Background Paper 6.3 Ischaemic heart disease

Priority Medicines for Europe and the World

"A Public Health Approach to Innovation"

Update on 2004 Background Paper

Written by Bruce Neal

Background Paper 6.3

Ischaemic heart disease

By Dr Ruth Webster and Professor Anthony Rodgers

The George Institute for Global Health

Level 13, 321 Kent St

Sydney, NSW 2000, Australia

Tel +61 2 9993 4557

Update on 2004 Background Paper, BP 6.3 Cardiovascular Disease

6.3-2

Table of Contents

1. Introduction ............................................................................................................................................. 4

2. What is the size and nature of the disease burden? ................................................................................. 4

3. What is the control strategy? ................................................................................................................. 11

3.1 Lifestyle intervention ........................................................................................................................... 11

3.2 Lipid-lowering therapy ......................................................................................................................... 13

3.3 Blood pressure lowering therapy ......................................................................................................... 14 3.3.1 Evidence on potential benefits of regimen simplification and use of two-drug combination pills. 15 3.3.2 Evidence on hypertension combination pills containing more than two medications ................... 16

3.4 Anti-platelet therapy ........................................................................................................................... 16

4. Why does the disease burden persist? ................................................................................................... 17

4.1 Non-optimal use of existing effective medications .............................................................................. 17

4.2 New innovative therapies .................................................................................................................... 19

5. What can be learnt from past/current research into pharmaceutical interventions for this condition? . 20

5.1 Previous trials – polypill versus placebo or no treatment .................................................................... 22 5.1.1 Summary of TIPS 1 and 2 ................................................................................................................. 22 5.1.2 Summary of Wald and Law trial ...................................................................................................... 23 5.1.3 PILL Collaborative Group ................................................................................................................. 24 5.1.4 Other trials ...................................................................................................................................... 25 5.1.5 Conclusions from previous trials of polypill versus placebo or no treatment ................................. 26

5.2 Ongoing trials – polypill versus placebo .............................................................................................. 26

5.3 Previous trials – polypill versus usual care ........................................................................................... 26 5.3.1 FP7-funded UMPIRE trial ................................................................................................................. 26

5.4 Ongoing trials versus usual care (Annexes 6.3.7) ................................................................................ 30 5.4.1 FP7 funded FOCUS trial ................................................................................................................... 30 5.4.2 Kanyini-GAP ..................................................................................................................................... 30 5.4.3 IMPACT ............................................................................................................................................ 30 5.4.4 SPACE Collaboration meta-analysis................................................................................................. 30

6. What is the current “pipeline” of products that are to be used for this particular condition? .................... 31

7. What are the opportunities for research into new pharmaceutical interventions? .................................... 31

8. What are the gaps between current research and potential research issues which could make a difference are affordable and could be carried out in a) five years or b) in the longer term? .......................................... 32

8.1 Need for large-scale trials among people with established cardiovascular disease and other indications for treatment .................................................................................................................................. 32

8.2 What are the effects of implementing a polypill strategy on cardiovascular outcomes? ................... 33

8.3 Potential benefits of next generation polypills .................................................................................... 33 8.3.1 Additional benefits from use of newer agents ................................................................................ 33 8.3.2 How many dose versions for each polypill? .................................................................................... 34 8.3.3 Low dose or high dose polypill components? ................................................................................. 34

8.4 Polypill approach in specific patient populations ................................................................................ 35

8.5 Expanding the polypill concept to acute care ...................................................................................... 35


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9. For which of these gaps are there opportunities for pharmaceutical research? ..................................... 36

10. Conclusion ......................................................................................................................................... 36

11. Declarations ...................................................................................................................................... 38

References ..................................................................................................................................................... 38

Annexes ......................................................................................................................................................... 46

Annex 6.3.1: Mortality and burden of disease from IHD per age group and per region .................................. 47

Annex 6.3.2: Baseline characteristics of previous randomised controlled trials – versus placebo or no treatment .......................................................................................................................................................... 51

Annex 6.3.3: Actual versus expected reductions in systolic blood pressure and LDL-cholesterol in trials of ‘polypills’ versus placebo or no treatment ........................................................................................................ 53

Annex 6.3.4: Baseline characteristics of UMPIRE Trial ..................................................................................... 54

Annex 6.3.5: Ongoing randomised controlled trials – polypill versus usual care .............................................. 55

Annex 6.3.6: Ongoing trials of “hypertension polypills” ................................................................................... 56

Annex 6.3.7: Ongoing trials – polypill versus placebo or no treatment ............................................................ 57

Annex 6.3.8: Pipeline of polypills ...................................................................................................................... 58


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1. Introduction

In 2004 Warren Kaplan and Richard Laing wrote the “Priority Medicines for Europe and the

World Report”.1 In this report they placed great emphasis on the background paper written

by Bruce Neal titled “Secondary Prevention of Cardiovascular Disease: Fixed Dose

Combinations.” (http://archives.who.int/prioritymeds/report/background/cardiovascular.

doc). In the 2004 report Kaplan and Laing stated “The simple solution to this deficiency (in the

effective treatment of patients with proven cardiovascular disease) is to develop and test a fixed-dose

combination (FDC) product of these proven effective medicines. The research agenda proposed in this

section is different to that of the other sections because this approach offers the greatest potential short-

to-medium term impact of all of the possible research activities in this Report.”(Page 58). This

background paper to the 2013 update of the Priority Medicines for Europe and the World

reports on the work that has been done since 2004 making the case that what was proposed

in 2004 has now been undertaken and that the next stage is to undertake large scale pan

European and global clinical trials to understand the place of “polypills” in the treatment of

individuals who have suffered from cardiovascular and/or cerebrovascular events. There

have been two large scale clinical trials funded in this area. One of these studies (the

UMPIRE trial) has since reported positive results as outlined in detail in this background

paper. This report updates the information on this topic.

This report updates the potential information on this topic and therefore continues to focus

on secondary prevention among patients who have already suffered a cardiovascular event.

The majority of such patients have IHD, but a significant minority have cerebrovascular

disease or peripheral vascular disease.

In addition to secondary prevention with the polypill, a number of other pharmacological

approaches to prevention and treatment of IHD will need to be researched in order to

provide more effective, safer and individualized intervention strategies. These include the

development of new lipid-lowering drugs; pharmacological means to address novel

mechanistic concepts of vessel wall damage and protect against conditions such as chronic

inflammation and local angiogenesis; and regenerative medicine/cell therapy approaches.

Similarly, new pharmacological treatment strategies need to be developed for heart failure

and arrhythmias, frequent consequences of IHD.

2. What is the size and nature of the disease burden?

Detailed analysis of overall global trends in burden of disease is available in Chapter 5,

however a summary of disease burden attributable to cardiovascular disease is included

here. Each year about 15.6 million deaths (30% of global mortality) occur from cardiovascular

disease (CVD) making it the leading cause of death.2 Worldwide, ischaemic heart disease

(IHD) is ranked as the leading specific cause of death, with 13.3 % of total deaths, followed

by cerebrovascular disease (11.1%) (Table 6.3.1).Together IHD and all forms of stroke

worldwide killed an estimated 12.9 million people in 2010, a quarter of the global total, an

increase from one in five deaths worldwide 20 years earlier.2

http://archives.who.int/prioritymeds/report/background/cardiovascular.doc

http://archives.who.int/prioritymeds/report/background/cardiovascular.doc


6.3-5

Following global trends, the largest single cause of death in the 2010 Global Burden of

Disease study in the combined region of Central, Eastern and Western Europe was ischaemic

heart disease (26.6% of all deaths), closely followed by cerebrovascular diseases (ischaemic

and haemorrhagic and other non-ischaemic stroke) with 11.0% of the total number of deaths

(Table 6.3.1).

The most common specific cause of cardiovascular death is IHD which accounts for 45% of

global cardiovascular deaths and 54.6% of European cardiovascular death. Cerebrovascular

diseases account for 37.6% of cardiovascular diseases globally and 31.4% in Europe.

Hypertensive heart disease is the third biggest contributor to this group of diseases with

5.6% of global cardiovascular mortality and 3.7% of the total cardiovascular mortality in

Europe.

Table 6.3.1: DALY and mortality data for the most common cardiovascular diseases, for

the European regions and the world.

Eastern, Western

and Central

Europeb

World Eastern, Western

and Central Europe

World

DALYs % of

total

DALYs % of

total

Mortality

(total

deaths)

% of

total

Mortality

(total

deaths)

% of

total

Ischemic heart

disease 32 928 727 13.8 129 819 898 5.2 2 204 942 26.6 7 029 270 13.3

Cerebrovascular

disease 16 913 463 7.1 102 232 304 4.1 1 269 233 11.0 5 874 182 11.1

Hypertensive heart

disease 1 857 167 0.8 15 324 193 0.6 150 413 1.8 873 152 1.7

Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010

(GBD 2010) Results by Cause 1990-20103 b Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Hungary, Macedonia, the Former Yugoslav Republic of Montenegro, Poland,

Romania, Serbia, Slovakia, Slovenia, Belarus, Estonia, Latvia, Lithuania, Moldova, Russian Federation, Ukraine, Andorra , Austria,

Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Netherlands, Norway,

Portugal, Spain, Sweden, Switzerland, United Kingdom.


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Figure 6.3.1: Distribution of global and European mortality for cardiovascular and

circulatory diseases.


(GBD 2010) Results by Cause 1990-2010 3 a Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Hungary, Macedonia, the Former Yugoslav Republic of

Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, Belarus, Estonia, Latvia, Lithuania, Moldova, Russian Federation,

Ukraine, Andorra , Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy,

Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom.

In addition, cardiovascular disease causes a large non-fatal global disease burden as a

consequence of prevalent disease states such as angina. When the non-fatal disease burden is

taken in conjunction with the healthy life years lost due to premature death the total overall

disease burden attributable to cardiovascular and circulatory diseases accounted for 11.8% of

global DALYs (Disability Adjusted Life Years) in 2010.4 The major diseases within this group

worldwide are, just as with mortality data, ischaemic heart disease (5.2%), cerebrovascular

diseases (4.1%), and hypertensive heart disease (0.6%). In Central, Eastern and Western

Europe, 13.8% of the total DALY burden can be attributed to IHD, 7.1% to cerebrovascular

disease and 0.8% to hypertensive heart disease (Table 6.3.1).

Not only is CVD currently the greatest cause of death and disability worldwide, CVD

mortality is predicted to rise to approximately 23.4 million by 2030 with CVD predicted to

remain the leading cause of death.5 Recent data from the Global Burden of Disease study

2010 confirms the likelihood of reaching these predictions. Cardiovascular diseases and more

specifically ischaemic heart disease increased by 31.2% and 34.9%, respectively, in terms of

absolute deaths in the past two decades. In terms of years of life lost (YLLs), ischaemic heart

disease increased in rank from fourth in 1990 to first in 2010, reflecting an increase of 28%.

Cerebrovascular disease is currently ranked third globally for YLLs, but in some Asian

regions is ranked first. Ischaemic heart disease is ranked first in almost all regions other than

Asia. In addition, from 1990 to 2010, both ischaemic heart disease (IHD) and cerebrovascular

disease have risen in their position amongst the top 10 causes of DALYs – IHD from position

number four to number one and stroke from position number five to number three,

reflecting increases of 29% and 19% respectively.4 In Europe, ischaemic heart disease and

54.6%

31.4%

3.7% 6.9% 2.3% 1.1%

Central, Eastern and Western Europea

45.0%

37.6%

5.6%

7.0%

2.6% 2.2%

World

Ischemic heart disease

cerebrovascular disease(stroke)Hypertensive heartdiseaseOther cardiovascularand circulatory diseasesCardiomyopathy andmyocarditisRheumatic heartdisease


6.3-7

stroke have maintained their ranking as the leading and second most common causes of

death and YLLs over the past 20 years. In central and eastern Europe they have maintained

their respective highest and second highest rankings for DALYs also, however in western

Europe, low back pain has now emerged as the foremost cause for DALYs in that region.

IHD and stroke come in at numbers two and three.3

Figure 6.3.2 shows the amount of absolute disability-adjusted life years (DALYs) caused by

ischaemic heart disease (IHD) by age group for the world, Central, Eastern and Western

Europe. The highest burden of disease from ischaemic heart disease, amongst the three

European regions, is present in Eastern Europe in all age groups, followed by Western

Europe. The amount of DALYs caused by ischaemic heart disease peaks at 80 years and

above in all four regions.

Figure 6.3.3: Absolute deaths caused by ischaemic heart disease by age group and region

demonstrates the mortality rates for ischaemic heart disease, in absolute death numbers, by

age group and region.3 As with the DALYs, Eastern Europe has the highest number of deaths

from ischaemic heart disease amongst the European regions in all age groups, except for in

the over 80 years age group, where Western Europe has slightly higher numbers of deaths

due to IHD. This is remarkable since Western Europe has approximately half the number of

deaths in the other age groups, compared to Eastern Europe. Furthermore, it’s striking that

Central Europe has less than half the number of deaths due to IHD than Eastern Europe or

Western Europe.

More figures for mortality and burden of disease from IHD per region and age group can be

found in the annexes of this background paper.


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Figure 6.3.2: Absolute DALYs caused by ischaemic heart disease by age group and region.3

Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD

2010) Results by Cause 1990-2010

Figure 6.3.3: Absolute deaths caused by ischaemic heart disease by age group and region.3


(GBD 2010) Results by Cause 1990-2010


6.3-9

Common interests between Europe and the world

Despite the common misperception that CVD is a ‘rich man’s disease’, 80% of CVD deaths

occur in low- or middle-income countries (LMIC).6 These deaths in LMICs are not only

occurring more frequently than in high income countries but are also occurring earlier in life

causing a greater social and economic impact in these countries. Many of these countries

typically are least equipped to deal with this epidemic of CVD due to inadequate health care

systems and significant levels of poverty.

