journal of Cardiology. 2014;30:520-526.

[53] Castellano JM, Sanz G, Peñalvo JL, Bansilal S, Fernández-Ortiz A, Alvarez L,

Guzmán L, Linares JC, García F and D’Aniello F. A polypill strategy to improve

adherence: results from the FOCUS project. Journal of the American College of

Cardiology. 2014;64:2071-2082.

[54] Berben L, Bogert L, Leventhal ME, Fridlund B, Jaarsma T, Norekvål TM, Smith

K, Strömberg A, Thompson DR and De Geest S. Which interventions are used

by health care professionals to enhance medication adherence in cardio-

vascular patients? A survey of current clinical practice. European Journal of

Cardiovascular Nursing. 2011;10:14-21.

[55] Nieuwkerk PT, Nierman MC, Vissers MN, Locadia M, Greggers-Peusch P, Knape

LP, Kastelein JJ, Sprangers MA, de Haes HC and Stroes ES. Intervention to

improve adherence to lipid-lowering medication and lipid-levels in patients

with an increased cardiovascular risk. The American journal of cardiology.

2012;110:666-672.

[56] Hohmann C, Neumann-Haefelin T, Klotz JM, Freidank A and Radziwill R.

Adherence to hospital discharge medication in patients with ischemic stroke

A prospective, interventional 2 phase study. Stroke. 2013;44:522-524.

[57] Kalichman SC and Grebler T. Stress and poverty predictors of treatment adher-

ence among people with low-literacy living with HIV/AIDS. Psychosomatic

medicine. 2010;72:810.

[58] Parashar S, Palmer AK, O’Brien N, Chan K, Shen A, Coulter S, Montaner JS and

Hogg RS. Sticking to it: the effect of maximally assisted therapy on antiretrovi-

ral treatment adherence among individuals living with HIV who are unstably

housed. AIDS and Behavior. 2011;15:1612-1622.

[59] Nieuwlaat R, Wilczynski N, Navarro T, Hobson N, Jeffery R, Keepanasseril A,

Agoritsas T, Mistry N, Iorio A and Jack S. Interventions for enhancing medica-

tion adherence. Cochrane Database Syst Rev. 2014;11.

[60] Eurostat. Database -Eurostat.

last page reference


Global burden of cardiovascular disease: a call for action

Cardiovascular disease (CVD) is the leading cause of morbidity

and mortality worldwide. The last decade has attested to the rapid

globalization of the consumer society, which has profoundly

impacted lifestyles and cardiovascular (CV) risk factors at a global

scale. The growth of poor eating habits, obesity, and hypertension

are relentlessly contributing to the development of an epidemic

of CVD, the consequences of which have had the highest toll

on low and middle-income economies (LMIC). The immediate

consequence of this socio-demographic shift had a landmark in

2010 when the World Health Organization (WHO) reported more

than 17 million deaths globally were attributed to CVD, over 80%

of which occurred in LMIC [1]. Moreover, global CVD mortality

estimates project more than 23.6 million CVD related deaths by

2030 [2]. Ischaemic heart disease and cerebrovascular diseases,

the most frequent CVDs, are major causes of disability resulting

in 130 million disability-adjusted life years (DALYs) lost in 2010

[1].

In parallel, high income countries, where accessibility to

resources is high, are encountering what has been termed as

the ‘CVD mortality paradox’ [3], which describes the inverse

relationship between CVD mortality and cost. In the US, the

death rate from CVD has fallen about 39 percent between 2001

and 2012 [2] as well as in most European countries [4], yet the

burden and risk factors remain alarmingly high and the costs of

treating CVD in high income countries are staggering. Data from

the Heart Disease and Stroke Statistics from 2015 showed that

the annual direct and indirect cost of CVD and stroke in the US

United States is an estimated $320.1 billion. This figure includes

$195.6 billion in expenditures (direct costs, which include the

cost of physicians and other professionals, hospital services,

prescribed medications, and home health care, but not the cost of

nursing home care) and $124.5 billion in lost future productivity

attributed to premature CVD and stroke mortality in 2011

(indirect costs) [2]. In other words, CVD and stroke accounted

for 15% of total health expenditures in 2011, more than any major

diagnostic group [5]. In Europe, the total cost of CVD is estimated

at €196 billion a year, of which 54% is due to health care costs,

K E Y W O R D S

Cardiovascular polypill


Primary prevention

Treatment adherence

A B S T R A C T

Cardiovascular risk modification in terms of comprehensive medical therapy (antithrombotic therapy,

lipid-lowering therapy, antihypertensive medication) and lifestyle modification (healthy diet, regular

exercise, weight loss, smoking cessation) is the cornerstone of secondary prevention. It is now clear

that even in those undergoing PCI or bypass surgery, appropriate lifestyle modification and aggressive

medical therapy are paramount for optimizing long-term outcomes. However, what has emerged from

studies that examined the role of medical therapy in the context of coronary heart disease is that

only ~50% of the patients in these studies are achieving target treatment goals for blood pressure,

lipid and glycemic control. Non-adherence is thought to be a very large contributor to this problem;

across all health-care categories, non-adherence is estimated to account for $290 billion of annual

health-care expenditure in the United States and €1.25 billion in European Union, with poor adherence

to CVD medication accounting for 9% of all European CVD events. Socioeconomic factors may have a

role in patients’ discontinuing their medications, and a major initiative to combat this problem is the

increasing focus on the polypill. The idea of combining numerous medications into a single tablet

to reduce CV risk was first proposed more than a decade ago. This combined formulation not only

significantly enhances patient convenience and adherence but also drives savings for the healthcare

systems. Several randomized clinical trials have consistently demonstrated the effects of polypills

on CV risk factors and adherence, and major trials are underway to study the effect on hard clinical

outcomes.


The cardiovascular polypill: clinical data and ongoing studies

José M. Castellanoa,b,c, Héctor Buenoa,d,e, Valentín Fustera,c,*

a Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainb Hospital Universitario Montepríncipe, HM Hospitales, Madrid, Spaind Hospital Universitario 12 de Octubre and Instituto de investigación i+12, Madrid, Spaine Universidad Complutense de Madrid, Madrid, Spainc Mount Sinai Cardiovascular Institute, New York, USA

* Corresponding author at: Mount Sinai Heart, One Gustave L. Levy Place,

Box 1030 New York City, NY 10029. Tel.: +1 212 241 3852; fax: +1 212 423 9488.






J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14 S9

24% due to productivity losses and 22% due to informal care

of people with CVD [4]. Health care costs represent €212 per

capita per annum, which is around 9% of the total health care

expenditure across the EU. The economic impact of CVD in LMICs

has been estimated to reduce gross domestic product by up to

6.77% [6], which has already been impairing economic growth

in certain regions.

Optimizing secondary prevention in patients with CVD

remains as a big unmet need worldwide. The causes of inade-

quate secondary prevention are multiple. First, lack of treatment

adherence in patients is a serious problem that has been

overlooked in recent decades. The problem is most apparent

in patients with chronic diseases and has been reported in

all countries studied, irrespective of the health care system,

economic situation, and education level [7]. Levels of adherence

in secondary prevention, irrespective of the assessment tool,

have consistently been shown to be about 50% [8,9]. Together

with the type of drug, one of the main reasons for treatment

discontinuation is its complexity and, particularly, the number

of doses (ie, pills, capsules) that the patient must take every

day [10]. The problem is bigger in LMIC, where access to the

healthcare system may be limited and medical attention deficient.

Medication is frequently unavailable or too expensive, given that

health care coverage in LMIC is practically nonexistent and drugs

in the private sector are expensive. The WHO-PREMISE study

found that in some LMICs fewer than 40% of acute myocardial

infarction patients received ACEIs, and only 20% received statins

[11]. The Prospective Urban Rural Epidemiological (PURE) study

included individuals from rural and urban communities in

countries at various stages of economic development in order

to establish accessibility to CV pharmacotherapy. The study

confirmed that adherence with drugs for secondary prevention

in patients with established CVD was generally low and worst in

the low-income countries; with over 80% receiving none of the

effective drug treatments in South Asia [12]. Thus, any attempt

to apply individualized medicine in those countries according to

our standards is a pipe dream. Despite the efforts of healthcare

authorities, professionals, and scientific bodies, the situation

in developed countries is still far from ideal. In countries with

adequate accessibility to treatment, there is a need to increase

effectiveness, which demands improving treatment adherence.

Evolution of the polypill concept

Limitations on real world applicability of various public

health strategies to influence dietary and physical habits

make it unfeasible to have a significant impact in a reasonable

timeframe (such as educational efforts, legislation, dietary

recommendations, public health system infrastructure to meet

preventive needs, etc.). Hence, the concept of the polypill was

proposed as a simple, innovative and cost-effective public health

strategy to influence accessibility to medications and adherence

to treatment at a global scale. For some health professionals,

the idea of a polypill for CV prevention is merely an interesting

concept that is of limited usefulness and applicability. For

others, however, the polypill could save thousands of lives if

used in the proper context and with the correct indication. What

is clear to most is that the global burden of CVD requires new,

simple approaches to impede the growth of CVD by effectively

improving quality of care.

The concept of the CV polypill is now more than a decade old.

It was originally proposed in 2001 by a WHO and Wellcome Trust

expert group [13] and subsequently specified as a combination of

four drugs (beta-blocker, angiotensin converting enzyme [ACE]

inhibitor, aspirin and a statin), which was estimated to reduce

CVD events by 75% in people with clinical evidence of CVD

[14]. Reservations about this CV prevention strategy certainly

are multifactorial, but a decisive part has clearly been played

by the original interpretations of the role of the polypill and

its possible indications. In 2003, 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% [15]. 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.

Based on Wald and Law’s initial idea, various authors

proposed a more selective use of polypills for primary prevention

in individuals without CVD but high CV risk [16]. 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 [17,18]. Overall, the studies show that the use of a

CV polypill significantly increases treatment adherence [19–21].

None of these studies had the power to detect differences in

the rate of new coronary events. Therefore, 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 use of a polypill strategy has been advocated for secon-

dary prevention in patients with CVD, particularly those who

have already had a myocardial infarction [22]. This strategy may

improve treatment accessibility and affordability in developing

countries and increase treatment adherence, still poor in all

socioeconomic levels, which increases subsequent event rates

and health care costs. The main strengths of a polypill strategy

are the significant beneficial impact on adherence, as shown

in numerous randomized clinical trials [9,19–21], and cost-

effectiveness, where polypills have been shown to be cost

saving for health care systems [23–27]. Therefore, polypill

based strategies for optimizing CV prevention are attractive

options both for LMIC and developed countries. In this context,

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 polypill was designed as

a key element for a comprehensive public health program of CV

prevention, which necessarily must include education of patients

and physicians on health promotion and changes in lifestyle.

From conceptual debate to worldwide reality: clinical evidence supporting the use of a cardiovascular polypill as a public health strategy

Evidence is available on the efficacy, safety, tolerability,

affordability and effect on adherence of polypills for the primary

and secondary prevention of CVD. All CV polypills that have

been developed before the Fuster-CNIC-Ferrer CV polypill have

not achieved the regulatory requirements to be approved in any

European country or in USA.

Primary prevention

Several pilot studies have demonstrated the feasibility of the

polypill-based primary prevention strategy [28–31]. In summary,

these randomized trials have shown that the combination

S10 J.M. Castellano et al. / International Journal of Cardiology 201 S1 (2015) S8–S14

of several antihypertensive agents, a statin, and aspirin can

substantially reduce blood pressure and lipid levels (Table 1). The

pills were well tolerated and showed low rates of adverse effects

and discontinuation. The trials have also shown high adherence

rates, although most have studied for short duration.