The commonality between high income countries and low income countries of risk factors

responsible for the identical leading causes of death ensures that any solutions that are found

have the potential (within the bounds of adaptation to local conditions) to advantage a broad

range of countries across the economic spectrum. Any intervention that has the capacity to

affect significant public good in Europe can be applied globally in many different settings.

This well documented epidemic of CVD is due to two main factors – ageing of the world’s

population, and epidemiological transition in LMIC leading to global exposure to the key

risk factors for CVD.7

Population Ageing

Chapter 5 provides significant detail on global ageing and will not be repeated here. Figures

5.1 and 5.2 in particular show the predicted ageing of the population globally and

particularly in the European Region. Such increases in life expectancy, although showing

global ‘successes’ in modernization and improvements in standards of living and health care,

mean that more people are living to an age where they are more likely to have a

cardiovascular event and if they survive that event, live longer with the disability associated

with that event.

Risk Factors

Risk factors associated with CVD are well established through multiple large

epidemiological studies which show that CVD is overwhelming preventable.8,9 Fifty-seven

per cent of CVD deaths (19% of global deaths) can be attributed to just eight risk factors

associated with poor diet and low rates of physical activity: high blood pressure, high blood

glucose, physical inactivity, being overweight or obese, high cholesterol and low fruit and

vegetable intake.10 The other key risk factor is tobacco use which accounts for nearly 10% of

CVD.10 The 2010 Global Burden of Disease study reported that the two leading risk factors

for global disease burden overall were high blood pressure (9.4 million deaths and 7% of

global DALYs) and tobacco smoking including second-hand smoke (6.3 million deaths and

6.3% DALYs) both of which are key factors in increasing risk of CVD. The leading risk factor

for Europe was also high blood pressure with smoking ranked either second or third

(depending on the region of Europe). Detailed proportions of global IHD DALYs attributable

to individual risk factors are presented in Table 6.3.2: Proportion of ischaemic heart disease

DALYs attributable to individual risk factors, worldwide, 201011 These risk factors are all

similarly implicated in other atherosclerotic disease such as stroke.

Of note is the high proportion of IHD DALYs attributable to excessive alcohol use. Although

significant, excessive alcohol use and the consequent disease states, treatment options and

recommendations for further research are covered in detail in Chapter 6.14: Alcohol use


6.3-10

disorders and alcoholic liver disease and the accompanying background paper. Hence, this

will not be addressed in this background paper.

Table 6.3.2: Proportion of ischaemic heart disease DALYs attributable to individual risk

factors, worldwide, 2010.

Disability adjusted life-years (%)

Physiological risk factors

High blood pressure 53%

High total cholesterol 29%

High body-mass index 23%

High fasting plasma glucose 16%

Alcohol use 33%

Tobacco smoking including second-hand

smoke

31%

Dietary risk factors and physical inactivity

Diet low in nuts and seeds 40%

Physical inactivity and low physical

activity

31%

Diet low in fruits 30%

Diet low in seafood omega-3 fatty acids 22%

Diet low in whole grains 17%

Diet high in sodium 17%

Diet high in processed meat 13%

Diet low in vegetables 12%

Diet low in fibre 11%

Diet low in polyunsaturated fatty acids 9%

Diet high in trans fatty acids 9%

Diet high in sugar-sweetened beverages 2%

Air pollution

Ambient particulate matter pollution 22%

Household air pollution from solid fuels 18%

Other environmental risks

Lead exposure 4%

Source: Lim SS et al. Lancet, 201211

Summary:

From the previously presented data, it is immediately apparent that CVD must be a priority

for any attempt to reduce burden of disease at a global level and within Europe. The

potential for public health benefit from the development of new or improved medical

interventions to address the pandemic of CVD is incontrovertible. Not only would this have

a major impact on Europe but would also potentially improve the lives of millions of patients

in LMIC as well. The most significant contributors to IHD (and via extrapolation of other

CVD) DALYs are amenable to pharmacological intervention i.e. the physiological risk factors

and tobacco smoking. Despite much progress in the development of pharmaceutical


6.3-11

interventions to prevent CVD, there is significant opportunity to further invest in this area,

as will be described in the remainder of this background paper.

3. What is the control strategy?

Recommended strategies for prevention of CVD (both primary and secondary) can be

categorized into lifestyle versus pharmacological interventions. Most attention in this

chapter will focus on pharmaceutical interventions.

3.1 Lifestyle intervention

Since most of the major risk factors for CVD are related to lifestyle; advocacy and promotion

at the population and patient level to modify poor lifestyle choices will always be an

important and critical method to reduce the burden of CVD. When adhered to by patients

not only is it cost-effective but will always be more effective that simply directly

recommending pharmaceutical therapy. Smoking cessation has been shown to significantly

decrease the smoking-attributable risk of disease and CVD risk return to that of a non-

smoker within about five years.12,13 Intuitively, modification of diet and activity levels will

positively benefit an individual’s cardiovascular risk factor profile. Physical activity and

dietary modification have not only been shown to have a significant favourable effect on

other major risk factors (including lipids, blood pressure and insulin resistance) but also to

have an independent role in prevention of cardiovascular disease.14,15,16,17,18 Taken in

conjunction, data has shown that adherence to lifestyles guidelines advocating moderate

physical activity, cardio-protective diet and abstinence from smoking can reduce the

incidence of cardiovascular disease by more than 80% compared to the rest of the

population. However, studies have shown that the general population nor (more

surprisingly) people with established CVD typically adhere to these recommended

guidelines. Recent data from the United States NHANES 2005 to 2010 study 19 showed that

22.6% of respondents were current smokers and 24.1% were former smokers. Thirty-two per

cent did not engage in any physical activity with a further 23% only engaging in

intermediate activity (better but still not reaching the ideal level of activity). A total of 77.7%

of people surveyed scored less than two out of out on a healthy diet score that included

consumption of fruit and vegetables, wholegrains, and fish, and limiting sugar and salt

intake. These figures have not changed significantly since previous NHANES surveys.19

It is not only the general population who are failing to follow lifestyle advice. The European

Action on Secondary and Primary Prevention by Intervention to Reduce Events

(EUROASPIRE) studies have completed three surveys on lifestyle and risk factor

management in patients with coronary heart disease (CHD).20,21,22 Each study recruited

consecutive patients with first or recurrent diagnosis or treatment for CHD across multiple

hospitals in nine to 22 countries and interviewed between six months and three years later to

see how many were adhering to recommended lifestyle and treatment measures. Arguably

this population should be the most motivated to apply and adhere to lifestyle guidelines,

having already experienced CVD and being at high risk of a recurrent event. In the latest

round of surveys in 2006 to 2007, the investigators found that 51.9% of smoking patients

persisted after their event and only 51.8% of obese patients had followed dietary


6.3-12

recommendations to lose weight, with only 38.2% of obese patients increasing their regular

physical activity.22 Of the overall cohort, only 48% increased their overall physical activity.

An impressive 92% of the cohort attempted to change their diet however this subjective

reporting is undermined by the objective measures of obesity (35.3%) and central obesity

(52.7%). Many of these high risk patients were not taking medicines that have been proven to

prevent reoccurrence of cardiac events.

The EUROASPIRE investigators also compared the results of the three different surveys to

see if any improvements had been made over time.23 Disappointingly, between the first and

third surveys rates of smoking in younger female patients increased (despite an overall

decrease in smoking) and prevalence of obesity increased by 13%. Raised blood pressure

increased by 3.4% and reporting of diabetes mellitus increased by 9.3%. Full prevalence data

for coronary heart disease risk factors in EUROASPIRE III are shown in Table 6.3.3:

Prevalence (%) of coronary heart disease risk factors in EUROASPIRE III, by country, age

and diagnostic category22

Table 6.3.3: Prevalence (%) of coronary heart disease risk factors in EUROASPIRE III, by

country, age and diagnostic category.

Source: Kotseva K et al. Eur J Cardiovasc Prev Rehabil, 200922


6.3-13

These data indicate that, despite public awareness campaigns and educational efforts,

population based lifestyle change is not happening. Into this evidence-practice gap fits the

opportunity for modification of CVD risk with pharmacological management. The role of

cholesterol lowering therapy, blood pressure lowering therapy and anti-platelet therapy is

now incontrovertible having been proven effective in large meta-analyses in all three

medication categories.

3.2 Lipid-lowering therapy

The role of lipids as a major risk factor for cardiovascular disease has been well established

and has been estimated to cause approximately a third of global ischaemic heart disease.24

Furthermore, the relationship between serum cholesterol and the risk of cardiovascular

disease has been shown to be continuous 25,26 with no defined level below which a person can

be considered to be at ‘low risk’. The discovery of the 3-hydroxy-3-methylglutaryl coenzyme

A (HMG-CoA) reductase inhibitors (statins) has dramatically impacted the treatment of

cardiovascular risk. Ongoing individual patient data meta-analyses by the Cholesterol

Treatment Trialists (CTT) Collaboration of large scale clinical trials of statins have shown

with standard statin regimes a consistent reduction in major vascular events over five years

of around 20% per 1 mmol/L decrease in LDL regardless of baseline lipid levels or other

patient characteristics.27 This benefit is seen even in those at lowest baseline risk with

demonstrated reduction in events greatly exceeding any known hazard of statin therapy.28

This raises the possibility that indications for treatment, which are currently aimed at

patients at high risk should possibly be widened to include those at 5 to 10% absolute

cardiovascular risk over five years.28 No level has been demonstrated below which reduction

in LDL produces an increase in adverse events, demonstrating an acceptable safety profile

for intensive treatment regimes capable of further LDL reductions.29

The observed benefit from statins improves with the length of time taken with only a 10%

decrease in events seen in the first year but up to 28% reduction in events by the third or

fourth year. These estimates of benefit are in fact likely to be an underestimate of the true

effect of long term benefit from statin therapy due to the problem of long term non-

adherence by patients. Full compliance would achieve larger overall reductions in LDL, up

to 1.5 – 1.8 mmol/L predicted in some cases 30,31 which would result in closer to a one third

reduction in vascular events overall.27

In addition to statins’ role in reducing LDL cholesterol, fibrates (agonists of the peroxisome

proliferator receptors selective for the α receptors - PPAR) have a clear role in raising HDL

cholesterol and reducing triglyceride concentrations 32 and consequently have recently been

shown in meta-analysis to be effective in reducing cardiovascular events in their own right

primarily by preventing coronary events.33 The relative risk reductions shown for fibrates

(10% for major cardiovascular events, 13% for coronary events, no effect on stroke) are much

less than for statins, however offer the potential for additive effects in risk reduction due to

targeting of different cholesterol sub fractions and hence addressing the ‘residual risk’

remaining after treatment with statins particularly those patients with combined

dyslipidemia. Despite this, the potential for increased risk of side effects, in particular muscle

damage (myopathy) when taken together with statins has somewhat limited concurrent use

of these drugs together, in particular gemfibrozil.34


6.3-14

Ezetimibe is a newer lipid-lowering agent which inhibits cholesterol absorption from the gut

available as monotherapy as well as combination therapy with simvastatin. Although shown

to be effective in significantly lowering LDL cholesterol (including an extra 12 to 19% when

coadministered with a statin35,36), there is still controversy about its use with three separate

trials showing paradoxical results in effect on carotid-artery intima-media thickness and also

superficial femoral artery atherosclerosis.37,38,39 Results from the ongoing IMPROVE-IT trial

(http://clinicaltrials.gov/show/NCT00202878) are required to determine the true value of

ezetimibe in CVD prevention.

Two other products of note are niacin and omega-3 fatty acids. Despite marketing approval

for nicotinic acid/laropiprant (niacin) being granted in 2008 by the European Medicines

Agency to treat adults with dyslipidemia, this approval was suspended in January, 2013 40

following the preliminary reporting of the HPS2-THRIVE study’s

(http://www.thrivestudy.org/) primary outcome and safety data which showed no

advantage of niacin in addition to statins on the outcome of CVD events and an increase in

non-fatal but serious side effects. Omega-3 fatty acids have received widespread publicity

and now represent a multi-million dollar industry due to positive findings in prevention of

CVD in early trials. Later trials however produced conflicting results. A recent systematic

review and meta-analysis 41 did find a significant effect of omega-3 fatty acids on vascular

death (RR 0.86, 0.75-0.99) however no significant effect on all other outcomes studied (it was

noted that there was significant heterogeneity between the trials which may have impacted

the overall results). The authors concluded that although there does seem to be a positive

effect on some cardiovascular outcomes, perhaps the public and physician’s expectations of

the true benefit should be lowered somewhat.

3.3 Blood pressure lowering therapy

Suboptimal blood pressure (systolic >115 mmHg) has been estimated to account for about

62% of global cerebrovascular disease and 49% of ischaemic heart disease globally.42 The

majority of adult blood pressures are this category, and only about half of the attributable

burden occurs among those with ‘hypertension’. This is true for both developing and

developed countries although in developed regions blood pressure levels are particularly

high.11 Major prospective observational studies have shown conclusively that blood pressure

(both diastolic and systolic) has a continuous, independent relationship with the risk of

cardiovascular disease.43,44,45

Evidence for the effectiveness of blood pressure lowering therapies 43,46,47 has led to a plethora

of such drugs in multiple classes. All commonly used regimens (including ACE inhibitors,

calcium channel antagonists, diuretics and beta blockers) have been shown to reduce

cardiovascular risk similarly with larger reductions in blood pressure producing larger

reductions in risk.46 As is the case for cholesterol lowering, an approximately consistent

proportional difference in CV risk (35 to 40% for stroke and 20 to 25% coronary heart

disease) is associated with each given absolute reduction in blood pressure (5-6 mmHg of

diastolic blood pressure) regardless of the BP at baseline.43 It follows then that if the size of

the absolute risk reduction is related to baseline untreated risk, then the greatest risk

reductions occur in those whose baseline risk is highest.47 In Europe, although no particular

medication class is recommended for treatment of uncomplicated high blood pressure,

certain classes have been recommended in certain clinical conditions (Table 6.3.4) 48 and new

guidelines are in development.