The potential value of applying the polypill concept for

secondary prevention has been recognized by different expert

panels, including the WHO and the Combination Pharmacotherapy

and Public Health Research Working Group who advocate

carrying out research that provides further evidence on the use

of a polypill in this area [32–34]. For secondary prevention, TIPS-

2 reported significant reductions in BP and LDL-C in patients with

stable CVD or diabetes with the use of the combination drugs

used in TIPS-1, that is a polypill containing 3 BP-lowering drugs

(atenolol 50 mg, hydrochlorothiazide 12.5 mg, and ramipril 5

mg), 20 mg of simvastatin, and 100 mg of aspirin. In total, 518

individuals eligible for secondary prevention were randomly

allocated to receive either a single polypill, or 2 capsules of the

polypill plus K+ supplementation for 8 weeks. Compared with

Table 1Principal Clinical Trials using a CV Polypill

Trial/Sample Size/Principal Investigator(s)

Population Polypill Composition Outcomes Status

Primary prevention

Indian Polycap Study (TIPS)

n=2053

Yusuf S, Pais P

Men and women aged 40–80 years

without CVD and with at least 1 CV

risk factor in India

Aspirin 100 mg, simvastatin

20 mg, ramipril 5 mg,

hydrochlorothiazide 12.5 mg,

atenolol 50 mg

Feasibility; effect

on risk factor levels;

safety and tolerability

Completed

Poly-Iran: Phase II Study of Heart

Polypill Safety and Efficacy in Primary

Prevention of CV Disease

n=475

Marshall T, Malekzadeh R,

Malekzadeh F

Men and women aged

50–80 years without indications or

contraindications for aspirin,

BP-lowering drugs, and statins in

Iran

Aspirin 81 mg,


enalapril 2.5 mg,

atorvastatin 20

Effect on risk factor

levels; safety and

tolerability

Completed

Combination Therapy Trial

n=200

Furberg C, Mendis S, Soliman EZ.

Age >40 years without CVD and with

estimated 10-year total CVD risk

score >20% in Sri Lanka


10 mg, lisinopril 10 mg,

hydrochlorothiazide 10 mg

(Red Heart Pill 2b)

Effect on estimated

10-year total CVD risk

score

Completed

IMProving Adherence using

Combination Therapy (IMPACT)

n=497

Rodgers A, Selak A.

Established CVD or 5-year risk ≥15% Aspirin 75 mg, simvastatin

40 mg, and lisinopril 10 mg

with either atenolol 50 mg or

hydrochlorothiazide 12.5 mg

Effect on adherence to

recommended drugs

and mean change in

blood pressure and

LDL-chol at 12 months

Completed

Indian Polycap Trial (TIPS)-3

n=5000

Yusuf S, Pais P, Xavier D, Liu L.

Primary prevention with estimated

yearly CVD event rate of >1% using

the INTERHEART risk score in China

and India

Polycap; dose to be chosen

after completion of the

TIPS-K trials

Major CVD events;

neurocognitive

function

Estimated study

completion date:

January 2019

Heart Outcomes Prevention Evaluation

(HOPE)-3

n=12,500

Yusuf S, Lonn E

Primary prevention in men aged >55

years and women aged >65 years

with at least 1 CV risk factor and

women aged >60 years with at least

2 risk factors and with average BP

and cholesterol levels in 22 countries

Rosuvastatin 10 mg,

candesartan 16 mg/

hydrochlorothiazide 12.5 mg

(2×2 factorial design)

Major CVD events;

neurocognitive

function; renal

function

Estimated study

completion date:

March 2016


FOCUS Trial in Secondary Prevention

Phase 1: n=2000, Phase 2: n=800

Fuster V

Survivors of myocardial infarction in

Spain and Latin American countries


40 mg, ramipril 2.5, 5, 10 mg

(Trinomia)

Adherence; feasibility;

effect on risk factor

levels; safety and

tolerability

Completed

Use of a Multidrug Pill In Reducing CV

Events UMPIRE

n=2000

Thom SA, Rodgers A

Established CVD or high-risk primary

prevention (5-year CVD risk of >15%)

in India, Netherlands, UK

Aspirin 75 mg, atenolol

50 mg, simvastatin 40 mg,

lisinopril 10 mg (Red Heart

Pill 1) or aspirin 75 mg,


simvastatin 40 mg, lisinopril

10 mg (Red Heart Pill 2)

Adherence; effect

on risk factor levels;

safety and tolerability;

CVD events

(secondary outcome)

Completed

Patel

n=623

Established CVD or high risk primary

prevention (5-year CVD risk of >15%)

Australia


40 mg, lisinopril 10 mg and

either atenolol 50 mg or

hydrochlorothiazide 12.5 mg.

Adherence to

medications, systolic

blood pressure and

total cholesterol.

Completed

SECURE Trial

n=3200

Fuster V, Castellano JM

Elderly population (>65 years) with a

diagnosis of AMI

Trinomia (Aspirin 100,

Ramipril 2.5, 5 or 10mg,

Atorvastatin 40mg)

Composite primary

endpoint of

cardiovascular

death, nonfatal MI,

nonfatal ischaemic

stroke and urgent

revascularization

Ongoing.

Estimated study

completion date:

April 2020.


the single dose, the double-dose, or full-dose, reduced systolic

and diastolic BPs and LDL-C levels by an additional 2.8 mmHg,

1.7 mmHg, and 6.6 mg/dl, respectively. Both doses were similarly

well tolerated. The investigators anticipate that the full-dose

regimen would reduce the risk of CHD by 75%, and of stroke by

65% [35].

The Use of a Multidrug Pill In Reducing cardiovascular Events

(UMPIRE) study was the first randomized trial designed to

assess the long-term effect of a polypill strategy in improving

patients’ adherence to medication in CV prevention [20]. This

trial included 2,004 patients (88% with CVD) from 3 European

countries and India. Two different polypill strategies were used

at the physicians’ discretion: 75 mg aspirin, 10 mg lisinopril,

40 mg simvastatin, and either 50 mg atenolol or 12.5 mg

hydrochlorothiazide. At the end of the study (median follow-up

15 months), adherence to medication in the polypill group was

85%, compared with 60% in the standard-care group (p<0.001).

BP and LDL-cholesterol levels were reduced with the polypill

strategy to a greater extent than with standard care, but the

differences were modest (2.6 mmHg and 4.2 mg/dl, respectively;

p<0.001 for each). No significant differences were reported in the

incidence of serious adverse effects between the groups.

The IMPACT trial evaluated 513 adults at high risk of CVD (with

established CVD or 5-year risk of ≥15%), who were recommended

for treatment with antiplatelet, statin, and 2 or more BP-

lowering drugs, and were randomized to continued usual care

or to polypill treatment (with 2 possible approaches: aspirin 75

mg, simvastatin 40 mg, and lisinopril 10 mg with either atenolol

50 mg or hydrochlorothiazide 12.5 mg) and included 12 months’

follow-up. The investigators found that, in line with other

studies, adherence to all 4 recommended drugs was greater

among polypill than usual care participants at 12 months (81% vs

46%; relative risk 1.75, 95% CI 1.52-2.03, p<0.001) [21].

Patel et al. recently published the results of an open-label,

randomized trial involving 623 participants recruited in

Australian general practices [36]. Participants had established

CVD or an estimated five-year CVD risk of ≥15%, with indications

for antiplatelet, statin and ≥2 blood pressure lowering drugs

(‘combination treatment’) and were randomized to the ‘polypill-

based strategy’ received a polypill containing aspirin 75 mg,

simvastatin 40 mg, lisinopril 10 mg and either atenolol 50 mg

or hydrochlorothiazide 12.5 mg. Participants randomized to

‘usual care’ continued with separate medications and doses

as prescribed by their physician. Primary outcomes were self-

reported adherence to medications, systolic blood pressure

and total cholesterol. After a median of 18 months, patients

randomized to the polypill presented a significantly higher

adherence than those receiving usual care (70% vs 47%, p<0.001).

The study found no significant differences in BP or LDL-C

between both groups, possibly due to limited power of the study.

The FOCUS (Fixed Dose Combination Drug for Secondary

Cardiovascular Prevention) study was the first to prove the

benefits of a polypill strategy in secondary prevention. FOCUS

was fully funded by the FP7 EC programme and consisted

of a cross-sectional study (Phase 1) of 2118 post MI patients

recruited in Argentina, Brazil, Italy, Paraguay, and Spain, aimed

to elucidate factors that interfere with appropriate adherence

to CV medications for secondary prevention after an AMI [37].

Additionally, 695 patients from phase 1 were randomized into

a controlled clinical trial (Phase 2) to test the effect of Fuster-

CNIC-Ferrer CV polypill (a polypill containing aspirin 100 mg,

simvastatin 40mg and ramipril 2.5, 5 or 10 mg) compared to

the three drugs given separately on adherence, blood pressure

(BP) and low density lipoprotein cholesterol (LDL-C), as well as

safety and tolerability over a period of 9 months of follow-up.

Primary end-point in phase 2 was adherence to the treatment

measured at the final visit by the self-reported Morisky-Green

Adherence Questionnaire (MAQ) and pill count (patients had to

meet both criteria for adherence at the in-person visit in order

to be considered adherent). The results of phase 1 showed a very

low overall CV medication adherence of 45.5%. In a multivariable

regression model, the risk of being non-adherent was associated

with younger age, depression, being on a complex medication

regimen, poorer health insurance coverage, and a lower level of

social support, with consistent findings across countries. In Phase

2, the polypill group showed improved adherence compared to

the group receiving separate medications after 9 months follow

up: 50.8% vs 41% (p=0.019; intention-to-treat population) and

65.7% vs 55.7% (p=0.012; per protocol population) when using

the primary endpoint, attending the final visit with MAQ and

high pill count (80–110%) combined, to assess adherence.

Adherence was also higher in the FDC group when measured by

MAQ alone (68% vs. 59%, p=0.049). No treatment difference was

found at follow-up in mean SBP (129.6 vs 128.6 mmHg), mean

LDL-C levels (89.9 vs 91.7 mg/dL), serious adverse events (23

[6.6%] vs. 21 [6%]) or death (1, 0.2% in each group). In consonance

with other clinical trials, compared with the three drugs given

separately, the use of a polypill strategy met the primary

endpoint for adherence – self-reported and direct measured

medication – for post-MI secondary prevention.

Ongoing clinical trials

Several large, ongoing studies are testing the ability of different

polypills to reduce the occurrence of new CV events in real-world

practice. TIPS-3, HOPE-3, Poly-Iran, and HOPE-4 are currently

underway testing different combination pills against placebo.

TIPS-3 will evaluate a preparation of the Polycap without aspirin

(either the doses used in the first TIPS trial or enhanced doses

based on results of the TIPS-K trial) versus placebo over 5 years

in 5,000 individuals without CVD and with an estimated risk of

major CVD of 1%/year in India and China. The ongoing HOPE-3

trial is evaluating the concept of combined BP and cholesterol

lowering medications in individuals without vascular disease

and with average BP and cholesterol levels [38] in 22 countries in

North and South America, Europe, Africa, Asia, and Australia and

will soon complete enrollment of 12,500 individuals at moderate

CV risk (men age 55 years, with women over 65 years with 1

risk factor or women over 60 years with 2 risk factors). Patients

are randomized to rosuvastatin 10 mg/day alone, a FDC of

candesartan 16 mg/hydrochlorothiazide 12.5 mg/day alone, both,

or neither (2×2 factorial design) for 5 years. The main outcomes

will include major CVD events and changes in cognitive and

renal function. The PolyIran study is seeking to determine the

effects of a PolyPill (a FDC of 2 anti-hypertensive medications,

atorvastatin, and aspirin) on primary and secondary prevention

of CVD in Iranian adults older than 50 years [39]. This ambitious

trial will divide the cohort in 3 arms: 3,500 randomly selected

participants will receive the PolyPill once daily and minimal care

(which consists of direct education and a pamphlet on CV risk

reduction, biannual follow-ups and BP measurements); 3,500

will receive only minimal care as described above; and 24,000

participants will receive usual care (standard primary health care

provided by the local physicians and Community Health Workers

for the whole participants of Golestan Cohort study, consistent

with the current Iranian Health Care System guidelines). The

first and second arms will be compared via a 2-armed open-

labeled cluster RCT. The comparisons between arm 3 and the

other 2 arms will be performed by means of a cohort multiple

RCT design. Endpoints will include major CV events (death and

hospitalization). HOPE-4 is a community cluster RCT that will

evaluate an evidence-based program for CVD risk assessment,


treatment, and control involving simplified screening and

treatment algorithms implemented by non-physician health

workers coupled with lifestyle counseling and combination-

pill therapy [40]. The initial risk factor phase of the study will

assess BP and cholesterol changes in Colombia and Malaysia (50

communities), with plans to expand to 190 communities in 8

countries to evaluate CVD events over 6 years.

The SECURE trial: comparing the efficacy of the Fuster-CNIC-Ferrer CV Polypill vs. usual care in reducing major adverse cardiovascular events during secondary prevention.

The SECondary prevention of cardiovascUlaR disease in the

Elderly (SECURE; EudraCT: 2015-002868-17; NCT0259612)

study is a multicenter, international, randomized trial designed

to evaluate the potential benefit of the Fuster-CNIC-Ferrer CV

polypill, containing aspirin 100 mg, ramipril 2.5, 5 or 10 mgs

and atorvastatin 40mg as a component of a cost-effective,

globally available and comprehensive treatment strategy for

secondary CV prevention. SECURE will enroll a total of 3206

patients >65 years old within 8 weeks of a MI to compare the

efficacy of this polypill in reducing major cardiovascular events

(cardiovascular death, nonfatal MI, nonfatal ischemic stroke,

and urgent revascularization) after a minimum of 2 years

follow-up. The SECURE trial is funded by the European Union

Horizon 2020 Research Support Program and coordinated by

the Centro Nacional de Investigaciones Cardiovasculares (CNIC)

in Spain. SECURE will start enrolling patients soon in in seven

EU countries: Spain, Italy, Germany, France, Poland, Hungry and

Czech Republic.

Polypill as a cost effective strategy in cardiovascular prevention

Considering the rising healthcare costs and their impact on

the economy, it is critical to understand what the future might

hold for CVD prevalence and cost. Currently, CVD is the leading

cause of death and in the United States it already constitutes

17% of overall national health expenditures. Projections show

that between 2010 and 2030, real total direct medical costs of

CVD are projected to triple, from $272.5 billion to 818.1 billion

[5] (Figure 1). Part of the huge economic burden of CVD falls

on the limited effectives of pharmacological treatment due to

non-adherence to medication. In fact, direct and indirect costs

of non-adherence to chronic treatments have been calculated

between $100billion and $289billion annually in the US [41,42].

Non-adherence leads up to €1.25 billion in annually within

the European Union with poor adherence to CVD medication

accounting for 9% of all European CVD events [43]. Therefore,

efforts to promote adherence are gathering worldwide attention

from patients, providers, payers and regulators. A variety of

interventions have been proposed, and range from blister

packaging, case management, education with behavioral

support, reminder calls, pharmacist-led, multicomponent inter-

ven tions, education with behavioral support, collaborative

care, shared decision making. Not all interventions, however,

provided evidence of benefit [44]. Complex interventions

are generally believed to be more effective that simple ones,

however little is known about potential trade-off between their

increased costs and the cost saving that might be reduced from

increased adherence. Moreover, complex interventions that may

show effectiveness in a high income settings are generally non

applicable to limited resource settings, where the burden of CVD

is highest. For this reason, there has been a tremendous effect

in analyzing the potential cost effectiveness of a CV polypill in

various resource settings.

The cost-effectiveness of a polypill regimen for patients at

high risk for CVD specifically in the setting of LMIC has also

been tested. Gaziano et al. [26] performed a pharmacoeconomic

study assessing 2 combination regimens, 1 for primary preven-

tion (which included aspirin, a calcium channel blocker, an

angiotensin-converting enzyme inhibitor, and a statin) and

another for secondary prevention (which included the same

combination of drugs in group 1 but substituted a beta-blocker for

the calcium channel blocker). The incremental cost-effectiveness

ratio for the secondary regimen was between $306 and $388 per

quality-adjusted life-year indicating a cost-effective intervention

for patients with CVD in all developing regions, even in low-

income countries.

The results of a Markov-model-based cost-effectiveness

analysis of the use of a polypill in the UK for secondary CVD

prevention from improved adherence, have been recently

published [27]. The model compared the use of Trinomia (Fuster-

CNIC-Ferrer polypill brand name containing 100 mg aspirin, 20

mg atorvastatin and 2.5, 5, or 10 mg ramipril) with multiple

monotherapy. Outcome measures were CV events prevented per

1000 patients; cost per life-year gained; and cost per quality-

adjusted life-year (QALY) gained. The model estimates that for

each 10% increase in adherence, an additional 6.7% fatal and

non-fatal CV events can be prevented. In the base case, over

10 years, the polypill would improve adherence by ~20% and

thereby prevent 47 of 323 (15%) fatal and non-fatal CV events

per 1000 patients compared with multiple monotherapy, with

an incremental cost-effectiveness ratio (ICER) of £8200 per

QALY gained. Probabilistic sensitivity analyses for the base-

case assumptions showed an 81.5% chance of the polypill being

cost-effective at a willingness-to-pay threshold of £20,000 per

QALY gained compared with multiple monotherapy. In scenario

analyses that varied structural assumptions, ICERs ranged

between cost saving and £21,430 per QALY gained. Based on

this model, the polypill appears to be a cost-effective strategy

to prevent fatal and non-fatal CV events in the UK. Furthermore,

assuming that some 450,000 adults are at risk of MI, a 10

percentage point uptake of the polypill could prevent 3260 CV

events and 590 CV deaths over a decade [27].

Conclusions

The concept of a polypill, composed of a combination of

medications that are known to effectively treat CVD, has been

proposed as a simple, cost effective and innovative public health

strategy to combat the CVD epidemic on a global scale. Several

studies have shown the polypill to be well tolerated and superior

in terms of adherence to standard of care.

Fig. 1. Projection of rise in cost of treating CVD in the US (in billions US) [5].


Perhaps the best evidence for the polypill concept is in

secondary prevention of CVD where its use has the potential to

close the treatment gap that exists. Large CV clinical trials, such

as FREEDOM, BARI-2D, and COURAGE have demonstrated that

current treatment strategies for secondary prevention are not

effectively improving the risk profiles of patients with CVD [45].

Also, large epidemiological studies have shown CVD therapy

to vary across socioeconomic levels with the worst outcomes

in LMICs [12]. Polypills have emerged as a way to bridge this

treatment gap through simplifying treatment algorithms,

improving patient adherence, improving accessibility, and

reducing CV events and associated costs. The World Health

Organization, citing positive study results, has recognized the

polypill concept as a potential to bridge the treatment gap and

named it a “best buy for cardiovascular disease prevention and

control” in the setting of secondary prevention (post-MI and

stroke). This has led to regulatory approval of the Fuster-CNIC-

Ferrer 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.


Drs. Fuster, Castellano and Bueno are PI, co-PI and scientific

coordinator, respectively, of the SECURE trial. No other conflicts

of interest to report.

References

[1] Organization WH. Global status report on noncommunicable diseases 2010.

Geneva, 2011. 2012.

[2] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.

Executive Summary: Heart Disease and Stroke Statistics—2015 Update A

Report From the American Heart Association. Circulation. 2015;131(4):434–41.

[3] Fuster V, Mearns BM. The CVD paradox: mortality vs prevalence. Nat Rev

Cardiol. 2009;6(11):669.

[4] Nichols M, Townsend N, Scarborough P, Rayner M. Cardiovascular disease in

Europe: epidemiological update. Eur Heart J. 2013;34(39):3028–34.

[5] Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz

MD, et al. Forecasting the future of cardiovascular disease in the United

States a policy statement from the American heart association. Circulation.

2011;123(8):933–44.

[6] Daar AS, Singer PA, Persad DL, Pramming SK, Matthews DR, Beaglehole R,

et al. Grand challenges in chronic non-communicable diseases. Nature.

2007;450(7169):494–6.

[7] Castellano JM, Copeland-Halperin R, Fuster V. Aiming at strategies for a com-

plex problem of medical nonadherence. Global Heart. 2013;8(3):263–71.

[8] Naderi SH, Bestwick JP, Wald DS. Adherence to drugs that prevent cardiovas-

cular disease: meta-analysis on 376,162 patients. Am J Med. 2012;125(9):882–

7. e1.

[9] Castellano JM, Sanz G, Peñalvo JL, Bansilal S, Fernández-Ortiz A, Alvarez L, et

al. A polypill strategy to improve adherence: results from the FOCUS project. J

Am Coll Cardiol. 2014;64(20):2071–82.

[10] Claxton AJ, Cramer J, Pierce C. A systematic review of the associations

between dose regimens and medication compliance. Clin Therapeutics.

2001;23(8):1296–310.

[11] Mendis S, Abegunde D, Yusuf S, Ebrahim S, Shaper G, Ghannem H, et al. WHO

study on Prevention of REcurrences of Myocardial Infarction and StrokE

(WHO-PREMISE). Bull World Health Organization. 2005;83(11):820–9.

[12] Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, et al. Use of

secondary prevention drugs for cardiovascular disease in the community in

high-income, middle-income, and low-income countries (the PURE Study): a

prospective epidemiological survey. Lancet. 2011;378(9798):1231–43.

[13] World Health Organization. Secondary prevention of noncommunicable dis-

ease in low and middle income countries through community-based and

health service interventions. (WHO-Wellcome Trust meeting report 1–3.).

2002. Geneva.

[14] Yusuf S. Two decades of progress in preventing vascular disease. Lancet.

2002;360(9326):2–3.

[15] Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than

80%. BMJ. 2003;326(7404):1419.

[16] Castellano JM, Sanz G, Fernandez Ortiz A, Garrido E, Bansilal S, Fuster V. A

polypill strategy to improve global secondary cardiovascular prevention: from

concept to reality. J Am Coll Cardiol. 2014;64(6):613–21.

[17] Study TIP. Effects of a polypill (Polycap) on risk factors in middle-aged indi-

viduals without cardiovascular disease (TIPS): a phase II, double-blind, ran-

domised trial. Lancet. 2009;373(9672):1341–51.

[18] Yusuf S, Pais P, Sigamani A, Xavier D, Afzal R, Gao P, et al. Comparison of Risk

Factor Reduction and Tolerability of a Full-Dose Polypill (With Potassium)

Versus Low-Dose Polypill (Polycap) in Individuals at High Risk of Cardiovascular

Diseases The Second Indian Polycap Study (TIPS-2) Investigators. Circulation:

Cardiovascular Quality and Outcomes. 2012;5(4):463–71.

[19] Patel A, Cass A, Peiris D, Usherwood T, Brown A, Jan S, et al. A pragmatic ran-

domized trial of a polypill-based strategy to improve use of indicated pre-

ventive treatments in people at high cardiovascular disease risk. European

journal of preventive cardiology. 2014:2047487314530382.

[20] Thom S, Poulter N, Field J, Patel A, Prabhakaran D, Stanton A, et al. Effects of

a fixed-dose combination strategy on adherence and risk factors in patients

with or at high risk of CVD: the umpire randomized clinical trial. JAMA.

2013;310(9):918–29.

[21] Selak V, Elley CR, Bullen C, Crengle S, Wadham A, Rafter N, et al. Effect of fixed

dose combination treatment on adherence and risk factor control among

patients at high risk of cardiovascular disease: randomised controlled trial in

primary care. BMJ. 2014;348.

[22] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovas-

cular prevention: rationale, selection of drugs and target population. Nat Clin

Prac Cardiovasc Med. 2009;6(2):101–10.

[23] Bautista LE, Vera-Cala LM, Ferrante D, Herrera VM, Miranda JJ, Pichardo R, et

al. A ‘polypill’aimed at preventing cardiovascular disease could prove highly

cost-effective for use in latin america. Health Affairs. 2013;32(1):155–64.

[24] Shroufi A, Chowdhury R, Anchala R, Stevens S, Blanco P, Han T, et al. Cost

effective interventions for the prevention of cardiovascular disease in low

and middle income countries: a systematic review. BMC Public Health.

2013;13(1):285.

[25] Ito K, Shrank WH, Avorn J, Patrick AR, Brennan TA, Antman EM, et al.

Comparative Cost-effectiveness of interventions to improve medication

adherence after myocardial infarction. Health Serv Res. 2012;47(6):2097–117.

[26] Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with

a multidrug regimen in the developing world: a cost-effectiveness analysis.

Lancet. 2006;368(9536):679–86.

[27] Becerra V, Gracia A, Desai K, Abogunrin S, Brand S, Chapman R, et al. Cost-

effectiveness and public health benefit of secondary cardiovascular disease

prevention from improved adherence using a polypill in the UK. BMJ Open.

2015;5(5).

[28] Xavier D, Pais P, Sigamani A, Pogue J, Afzal R, Yusuf S, et al. The need to test the

theories behind the Polypill: rationale behind the Indian Polycap Study. Nat

Clin Prac Cardiovasc Med. 2009;6(2):96–7.

[29] Malekzadeh F, Marshall T, Pourshams A, Gharravi M, Aslani A, Nateghi A, et

al. A pilot double-blind randomised placebo-controlled trial of the effects of

fixed-dose combination therapy (‘polypill’) on cardiovascular risk factors. Int J

Clin Prac. 2010;64(9):1220–7.

[30] Soliman EZ, Mendis S, Dissanayake WP, Somasundaram NP, Gunaratne PS,

Jayasingne IK, et al. A Polypill for primary prevention of cardiovascular dis-

ease: a feasibility study of the World Health Organization. Trials. 2011;12:3.