6.3-15

Table 6.3.4: Position statement: Antihypertensive treatment: Preferred drugs. European

Society of Hypertension and European Society of Cardiology.

Subclinical organ damage Preferred drugs

LVH ACEI, CA, ARB

Asymptomatic atherosclerosis CA, ACEI

Microalbuminuria ACEI, ARB

Renal dysfunction ACEI, ARB

Clinical event

Previous stroke any BP lowering agent

Previous MI BB, ACEI, ARB

Angina pectoris BB, CA

Heart failure diuretics, BB, ACEI, ARB, anti-

aldosterone agents

Atrial fibrillation

Recurrent ARB, ACEI

Permanent BB, non-dihydropiridine CA

ESRD/proteinuria ACEI, ARB, loop diuretics

Peripheral artery disease CA

Condition

ISH (elderly) diuretics, CA

Metabolic syndrome ACEI, ARB, CA

Diabetes mellitus ACEI, ARB

Pregnancy CA, methyldopa, BB

Blacks diuretics, CA Abbreviations: LVH: left ventricular hypertrophy; ISH: isolated systolic hypertension; ESRD: renal failure;

ACEI: ACE inhibitors; ARB: angiotensin receptor antagonists; CA: calcium antagonists; BB: β-blockers

Source: Mancia G, et al. J Hypertens, 2009 49

Combination therapy for lowering blood pressure

Hypertension management strategies, such as those endorsed by most practice guidelines

including the European Society of Hypertension 49 have traditionally focussed on “tailored

therapy” and “stepped-care” approaches. These tend to be time consuming for doctor and

patient, only cautiously recognise that contemporary BP targets almost always necessitate

additional medication and ignore the auto-regulatory mechanisms that limit responsiveness

to a single drug administered alone.

3.3.1 Evidence on potential benefits of regimen simplification and use of two-

drug combination pills

Most patients with hypertension require BP lowering medication from two or more classes to

achieve adequate control.50 The need for titration of medication and addition of multiple

classes of drug requires multiple physician visits and this in itself triggers poor adherence to

prescribed medication and poor attendance at scheduled visits.51 The requirement to take

multiple medications in complex regimes also results in poor adherence.52 For physicians, the

need for repeated up-titrating or adding extra medications can lead to inertia and complicit


6.3-16

acceptance of inadequate BP control.53,54 Dual combination BP lowering medication has been

shown to improve achieved BP reductions as well as cardiovascular event rates.55 Initiating

anti-hypertensive treatment with dual combination therapy not only accelerates the time

taken to achieve control but also attains a lower final target.56,57 For the patient, improved

adherence has also been demonstrated without adversely affecting the side effect profile.58 59

Further benefits in BP control are also available via simplifying up-titration regimes.57

3.3.2 Evidence on hypertension combination pills containing more than two

medications

There are sound pharmacological principles to expect the maximum benefit to side effect

ratio from low-dose triple combinations.59,60,61 In short, benefits of each component are

additive, and low doses typically avoid most side effects while achieving most blood

pressure reduction. Thus for example, three half-dose medications would typically lower

blood pressure about as much as two full-dose medications, but with fewer side effects.59

A number of important questions however remain to be answered. The triple BP lowering

pills that have recently become available in western countries, have focussed exclusively on

severe hypertension that remains uncontrolled with full dose dual combination therapy.

Furthermore, previous trials have been within the mode of traditional stepped care, and

have not tested the integration of a low-dose triple combination within a simplified regimen.

For example, the recent trial of Exforge® 62 involved patients with baseline BP of 170⁄107

mmHg, randomised to receive five weeks of treatment with amlodipine ⁄valsartan ⁄HCTZ 10

⁄320 ⁄25 mg or one of the three dual therapies indicated previously herein. Perhaps

unsurprisingly, this trial showed that patients on triple therapy achieved better BP

reductions than patients on dual combination therapy.

To date no clinical trial has tested the benefits or cost-effectiveness of combination therapy

with three, low dose BP lowering drugs in hypertension. One such trial, the TRIUMPH

(TRIple Pill versus Usual care Management for Patients with mild-to-moderate

Hypertension) study

(https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363169), a 700 patient

randomised controlled trial of a triple low dose blood pressure lowering pill versus usual

care is currently starting up in India with the aim of answering these questions.

3.4 Anti-platelet therapy

A meta-analysis by the Antithrombotic Trialists’ Collaboration in 2002 63 showed that use of

antiplatelet agents (primarily aspirin) in patients at high risk due to a pre-existing occlusion

or predisposing condition, decreased the occurrence of serious vascular events by one

quarter, with a third reduction in non-fatal myocardial infarction (MI) and a quarter

reduction in non-fatal stroke. Vascular mortality overall was decreased by one sixth. They

concluded that the absolute benefits of antiplatelet therapy substantially outweighed the

absolute risks of major extra-cranial bleeding in patients with vascular disease. The balance

of benefits and risks is less clear in lower risk populations, and conclusions have been

hampered by not recognising the heterogeneity of this “primary prevention” population. A

more detailed meta-analysis by the Antithrombotic Trialists’ Collaboration stratified results

by estimated cardiovascular risk, and showed that even in medium risk population the

number of excess haemorrhagic events (mostly gastrointestinal) was broadly similar to the


6.3-17

number of major vascular events prevented.64 However, further modelling and research is

required to determine appropriate patient populations, given the emerging evidence

showing that aspirin reduces the risk of several major cancers,65 and the changing

background rates of gastrointestinal haemorrhage and vascular events.

Clopidogrel is the next most commonly used anti-platelet agent, and has similar efficacy to

aspirin.63 Clopidogrel confers additional benefit when added to aspirin treatment in ST

elevation myocardial infarction (RRR 9%, 3-14) 66, non-ST elevation myocardial infarction

(RRR 20%, 10 – 28) 67 and long-term following percutaneous coronary intervention (RRR

26.9%, 3.9-44.4).68 Prior to coming off patent in May 2012, opinions varied as to the cost-

effectiveness of clopidogrel compared to aspirin,69,70 and LMIC cost almost certainly would

have limited its use significantly. However, now that generic clopidogrel is becoming

available, its use in prevention of CVD is likely to increase.

4. Why does the disease burden persist?

4.1 Non-optimal use of existing effective medications

Despite large-scale clinical trial/meta-analyses having demonstrated substantial reductions

in the risks of cardiovascular events with antiplatelet,63 blood pressure lowering 46 and

cholesterol lowering therapy 71 in patients with established CVD and those at high calculated

risk of CVD current treatment gaps among this patient group are very large. Despite the

majority of people with established CVD in high income countries being started on

recommended medications, significant numbers of people in high income countries 23,72,73

and even larger numbers in low and lower middle income countries do not either receive or

remain adherent to these treatments long-term.74,75,76 (Figure 6.3.4)

Within Europe, the EUROASPIRE III study22 showed that the majority of coronary patients

that required BP lowering and lipid lowering medications were not receiving them on a

long-term basis and if patients were receiving them, they were not reaching their BP and

lipid targets (Table 6.3.5) suggesting either poor adherence by the patient or insufficient

titration by physicians.


6.3-18

Figure 6.3.4: PURE study: Number of drugs taken by individuals with established

cardiovascular or cerebrovascular disease by country economic status.

Source: Yusuf S, et al. Lancet. 2011 For coronary heart disease (A), drugs counted were aspirin, β blockers, ACE inhibitors or ARBs, or

statins. For stroke (B), drugs counted were aspirin, statins, ACE inhibitors or ARBs, or other blood-

pressure-lowering drugs (e.g., β blockers, diuretics, and calcium-channel blockers). ACE=angiotensin-

converting enzyme. ARB=angiotensin-receptor blocker.76

Table 6.3.5: Percentage of patients reaching BP and lipid targets in EUROASPIRE III

Reaching Target (%)

On BP lowering medication 43.9

Not on BP lowering medication 48.3

On lipid lowering medication 55.0

Not on lipid lowering medication 25.4

Source: Kotseva K et al. Eur J Cardiovasc Prev Rehabil, 200922

Various factors may underlie the suboptimal treatment of high risk patients, such as the need

to navigate complex guidelines by doctors, low continuation rates by patients, inequities in

health care and resistance to costs by both doctors and patients.

Non-adherence to therapy is one of the main obstacles for the unsatisfactory reduction of risk

factors, particularly in developed countries. It is characterized by the premature cessation of

treatment together with suboptimal use of medication, and is correlated with an increased

risk of mortality.77 Non-adherence is especially relevant in chronic, asymptomatic diseases as

cessation of treatment does not lead to symptoms in patients but they remain at high risk of

serious micro- and macrovascular complications in the case of atherosclerotic cardiovascular

diseases. Patients often do not understand the importance of taking long-term medication for

chronic diseases, particularly those that are generally symptom-free. Reported long-term

adherence is low with only 70% adherence to aspirin therapy and only 45% to lipid- and BP-


6.3-19

lowering therapy after 12 months.78 The main determinants of non-adherence are multiple

medications with complex dosing regimens, inadequate knowledge about the medications

and cost.79,80,81,82,83 Increasing age, established cardiovascular disease and/or type 2 diabetes

usually indicate the usage of more than five drugs per day (polypharmacy).84 Treating high

risk patients often requires polypharmacy even though this is known to be associated with

patients’ non-adherence, inadequate prescription of medication by doctors and drug

interactions. Therefore the complexity of the prevention of cardiovascular diseases requires

simplicity.

The lack of affordability of therapy largely affects treatment gaps in developing countries

since in developing countries most healthcare services are paid for out-of-pocket with little

or no subsidy through health insurance or the government. The economic burden of

secondary prevention of cardiovascular diseases is enormous, especially among the rural

and urban citizens. As a month’s treatment costs ranges from 1 to 18 days’ wages of

government workers, preventive drugs are unaffordable for the majority of individuals in

developing countries.85,86 Patients can delay or omit drug doses and not fill prescriptions as

strategies for cost reduction. Though the efficacy of preventive strategies may be proven and

recognized at a high level, supply and access at the population level remains the major

challenge.

Practical and affordable approaches to closing these treatment gaps are required.

Combination pills or ‘polypills’ may play a role in closing these treatment gaps in ischaemic

and cerebrovascular disease, and their use has been advocated for almost a decade.87,88,89

Reducing the complexity, number and costs of medication regimens with a ‘polypill’

containing off patent generic medicines will potentially improve adherence and hence

reduce cardiovascular events.

4.2 New innovative therapies

Further research into new, innovative therapies for the prevention and treatment of CVD is

ongoing particularly amongst the larger pharmaceutical companies. Advancements in the

knowledge of the pathophysiology and underlying determinants of the various types of

CVD (including advances in genomics and targeted population groups) are constantly

opening up new lines of enquiry into the possibility for a newer drug that may perhaps

target a more specific mechanism or a targeted clinical population which, when added to the

currently available medication options, may offer increased prevention or treatment for

CVD. There is clearly a need for development of new medication types as even if all of the

previously mentioned available therapies are utilized maximally, patients still have a

residual risk of CVD. The reality though is that development of a new drug costs well over a

billion US dollars. This scope of research is well outside any publically funded research

scheme and therefore will not be addressed in this background paper. Although new

innovative therapies are potentially worthwhile, the most cost-effective measure for

preventing CVD currently is improving access and adherence to currently available, generic

medications.


6.3-20

5. What can be learnt from past/current research into

pharmaceutical interventions for this condition?

Research over the last half century involving hundreds of thousands of patients in clinical

trials has provided an enormous body of evidence on the efficacy and safety of different

blood pressure lowering, statin and antiplatelet agents in the control of cardiovascular

disease.88,89 The large majority of these trials were designed to assess the effects of individual

medicines given the understandable clinical, regulatory and commercial requirements to

assess the benefits and risks of specific drugs before access and uptake in the market. Hence

trials typically involved randomization of a single agent versus placebo, on top of a

background of usual care treatments at that time. Systematic reviews of these trials reveal an

overall finding of broad relevance to clinical and public health practice, and to development

of polypills: an approximate constancy of relative risk reduction (i.e. lack of interaction or

effect modification) of each modality (BP lowering, cholesterol lowering and anti-platelet

effect), irrespective of whether the other modality is present or absent.31,90,91 More specifically,

these systematic reviews of clinical trials have shown that proportional reductions in cause-

specific outcomes (such as CVD mortality) are closely similar across a wide range of patient

populations, with no major differences between agents (after accounting for the extent of risk

factor reduction for SBP and LDL) and even when event rates vary tenfold or more.For

example, aspirin produces a one-fifth reduction in CHD and ischaemic stroke risk in

‘primary’ and ‘secondary’ prevention, even though event rates differ by an order of

magnitude. There is clear evidence that the proportional reductions in major outcomes

achieved with each treatment modality are approximately the same in the presence or

absence of other interventions and across a range of risk factor levels which is expected given

the lack of interaction between treatments in terms of risk factor reduction and the

epidemiology of blood pressure and cholesterol joint effects– this is outlined in Figures 6.3.5

and 6.3.6.

Given this consistency in proportional reductions, it is an expectation that combination

therapy will have beneficial effects. More specifically, the combined effects are best estimated

by multiplying relative risks together, after adjusting for the size of SBP and LDL-cholesterol

reductions.


6.3-21

Figure 6.3.5: Reduction in vascular events with a statin in the Heart Protection Study92 and

reduction in stroke events with blood pressure lowering in the PROGRESS study93 by

concomitant treatments and other factors

Source: Heart Protection Study Collaborative Group. Lancet, 2002

Progress Collaborative Group. Lancet, 2001

Figure 6.3.6: Reduction of serious vascular events with aspirin, by blood pressure and

cholesterol levels

Source: Baigent C et al. Lancet, 2009 90


6.3-22

The concept of combining multiple classes of cardiovascular medications into a single pill

also has a long history – for example, the term “asp-olol” was coined for an aspirin and

atenolol combination in the 1970’s. Patents claiming rights over combinations of various

cardiovascular medications had been filed since the late 1990s (for example 94,95,96). The first

major scientific meeting on the concept of a fixed dose combination pill for CVD prevention

was held in 2001, when the World Health Organization and the Wellcome Trust convened a

meeting of experts to discuss evidence-based and affordable interventions for non-

communicable diseases.87 A major impetus for the meeting was the potential for fixed-dose

combination pills containing aspirin, statin, and BP-lowering agents, noting ‘the use of a single

pill could well encourage patients to adhere to treatment as well as seriously reduce the cost of the

drugs’. In the medical literature, the concept of a fixed-dosed combination pill was discussed

by Yusuf in a Lancet editorial in 2002 88 and effectiveness and cost-effectiveness analyses

were conducted in the 2002 World Health Report.97 The term ‘polypill’ itself was introduced

with the publication of the Wald and Law’s seminal paper in 2003.89 Wald and Law

estimated that the use of a single pill (containing aspirin, a statin, three BP-lowering drugs,

and folic acid) in all people aged over 55 years would reduce cardiovascular disease by more

than 80%.

Over the ensuing decade several clinical trials in the area of fixed dose combination pills

have been conducted. These trials can be broadly grouped into two main areas:

- Comparisons of polypill versus usual care - in patient populations with established

indications for all the component medications e.g. previous coronary disease

- Comparisons of polypill versus placebo/no treatment - in patient populations with

established indications for none of the component medications e.g. those without

hypertension, dyslipidaemia or vascular disease but who are nonetheless at raised

cardiovascular risk

The 2004 Priority Medicines for Europe and the World Report1 and its recommendation to

prioritize research into fixed dose combinations for the secondary prevention of CVD led to

the European Commission funding of the largest Request for Proposal in this area, and hence

two of the largest polypill trials: the Use of a Multidrug Pill In Reducing cardiovascular

Events (UMPIRE) trial 98 and the Fixed Dose Combination Drug for secondary

Cardiovascular prevention (FOCUS) trial 99 and these will be discussed following a review of

other trials. While many of the patients involved in these trials suffered from IHD, some of

the patients included were suffering from cerebrovascular disease.

5.1 Previous trials – polypill versus placebo or no treatment

These trials are summarized in Annex 6.3.2 and main outcomes in Annex 6.3.3.

5.1.1 Summary of TIPS 1 and 2

The Indian Polycap Study (TIPS)100 was a randomised, partial factorial design trial of

Polycap® versus eight other medication combinations including aspirin alone, simvastatin

alone and different combinations of hydrochlorothiazide, ramipril, and atenolol (see

reference 100) for details of various combinations). Over two-thousand participants with at

least one risk factor for CVD (such as hypertension, diabetes, current smoker, raised lipids or

raised waist: hip ratio) were randomly allocated to one of the nine groups and followed up

for 12 weeks. Outcomes included effect on blood pressure, heart rate, lipids and urine


6.3-23

thromboxane B2 as well as safety and tolerability. The study showed that the BP lowering

effect of the Polycap® was comparable to the additive effects of each of the three component

BP lowering drugs. A lesser effect on LDL cholesterol than simvastatin alone was noted (0.13

mmol/L) which was significant. Mean changes in blood pressure and LDL are shown in

Figure 6.3.7 below.

Figure 6.3.7: Mean changes in blood pressure and LDL in the TIPS study

Source: The Indian Polycap Study (TIPS). Lancet, 2009

Error bars indicate 95% CI. Mean changes from baseline in the nine groups in the TIPS trial, and the

effects of no blood-pressure-lowering drugs (As, S), one blood-pressure-lowering drug (T), two blood-

pressure-lowering drugs (T+R, T+At, or R+At), or three blood-pressure-lowering drugs (T+R+At,

T+R+At+S), or the Polycap (P)

5.1.2 Summary of Wald and Law trial

Wald and Law 101 conducted a randomised, double-blind, cross-over trial of the polypill

studied containing three half-dose BP lowering medications and a statin in 86 participants

over the age of 50 with no history of CVD. Each participant took placebo or polypill for 12

weeks sequentially. Mean systolic blood pressure was reduced by 17.9 mmHg (95% CI, 15.7–

20.1) on a polypill, diastolic blood pressure by 9.8 mmHg (8.1–11.5), and LDL cholesterol by

1.4 mmol/L (1.2–1.6), reductions of 12%, 11%, and 39% respectively (Figure 6.3.8). These

results were almost identical to those predicted from previous trials of individual

components. This trial is in effect a large Phase 1 study of the polypills efficacy in patients

without cardiovascular disease.


6.3-24

Figure 6.3.8: Observed and expected reduction of blood pressure and LDL-cholesterol in a

2x12 week crossover trial. 101

Source: Wald DS, et al. PLoS ONE, 2012

5.1.3 PILL Collaborative Group

The Pill Pilot study 102 was a randomised, double-blind placebo-controlled trial of a polypill

(containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20

mg) in 378 individuals without an indication for any component of the polypill, but who had

an estimated five year cardiovascular disease risk over 7.5%. Over 12 weeks, polypill

treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95%

CI 0.6 to 0.9) mmol/L.


6.3-25

Figure 6.3.9: Change in BP and LDL cholesterol at 12 weeks in the Pill Pilot study.

Source: Pill Collaborative Group, Rodgers A, et al. PloS one, 2011.

5.1.4 Other trials

Two other trials have been conducted however have significant issues associated with them

meaning that their results must be interpreted very cautiously.

Malekzadeh et al 103 conducted a double-blind randomized, placebo controlled trial in Iran in

475 participants over 50 years without CVD. They found a small but significant different in

SBP at 12 months (4.5/1.6 mmHg) as well as LDL cholesterol (0.46 mol/L) however a

significant difference of 6 mmHg of SBP at baseline between the two groups infers failure of

the randomization process. Furthermore, the less than expected effects of the polypill on

their outcomes raises concern about the reliability of reported compliance with medication.

Soliman et al 104 reported on an open-label, randomized controlled trial of a polypill versus

usual care in 216 patients without CVD. No significant difference was found in SBP or total

cholesterol after three months which was presumed by the authors to be due to the usual

care arm receiving a higher than usual standard of care during the trial than would occur in

usual practice. Further, larger than expected reductions in risk factors (e.g. for SBP a decrease

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

0 2 4 6 8 10 12

LDL

(mm

ol/

L)

Follow-up (weeks)

0

20

40

60

80

100

120

140

160

0 2 4 6 8 10 12

Bloo

d pr

essu

re (m

mH

g)

Follow-up (weeks)

ΔLDL-cholesterol 0.8 mmol/L (0.6-0.9)

ΔSBP 9.9 mmHg (7.1-12.1)

ΔDBP 5.3 mmHg (3.3-6.7)


6.3-26

of 28.8 mmHg versus 26.9 mmHg in usual care) also raised concerns about standardization

of measurement of risk factors.

For the above mentioned reasons, these two studies are not generally considered to be

reliable representations of the true effect of polypill care.

5.1.5 Conclusions from previous trials of polypill versus placebo or no treatment

The key conclusions from the previous trials of polypill versus placebo/no treatment are that

short term risk factor reductions are of approximately the size expected from individual

agents, after taking into account loss to follow-up and non-adherence. The size of the

underestimation due to loss to follow-up and non-adherence was very small in some trials

(Wald et al, Pill Collaborative Group) and very large in others (Iranian Trial, Sri Lanka trial),

with consequent differences in the observed to expected risk factor reductions. The trials

provided relatively few data on side effects and tolerability but overall these were consistent

with effects known from the separate medications. There were no reliable data on long-term

risk factor reductions or cardiovascular outcomes though these would not be expected in

such short term small studies.

5.2 Ongoing trials – polypill versus placebo

Several large scale randomized trials have commenced (Annex 6.3.7) which aim to address

the question of the effect of a polypill on CVD outcomes (in particular CVD events) in

primary prevention. This is a patient population in which perhaps use of a polypill may be

considered more controversial as some may argue that the benefits of treatment may not

outweigh the risks of treating such patients (particularly in relation to the use of aspirin).

Three trials are recruiting/following-up patients who are at moderate risk of CVD in large

scale, long-term trials which are powered to assess the risk-benefit ratio of polypills in

primary prevention and particularly the effect on CVD events. The results of these trials will

also give an indication of the effect of a polypill on adherence over time in a group of

patients who, being asymptomatic without a diagnosis of CVD, may well be less inclined to

be adherent to preventive medication.

5.3 Previous trials – polypill versus usual care

5.3.1 FP7-funded UMPIRE trial

The “Use of a Multidrug Pill In Reducing cardiovascular Events” (UMPIRE) trial aimed to

assess whether a polypill-based strategy for delivery of medications (aspirin, statin and two

blood pressure lowering agents) compared to usual care would improve long-term

adherence to guideline-indicated therapy, systolic blood pressure (SBP) and low density

lipoprotein (LDL)-cholesterol in people with CVD or at similarly high risk. The trial was a

prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial among 2004

participants from India and Europe. The main eligibility criteria were established CVD or an

estimated five-year CVD risk of ≥15%. Participants were randomly assigned (1:1) to a fixed-

dose combination POLYPILL-based strategy or usual care. In the POLYPILL group,

physicians could use a POLYPILL that contained aspirin 75 mg, simvastatin 40 mg, lisinopril

10 mg and atenolol 50 mg or one containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10

mg and hydrochlorothiazide 12.5 mg. In the usual care group, treatment continued


6.3-27

according to physician discretion. Adherence to medication (defined as self-reported use of

antiplatelet, statin and ≥2 BP-lowering medications) and changes in SBP and LDL-cholesterol

from baseline were the main outcomes. At baseline, mean blood pressure was 137/78 mmHg,

LDL-cholesterol was 91.5 mg/dl and 1233/2004 (61.5%) participants reported use of

antiplatelet, statin and ≥2 BP lowering medications. Full baseline characteristics are provided

in Annex 6.3.4.

Median follow-up was 15 months. Allocation to the POLYPILL group improved adherence

by one-third (RR 1.33, [95% CI 1.26, 1.41] p<0.0001), with reductions in SBP (-2.6 mmHg [95%

CI -4.0, -1.1] p=0.0005) and LDL-cholesterol (-0.11 mmol/l [95% CI -0.17, -0.05] p=0.0005) that

which corresponds to 4.6 patients needing to be treated with the polypill in order to gain one

additional adherent patient. These results are shown in Figure 6.3.10.

Figure 6.3.9: Adherence to indicated medications by treatment group over follow-up in the

FP7-funded UMPIRE trial

Source: personal communication, S Thom

Legend: Figure shows overall adherence (panel A), statin (panel B), antiplatelet drug (panel C), and ≥2

BP lowering drugs (panel D) by follow-up time in the POLYPILL and usual care groups. M6-M24 are

visits at months six to 24

In

dic

ate

d m

ed

ic

atio

ns

(

%)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

B a s e l in e M 6 M 1 2 M 1 8 M 2 4

U s u a l c a re

F D C

1 .3 6 (9 5 % C I 1 .3 0 ; 1 .4 3 ) , p < 0 .0 0 0 1

6 3 .45 9 .7

6 3 5 /1 0 0 25 9 8 /1 0 0 2

6 8 .3

9 7 .3

6 7 .2

9 2 .0

6 5 7 /9 7 88 9 9 /9 7 7

6 5 .1

8 8 .4

6 0 2 /9 2 58 2 7 /9 3 5

6 4 .0

8 6 .3

3 3 4 /5 2 24 5 2 /5 2 4

5 0 .0

7 6 .5

1 8 /3 62 6 /3 4

Sta

tin

(

%)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

B a s e l in e M 6 M 1 2 M 1 8 M 2 4

U s u a l c a re

F D C

8 7 .68 8 .0

8 7 8 /1 0 0 28 8 2 /1 0 0 2

9 3 .9

9 8 .9

9 3 .1

9 6 .7

9 1 1 /9 7 89 4 5 /9 7 7

9 1 .0

9 4 .5

8 4 2 /9 2 58 8 4 /9 3 5

8 9 .8

9 2 .4

4 6 9 /5 2 24 8 4 /5 2 4

8 3 .3

9 1 .2

3 0 /3 63 1 /3 4

An

tip

la

te

le

t d

ru

g (

%)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

B a s e l in e M 6 M 1 2 M 1 8 M 2 4

U s u a l c a re

F D C

9 1 .09 1 .8

9 1 2 /1 0 0 29 2 0 /1 0 0 2

9 4 .8

9 9 .4

9 4 .7

9 7 .5

9 2 6 /9 7 89 5 3 /9 7 7

9 3 .4

9 5 .9

8 6 4 /9 2 58 9 7 /9 3 5

9 1 .0

9 2 .7

4 7 5 /5 2 24 8 6 /5 2 4

7 2 .2

8 8 .2

2 6 /3 63 0 /3 4

2 o

r m

or

e B

P-

lo

we

rin

g d

ru

gs

(

%)

0

1 0

2 0

3 0

4 0

5 0

6 0

7 0

8 0

9 0

1 0 0

B a s e l in e M 6 M 1 2 M 1 8 M 2 4

U s u a l c a re

F D C

7 1 .06 5 .9

7 1 1 /1 0 0 26 6 0 /1 0 0 2

7 4 .3

9 7 .9

7 3 .6

9 3 .0

7 2 0 /9 7 89 0 9 /9 7 7

7 3 .3

9 0 .8

6 7 8 /9 2 58 4 9 /9 3 5

7 3 .8

8 9 .3

3 8 5 /5 2 24 6 8 /5 2 4

7 2 .2

8 5 .3

2 6 /3 62 9 /3 4


6.3-28

Figure 6.3.10: Systolic blood pressure and LDL-cholesterol by treatment group over

follow-up in the FP7-funded UMPIRE trial


Legend: Systolic blood pressure (panel A) and LDL-cholesterol (panel B) values shown at baseline,

during follow-up and at end of study (EOS) in the polypill and usual care groups.