[31] Group PC, Rodgers A, Patel A, Berwanger O, Bots M, Grimm R, et al. An inter-

national randomised placebo-controlled trial of a four-component combi-

nation pill (“polypill”) in people with raised cardiovascular risk. PloS One.

2011;6(5):e19857.

[32] Ezzati M, Hoorn SV, Rodgers A, Lopez AD, Mathers CD, Murray CJ, et al.

Estimates of global and regional potential health gains from reducing multiple

major risk factors. Lancet. 2003;362(9380):271–80.

[33] Narayan KM, Mensah GA, Sorensen S, Cheng YJ, Vinicor F, Engelgau MM, et

al. Combination pharmacotherapy for cardiovascular disease prevention:

threat or opportunity for public health? Am J Preven Med. 2005;29(5 Suppl

1):134–8.

[34] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovas-

cular prevention: rationale, selection of drugs and target population. Nat Clin

Prac Cardiovasc Med. 2009;6(2):101–10.

[35] Yusuf S, Pais P, Sigamani A, Xavier D, Afzal R, Gao P, et al. Comparison of risk

factor reduction and tolerability of a full-dose polypill (with potassium)

versus low-dose polypill (polycap) in individuals at high risk of cardiovas-

cular diseases: the Second Indian Polycap Study (TIPS-2) investigators. Circ

Cardiovasc Qual Outcomes. 2012;5(4):463–71.

[36] Patel A, Cass A, Peiris D, Usherwood T, Brown A, Jan S, et al. A pragmatic ran-

domized trial of a polypill-based strategy to improve use of indicated pre-

ventive treatments in people at high cardiovascular disease risk. Eur J Prev

Cardiol. 2015;22(7):920-30.

[37] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, et


Am Coll Cardiol. 2014;64(20):2071–82.


[38] Heart Outcomes Prevention Evaluation-3 (HOPE-3), available at http://clini-

caltrials.gov/show/NCT00468923

[39] Prevention of Cardiovascular Disease in Middle-aged and Elderly Iranians

Using a Single PolyPill (PolyIran) avaliable at http://clinicaltrials.gov/ct2/

show/NCT01271985

[40] HeartOutcomes Prevention and Evaluation 4(HOPE-4). http://www.clinical-

trials.gov/show/NCT01826019

[41] Peterson AM, Takiya L, Finley R. Meta-analysis of trials of interventions to

improve medication adherence. Am J Health Sys Pharm. 2003;60(7):657–65.

[42] Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.

2005;353(5):487–97.

[43] Chowdhury R, Khan H, Heydon E, Shroufi A, Fahimi S, Moore C, et al. Adherence

to cardiovascular therapy: a meta-analysis of prevalence and clinical conse-

quences. Eur Heart J. 2013;34(38):2940–8.

[44] Viswanathan M, Golin CE, Jones CD, Ashok M, Blalock SJ, Wines RC, et al.

Interventions to improve adherence to self-administered medications for

chronic diseases in the United States: a systematic review. Ann Intern Med.

2012;157(11):785–95.

[45] Farkouh ME, Boden WE, Bittner V, Muratov V, Hartigan P, Ogdie M, et al. Risk

factor control for coronary artery disease secondary prevention in large rand-

omized trials. J the Am Coll Cardiol. 2013;61(15):1607–15.


1. The Fuster-CNIC-Ferrer CV Polypill: making the leap from conceptual debate to worldwide reality

Moving from the theoretical proposal of a CV polypill to

the actual pharmaceutical development of a combination pill

presents several challenges. The selection of the medications

to include in the combination pill is a complex process. Wald

and Law suggested a pill composed of 6 different compounds

in order to maximize potential benefit [1]. Although the idea

of combining so many compounds into a single pill may seem

attractive for some patient populations, the reality is that the

difficulty of manufacturing a combination pill increases with each

component due to challenges related to the chemical properties

of each substrate (Figure 1). The concept of a CV polypill for

secondary prevention proposed by Fuster et al. resulted from

having a clear picture of the global burden of cardiovascular

disease (CVD) [2]. The effectiveness of the drugs included in a

polypill are generally well understood, and the principles behind

using pharmacotherapy at a population level are that the drugs

themselves should have a well-known risk/benefit ratio and

should be supported by an evidence-based efficacy and safety in

secondary CV prevention. On the other hand, a polypill is simple

to administer and is an effective option to increase adherence in

order to reduce CV events on top of the promotion of lifestyle

changes for multiple risk factor control [3].

The Fuster-CNIC-Ferrer CV polypill (commercialized under

Trinomia®, Sincronium® and Iltria® brand names) was developed

within a very clear conceptual framework: to provide

accessibility of treatment to as many patients worldwide for the

longest periods of time so as to prevent recurrence of events and

death, by simplifying treatment in a cost effective way [2,4]. At

the core of this concept lies the decision of including guideline

recommended therapy for secondary prevention, namely,

blood pressure control and prevention of the LV remodeling

process that accompanies cardiac dysfunction after myocardial

infarction (MI), cholesterol lowering, plaque stabilization and

use of antiplatelet drugs to prevent further CVD events, all of

which are known to be effective in secondary prevention [5,6].

From a clinical standpoint, each additional drug presents the

possibility for more adverse effects (AEs) and thus using too

many components could limit the potential patient population.

Furthermore, when choosing the components of the pill, the

target population of the therapy must be considered because

the benefit for some of the drugs varies with respect to use in

primary and secondary prevention of CVD. For example, a polypill

that targets secondary prevention might favor the inclusion of

an antithrombotic agent, a statin and blood pressure lowering

agents (an angiotensin-converting enzyme (ACE) inhibitor and

beta-blocker (BB) over a calcium channel blocker (CCB)) given

the known mortality benefit of the former medications in post-

MI patients. The Fuster-CNIC-Ferrer CV polypill does not include

K E Y W O R D S

Trinomia®

Sincronium®

Iltria® cardiovascular polypill

Ramipril

Atorvastatin

Simvastatin

Aspirin


A B S T R A C T

During the last decade, there has been a tremendous effort to develop different cardiovascular

polypills in response to the upsurge in global cardiovascular disease worldwide. The pharmacological

development of such a strategy has proven to be extremely complex from a formulation standpoint.

Not all drugs are suitable for use in a polypill because of potential drug incompatibilities between them.

Candidate agents must be safe, well tolerated, effective, guideline recommended and physiochemically

compatible with the other components of the pill.

The Fuster-CNIC-Ferrer cardiovascular (CV) polypill has been found to be the first-in-class polypill to

be approved and commercialized in Europe and Latinamerican Countries. In this article, we review the

pharmacological properties of its three components, including the clinical evidence supporting their

use in patients with established cardiovascular disease, their pharmacokinetic properties, adverse

effects, drug interactions and contraindications.


The Fuster-CNIC-Ferrer Cardiovascular Polypill: a polypill for secondary cardiovascular prevention

Juan Tamargoa, José M. Castellanob,c,d, Valentín Fusterb,d,*

a Department of Pharmacology, School of Medicine, Universidad Complutense, 28040, Madrid, Spainb Centro Nacional de Investigaciones Cardiovasculares (CNIC) Carlos III, Madrid, Spainc HM Hospitales, Hospital Universitario Montepríncipe, Madrid, Spaind Mount Sinai Cardiovascular Institute, New York, USA

* Corresponding author at: Mount Sinai Heart, One Gustave L. Levy Place,

Box 1030 New York City, NY 10029. Tel.: 212.241.3852; fax: 212.423.9488.






S16 J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22

a BB in their combination pill, based on clinical and technical

aspects. Clinically, beta-blockers appropriately titrated are

indicated in patients with STEMI, NSTE-ACS and LV dysfunction

with or without signs of heart failure [7,8]. In stable coronary

heart disease (CHD), there is solid evidence to show that BB

effectively relieve anginal symptoms and improve myocardial

ischemia, and are therefore recommended as first-line agents

for symptom relief in both U.S. [9] and European [10] guidelines.

However, the evidence base for the use of BB to improve

prognosis in asymptomatic patients, who represent about

80% of the stable CHD population [11], is less robust and not

supported by data from an appropriately powered randomized

trial [12]. Additionally, a recent report from the REACH registry

has demonstrated that BB usage in patients with stable CHD

was not associated with a reduced rate of CV death, nonfatal MI,

nonfatal stroke, hospitalization for an atherothrombotic event,

or revascularization, even in patients with previous MI [13].

While guidelines currently recommend 3 years of BB treatment

after presentation with acute coronary syndrome (ACS) [9],

should side effects occur there is no definitive evidence to

insist on continued treatment citing concerns about needing to

increase the number of formulations of the pill to allow for dose

adjustments in order to limit side effects.

The concern about limiting the number of formulations of

the combination pill is well founded because from a technical

standpoint there is an almost linear relationship between the

number of active components in the polypill and the difficulty

of formulation (Figure 1). The difficulty of formulation relates

to the different characteristics of each component with respect

to chemical and physical stability. Combining compounds

with differing solubility and sensitivity to heat and moisture

requires significant development time and cost. The dosages

of the different components of the polypill also complicate

the development process. The use of certain components in

very low doses (such as ramipril at 2.5 mg) combined with

another compound at a much higher dose (such as ASA at 100

mg) causes technical problems with the analytical methods

used in purification and bioanalytics. The formulation of a

combination polypill also has illustrated the potential for drug

incompatibilities and issues with bioavailability.

The Fuster-CNIC-Ferrer CV Polypill has been developed by

a technologic platform patented by Ferrer. The combination of

different active ingredients in a single capsule has been achieved

avoiding the physico-chemical incompatibilities conserving

at the same time the biopharmaceutical and pharmacokinetic

properties of every one of its components (Figure 2).

The combination of atorvastatin, rampiril and acetylsalicylic

acid (ASA) shows a clear chemical incompatibility between the

three active ingredients. The employed technology achieves the

stabilization of all of them inside one single pharmaceutical

form, a capsule.

At the same time, some of the components show a very

high pharmacokinetic variability which difficults enormously

the bioequivalence achievement. The Fuster-CNIC-Ferrer CV

polypill technology has allowed the administration of a single

pharmaceutical form to be equivalent to the concomitant

use of every one of the single active ingredient individually

administered.

The Fuster-CNIC-Ferrer CV polypill includes ASA (100 mg),

ramipril (in doses of 2.5, 5, or 10 mg) and Atorvastatin 20 mg.

2. Pharmacological characteristics of Trinomia®

Extensive controlled, randomised studies have demonstrated

that treatment with the proposed dosages of ASA, atorvastatin,

and ramipril decrease mortality in patients with established

CVD [14–16]. There is also extensive experience with the

combination therapy of these medications in free combinations

for CV prevention, with an adequate risk/benefit ratio, in clinical

practice.

2.1. In vivo and in vitro studies with Trinomia®

2.1.1 In vitro: biopharmaceutical studies

A battery of comparative in vitro dissolution studies between

the biobatch for the fixed-dose combination (test) and the

reference products for ASA (Aspirine N® 100mg), Ramipril

10mg (Acovil®), and atorvastatin (Cardyl® 20 mg) used in the

bioequivalence studies, found that there is a similar in vitro

dissolution profile between the biobatch and the reference

products used in the bioequivalence study [17].

2.1.2 In vivo: biopharmaceutical studies: bioequivalence study

Ferrer Internacional, S.A. (Barcelona, Spain) performed a

randomised, open-label, two-period, two-sequence, controlled,

cross-over, bioequivalence study of single-dose atorvastatin 20

mg, ramipril 10 mg, and ASA 100 mg fixed-dose combination

capsule vs. equivalent doses of Cardyl® 20 mg film-coated

tablets + Acovil® 10 mg tablets + Aspirin N® 100 mg tablets

(reference formulations), in order to establish the rate and

extent of absorption of Trinomia® compared to the individual

components. The study was carried out under fasting conditions

(bioequivalence studies in fasting conditions are considered

Fig. 1. Relationship between the number of drugs in a polypill and the formulation

challenges, patentability, and clinical value. Adapted from Guglietta A, and

Guerrero M. (reprinted with permission, license number: 3640791509009).

Fig. 2. The Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®, Iltria®)

technology.

J. Tamargo et al. / International Journal of Cardiology 201 S1 (2015) S15–S22 S17

to be the most sensitive condition to detect a potential

difference between formulations). Even though there are no

relevant interactions with food for any of the components, it

is recommended to take the Fuster-CNIC–Ferrer CV polypill

after meals in order to improve tolerability mainly related to

aspirin. In accordance with the Guideline on the Investigation

of Bioequivalence [18], this study confirms the bioequivalence of

Trinomia as the geometric 90% confidence intervals for the log-

transformed results of the area under the plasma concentration-

time curve from time 0 to the last sampling time [AUC(0t)

] and

peak plasma concentrations (Cmax

) within the acceptable interval

of 80% to 125% for aspirin, atorvastatin, and ramipril (Table 1).