There was broad consistency of effects across pre-defined subgroups including

cardiovascular history, gender, smoking status, diabetic status, region (Western Europe

versus India) and choice of POLYPILL. In addition, there was consistent evidence of larger

benefits among patients with lower adherence at baseline i.e. those who were not already

receiving antiplatelet, statin and two blood pressure drugs at baseline (Table 6.3.6). It should

be noted that the adherence rates of the non POLYPILL control patients was high as

compared to the results of normal care as reported in the EUROASPIRE studies described

above.

Table 6.3.6: Primary outcomes in UMPIRE trial, according to baseline adherence

Outcome Mean difference and 95% CI,

polypill versus usual care p-value for

heterogeneity Adherent* at

baseline

Not adherent* at

baseline

Adherence* (relative risk) 1.04 (1.01,1.08) 3.35 (2.74, 4.09) <0.001

Systolic BP (mmHg) -1.0 (-2.9, 0.8) -4.9 (-7.3,-2.6) 0.01

LDL cholesterol (mmol/l) -0.07 (-0.15, 0.01) -0.17 (-0.27, -0.07) 0.1


* defined as taking statin, antiplatelet and two or more blood pressure lowering agents


6.3-29

In absolute terms, the improvement in adherence was particularly large in the group who

were under-treated at baseline (73.4% versus 23.1%) compared to those who were taking

medications from all recommended classes at baseline (92.1% versus 88.1%). There were no

significant differences in serious adverse events between the groups.

The trial had several strengths, in terms of sample size, duration of follow-up and

completeness of data collection. However, there are several issues to be considered when

interpreting results from adherence trials in general and this study in particular. Most

importantly, the trial likely under-estimated benefits in a general population setting with

typical adherence levels, since volunteers for clinical trials tend to be relatively motivated

and clinical management in a trial setting tends to be more intensive than usual care.105 The

size of this under-estimation is suggested in the minority of individuals who were not taking

indicated medications at baseline, in whom randomization to POLYPILL resulted in a three-

fold increase in adherence levels and larger reductions in SBP and LDL-cholesterol. Effects

were nonetheless observed in a trial population of whom 82% initially reported use of statin,

antiplatelet and blood pressure lowering drug(s), whereas comparable combination

treatment rates are around 50% in high income countries and 5 to 20% in low and middle

income countries.76 Furthermore, improvements were observed compared to a usual care

group in whom treatment rates rose initially and remained higher than baseline throughout

the study, whereas adherence typically reduces over time 78,106 and in the usual care group,

approximately three-quarters of all statin prescriptions were for atorvastatin or rosuvastatin

which are newer and somewhat more efficacious statins at the doses used.

Ethics Committees required the researchers to provide the polypill free of charge, whereas

the usual care group continued to receive their medications with attendant costs or subsidies.

In one sense, this reflects the real impact if the polypill were to be made available at low or

zero cost to the patient, for example as part of a universal health care program. Among this

trial population, the economic advantage for the polypill group would likely have been

modest, both in India given the generally low cost of medicines and relative affluence of

participants from tertiary care settings, and in Europe given the prevalence of medication

and prescription subsidies. A large United States trial recently showed that elimination of

copayments for core cardiovascular medicines improved adherence by about 5% in absolute

terms, which is smaller than the treatment effect seen here.107

The trial did not identify an effect on cardiovascular events, but with only 85 events it

provided little power to detect meaningful differences between groups. Based on observed

differences in SBP, LDL cholesterol and aspirin use, relative risk reductions of around 15% in

coronary disease and stroke are anticipated after a few years.102 However, a clinical trial

would need to observe over 1 000 events to reliably detect a relative risk reduction of 15%.108

Among patients who were under-treated at baseline, the observed risk factor reductions

would be expected to lead to about a 30% reduction in cardiovascular events.

The main conclusion overall from UMPIRE was that among a well-treated population with

CVD or at similarly high risk, long-term provision of indicated cardiovascular preventive

medication as a polypill led to improvements in adherence, SBP and LDL-cholesterol.


6.3-30

5.4 Ongoing trials versus usual care (Annexes 6.3.7)

5.4.1 FP7 funded FOCUS trial

The second trial funded by the FP7 program is the Fixed Dose Combination Drug

for Secondary cardiovascular Prevention (FOCUS) trial (www.focus-fp7.eu), which includes

a multi-country 4 000 patient descriptive non-interventional study aiming to provide a

comprehensive analysis of potential factors precluding adequate secondary prevention,

including health system characteristics, drug affordability and availability, as well as patient

characteristics. The second component will be a 1 340 patient randomised trial of the effect of

a polypill on adherence, BP and lipid levels at six to 9 months in participants with

established CVD. Phase 2 will also include a prospective economic evaluation. Patient

recruitment has commenced in this trial however results are not expected for some time yet.

5.4.2 Kanyini-GAP

The Kanyini guidelines adherence with the polypill (Kanyini-GAP) study 109 is an Australian

623 patient randomised controlled trial of the effect of a polypill on adherence, SBP and total

cholesterol in indigenous and non-indigenous populations with established CVD or five year

CVD risk of at least 15%. This study was completed in September 2012 and is undergoing

analysis of results. Of note, the Kanyini-GAP trial aimed to recruit patients and conduct the

trial in as ‘real-life’ a setting as possible. This included:

• Recruitment and follow-up conducted through patient's usual primary care provider

to reflect actual practice once a ‘polypill’ enters the market

• Recruitment in urban, rural and remote settings to accurately reflect the challenges

inherent in following up patients in a range of clinical settings

• Patients pay the relevant co-payment amount for their Red Heart Pill (polypill)

prescription to reflect actual required payment once the Red Heart Pill is available in

the Australian market.

5.4.3 IMPACT

The IMProving Adherence using Combination Therapy (IMPACT) trial 110 is a New Zealand

513 patient randomised controlled trial investigating the impact of a polypill on adherence,

SBP and LDL cholesterol in both Maori and non-Maori populations with established CVD or

five year CVD risk of at least 15%. The study has completed recruitment and is currently

conducting final patient visits with results expected in late 2013. As for the Kanyini-GAP

trial, patients were recruited and followed up in as ‘real-life’ a setting as possible including

recruitment through general practitioners, in a variety of urban and rural settings and

including the relevant medication co-payment that would be required from a patient once a

polypill is available on the market.

5.4.4 SPACE Collaboration meta-analysis

The UMPIRE, Kanyini-GAP and IMPACT trials are all part of the Single Pill to Avert

Cardiovascular Events collaboration (www.spacecollaboration.org), an international group

of investigators who aim:

http://www.spacecollaboration.org/


6.3-31

1. To facilitate the conduct of independent clinical trials of a fixed dose combination pill

containing aspirin, a statin and blood pressure lowering drugs in individuals at high

cardiovascular risk

2. To promote the opportunities for such trials in low and lower middle income countries

and in marginalized populations in high income countries

3. To ensure as much uniformity between trials as possible to enable subsequent data

pooling

4. To undertake IPD meta-analysis at the conclusion of all the trials.

Having individual patient data (IPD) available for meta-analysis will provide the ability to

perform more complex analyses (survival and multivariate analyses), investigate the

influence of covariates on heterogeneity of treatment effects, both within and between trials,

facilitate greater flexibility in the categorization of subgroups and reduce potential biases by

allowing consistency checks with individual study results.

Results from this IPD meta-analysis are expected in early 2014.

6. What is the current “pipeline” of products that are to be used for this

particular condition?

An exhaustive review of the pipeline of all products relevant to cardiovascular disease

control is beyond the scope of this Background Paper. A summary of the polypills that are in

development is given in Annex 6.3.8. As can be seen, there are several products in the

research pipeline that have aspirin, statin and one or more blood pressure lowering agents.

There are also a number of ‘semi-polypills’ in development, combining across two

therapeutic classes e.g. a statin and an anti-diabetic agent.

7. What are the opportunities for research into new pharmaceutical

interventions?

The use of fixed dose combinations in cardiovascular disease has stimulated much

discussion and debate in the medical literature. Criticism of the polypill strategy was based

on the view that it would largely be applied in the primary prevention of a population at a

relatively low absolute risk of cardiovascular disease. It was argued that a large proportion

of the population would be medicated unnecessarily. Furthermore, there was concern that

the polypill might induce a sense of protection and deflect attention from healthy lifestyle

behaviours like low fat diet and physical activity. The counter-arguments however are

strong. Although Professors Wald and Law still promote the concept of generic prescription

of a ‘polypill’ to all patients in a certain age group, it is worth clarifying that the majority of

clinical researchers working in the area of fixed dose combination pills for CVD prevention

do not agree with this proposal. Instead, the majority of work conducted so far in this area

has focused on proof of concept, placebo-controlled, pharmacodynamics trials, primary

prevention for patients with moderate CVD risk versus placebo trials, and polypill versus

usual care in secondary prevention and high risk primary prevention population trials.


6.3-32

Several paradigm changes have been proposed in the area of fixed dose combinations, both

as and by the Wald and Law papers published in 2003 are involved in the “polypill” concept,

as broadly defined in Table 6.3.7.

Table 6.3.7: Paradigm changes in the field of polypill research.

Paradigm change / research question Relevant trials

ongoing

Gaps

Use in established indications: do any

benefits of fixed combinations of

indicated medicines (access,

adherence, treatment inertia)

outweigh any problems (lack of

tailoring, dose titration etc.)

UMPIRE, Kanyini-

GAP, IMPACT

None in specific disease

areas e.g. diabetes

No CV events (but see

discussion of limited trial

size and infrequent

events)

Prevention: new approach to

preventing CVD (indication not

available for separate components)

TIPS-3 High dose – side effects

may be too high

Sample size may be too

small

Use of low doses of three BP drugs TRIUMPH

TIPS-4

No event trials

Treatment initiation – based on CV

risk not risk factor level. In most

extreme form age is only risk

indicator needed

All trials have entry

based on CV risk

except Wald (age only)

Not amenable to trials -

more analysis and policy

Treatment monitoring – based only

on adherence, not based on risk factor

levels, or e.g. hypertension control

None Trial needed

8. What are the gaps between current research and potential research

issues which could make a difference are affordable and could be

carried out in a) five years or b) in the longer term?

8.1 Need for large-scale trials among people with established

cardiovascular disease and other indications for treatment

There are numerous reasons to focus on people with established cardiovascular disease and

other clear indications for future polypill research. From a public health viewpoint, this is a

large, easily identified, high-risk patient population among whom almost half of all

cardiovascular events occur.111 There are well-established large reductions in cardiovascular

events and mortality that can be achieved when patients are prescribed and adhere to

recommended preventive medications such as cholesterol lowering,27 blood pressure

lowering 112 and anti-platelet drugs,90 yet large treatment gaps still persist. Following an

acute myocardial infarction, if left untreated, patients with CVD have a persistent 5% risk of


6.3-33

mortality each year.113 In this context, the ‘low hanging fruit’ of CVD prevention is to make

available, prescribe and promote adherence to essential medications in those at highest risk

i.e. those who have established CVD. The FP7-funded UMPIRE trial showed that promising

improvement in adherence and clinical indicators could be achievement with provision of a

polypill in this patient group in different environments. However, a number of research

questions remain outstanding, and these include the following questions.

8.2 What are the effects of implementing a polypill strategy on

cardiovascular outcomes?

In circumstances in which individual medicines are already proven to be efficacious, there

should be no need to doubt or require repeat evidence of the benefit of combined therapy,

unless some new interaction or some new issue related to concomitant starting or stopping;

or that there perhaps exists benefits for some components and hazards for others. Thus

generally improvement in adherence can (and should) be taken as improvement in CV

outcomes. However there are legitimate reasons to assess the size of benefits, and risks, of

implementing a polypill strategy on a large scale. Many of the factors involved in scale-up

are system-level e.g. training, education, task shifting, electronic decision support, and many

of the patients, clinicians and environments most in need of adherence-improving strategies

are those least likely to join a standard clinical trial. Therefore the area would be well served

with a very large implementation trial, or a series of sister trials, with the following features

• cluster or step wedge implementation114

• unit of randomisation: primary healthcare facility

• denominator/patient population: individuals with established CVD stratified into

different population groups

• numerator/outcome: CV outcomes, and also to assess generalizability in subgroups

the percentage taking guideline-recommended medicines, and LDL and SBP levels

The UMPIRE trial showed improvements in risk factor reductions that would be expected to

result in a 10 to 15% reduction in CV events in that trial population, but that benefit might be

at least twice as great among a group not taking all indicated medications. One would

therefore require trials involving several tens of thousands of participants in order to reliably

assess CV outcomes, and assess consistency in different patient groups and in different

health systems. However if such a trial was successful it would result in the transformation

of the standard of care for patients with proven cardiovascular disease and save hundreds of

thousands of lives.

Several other pressing research questions exist, which could be addressed as part of the

above trial(s), or as separate trials.

8.3 Potential benefits of next generation polypills

8.3.1 Additional benefits from use of newer agents

Several agents have recently come off patent (e.g. atorvastatin, clopidogrel) and could

conceivably be included in the next generation of polypills, and other agents will be coming

off patent within five years (e.g. rosuvastatin). Research could usefully be directed to

assessment of the additional benefits of including these agents for specific patient

populations or having them replace agents in the existing polypills.


6.3-34

8.3.2 How many dose versions for each polypill?

The ‘default’ option from a regulatory point of view is to make available all conceivable dose

versions, excluding perhaps those that are rarely or never used, whereas the original concept

of the polypill was based on a single dose version. An important research question is

whether the advantages of therapeutic flexibility outweigh the advantages of regimen

simplicity and avoidance of resistance to treatment.

8.3.3 Low dose or high dose polypill components?

The ideal dose(s) of component medications is a topic of intense debate in the area. In the

simplest case, there is little doubt that low doses of aspirin are ideal, given that higher doses

are associated with more side effects but not greater benefits.63 Statins have a shallow dose

response curve in terms of benefits, with each doubling of dose only leading to about a 7%

increase in LDL reduction.31 However, side effects are low at all doses except maximal ones.

In the context of combination therapy, there are surprisingly modest marginal benefits in

cardiovascular risk reduction of increased dosages of the blood pressure lowering drugs, at

the cost of an increase in side effects. Evidence from a very large number of clinical trials has

shown that doubling the dose of a blood pressure agent typically leads to much less than a

doubling in blood pressure reduction, but a moderate increase in side effects.115,116 The small

expected difference in overall cardiovascular event reduction for polypill formulations

differing in their extent of BP reduction is shown in Figure 6.3.8.

The recently completed TIPS 2 trial 117 suggests that maximal dose polypill versions will

achieve only a few mmHg additional SBP difference at most in the long-term. This trial

observed an increased SBP reduction of only 2.8 mmHg after doubling the dose of three

blood pressure lowering agents (i.e. one arm taking a single polycap containing ramipril 5

mg, atenolol 50 mg, hydrochlorothiazide 12.5 mg was compared to an arm taking two

polycaps). Furthermore, there was attenuation of the already small treatment differences at

week 12 compared to weeks two to eight. However increasing blood pressure lowering

drugs to maximal doses results in appreciable increases in side effects, which can reasonably

be expected to reduce long-term adherence.116


6.3-35

Table 6.3.8: Expected reduction in coronary heart disease risk with polypill versions

containing different doses of blood pressure lowering agents

Expected reduction in CHD risk

Modality

Polypill

– base

case

Polypill versions that achieve incremental

additional SBP reductions of:

1 mmHg 2 mmHg 3 mmHg 4 mmHg

BP reduction 26% 28% 29% 31% 33%

LDL reduction 42% 42% 42% 42% 42%

Aspirin 20% 20% 20% 20% 20%

Combination 66% 66% 67% 68% 69%

Data sources and assumptions:

Polypill “base case” version reduces SBP by 12 mmHg and LDL by 1 mmol/l (39 mg/dL)

Relative risks provided by systematic reviews of trials of aspirin,64 blood pressure lowering 115 and

cholesterol lowering.118,119 Since 1 mmol/L LDL-cholesterol reduction, 10 mmHg SBP reduction

and aspirin each individually lower CHD risk by 42% 118, 22% 120 and 20% 64 respectively (i.e. RRs

are 0.58, 0.78 and 0.80 respectively), the expected joint effects of a 1 mmol/L LDL-cholesterol

reduction, 16 mmHg SBP reduction and aspirin would be approximately a 69% lower CHD risk

(since 0.581.0/1.0 x 0.7816/10 x 0.80 = 0.41, and (1-0.41) x 100% = 69%).

8.4 Polypill approach in specific patient populations

The polypill approach can be adapted and adopted for other disease conditions, particularly

those with a large disease burden, for which adherence is a major factor. Polypills could be

developed in several of these areas, for example:

• a ‘diabetes polypill’, incorporating one or two hypoglycaemic agents as well as a

statin and an ACE-inhibitor

• A ‘hypertension polypill’ – incorporating three or even four very low dose

medications (see Annex 6.3.6 for current trials assessing this concept).

However, use in these conditions will likely require direct evidence of efficacy to convince

regulators and key opinion leaders, requiring trials similar to UMPIRE and FOCUS.

8.5 Expanding the polypill concept to acute care

To date, polypill trials have been conducted among a population with long-established

cardiovascular disease. However key issues arise concerning whether treatment should be

started sooner after an acute event:

• Are there greater benefits if people are started in hospital soon after an acute event?

• Can benefits accrue in the first year after acute coronary syndrome, when the greatest

risk for drop-off in adherence and for another major event are highest?

Therefore, trials of next generation polypills started in acute or semi-acute disease are

required.


6.3-36

9. For which of these gaps are there opportunities for

pharmaceutical research?

There are considerable formulation challenges in simultaneously achieving bioequivalence,

long-term stability and maintaining a size for the polypill that is acceptable to patients.

Pharmaceutical research could be usefully directed to developing and testing new ways to

develop and manufacture polypills, including with some of the newer ingredients outlined

above.

An example of such research is the TI Pharma project “Design quality into products”

(http://www.tipharma.com/pharmaceutical-research-projects/production-technologies/

dosage.html, Accessed February 22nd, 2013) in which researchers successfully created a

production process that achieves homogeneity in drug mixtures, a process which is essential

in the creation of polypills as each pill must contain exactly the same dose of each of the

component drugs.

10. Conclusion

In the eight years since the last ‘Priority Medicines for Europe and World’ report, much work

has been done in the area of medication use for prevention of CVD. However the biggest

opportunity to have maximal impact on CVD prevention still remains further research into

ensuring widespread availability of fixed dose combination therapy (or polypills) that

include medications that have been demonstrated to be highly effective in CVD prevention,

are available in cheap generic formulations but are underutilized in almost every clinical

setting globally. Development of new medications for CVD prevention still has a role to play

but despite ongoing research costing billions of dollars, no new ‘blockbuster’ medication has

come to light recently that has the potential for greater effect than ensuring what already

exists is available and prescribed globally to patients with established CVD.

The FP7 funded UMPIRE trial has shown that even in a clinical trial population who were

already highly adherent at baseline, opportunity exists to improve BP and cholesterol control

via improved adherence with a polypill. In patients who were not adherent to all medication

classes at baseline, a massive 300% increase in adherence to all recommended classes of

medication was seen. If such a polypill were applied across non-adherent patients across

Europe the scale of potential prevention of CVD events would be counted in the hundreds of

thousands. Extension of this potential to LMIC where the bulk of the disease burden lies

extends this to millions of people. Funding from FP7 has contributed significantly to the

progress so far in understanding the potential benefit of polypills in CVD prevention

however further funding is required to build upon the available evidence.

The scale of funding required to further develop the evidence base that has already been

achieved in the area of polypill research is unlikely to be committed to by major

pharmaceutical companies as their focus lies in the development of newer patent-protected

products which are likely to have higher profit margins. Meanwhile, generic pharmaceutical

companies do not have the research budgets that would enable them to invest in such large-

http://www.tipharma.com/pharmaceutical-research-projects/production-technologies/dosage.html

http://www.tipharma.com/pharmaceutical-research-projects/production-technologies/dosage.html


6.3-37

scale clinical trials. Major public funding commitment is therefore needed to ensure that

what has been achieved so far is built upon and to provide the evidence necessary for

regulatory approval in both Europe and worldwide. The potential benefits of the widespread

use of polypills are enormous.

Other issues in this area that require further research include:

Potential additional benefits from newer agents now off-patent

Number of dose versions

Low-dose versus high-dose polypills

Specific populations (e.g. diabetes polypill, hypertension polypill)

Use in acute care (e.g. immediately after a heart attack versus use in chronic care).

Other cardiovascular research areas

As mentioned in the introduction, there are many other areas of research into

pharmacological approaches to IHD that may need to be supported. These include the

development of new lipid-lowering drugs; pharmacological means to address novel

mechanistic concepts of vessel wall damage and protect against conditions such as chronic

inflammation and local angiogenesis; as well as regenerative medicine/cell therapy

approaches. Similarly, new pharmacological treatment strategies need to be developed for

heart failure and arrhythmias, frequent consequences of IHD. While these areas have not

been investigated in this background paper or the chapter, opportunities for research may

exist that are not being addressed by the pharmaceutical industry.


6.3-38

11. Declarations

The authors have received grants from several research charities and national funding

agencies for research on cardiovascular fixed dose combination medications, and from Dr

Reddys Ltd for co-ordination of the SPACE program (www.spacecollaboration.org). The

George Institute for Global Health obtained an exclusive global license in December 2012 for

the fixed dose combinations used in the SPACE trials following a decision by Dr Reddy’s Ltd

not to proceed with taking the products to market because of uncertainty in regulatory

requirements.

References

1 Kaplan W, Laing R. Priority Medicines for Europe and the World. Geneva: World Health

Organization; 2004.

2 Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality

from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global

Burden of Disease Study 2010. Lancet. 2013; 380(9859): 2095-128.

3 Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD

2010) Results by Cause 1990-2010. 2013 [cited 17th January, 2013]; Available from:

http://www.healthmetricsandevaluation.org/ghdx

4 Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted life

years (DALYs) for 291 diseases and injuries in 21 regions, 1990-2010: a systematic analysis for the

Global Burden of Disease Study 2010. Lancet. 2013; 380(9859): 2197-223.

5 World Health Organization. The Global Burden of Disease: 2004 update. Geneva: World Health

Organization; 2008.

6 World Health Organization. Global status report on noncommunicable diseases 2010. Geneva,

Switzerland: World Health Organization; 2011.

7 Beaglehole R, Bonita R, Horton R, Adams C, Alleyne G, Asaria P, et al. Priority actions for the non-

communicable disease crisis. Lancet. 2011; 377(9775): 1438-47.

8 Yusuf S, Hawken S, Ounpuu S, Daversus T, Avezum A, Lanas F, et al. Effect of potentially

modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART

study): case-control study. The Lancet. 2004; 364: 937 - 52.

9 O'Donnell MJ, Xavier D, Liu L, Zhang H, Chin SL, Rao-Melacini P, et al. Risk factors for ischaemic

and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control

study. Lancet. 2010; 376(9735): 112-23.

10 World Health Organization. Global health risks : mortality and burden of disease attributable to

selected major risks. Geneva, Switzerland: World Health Organization; 2009.

11 Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk

assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in

http://www.healthmetricsandevaluation.org/ghdx


6.3-39

21 regions, 1990?2010: a systematic analysis for the Global Burden of Disease Study 2010. The

Lancet. 2012; 380(9859): 2224-60.

12 Kawachi I, Colditz GA, Stampfer MJ, Willett WC, Manson JE, Rosner B, et al. Smoking cessation and

time course of decreased risks of coronary heart disease in middle-aged women. Archives of

Internal Medicine. 1994; 154(2): 169-75.

13 Bakhru A, Erlinger TP. Smoking cessation and cardiovascular disease risk factors: results from the

Third National Health and Nutrition Examination Survey. PLoS Med. 2005; 2(6): e160.

14 Hooper L, Summerbell C, Higgins J, Thompson R, Clements G, Capps N, et al. Reduced or modified

dietary fat for preventing cardiovascular disease [Systematic Review]. Cochrane Database of

Systematic Reviews. 2006; 3.

15 Ness AR, Powles JW. Fruit and vegetables, and cardiovascular disease: a review. International

Journal of Epidemiology. 1997; 26(1): 1-13.

16 Parikh P, McDaniel MC, Ashen MD, Miller JI, Sorrentino M, Chan V, et al. Diets and cardiovascular

disease: an evidence-based assessment. Journal of the American College of Cardiology. 2005; 45(9):

1379-87.

17 Thompson PD, Buchner D, Pina IL, Balady GJ, Williams MA, Marcus BH, et al. Exercise and

Physical Activity in the Prevention and Treatment of Atherosclerotic Cardiovascular Disease: A

Statement From the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and

Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on

Physical Activity). Circulation. 2003; 107(24): 3109-16.

18 de Lorgeril M, Salen P, Martin JL, Monjaud I, Delaye J, Mamelle N. Mediterranean diet, traditional

risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of

the Lyon Diet Heart Study.[see comment]. Circulation. 1999; 99(6): 779-85.

19 Yang Q, Cogswell ME, Flanders WD, Hong Y, Zhang Z, Loustalot F, et al. Trends in cardiovascular

health metrics and associations with all-cause and CVD mortality among US adults. JAMA. 2012;

307(12): 1273-83.

20 EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison of

EUROASPIRE I and II in nine countries. The Lancet. 2001; 357(March 31): 995-1001.

21 EUROASPIRE II Group. Lifestyle and risk factor management and use of drug therapies in coronary

patients from 15 countries; prinicipal results from EUROASPIRE II Euro Heart Survey Programme.

European Heart Journal. 2001; 22(7): 526-8.

22 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, et al. EUROASPIRE III: a survey

on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary patients from 22

European countries. European Journal of Cardiovascular Prevention & Rehabilitation. 2009; 16(2):

121-37.

23 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, Keil U. Cardiovascular prevention

guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European

countries. The Lancet. 2009; 373(9667): 929-40.