Thus, the Fuster-CNIC–Ferrer CV polypill is the first-in-class

polypill that has been found bioequivalent as compared with the

individual components of the polypill.

Regarding safety, the results of this bioequivalence study also

confirmed that there is no difference in tolerance and safety

between the two treatment groups.

2.2. Pharmacodynamic properties of the components of Trinomia®

Long-term, controlled, randomised studies have demonstrated

that treatment with the dosages of ASA, atorvastatin, and

ramipril contained in the Fuster-CNIC-Ferrer CV polypill decrease

mortality in patients with established CVD. There is also extensive

experience with the combination therapy of these medications

in free combinations for CV prevention, with an adequate risk/

benefit ratio, in clinical practice [10].

2.2.1. Ramipril

This angiotensin converting enzyme inhibitor (ACEI) decreases

plasma and tissular levels of angiotensin II (Figure 3A) [19]. The

maximum inhibition of plasma ACE activity (>90%) appeared

within 1–4 hours and persisted inhibited by 80% after 24 hours.

Epidemiological studies have consistently demonstrated that

high blood pressure levels correlate with the risk of CVD and

cerebrovascular accidents [20] and antihypertensive drugs reduce

the risk of both conditions, not only in hypertensive patients, but

also in those who have a high CVD risk and normal blood pressure.

Present ESC guidelines recommend ACEIs in hypertensives with

LV hypertrophy, HF or LV dysfunction, myocardial infarction (MI),

diabetes, peripheral artery disease, chronic kidney disease or

microalbuminuria, metabolic syndrome and atherosclerosis [21].

The Heart Outcomes Prevention Evaluation (HOPE) trials showed

that in high risk patients ≥55 years of age with evidence of CVD

or diabetes plus a CV risk factor ramipril (10 mg/day over 5 years)

significantly reduced the rates of death, MI, and cerebrovascular

accidents [22]. A similar benefit was reproduced in diabetic

patients. In this study, ramipril also significantly reduced the

development of HF in patients without known low LV ejection

fraction or HF and in elderly patients reduced the risk of major

CV events, CV deaths, MI, and cerebrovascular accidents.

A meta-analysis of the HOPE, the European trial on Reduction

Of cardiac events with Perindopril among patients with stable

coronary Artery disease (EUROPA), and the Prevention of Events

with ACE inhibition (PEACE) trials found that ACEIs significantly

reduce serious vascular events in patients with atherosclerosis

without known evidence of HF or LV systolic dysfunction [23].

Similarly, ACEIs reduce total mortality and major CV end points

in patients who have CHD and no LV systolic dysfunction or

HF [24]. In patients with MI the Acute Infarction Ramipril

Efficacy (AIRE) Study [15] showed that ramipril produces a 27%

risk reduction (RR) in mortality compared with placebo. This

benefit persisted in patients taking aspirin. Interestingly, ACEIs

were effective when administered with antiplatelet and lipid-

lowering agents. In the Ramipril Efficacy in Nephropathy (REIN)

trial ramipril reduced the glomerular filtration rate decline more

than expected from the blood pressure drop [25]. Therefore,

present AHA/ACC and ESC guidelines recommend ACEIs for all

patients with an EF £40% to reduce the risk of HF hospitalization

and the risk of premature death [6,9] and in all patients after an

ACS in the absence of contraindications [10].

2.2.2. Atorvastatin

This selective and competitive inhibitor of the (3-hydroxy-

3-methyl-glutaryl-CoA (HMG-CoA) reductase reduces the

hepatic synthesis of cholesterol (Figure 3B). In patients with

hypercholesterolemia or with mixed hyperlipidemia, ator-

vastatin dose-dependently (10–80 mg daily) decreases total

cholesterol (30–46%), LDL-C (37–55%), apolipoprotein B (34–

50%) and triglycerides (14–33%) plasma levels, and produces

variable increases in HDL-C (2–12%) [26].

Statins are effective in the primary prevention and secondary

prevention of CV diseases [27]. In a meta-analysis of 27 trials

(n=174,149), a 1 mmol/L (40 mg/dL) reduction in LDL-C levels

by statin therapy results in a 21% RR in major vascular events

(MI, coronary death, coronary revascularization, or stroke) and

a 12% RR in vascular mortality [28]. In the GREek Atorvastatin

and Coronary-heart-disease Evaluation (GREACE) study, long-

term treatment of CHD with atorvastatin (mean dose 24 mg/day)

significantly reduced the relative risk, in comparison to usual

care, of all-cause (RRR 43%), coronary mortality (RRR 47%) and

morbidity (RRR 54%) and stroke (RRR 47%) [14]. In a cohort study,

statin therapy produced a 40% RRR in hospitalisation for acute

MI; the 20 mg daily of atorvastatin was equipotent to 80 mg

of pravastatin, 160 mg of fluvastatin, and 40 mg of simvastatin

[29]. Furthermore, early atorvastatin therapy (20 mg/day

within 48 hours) reduced long-term major adverse cardiac and

cerebrovascular events (MACCE) as compared with placebo.

(30) A review of 52 clinical studies recommended 20 mg of

atorvastatin as the standard initial dose in patients requiring a

LDL-C reduction of 35-50% [31]. In the NICE Guideline 2014 Lipid

modification [32] a daily 20 mg dose of atorvastatin reduces

LDL-C to a similar extent (43%) than 10 mg of rosuvastatin and

80 mg of simvastatin, and more than 40 mg of pravastatin and

40 mg of simvastatin. This guideline recommends atorvastatin

20 mg for the primary prevention of CVD to people with or

without type 2 diabetes who have a 10% or greater 10-year risk of

developing CVD, for the secondary prevention of CVD to people

with chronic kidney disease (CKD) and for people ≥85 years to

reduce the risk of non-fatal MI. Because 20 mg atorvastatin dose

presents a good overall balance between efficacy and safety, this

dose was selected for Trinomia®.

Table 1Results of bioequivalence studies comparing components of the

Fuster-CNIC-Ferrer CV Polypill to monocomponents

Drug Parameter 90% CI

Acetyl salycilic acid

AUC0–t

96.92–104.47 BE

Cmax

84.51–95.78 BE

Ramipril

AUC0–t

108.13–120.11 BE

Cmax

91.51–112.62 BE

Atorvastatin

AUC0–t

95.50–105.93 BE

Cmax

94.58–116.14 BE

The upper and lower CL (confidence level) demonstrate that the ratio

and corresponding 90% confidence interval of the relative AUC0-t

and Cmax

geometric least square means of the Test to Reference formulation are in the

pre-specified 80.00 to 125.00% bioequivalence range for all components of the

fixed combination.

AUC 0-t

area under the curve. Cmax:

maximun plasma concentration. CI:

confidence interval. BE: bioequivalence


2.2.3. Aspirin

Aspirin inhibits platelet aggregation by irreversibly inhibiting

the enzyme cyclooxygenase-1 (Figure 3C) and its antiplatelet

effect last for the duration of platelet life (~10 days) [33]. In

randomised, controlled trials in patients with one or more major

CV risk factors or who have suffered a MI have demonstrated the

efficacy of low-doses of aspirin in the prevention of CV deaths and

total cerebrovascular accidents [34]. Interestingly, the efficacy of

low doses of aspirin (up to 325 mg/day) in preventing the risk of

MI or stroke is greater than with higher doses. A meta-analysis of

287 randomised trials confirmed that long-term treatment with

aspirin (75–125 mg/day) for secondary prevention in a wide

range of patients with high CV risk (patients with a history of MI,

stroke or transient ischemic attacks, or some major CV events)

achieved a RRR of 32% in the incidence of new cardiovascular

events, with no apparent adverse effect on non-cardiovascular

deaths whereas the RRR for the same outcomes was a 26% for

the dose range from 160–325 mg and only of 19% with doses

ranging from 500 mg to 1500 mg [35]. Because of its favorable

benefit-risk ratio, lifelong low-doses of aspirin (75–125 mg) are

the cornerstone for the secondary prevention of MI and death in

patients with coronary artery disease and other atherosclerotic

cardiovascular disease unless contraindicated [6,9,36].

The Fuster-CNIC-Ferrer CV polypill contains 100 mg of ASA,

dose included in the most favourable recommended dosage

range by the current prevention guidelines [6].

2.3. Pharmacokinetic properties of the components of

Fuster-CNIC-Ferrer CV Polypill (Table 2)

2.3.1. Ramipril

It is rapidly absorbed, reaching peak plasma concentrations

(Cmax

) within 1 h. The rate, but not the extent, of absorption

is delayed with food.(19) Ramipril is almost completely

biotransformed in the gut wall and the liver into its metabolite

ramiprilat, which has about 6 times the ACE inhibitory activity

of ramipril and reaches its Cmax

within 2–4 h and steady-state

plasma levels after 4 days. The Cmax

and the 24-hour AUC for

ramiprilat are linear at doses of ramipril between 2.5 and 10 mg

[37]. Ramipril and ramiprilat bind to plasma proteins and are

widely distributed, reaching higher concentrations in kidneys

and lungs than in blood [37]. Ramipril and its metabolites are

excreted in urine (60%, but <2% as unchanged ramipril) and

faeces. After multiple daily doses of 5 and 10 mg of ramipril, the

half-life of ramiprilat is 13–17 hours. ACEIs can cause fetal and

neonatal morbidity and death when given to pregnant women

(Pregnancy Category D). There is no information on the use of

ramipril during breastfeeding.

2.3.2. Atorvastatin

It is rapidly orally absorbed, but presents low oral bioavailability

due to high pre-systemic clearance. Food can decrease the rate

and extent of drug absorption, but does not modify the reduction

Fig. 3. Mechanism of action of (A) ramipril, (B) atorvastatin and (C) acetylsalicilic acid. ACE: angiotensin-converting enzyme. COX: cyclo-oxigenase. ET-1: endothelin-1. GI:

gastrointestinal. NO: nitric oxide. ROS: reactive oxygen species. PGs: prostaglandins. PP: pyrophosphate.


on LDL-C. Atorvastatin highly binds to plasma proteins and

presents a large volume of distribution; thus, hemodialysis does

not increase drug clearance [38]. Atorvastatin is a substrate of

the hepatic uptake transporter OATP1B1 and is predominantly

metabolised by cytochrome P450 3A4 (CYP3A4) into metabolites

that are responsible for 70% of its LDL-C lowering effects, undergo

further metabolism via glucuronidation and are eliminated in

bile. The Cmax

and AUC of atorvastatin are 4- and 11-fold greater

in patients with Childs-Pugh A and B disease, respectively. Thus,

Fuster-CNIC-Ferrer CV Polypill® is contraindicated in patients

with severe liver failure. Conversely, since <2% of the dose is

excreted in urine, dose adjustment are not necessary in patients

with mild-moderate CKD [39]. The half-life of atorvastatin is

~14 hours, but the half-life of the inhibitory activity for HMG-

CoA reductase is 20-30 hours due to its active metabolites. This

explains why LDL-C reduction is the same regardless the time

the drug is administered. Atorvastatin use is contraindicated in

pregnancy (Pregnacy Category X), but it is unknown whether the

drug or its metabolites are excreted in human breast milk [19].

2.3.3. Aspirin

It is rapidly and almost completely absorbed in the stomach

and small intestine [41], reaches the Cmax

within 15–20 minutes

and platelet function is inhibited within 1 hour. Aspirin is

rapidly biotransformed by plasma and tissular esterases into

salicylic acid being undetectable 1–2 h after dosing (half-life

~15–20 min). Salicylic acid reaches the Cmax

within 1–2 h, binds

to plasma proteins (90–99%) and is widely distributed to all

tissues, crosses the blood-brain barrier and the placenta and is

excreted into breast milk. At low doses (<250 mg), salicylic acid is

glucoconjugated in the liver with glycin (salicyluric acid) and to

a lesser extent with glucuronic acid and presents an elimination

half-life of 2–4 hours [60]. Salicylic acid is excreted mainly in

urine, but its urinary excretion increases 10–20 times (from 5%

to more than 80%) when urine pH rises from 5 to 8 [42]. Pregnant

women (Pregnacy Category D) and those breastfeeding should

avoid taking aspirin unless specifically advised by their doctor.

2.4. Safety of the components of Fuster-CNIC-Ferrer CV Polypill

Acetylsalicylic acid, atorvastatin, and ramipril have been

marketed at the proposed dosages worldwide for decades,

with an established safety profile, and are available as generic

products. This extensive, long-term use of the three drugs in

clinical practice provides a large patient population for analysing

the safety of these three drugs. On the other hand, the dosage

regimen proposed for this polypill (once per day) is the same

as for all of the active components. Therefore, it is not expected

that changing from the concurrent use of the three individual

pills in free combination to the polypill will result in a potentially

different safety profile.

2.4.1. Ramipril

Adverse effects are mild and transient, and drug dis con-

tinuation due to AEs effects is observed in 3% of patients.

The most common AEs include hypotension, dry cough,

dizziness, headache, asthenia, nausea and gastrointestinal (GI)

disturbances [43]. Other AEs include a decrease in hemoglobin

or hematocrit, dermatological reactions (rash, urticaria, pruritus,

photosensitivity), neurologic reactions (headaches, blurred

vision) and impotence. Because ramipril decreases aldosterone

release, hyperkalemia can occur, particularly in patients with

renal failure.

Hypotension can be observed at the beginning of the treat-

ment, particularly in patients with HF post-MI, renal artery

stenosis, hyponatremia, hypovolemia or increased serum

creatinine (1.5–3 mg/dL or 135–265 mol/L). Ramipril produces

a preferential vasodilatation of glomerular efferent arterioles,

reduces the intraglomerular pressure and may increase serum

creatine levels at the beginning of treatment in patients with

hypotension, hyponatremia or renal insufficiency and in

hypertensive patients with unilateral or bilateral renal artery

stenosis. ACEIs can produce angioedema, particularly in blacks;

warning signs include facial swelling, unilateral facial or

periorbital oedema [44].

2.4.2. Atorvastatin

The most frequently described AEs are GI (anorexia, nausea,

flatulence, and constipation), headache, skin rashes, dizziness,

blurred vision, insomnia, and dysgeusia [45]. Myopathy,

characterised by myalgia and muscle weakness with increased

levels of creatine phosphokinase (CPK) >10 times the upper

limit of normal (ULN) has been reported, especially in patients

treated potent CYP3A4 inhibitors, cyclosporine, fibrates or

niacin (Table S1) [46,47]. Rhabdomyolysis is a very rare AE

(~1 per 100,000 patient-years); if suspected or diagnosed,

Table 2Pharmacokinetic profile of the components of the Fuster-CNIC-Ferrer CV Polypill

Drug Atorvastatin Aspirin Ramipril

Bioavailability (%) 14 68 Ramipril - 28

(30 metabolites) Ramiprilat - 44

Cmax

(h) 1–2 0.25–0.3 Ramipril - 0.1–1

Ramiprilat - 2–4

Tmax

(h) 5–7 0.33 Ramipril - 1–2

1–2 (salycilic acid) Ramiprilat - 3.0

PPB (%) ≥98 99 (salycilic acid) Ramipril - 73

Ramiprilat - 56

Vd (L/kg) 5.4 0.15 -

Metabolism Hepatic CYP450 3A4 Hepatic (multiple) Hepatic hydrolysis

Active metabolites yes yes Ramiprilat

Half-life (h) 14 15-20 min Ramipril - 5

2-4 h (low doses) Ramiprilat - 13-17

Excretion (%) Renal – 2 Renal – 5 Renal - 60

Feces - 98 Depend on urinary pH Feces - 40

Breast milk yes yes no

Abbreviations: Cmax

: peak plasma drug concentrations. h: horas. PPB: plasma protein binding. Tmax

: time to reach peak plasma levels or Cmax. Vd. Volume of

distribution


atorvastatin should be discontinued immediately. Transaminase

elevations >3 times ULN occurs in 0.2%, 0.2%, 0.6% of patients

treated with atorvastatin 10, 20 and 40 mg, but serious liver

injury rarely occurs. Other reported AEs include amnesia,

increased weight, nightmares, paresthesia, peripheral edema

and thrombocytopenia. New-onset diabetes has been reported,

but the risk is low both in absolute terms and when compared

with the reduction in coronary events [48]. Treatment with

statins for 4 years resulted in 1 extra case of diabetes, whereas

5.4 coronary events (coronary death, non-fatal MI) are prevented

[49]. In postmarketing studies, rare and reversible AEs,

including hepatitis, pancreatitis, depression, bullous rashes and

hypersensitivity reactions, have been reported.

2.4.3. Aspirin

The most common AEs are GI (dyspepsia, nausea, and

diarrhea). (46) These AEs are usually mild, although in patients

a peptic ulcer severe GI hemorrhage may occur [50]. Aspirin

increases major (hemorraghic stroke) and minor bleeding

(epistaxis, hematuria, melena, bruising), but when used in

secondary prevention, the balance clearly favors benefit. In a

meta-analysis, aspirin (75–325 mg/day) increased the risk of

major GI bleeding and intracranial bleeding versus placebo [51],

but 769 patients (95% CI 500–1250) need to be treated to cause

1 additional major bleeding episode annually. The risk of GI

bleeding increases when aspirin is co-administered with other

NSAIDs, antiaggregants or anticoagulants [52]. In patients at

increased risk of GI bleeding, a proton pump inhibitor should be

used.

Others adverse effects include weakness, dizziness, tinnitus,

edema, hyperkalemia and deterioration of renal function. Allergic

responses (anaphylactic shock, skin rash, asthma) are rare

(<0.5%), but aspirin may precipitate bronchospasm in patients

with asthma or NSAID-precipitated bronchospasm. Aspirin has

been implicated in some cases of Reye syndrome, so it should not

be prescribed in children and adolescents under 18 years of age.

In recent decades, there has been concurrent use worldwide

of the three drugs for secondary prevention of CVD as a

free combination, which has provided solid evidence on the

appropriate risk/benefit ratio. This drug combination has not

been associated with an increased incidence of adverse effects.

The conclusions of the fixed-dose combination safety study

carried out by Yusuf et al. with Polycap with five components,

although carried out in primary prevention, confirmed that the

safety of the fixed-dose combination was similar to treatment

with each drug in monotherapy. The study found there were no

increases in adverse events specific to the drug [53].

The recent published FOCUS study with a polypill contain-

ing asprin, simvastatin and ramipril compared to the

monocomponents in 695 post MI patients also confirmed that

there were no differences in the occurrence of adverse events

between both groups whereas the polypill treated group showed

a significantly greater adherence rate compared to the control

group after 9 months of follow up [4].

2.5. Drug Interactions

The main drug interactions of ramipril, atorvastatin and

aspirin are summarized in Additional file 1 (Table S1).

A potential interaction between ACEIs and aspirin was

proposed as aspirin inhibits prostaglandin synthesis and causes

sodium and water retention which might potentially counteract

the blood pressure lowering effects of ramipril. However, the

evidence of this potential interaction came from clinical trials

not designed to examine this issue [54]. Indeed, several studies

and two meta-analysis confirmed the efficacy and safety of ACEIs

in patients treated with aspirin [55,56]. A meta-analysis of 6

long-term trials (22,060 patients) found that ACEIs significantly

reduced the risk of the major clinical outcomes, both among

in patients receiving (OR 0.80, 99% CI 0.73–0.88) or not aspirin

at baseline (0.71, 99% CI 0.62–0.81) [57]. In 96,712 patients

allocated to receive ACEIs or standard therapy in the acute phase

of MI (0–36 h from onset), ACEI therapy was associated with

similar reductions in 30-day mortality, irrespective of whether

or not aspirin was given [58]. Furthermore, in patients with CAD

and diagnosis of HF, the use of aspirin in conjunction with ACEIs

does not worsen long-term survival compared to the use of ACEIs

without aspirin [55]. Thus, there is no evidence of a decreased

efficacy of ACEIs when coadministered with low doses of aspirin

(up to 200 mg).

Interestingly, a synergy between statins and ACEIs has been

suggested [59]. In a post hoc analysis of the GREek Atorvastatin

and Coronary-heart-disease Evaluation (GREACE) trial in

high-risk patients with CAD treatment with statins and ACEIs

significantly reduced the cardiovascular events (all-cause and

coronary mortality, nonfatal MI and stroke) more than statins

alone and considerably more than ACEIs alone [60]. Moreover,

in the HOPE trial the benefit of ramipril was observed in patients

already treated with aspirin, beta-blockers, and statins [22].

2.6. Posology

The Fuster-CNIC-Ferrer CV Polypill should be administered

once daily, preferably after food and accompanied by liquid to

reduce the risk of GI effects caused by the aspirin. The capsules

should not be opened, chewed, or crushed. For the prevention

of CV events, the recommended maintenance dose of ramipril

is 10 mg daily. In elderly patients, treatment should be initiated

with precaution due to the higher risk of adverse effects. In

patients with CKD the daily dose of Fuster-CNIC-Ferrer CV

Polypill should be based on creatinine clearance (crCl). When

the crCl is ≥60 mL/min, the maximum daily dose of ramipril

is 10 mg, if crCl is 30-60 mL/min the maximum daily dose of

ramipril is 5 mg, but the Fuster-CNIC-Ferrer CV Polypillis

contraindicated in patients in hemodialysis or with severe

kidney failure (CrCl <30 mL/min) (Table 3) [16]. Liver function

tests should be carried out in patients with liver disease before

beginning treatment with the Fuster-CNIC-Ferrer CV Polypill and

periodically afterwards. Patients who developed increased levels

of transaminases should be monitored until the abnormality

is resolved and the Fuster-CNIC-Ferrer CV Polypill should be

discontinued if the increase in transaminase is >3× the ULN. The

maximum daily dose of ramipril in this patient group is 2.5 mg.

2.7 . Contraindications

The main contraindications of the Fuster-CNIC-Ferrer CV

Polypill are a compilation of the ones described in the summary

of product characteristics of each of the single components and

are summarized in Table 3. The Fuster-CNIC-Ferrer CV Polypill

is therefore contraindicated in women who are pregnant, trying

to become pregnant, or suspected to be pregnant because it can

produce teratogenic effects [19]. It should also be avoided during

lactation as small amounts of statins and aspirin are found in the

mother’s milk and is contraindicated in children and adolescents

under 18 years of age [16].

3. Fuster-CNIC-Ferrer CV polypill marketing authorization

The Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®,

Iltria®) including aspirin (100 mg), ramipril (in doses of 2.5, 5,

or 10 mg to allow for titration) and atorvastatin 20 mg has been


approved at present by the Medicine Agencies of 15 European

countries (Austria, Belgium, Bulgaria, Czech Republic, Finland,

France, Germany, Greece, Ireland, Italy, Poland, Portugal,

Rumania, Spain, Sweden) and Chile for its use in secondary

prevention of CV events. The indication for its use is for the

secondary prevention of CV events as substitution therapy in

adult patients adequately controlled with the monocomponents

given concomitantly at equivalent therapeutic dosages [13].

Currently it has been marketed in Spain, Portugal, Romania

and Germany under two different brand names: Trinomia® and

Sincronium®.

During the next years, it has been planned to launch the

Fuster-CNIC-Ferrer CV polypill in additional European countries

as well as worldwide.

4. Conclusions

The concept of a pill containing guideline recommended

therapy for secondary prevention, composed of aspirin, an

antihypertensive agent and a statin has been suggested for over

a decade to simplify treatment complexity, increase accessibility

to treatment and serve as a cost effective public health

strategy to improve pharmacological treatment worldwide.

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.

Additional file

Additional file 1: Table S1 Drug interactions of the

components of the Fuster-CNIC-Ferrer CV Polypill (Trinomia®,

Sincronium®, Iltria®).

Financial disclosure

The authors have no financial disclosures or relationships to

report.


No conflict of interest to report.

References

[1] Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than

80%. BMJ. 2003;326(7404):1419.

[2] Sanz G, Fuster V. Fixed-dose combination therapy and secondary cardiovascu-

lar prevention: rationale, selection of drugs and target population. Nature Clin

Prac Cardiovasc Med. 2009;6(2):101-10.

[3] Castellano JM, Sanz G, Fuster V. Evolution of the polypill concept and ongoing

clinical trials. Can J Cardiol. 2014;30(5):520-6.

[4] Castellano JM, Sanz G, Penalvo JL, Bansilal S, Fernandez-Ortiz A, Alvarez L, et


Am Coll Cardiol. 2014;64(20):2071-82.

[5] Smith SC, Benjamin EJ, Bonow RO, Braun LT, Creager MA, Franklin BA, et al.