24 Global Atlas on cardiovascular disease prevention and control. Geneva; 2011.

25 Chen Z, Peto R, Collins R, MacMahon S, Lu J, Li W. Serum cholesterol concentration and coronary

heart disease in population with low cholesterol concentrations.[see comment]. BMJ. 1991; 303(6797):

276-82.

26 Stamler J, Wentworth D, Neaton JD. Is relationship between serum cholesterol and risk of premature

death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of

the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256(20): 2823-8.


6.3-40

27 Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of

cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14

randomised trials of statins. Lancet. 2005; 366(9493): 1267-78.

28 Cholesterol Treatment Trialists C. The effects of lowering LDL cholesterol with statin therapy in

people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.

The Lancet. 2012; 380(9841): 581-90.

29 Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. 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(9753): 1670-81.

30 Tobert JA. Lovastatin and beyond: The history of the HMG-CoA reductase inhibitors. Nature

Reviews Drug Discovery. 2003; 2(7): 517-26.

31 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein

cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ. 2003;

326(7404): 1423-.

32 Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Efficacy and safety of high-density lipoprotein

cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll

Cardiol. 2005; 45(2): 185-97.

33 Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, et al. Effects of fibrates on cardiovascular

outcomes: a systematic review and meta-analysis. Lancet. 2010; 375(9729): 1875-84.

34 Xydakis AM, Ballantyne CM. Combination therapy for combined dyslipidemia. Am J Cardiol. 2002;

90(10B): 21K-9K.

35 Ballantyne CM, Houri J, Notarbartolo A, Melani L, Lipka LJ, Suresh R, et al. Effect of ezetimibe

coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective,

randomized, double-blind trial. Circulation. 2003; 107(19): 2409-15.

36 Davidson MH, McGarry T, Bettis R, Melani L, Lipka LJ, LeBeaut AP, et al. Ezetimibe coadministered

with simvastatin in patients with primary hypercholesterolemia. J Am Coll Cardiol. 2002; 40(12):

2125-34.

37 Kastelein JJ, Akdim F, Stroes ES, Zwinderman AH, Bots ML, Stalenhoef AF, et al. Simvastatin with

or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008; 358(14): 1431-43.

38 Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L, Miller M, et al. Extended-release niacin or

ezetimibe and carotid intima-media thickness. N Engl J Med. 2009; 361(22): 2113-22.

39 West AM, Anderson JD, Meyer CH, Epstein FH, Wang H, Hagspiel KD, et al. The effect of ezetimibe

on peripheral arterial atherosclerosis depends upon statin use at baseline. Atherosclerosis. 2011;

218(1): 156-62.

40 European Medicines Agency. Tredaptive, Pelzont and Trevaclyn. 2013 [cited 2013 9th February];

Available from:

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Tredaptive,_Pelzo

nt_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0b01ac05805c516f

41 Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 Fatty acids and cardiovascular outcomes:

systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012; 5(6): 808-18.

42 World Health Organization. Adherence to long-term therapies: Evidence for action. Geneva: World

Health Organization; 2003.

43 Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, et al. Blood pressure, stroke,

and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Tredaptive,_Pelzont_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0b01ac05805c516f

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Tredaptive,_Pelzont_and_Trevaclyn/human_referral_prac_000014.jsp&mid=WC0b01ac05805c516f


6.3-41

randomised drug trials in their epidemiological context.[see comment]. Lancet. 1990; 335(8693): 827-

38.

44 Stamler J, Dyer AR, Shekelle RB, Neaton J, Stamler R. Relationship of baseline major risk factors to

coronary and all-cause mortality, and to longevity: findings from long-term follow-up of Chicago

cohorts. Cardiology. 1993; 82(2-3): 191-222.

45 Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and cardiovascular risks. US

population data. Archives of Internal Medicine. 1993; 153(5): 598-615.

46 Blood Pressure Lowering Treatment Trialists Collaboration. Effects of different blood-pressure-

lowering regimens on major cardiovascular events: results of prospectively-designed overviews of

randomised trials. The Lancet. 2003; 362(9395): 1527-35.

47 Gueyffier F, Boutitie F, Boissel J-P, Pocock S, Coope J, Cutler J, et al. Effect of Antihypertensive Drug

Treatment on Cardiovascular Outcomes in Women and Men: A Meta-Analysis of Individual Patient

Data from Randomized, Controlled Trials. Ann Intern Med. 1997; 126(10): 761-7.

48 Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 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). Eur Heart J. 2007; 28(12): 1462-536.

49 Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, et al. Reappraisal of

European guidelines on hypertension management: a European Society of Hypertension Task Force

document. J Hypertens. 2009; 27(11): 2121-58.

50 Cushman WC, Ford CE, Einhorn PT, Wright JT, Jr., Preston RA, Davis BR, et al. Blood pressure

control by drug group in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart

Attack Trial (ALLHAT). J Clin Hypertens (Greenwich). 2008; 10(10): 751-60.

51 Johnston A, Stafylas P, Stergiou GS. Effectiveness, safety and cost of drug substitution in

hypertension. Br J Clin Pharmacol. 2010; 70(3): 320-34.

52 Shaw E, Anderson JG, Maloney M, Jay SJ, Fagan D. Factors associated with noncompliance of

patients taking antihypertensive medications. Hosp Pharm. 1995; 30(3): 201-3, 6-7.

53 Faria C, Wenzel M, Lee KW, Coderre K, Nichols J, Belletti DA. A narrative review of clinical inertia:

focus on hypertension. J Am Soc Hypertens. 2009; 3(4): 267-76.

54 Okonofua EC, Simpson KN, Jesri A, Rehman SU, Durkalski VL, Egan BM. Therapeutic inertia is an

impediment to achieving the Healthy People 2010 blood pressure control goals. Hypertension. 2006;

47(3): 345-51.

55 Thijs L, Richart T, de Leeuw PW, Kuznetsova T, Grodzicki T, Kawecka-Jaszcz K, et al. Morbidity and

mortality on combination versus monotherapy: a posthoc analysis of the Systolic Hypertension in

Europe trial. J Hypertens. 2010; 28(4): 865-74.

56 Brown MJ, McInnes GT, Papst CC, Zhang J, MacDonald TM. Aliskiren and the calcium channel

blocker amlodipine combination as an initial treatment strategy for hypertension control

(ACCELERATE): a randomised, parallel-group trial. Lancet. 2011; 377(9762): 312-20.

57 Feldman RD, Zou GY, Vandervoort MK, Wong CJ, Nelson SA, Feagan BG. A simplified approach to

the treatment of uncomplicated hypertension: a cluster randomized, controlled trial. Hypertension.

2009; 53(4): 646-53.

58 Gupta AK, Arshad S, Poulter NR. Compliance, safety, and effectiveness of fixed-dose combinations

of antihypertensive agents: a meta-analysis. Hypertension. 2010; 55(2): 399-407.


6.3-42

59 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood

pressure lowering drugs: analysis of 354 randomised trials. BMJ. 2003; 326(7404): 1427.

60 Dolley CT. Pharmacological basis for combination therapy of hypertension. Annu Rev Pharmacol

Toxicol. 1977; 17: 311-23.

61 Gradman AH. Rationale for triple-combination therapy for management of high blood pressure. J

Clin Hypertens (Greenwich). 2010; 12(11): 869-78.

62 Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD. Triple antihypertensive therapy with

amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension. 2009;

54(1): 32-9.

63 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of

antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.

British Medical Journal 2002; 324: 71-86.

64 Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular

disease: collaborative meta-analysis of individual participant data from randomised trials. The

Lancet. 2009; 373(9678): 1849-60.

65 Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on

long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

The Lancet. 2011; 377(9759): 31-41.

66 Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, et al. Addition

of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment

elevation. N Engl J Med. 2005; 352(12): 1179-89.

67 Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects of clopidogrel in addition to

aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med.

2001; 345(7): 494-502.

68 Steinhubl SR, Berger PB, Mann JT, 3rd, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual

oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled

trial. JAMA. 2002; 288(19): 2411-20.

69 Gaspoz JM, Coxson PG, Goldman PA, Williams LW, Kuntz KM, Hunink MG, et al. Cost

effectiveness of aspirin, clopidogrel, or both for secondary prevention of coronary heart disease. N

Engl J Med. 2002; 346(23): 1800-6.

70 Karnon J, Brennan A, Pandor A, Fowkes G, Lee A, Gray D, et al. Modelling the long term cost

effectiveness of clopidogrel for the secondary prevention of occlusive vascular events in the UK.

Curr Med Res Opin. 2005; 21(1): 101-12.

71 Cholesterol Treatment Trialists Collaboration, Baigent C, Keech A, Kearney PM, Blackwell L, Buck

G, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data

from 90,056 participants in 14 randomised trials of statins. Lancet. 2005; 366(9493): 1267-78.

72 Kumar A, Fonarow GC, Eagle KA, Hirsch AT, Califf RM, Alberts MJ, et al. Regional and Practice

Variation in Adherence to Guideline Recommendations for Secondary and Primary Prevention

Among Outpatients With Atherothrombosis or Risk Factors in the United States: A Report From the

REACH Registry. Critical Pathways in Cardiology. 2009; 8(3): 104-11

10.1097/HPC.0b013e3181b8395d.

73 Webster RJ, Heeley EL, Peiris DP, Bayram C, Cass A, Patel AA. Gaps in cardiovascular disease risk

management in Australian general practice. Medical Journal Of Australia. 2009; 191(6): 324-9.


6.3-43

74 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). Bulletin of the

World Health Organization. 2005; 83(11): 820-9.

75 Sharma KK, Gupta R, Agrawal A, Roy S, Kasliwal A, Bana A, et al. Low use of statins and other

coronary secondary prevention therapies in primary and secondary care in India. Vascular Health &

Risk Management. 2009; 5: 1007-14.

76 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.

77 Gehi AK, Ali S, Na B, Whooley MA. Self-reported medication adherence and cardiovascular events

in patients with stable coronary heart disease: the heart and soul study. Arch Intern Med. 2007;

167(16): 1798-803.

78 Newby LK, LaPointe NM, Chen AY, Kramer JM, Hammill BG, DeLong ER, et al. Long-term

adherence to evidence-based secondary prevention therapies in coronary artery disease. Circulation.

2006; 113(2): 203-12.

79 Bailey JE, Lee MD, Somes GW, Graham RL. Risk factors for antihypertensive medication refill

failure by patients under Medicaid managed care. Clinical Therapeutics. 1996; 18(6): 1252-62.

80 Barat I, Andreasen F, Damsgaard EMS. Drug therapy in the elderly: what doctors believe and

patients actually do. British Journal of Clinical Pharmacology. 2001; 51(6): 615-22.

81 Miller NH, Hill M, Kottke T, Ockene IS. The Multilevel Compliance Challenge: Recommendations

for a Call to Action: A Statement for Healthcare Professionals. Circulation. 1997; 95(4): 1085-90.

82 Paes AH, Bakker A, Soe-Agnie CJ. Impact of dosage frequency on patient compliance. Diabetes

Care. 1997; 20(10): 1512-7.

83 Shaw E, Anderson JG, Maloney M, Jay SJ, Fagan D. Factors associated with noncompliance of

patients taking antihypertensive medications. Hospital Pharmacy. 1995; 30(3): 201-3.

84 Claxton AJ, Cramer J, Pierce C. A systematic review of the associations between dose regimens and

medication compliance. Clin Ther. 2001; 23(8): 1296-310.

85 Mendis S, Fukino K, Cameron A, Laing R, Filipe A, Jr., Khatib O, et al. The availability and

affordability of selected essential medicines for chronic diseases in six low- and middle-income

countries. Bull World Health Organ. 2007; 85(4): 279-88.

86 van Mourik MS, Cameron A, Ewen M, Laing RO. Availability, price and affordability of

cardiovascular medicines: a comparison across 36 countries using WHO/HAI data. BMC Cardiovasc

Disord. 2010; 10: 25.

87 World Health Organization. Secondary prevention of non-communicable disease in low and middle

income countries through community-based and health service interventions. . Geneva; 2002 1 - 3

August.

88 Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002; 360(9326): 2-3.

89 Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. British Medical

Journal 2003; 326(7404): 1419.

90 Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al. Aspirin in the primary and

secondary prevention of vascular disease: collaborative meta-analysis of individual participant data

from randomised trials. Lancet. 2009; 373(9678): 1849-60.


6.3-44

91 Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of

cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from

prospective epidemiological studies. BMJ. 2009; 338: b1665.

92 Heart Protection Study Collaborative G. MRC/BHF Heart Protection Study of cholesterol lowering

with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;

360: 7 - 22.

93 Progress Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering

regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;

358(9287): 1033-41.

94 Liang MH, Manson JE, inventors; Treatment of patients at elevated cardiovascular risk with a

combination of a cholesterol-lowering agent, an inhibitor of the renin-angiotensin system, and

aspirin. USA patent US patent: 6,576,256. 2001.

95 Tobert JA, Merck & Co Inc, inventors; Combination therapy for reducing the risks associated with

cardiovascular disease 1997.

96 Wald NJ, Law MR, inventors; Pharmaceutical formulation for the prevention of cardiovascular

disease patent GB 2361 185 A.

97 World Health Organization. The World Health Report 2002: Reducing risks, promoting healthy life.

Geneva; 2002.

98 Thom S, Field J, Poulter N, Patel A, Prabhakaran D, Stanton A, et al. Use of a Multidrug Pill in

Reducing cardiovascular Events (UMPIRE): rationale and design of a randomised controlled trial of

a cardiovascular preventive polypill-based strategy in India and Europe. European Journal of

Preventive Cardiology. 2012.