AHA/ACCF secondary prevention and risk reduction therapy for patients with

coronary and other atherosclerotic vascular disease: 2011 update: a guide-

line from the American Heart Association and American College of Cardiology

Foundation endorsed by the World Heart Federation and the Preventive

Cardiovascular Nurses Association. J Am Coll Cardiol. 2011;58(23):2432-46.

[6] Perk J, De Backer G, Gohlke H, Graham I, Reiner Ž, Verschuren M, et al.

European Guidelines on cardiovascular disease prevention in clinical practice

(version 2012) The Fifth Joint Task Force of the European Society of Cardiology

and Other Societies on Cardiovascular Disease Prevention in Clinical Practice

(constituted by representatives of nine societies and by invited experts)

Developed with the special contribution of the European Association for

Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2012:ehs092.

[7] Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, Borger MA, et al. ESC

Guidelines for the management of acute myocardial infarction in patients

presenting with ST-segment elevation. Eur Heart J. 2012:ehs215.

[8] Hamm CW, Bassand J-P, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines

for the management of acute coronary syndromes in patients presenting with-

out persistent ST-segment elevation. Eur Heart J. 2011;32(23):2999-3054.

[9] Fihn SD, Gardin JM, Abrams J, Berra K, Blankenship JC, Douglas PS, et al.

2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and

management of patients with stable ischemic heart disease: a report of the

American College of Cardiology Foundation/American Heart Association

task force on practice guidelines, and the American College of Physicians,

American Association for Thoracic Surgery, Preventive Cardiovascular Nurses

Association, Society for Cardiovascular Angiography and Interventions, and

Society of Thoracic Surgeons. J Am Coll Cardiol. 2012;60(24):e44-e164.

[10] Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, Budaj A, et al.

2013 ESC guidelines on the management of stable coronary artery disease. Eur

Heart J. 2013;34(38):2949-3003.

[11] Gehi AK, Ali S, Na B, Schiller NB, Whooley MA. Inducible ischemia and the risk

of recurrent cardiovascular events in outpatients with stable coronary heart

disease: the heart and soul study. Arch Intern Med. 2008;168(13):1423-8.

[12] Calhoun M, Cross LB, Cooper-DeHoff RM. Clinical utility of -blockers for

primary and secondary prevention of coronary artery disease. Expert Rev

Cardiovasc Ther. 2013;11(3):289-91.

Table 3Contraindications of the Fuster-CNIC-Ferrer CV Polypill [13]

• Hypersensitivity to the active substances, to any of the excipients, to other salicylates, to NSAIDs, to any other ACE inhibitor, or to tartrazine

• Hypersensitivity to soya or peanut

• History of previous asthma attacks or other allergic reactions to salicylic acid and other NSAIDSs

• Acute gastric and enteric ulcers

• Hemophilia and other clotting disorders

• Severe or active liver disease, or unexplained persistent elevations of serum transaminases ≥3× ULN

• Severe kidney failure (creatinine >221 mmol/L or eGFR £30 mL/min/1.73 m2) or haemodialysis

• Severe heart failure

• Concomitant treatment with methotrexate at a dosage ³15 mg per week

• Patients with nasal polyps associated to asthma induced or exacerbated by aspirin

• During pregnancy, lactation and in women of child-bearing potential not using appropriate contraceptive measures

• Concomitant treatment with tipranavir, ritonavir or cyclosporine due to the risk of rhabdomyolysis

• History of angioedema (hereditary, idiopathic or due to previous angioedema with ACE inhibitors or ARBs).

• Extracorporeal treatments which involve blood contact with negatively charged surfaces

• Bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney

• Ramipril should not be administered to hypotensive or hemodynamically unstable patients.

• Children and adolescents below 18 years of age during episodes of fever-causing or viral illness

Abbreviations: ACE: angiotensin-converting enzyme. ARBs: angiotensin II receptor blockers. GFR: glomerular filtration rate. NSAIDs: non-steroidal anti-

inflammatory drugs. ULN: upper limit of normal


[13] Bangalore S, Steg G, Deedwania P, Crowley K, Eagle KA, Goto S, et al. -Blocker

use and clinical outcomes in stable outpatients with and without coronary

artery disease. JAMA. 2012;308(13):1340-9.

[14] Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN,

Basayannis EO, et al. Treatment with atorvastatin to the National Cholesterol

Educational Program goal versus’ usual’care in secondary coronary heart dis-

ease prevention. Curr Med Res Opin. 2002;18(4):220-8.

[15] Cleland J, Erhardt L, Hall A, Winter C, Ball S, Investigators AS. Validation of

primary and secondary outcomes and classification of mode of death among

patients with clinical evidence of heart failure after a myocardial infarction: a

report from the Acute Infarction Ramipril Efficacy (AIRE) Study Investigators.

J Cardiovasc Pharmacol. 1993;22:S22-7.

[16] Study TAIREA. Effect of ramipril on mortality and morbidity of survivors of

acute myocardial infarction with clinical evidence of heart failure. Lancet.

1993;342(8875):821-8.

[17] Trinomia®. Summary of Product Characteristics. http://www.hpra.ie/img/

uploaded/swedocuments/LicenseSPC_PA1744-002-001_09022015101132.pdf

[18] Tamboli A, Todkar P, Zope P, Sayyad F. An Overview on Bioequivalence:

Regulatory Consideration for Generic Drug Products. J Bioequiv Availab

2: 086-092. doi:10.4172/jbb.1000037. OMICS Publishing Group J Bioequiv

Availab ISSN; 2010.

[19] Warner GT, Perry CM. Ramipril. Drugs. 2002;62(9):1381-405.

[20] Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment

Trialists’ Collaboration. Effects of ACE inhibitors, calcium antagonists, and

other blood-pressure-lowering drugs: results of prospectively designed over-

views of randomised trials. Blood pressure lowering treatment trialists’ col-

laboration Lancet. 2000;356(9246):1955-64.

[21] Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Böhm M, et al. 2013

ESH/ESC guidelines for the management of arterial hypertension: the Task

Force for the Management of Arterial Hypertension of the European Society

of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood

Pres. 2013;22(4):193-278.

[22] Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angi-

otensin-converting-enzyme inhibitor, ramipril, on cardiovascular events

in high-risk patients. The Heart Outcomes Prevention Evaluation Study

Investigators. N Engl J Med. 2000;342(3):145-53.

[23] Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-

enzyme inhibitors in stable vascular disease without left ventricular systo-

lic dysfunction or heart failure: a combined analysis of three trials. Lancet.

2006;368(9535):581-8.

[24] Danchin N, Cucherat M, Thuillez C, Durand E, Kadri Z, Steg PG. Angiotensin-

converting enzyme inhibitors in patients with coronary artery disease

and absence of heart failure or left ventricular systolic dysfunction: an

overview of long-term randomized controlled trials. Arch Intern Med.

2006;166(7):787-96.

[25] Ruggenenti P, Perna A, Gherardi G, Gaspari F, Benini R, Remuzzi G, et al. Renal

function and requirement for dialysis in chronic nephropathy patients on

long-term ramipril: REIN follow-up trial. Lancet. 1998;352(9136):1252-6.

[26] Nawrocki JW, Weiss SR, Davidson MH, Sprecher DL, Schwartz SL, Lupien P-J,

et al. Reduction of LDL cholesterol by 25% to 60% in patients with primary

hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor.

Arterioscler Thromb Vasc Biol. 1995;15(5):678-82.

[27] Stone NJ, Merz CNB, ScM F, Blum FCB, McBride FP, Eckel FRH, et al. 2013 ACC/

AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic

cardiovascular risk in adults. J Am Coll Cardiol. 2014;63(25):2889–934.

[28] Trialists CT. Efficacy and safety of cholesterol-lowering treatment: prospec-

tive meta-analysis of data from 90 056 participants in 14 randomised trials of

statins. Lancet. 2005;366(9493):1267-78.

[29] Penning-van Beest FJ, Termorshuizen F, Goettsch WG, Klungel OH, Kastelein JJ,

Herings RM. Adherence to evidence-based statin guidelines reduces the risk

of hospitalizations for acute myocardial infarction by 40%: a cohort study. Eur

Heart J. 2007;28(2):154-9.

[30] Dohi T, Miyauchi K, Okazaki S, Yokoyama T, Yanagisawa N, Tamura H, et al.

Early intensive statin treatment for six months improves long-term clinical

outcomes in patients with acute coronary syndrome (Extended-ESTABLISH

trial): a follow-up study. Atherosclerosis. 2010;210(2):497-502.

[31] Smith MB, Lee NJ, Haney E, Carson S. Drug class review: Hmg-coa reductase

inhibitors (statins) and fixed-dose combination products containing a statin:

Final report update 5. Drug Class Reviews. 2009.

[32] Rabar S, Harker M, O’Flynn N, Wierzbicki AS. Lipid modification and cardio-

vascular risk assessment for the primary and secondary prevention of cardio-

vascular disease: summary of updated NICE guidance. BMJ. 2014;349:g4356.

[33] Capone ML, Tacconelli S, Sciulli MG, Grana M, Ricciotti E, Minuz P, et al.

Clinical pharmacology of platelet, monocyte, and vascular cyclooxygenase

inhibition by naproxen and low-dose aspirin in healthy subjects. Circulation.

2004;109(12):1468-71.

[34] Taylor DW, Barnett HJ, Haynes RB, Ferguson GG, Sackett DL, Thorpe KE,

et al. Low-dose and high-dose acetylsalicylic acid for patients under-

going carotid endarterectomy: a randomised controlled trial. Lancet.

1999;353(9171):2179-84.

[35] Trialists’Collaboration A. Collaborative meta-analysis of randomised trials of

antiplatelet therapy for prevention of death, myocardial infarction, and stroke

in high risk patients. BMJ. 2002;324(7329):71-86.

[36] Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al.

Executive Summary: Heart Disease and Stroke Statistics—2015 Update A

Report From the American Heart Association. Circulation. 2015;131(4):434-41.

[37] Van Griensven J, Schoemaker R, Cohen A, Luus H, Seibert-Grafe M, Röthig H-J.

Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor

ramipril. Eur J Clin Pharmacol. 1995;47(6):513-8.

[38] Davidson MH, Robinson JG. Lipid-lowering effects of statins: a comparative

review. Expert Opin Pharmacother. 2006;7(13):1701-14.

[39] Lennernäs H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet.

2003;42(13):1141-60.

[40] Amir LH, Pirotta MV, Raval M. Breastfeeding: Evidence Based Guidelines for

the Use of Medicines. Austr Family Physician. 2011;40(9):684.

[41] Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA.

Use of nonsteroidal antiinflammatory drugs an update for clinicians: a

scientific statement from the American Heart Association. Circulation.

2007;115(12):1634-42.

[42] Dargan P, Wallace C, Jones A. An evidence based flowchart to guide the manage-

ment of acute salicylate (aspirin) overdose. Emerg Med J. 2002;19(3):206-9.

[43] Carré A, Vasmant D, Elmalem J, Thiéry P. Tolerability of ramipril in a mul-

ticenter study of mild-to-moderate hypertension in general practice. J

Cardiovasc Pharmacol. 1991;18:S141-S3.

[44] Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat

and enalapril in patients with hypertension: the Omapatrilat Cardiovascular

Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103-11.

[45] Newman CB, Palmer G, Silbershatz H, Szarek M. Safety of atorvastatin

derived from analysis of 44 completed trials in 9,416 patients. Am J Cardiol.

2003;92(6):670-6.

[46] Law MR, Wald NJ, Rudnicka A. Quantifying effect of statins on low density

lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic

review and meta-analysis. BMJ. 2003;326(7404):1423.

[47] Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C.

ACC/AHA/NHLBI clinical advisory on the use and safety of statins12. J Am Coll

Cardiol. 2002;40(3):567-72.

[48] Ma T, Tien L, Fang C-L, Liou Y-S, Jong G-P. Statins and new-onset diabetes: a

retrospective longitudinal cohort study. Clin Therapeut. 2012;34(9):1977-83.

[49] Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, et al. Statins

and risk of incident diabetes: a collaborative meta-analysis of randomised sta-

tin trials. Lancet. 2010;375(9716):735-42.

[50] Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary preven-

tion of cardiovascular events: a summary of the evidence for the US Preventive

Services Task Force. Ann Intern Med. 2002;136(2):161-72.

[51] McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events

of low-dose aspirin and clopidogrel in randomized controlled trials. Am J

Med. 2006;119(8):624-38.

[52] Delaney JA, Opatrny L, Brophy JM, Suissa S. Drug–drug interactions between

antithrombotic medications and the risk of gastrointestinal bleeding. Can

Med Assoc J. 2007;177(4):347-51.

[53] Study TIP. Effects of a polypill (Polycap) on risk factors in middle-aged indi-

viduals without cardiovascular disease (TIPS): a phase II, double-blind, ran-

domised trial. The Lancet. 2009;373(9672):1341-51.

[54] Peterson JG, Lauer MS. Using aspirin and ACE inhibitors in combination: why

the hullabaloo? Cleveland Clin J Med. 2001;68(6):569-73.

[55] Harjai KJ, Solis S, Prasad A, Loupe J. Use of aspirin in conjunction with angi-

otensin-converting enzyme inhibitors does not worsen long-term survival in

heart failure. Int J Cardiol. 2003;88(2):207-14.

[56] McAlister FA, Ghali WA, Gong Y, Fang J, Armstrong PW, Tu JV. Aspirin use and

outcomes in a community-based cohort of 7352 patients discharged after first

hospitalization for heart failure. Circulation. 2006;113(22):2572-8.

[57] Tea KK, Yusuf S, Pfeffer M, Kober L, Hall A, Pogue J, et al. Effects of long-term

treatment with angiotensin-converting-enzyme inhibitors in the presence or

absence of aspirin: a systematic review. Lancet. 2002;360(9339):1037-43.

[58] Latini R, Tognoni G, Maggioni AP, Baigent C, Braunwald E, Chen Z-M, et al.

Clinical effects of early angiotensin-converting enzyme inhibitor treatment

for acute myocardial infarction are similar in the presence and absence of

aspirin: systematic overview of individual data from 96,712 randomized

patients. J Am Coll Cardiol. 2000;35(7):1801-7.

[59] Krumholz HM, Chen Y-T, Wang Y, Radford MJ. Aspirin and angiotensin-con-

verting enzyme inhibitors among elderly survivors of hospitalization for an

acute myocardial infarction. Arch Intern Med. 2001;161(4):538-44.

[60] Athyros V, Mikhailidis D, Papageorgiou A, Bouloukos V, Pehlivanidis A,

Symeonidis A, et al. Effect of statins and ACE inhibitors alone and in com-

bination on clinical outcome in patients with coronary heart disease. J Hum

Hypertens. 2004;18(11):781-8.

Table S1Drug interactions of the components of the Fuster-CNIC-Ferrer CV Polypill (Trinomia®, Sincronium®, Iltria®)

Interacting drug(s) PD/PK consequence Clinical implications

Ramipril

• Antihypertensives

• Vasodilators (e.g. nitrates)

• Alcohol

• Anesthetic agents

• Antipsychotics

• Tricyclic antidepressants

Increase the antihypertensive response of

ramipril

Monitor blood pressure

ARBs, Beta-blockers, Heparin, K+-sparing diuretics, K+

supplements, Tacrolimus, Trimethoprim.

Increase the risk of hyperkalemia Monitor plasma potassium levels

Cyclosporine, NSAIDs, Vasopressor sympathomimetics Inhibit the antihypertensive response of ramipril Monitor blood pressure

NSAIDs May produce renal failure in the elderly or

dehydrated patients

Lithium salts Decreases lithium renal excretion and increases

plasma levels and toxicity.

Monitor lithium plasma levels

Oral antidiabetic agents or insulin Increase the risk of hypoglycaemia Monitor glucose plasma levels

Erythropoietin Higher doses of erythropoietin are needed in

dialysed patients

Aliskiren, ARBs Increased renal dysfunction Avoid the combination

Drugs eliminated by the kidney:

• Atenolol, Flecainide, Disopyramide, Nadolol,

Procainamide, Sotalol,

Ramipril decreases their renal clearance Monitor drug response

Temsirolimus Increased risk for angioedema With caution

Atorvastatin

Strong CYP3A4 inhibitors:

• Azole antifungals (Itraconazole, Ketoconazole,

Posoconazole, Voriconazole),

• Clarithromycin, Telithromycin

• HIV-protease inhibitors: Atazanavir, Darunavir,

Fosamprenavir, Indinavir, Lopinavir, Nelfinavir,

Ripanavir, Ritonavir, Saquinavir, Tipranavir

• Hepatitis C protease inhibitors: telaprevir

• Other: Ciclosporin, Delavirdine, Stiripentol

Significantly increased the Cmax

of atorvastatin

and the risk of myopathy

Atorvastatin should be used with caution and close

clinical monitoring is recommended.

Clarithromycin, itraconazole: caution at doses

>20 mg/day

HIV protease inhibitors: should be avoided if

possible. The dose of atorvastatin should not exceed

20 mg/day

Boceprevir

Moderate CYP3A4 inhibitors:

• Amiodarone, Erythromycin, Fluconazole, Fluoxetine,

Grapefruit juice, Lomipatide, Verapamil

They may increase the Cmax

of atorvastatin and

the risk of myopathy.

Starting dose: 10 mg/day

Ezetimibe, Fibrates, Fusidic acid, Gemfibrozil, Niacin Increased risk of myopathy and rabdomyolysis Avoid combination with gemfibrozil. Clinical

monitoring is recommended

CYP3A4 inducers:

• Carbamazepin, Eferivenz, Rifampin, St. John’s wort

Variable decrease in the plasma concentrations of

atorvastatin

OATP1B1 inhibitors: Cyclosporine It increases the Cmax

of atorvastatin Monitor clinical efficacy

Digoxin Plasma digoxin levels increase (20%) Monitor digoxin plasma levels

Colchicine Cases of myopathy and rhabdomyolysis, have

been reported

Caution when prescribing atorvastatin with

colchicine.

Oral contraceptives Increased AUC values for norethindrone and

ethinyl estradiol

Select the proper oralanticonceptive

Aspirin

• Alcohol

• Other antiaggregants

• Anticoagulants

• Systemic glucocorticoids

• Other NSAIDs/antirheumatics

• Platelet antiaggregants

• Selective serotonin and serotonin-norepinephrine

reuptake inhibitors

• Tositumomab

The risk of GI ulcers and bleeding increases Monitor for signs of external or internal bleeding

ACEIs, ARBs, beta-blockers, thiazides Aspirin can decrease their antihypertensive

effects

Monitor blood pressure

Antiacids Increase the renal excretion of aspirin Monitor drug response

COX-1 inhibitors: ibuprofen, naproxen) Can prevent the antiaggregant and

cardioprotective effects of aspirin

Avoid the combination

Ciclosporine NSAIDs may increase the nephrotoxicity of

ciclosporine

Careful monitoring of renal function

Digoxin Plasma digoxin levels increase (20%) Monitor digoxin plasma levels

Diuretics NSAIDs can cause acute renal failure in

dehydrated patients

Monitor hydratation of the patient

Methotrexate, tacrolimus Aspirin displace these drugs from plasma

proteins and decrease their renal excretion

Dose adjustment or more frequent monitoring of

renal function and hemogram

Oral antidiabetic agents or insulin Increase the risk of hypoglycaemia Monitor glucose plasma levels

Uric acid Aspirin inhibits kidneys’ ability to excrete uric

acid and reduce the effect of uricosuric drugs

With caution in patients with hyperuricemia, or

gout

Barbiturates, Lithium salts, Phenytoin, Zidovudine Aspirin increases their plasma levels. It decreases

the renal excretion of lithium

Monitor the patient’s response. Monitor plasma

lithium levels

Abbreviations: ACEIs: angiotensin converting enzyme inhibitors. ARBs: angiotensin receptor blockers. AUC: area under the plasma drug concentration-time

curve. Cmax

: peak plasma concewntrations. COX: cyclooxygenase. GI: gastrointestinal. NSAIDs. Non-steroidal anti-inflammatory drugs. OATP1B1: organic anion-

transporting polypeptide 1B1. PD/PK: pharmacodynamic/pharmacokinetic.

ScopeThe International Journal of Cardiology is a world journal of clinical cardiology. Articles relating to clinical cardiology and cardiovascular medicine in its widest sense are welcome. Articles relating purely to experimental or theoretical topics may be

fo stcepsa lla tneserp ot smia lanruoj ehT .ecnaveler lacinilc rieht fo srotide eht ecnivnoc ot deen lliw srohtua tub ,deredisnoc .snoitalupop ot seneg morf lacinilc eht ot ecnaveler fo enicidem ralucsavoidrac

Preference for publication will be given to articles reporting original observations or research. The journal commissions high quality review articles from distinguished authors; unsolicited reviews which pass the peer review process will also be accepted. Letters to the editor are welcome. Case reports can only be considered in the form of research letters.

Editor-in-ChiefProfessor Andrew J.S. Coats, The University of Sydney, NSW 2006 Australia, e-mail: [email protected]

Editorial ManagerDr. Louise Shewan, e-mail: [email protected]

Associate Editors


Stefan D. Anker (Metabolic Cardiology)Yi-Jen Chen (Cell Pathways)Carlo Di Mario (Interventional Cardiology)Rob Doughty (Cardioendocrinology)Gerasimos S. Filippatos (Acute Cardiology)Darrel P. Francis (Mathematical and Computing)Abdel J. Fuenmayor (Electrophysiology and Arrhythmias)Nobusada Funabashi (Imaging)Michael A. Gatzoulis (Congenital Heart Disease)Finn Gustafsson (Transplant and Devices)Stephan von Haehling (Biomarkers)Michael Y. Henein (Echocardiography)Johan Herlitz (Epidemiology)Livia C. Hool (Cardiac Myocytes)Martin St. John Sutton (Functional Imaging) Anthony Keech (Clinical Trials)Ijaz A. Khan (Clinical Cardiology)Kwang Kon Koh (Coronary Artery Disease)Mitja Lainscak (Heart and Lung)

Yat-Yin Lam (Cardiac Interventions)Francisco Leyva (Cardiovascular Medicine)Roberto Lorusso (Cardiac Surgery)Harry C. Lowe (Cardiology in Practice)Gishel New (Women and Heart Disease)Massimo Piepoli (Preventive Cardiology)Giuseppe M.C. Rosano (Metabolism and Endothelium)Christopher Semsarian (Molecular Cardiology)Ashok Seth (Interventional Cardiology)Simon Stewart (Cardiovascular Nursing)Lip-Bun Tan (Cardiac Function)Dimitris Tousoulis (Atherosclerosis)Konstantinos Toutouzas (Interventional Cardiology)Darren Walters (Interventional Cardiology)Maria Wartenberg (Stem Cells)Xander H.T. Wehrens (Cardiomyopathy)Leon de Windt (Molecular Biology)Cheuk-Man Yu (Pacing and Resynchronization)

Enrico Agabiti-Rosei (Brescia, Italy)Joseph S. Alpert (Tucson, USA)Jeroen J. Bax (Leiden, The Netherlands)Bradford Berk (Rochester, USA)Luciano Bernardi (Pavia, Italy)Mike Bristow (Denver, USA)Morris Brown (Cambridge, UK)Isabel Coma-Canella (Pamplona, Spain)John Deanfield (London, UK)Kenneth Dickstein (Stavanger, Norway)Rainer Dietz (Berlin, Germany)Gary S. Francis (Cleveland, USA)Yoichi Goto (Osaka, Japan)Masayasu Hiraoka (Tokyo, Japan)Masatsugu Hori (Osaka, Japan)Kevin Jennings (Aberdeen, UK)Itsuo Kodama (Nagoya, Japan)Michel Komajda (Paris, France)Gregory Lip (Birmingham, UK)Giuseppe Mancia (Monza, Italy)

Barrie Massie (San Francisco, USA)William McKenna (London, UK)John McMurray (Glasgow, UK)Seibu Mochizuki (Tokyo, Japan)Kazuo Momma (Tokyo, Japan)Takeshi Motomiya (Tokyo, Japan)Ryozo Nagai (Gunma, Japan)Yasuyuki Nakamura (Shiga, Japan)Ali Oto (Ankara, Turkey)Milton Packer (New York, USA)Tom Quinn (Surrey, UK)Jean Rouleau (Toronto, Canada)Patrick Serruys (Rotterdam, The Netherlands)Norman Sharpe (Auckland, New Zealand)Kenji Sunagawa (Fukuoka, Japan)Nagara Tamaki (Sapporo, Japan)Eric Topol (La Jolla, USA)Richard Underwood (London, UK)Alec Vahanian (Paris, France)Frans van de Werf (Leuven, Belgium)

Editorial Board

International Consulting Editor for China: Tsung O. Cheng

International Consulting Editor for Japan:Chuichi Kawai

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