99 Sanz G, Fuster V, Guzman L, Guglietta A, Arnaiz JA, Martinez F, et al. The fixed-dose combination

drug for secondary cardiovascular prevention project: improving equitable access and adherence to

secondary cardiovascular prevention with a fixed-dose combination drug. Study design and

objectives. American Heart Journal. 2011; 162(5): 811-7.e1.

100 The Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk factors in middle-aged

individuals wihtout cardiovascular disease (TIPS): a phase II, double-blind, randomised trial Lancet.

2009; 373: 1341-51.

101 Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over.

PLoS ONE. 2012; 7(7): e41297.

102 Pill Collaborative Group, Rodgers A, Patel A, Berwanger O, Bots M, Grimm R, et al. An

international randomised placebo-controlled trial of a four-component combination pill ("polypill")

in people with raised cardiovascular risk. PloS one. 2011; 6(5): e19857.

103 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. International Journal of Clinical Practice. 2010; 64(9): 1220-

7.

104 Soliman E, Mendis S, Dissanayake W, Somasundaram N, Gunaratne P, Jayasingne IK, et al. A

Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health

Organization. Trials. 2011; 12(1): 3.

105 Hulley SB. Designing clinical research. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins;

2007.

106 Benner JS, Glynn RJ, Mogun H, Neumann PJ, Weinstein MC, Avorn J. Long-term persistence in use

of statin therapy in elderly patients. JAMA. 2002; 288: 455-61.


6.3-45

107 Choudhry NK, Avorn J, Glynn RJ, Antman EM, Schneeweiss S, Toscano M, et al. Full coverage for

preventive medications after myocardial infarction. New England Journal of Medicine. 2011;

365(22): 2088-97.

108 Collins R, MacMahon S. Reliable assessment of the effects of treatment on mortality and major

morbidity, I: clinical trials. Lancet. 2001; 357: 373-80.

109 Liu HM, Patel A, Brown A, Eades S, Hayman N, Jan S, et al. Rationale and design of the Kanyini

guidelines adherence with the polypill (Kanyini-GAP) study: a randomised controlled trial of a

polypill-based strategy amongst Indigenous and non Indigenous people at high cardiovascular risk.

BMC public health. 2010; 10: 458.

110 Selak V, Elley CR, Crengle S, Harwood M, Doughty R, Arroll B, et al. Improving adherence using

combination therapy (IMPACT): Design and protocol of a randomised controlled trial in primary

care. Contemporary Clinical Trials. 2011; 32(6): 909-15.

111 Kerr AJ, Broad J, Wells S, Riddell T, Jackson R. Should the first priority in cardiovascular risk

management be those with prior cardiovascular disease? Heart. 2009; 95(2): 125-9.

112 Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events:

results of prospectively-designed overviews of randomised trials. Lancet. 2003; 362(9395): 1527-35.

113 Law MR, Watt HC, Wald NJ. The underlying risk of death after myocardial infarction in the

absence of treatment. Archives of Internal Medicine. 2002; 162(21): 2405-10.

114 Brown CA, Lilford RJ. The stepped wedge trial design: a systematic review BMC Med Res

Methodol. 2006 Nov 8;6:54.



prospective epidemiological studies. British Medical Journal. 2009; 338: b1665-.

116 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood

pressure lowering drugs: analysis of 354 randomised trials. British Medical Journal. 2003; 326(7404):

1427-31.

117 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: 463-71.

118 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein

cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. British

Medical Journal. 2003; 326: 1423-30.

119 Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of cholesterol-lowering

treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of

statins. Lancet. 2005; 366: 1267-78.



prospective epidemiological studies. British Medical Journal. 2009; 338(may19_1): b1665-.


6.3-46

Annexes

Annex 6.3.1: Mortality and burden of disease from IHD per age group and per region

Annex 6.3.2: Baseline characteristics of previous randomized controlled trials – versus

placebo or no treatment

Annex 6.3.3: Actual versus expected reductions in systolic blood pressure and LDL-

cholesterol in trials of ‘polypills’ versus placebo or no treatment

Annex 6.3.4: Baseline characteristics of UMPIRE trial

Annex 6.3.5: Ongoing randomized controlled trials – polypill versus usual care

Annex 6.3.6: Ongoing trials of “hypertension polypills”

Annex 6.3.7: Ongoing trials – polypill versus placebo or no treatment

Annex 6.3.8: Pipeline of polypills


6.3-47

Annex 6.3.1: Mortality and burden of disease from IHD per age group and

per region


(GBD 2010) Results by Cause 1990-2010

0

4,000,000

8,000,000

12,000,000

16,000,000

20,000,000

Ab

solu

te D

ALY

s

Age groups

Absolute DALYs due to IHD by age group in the world

0

200,000

400,000

600,000

800,000

1,000,000

1,200,000

1,400,000

Ab

solu

te D

ALY

s

Age groups

Absolute DALYs due to IHD by age group in Central Europe


6.3-48

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

4,000,000A

bso

lute

DA

LYs

Age groups

Absolute DALYs due to IHD by age group in Eastern Europe

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000

3,500,000

Ab

solu

te D

ALY

s

Age groups

Absolute DALYs due to IHD by age group in Western Europe


6.3-49

0

500,000

1,000,000

1,500,000

2,000,000

2,500,000

3,000,000A

bso

lute

de

ath

s

Age groups

Global mortality for IHD by age group

0

20,000

40,000

60,000

80,000

100,000

120,000

140,000

160,000

180,000

Ab

solu

te d

eat

hs

Age groups

Mortality for IHD by age group in Central Europe


6.3-50

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000A

bso

lute

de

ath

s

Age groups

Mortality for IHD by age group in Eastern Europe

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

400,000

450,000

500,000

Ab

solu

te d

eat

hs

Age groups

Mortality for IHD by age group in Western Europe


6.3-51

Annex 6.3.2: Baseline characteristics of previous randomised controlled trials – versus placebo or no treatment

Included Study Study population

characteristics

Mean age

(SD); female

gender (%)

Mean

SBP(SD)/D

BP (SD)

mmHg

Mean total

cholesterol

(SD); LDL

(SD)

mmol/L

‘Polypill’ contents

(dose); n

Comparison; n Duration of

follow-up;

Outcomes

assessed;

Notes

Malekzadeh

et al 2010 103*

Primary prevention (no

previous CVD)

Inclusion criteria: >50/55

years, no previous CVD; not

on active BP or lipid

lowering medications. No

exclusion for diabetes

59.1 (6.9);

33%

127.5 (17.3)

/ 79.8 (10.1)

5.26 (1.01);

2.99 (0.68)

Aspirin (81 mg),

Enalapril (2.5 mg),

Atorvastatin (20

mg) and

Hydrochloro-

thiazide (12.5 mg);

n=241

Placebo; n=234 12 months SBP, DBP,

Total

cholesterol,

LDL, AEs;

Imbalance in

baseline checks

suggests

inadequacy of

randomization;

Low follow-up

rate: 68% in

intervention,

78% in control

Pill

Collaborative

2011 121


previous CVD)

Inclusion criteria: five-year

CVD risk >7.5% (based on

Framingham risk score) or

5% to 7.5% and 2 CVD risk

factors. No exclusion for

diabetes

61.4 (7.2);

19%

134.0 (13.5)

/ 80.5 (9.0)

5.50 (1.05);

3.65 (0.90)

Aspirin (75 mg),

Lisinopril (10 mg)

Hydrochlorothiazid

e (12.5 mg) and

Simvastatin (20

mg); n=189

Placebo; n=189 12 weeks SBP, DBP,

Total

cholesterol,

LDL, AEs;

99% follow-up

Wald 2012 122 Primary prevention (no

previous CVD)

Inclusion criteria: over 50

years of age

59 (range 51-

77);

26%

143.0 (16) /

86.0 (10)**

5.9 (1.0); 3.7

(0.9)**

Amlodipine (2.5

mg) Losartan (25

mg),

Hydrochlorothiazid

e (12.5 mg) and

Simvastatin (40

mg); n=86

Placebo; n=86 12 weeks

(cross-over

RCT)

SBP, DBP,

Total

cholesterol,

LDL, AEs

98% follow-up

The Indian

Polycap

Study ‘TIPS’

2009 100 #


previous CVD)

Inclusion criteria: at least

one CV risk factor (including

diabetes)

53.6 (7.7);

44%

134.3 (12.3)

/ 85.2 (8.1)

4.7 (0.9); 3.0

(0.8)

Hydrochlorothiazid

e (12·5 mg),

Atenolol (50 mg),

Ramipril (5 mg),

Simvastatin (20

mg), Aspirin (100

mg); n=412

Aspirin (100

mg); n=205

(Simvastatin

20 mg group

added for BP

comparison

n=202)

12 weeks

(some 8-12

weeks);

SBP, DBP,

Total

cholesterol,

LDL, AEs;

85% follow-up

in these three

arms


6.3-52

* BP not assessed in meta-analysis as both arms contained an anti-hypertensive; ** Following placebo 12 weeks of cross-over RCT; # Double-blind nine-arm

with varying medication components and number of components. Only three arms were used in this meta-analysis: the polycap, aspirin and simvastatin

arms;

BP = blood pressure and measured in mmHg; SBP = systolic blood pressure; DBP = Diastolic blood pressure; Total chol. = total cholesterol in mmol/L; LDL =

LDL cholesterol in mmol/L; AE = adverse events; TLC = therapeutic lifestyle changes; SD = standard deviation; CVD = cardiovascular disease

121 Pill Collaborative Group, Rodgers A, Patel A, Berwanger O, Bots M, Grimm R, et al. An international randomised placebo-controlled trial of a four-

component combination pill ("polypill") in people with raised cardiovascular risk. PLoS ONE. 2011; 6(5): e19857. 122 Wald DS, Morris JK, Wald NJ. Randomized polypill crossover trial in people aged 50 and over. PLoS ONE. 2012; 7(7): e41297.


6.3-53

Annex 6.3.3: Actual versus expected reductions in systolic blood pressure and LDL-cholesterol in trials of ‘polypills’

versus placebo or no treatment

Trial

Actual versus Expected Reductions in Systolic Blood Pressure (SBP) Actual versus Expected Reductions in LDL-Cholesterol

Antihyper-

tensive(s)

Standard

dose

equivalent 123

Mean

baseline

SBP mm

Hg*

Expected

reduction

in SBP

mmHg**

Observed

mean

difference in

SBP mmHg

Observed

/expected

Statin Mean

baseline

LDL in

mmol/l

Expected

reduction in

LDL mmol/l

^

Observed

control-

adjusted

reduction in

LDL mmol/l

Observed

/expected

Malekzadeh,

2010

Enalapril 2.5 mg 0.25 130 10.2 # 2.4 24% Atorvastatin

20 mg

2.99 1.29 0.45 35%

Hydrochlorothia

zide 12.5 mg

0.5

PILL

collaboration,

2011

Lisinopril 10 mg 1 130 10.2 # # 9.9 97% Simvastatin 20

mg

3.65 1.17 0.75 64%

Hydrochlorothia

zide 12.5 mg

0.5

Wald, 2012 Hydrochlorothia

zide 12.5 mg

0.5 140 17.6 17.9 100% Simvastatin 40

mg

3.70 1.37 1.4 102%

Losartan 25 mg 0.5

Amlodipine 2.5

mg

0.5

The Indian

Polycap Study,

2009

Hydrochlorothia

zide 12.5 mg

0.5 130 18.2 β 7.4 41% Simvastatin 20

mg

3.00 0.96 0.72 75%

Atenolol 50 mg 1

Ramipril 5 mg 2

* rounded to nearest 10 mm Hg; ** based on mean baseline SBP & standard dose equivalence (from Law 2009)124; ^mean baseline LDL x percentage reduction in LDL cholesterol

for the statin at that dose (from Law 2003) 125# estimate: two drugs at half dose therefore an overestimate of likely effect; # # estimate: two drugs at half dose therefore an

underestimate of likely effect; 12.7 mmHg for two drugs at standard dose; β estimate: three drugs at standard dose; 15.2 mmHg for three drugs at half standard dose.

123 Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.

BMJ. 2003; 326(7404): 1427. 124 Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in

the context of expectations from prospective epidemiological studies. BMJ. 2009; 338: b1665. 125 Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic

review and meta-analysis. BMJ. 2003; 326(7404): 1423.


6.3-54

Annex 6.3.4: Baseline characteristics of UMPIRE Trial

FDC (N = 1002)

Usual care (N = 1002)

Age 62.1 (10.4) 61.6 (10.8)

Male 817 (81.5%) 825 (82.3%)

SBP (mmHg) 137.0 (21.3) 137.7 (21.1)

DBP (mmHg) 77.4 (12.0) 78.1 (11.5)

Heart rate (beats/ min) 71.0 (15.1) 70.8 (14.6)

Total cholesterol (mmol/L) 4.2 (1.0) 4.2 (1.1)

HDL cholesterol (mmol/L) 1.1 (0.3) 1.1 (0.3)

LDL cholesterol (mmol/L) 2.3 (0.8) 2.4 (0.9)

Triglycerides (mmol/L) 1.5 (0.9) 1.5 (0.9)

Glucose (mmol/L) 6.3 (2.4) 6.3 (2.3)

Creatinine (umol/L) 89.0 (22.10 89.7 (22.2)

Current smokers 131 (13.1%) 144 (14.4%)

Ever smoked cigarettes 541 (54.0%) 504 (50.3%)

Medical history

Coronary heart disease 769 (76.7%) 759 (75.7%)

Cerebrovascular disease 154 (15.4%) 157 (15.7%)

Peripheral vascular disease 56 (5.6%) 43 (4.3%)

Diabetes mellitus 283 (28.2%) 281 (28.0%)

Current drug treatment

Antihypertensive treatment

None 76 (7.6%) 66 (6.6%)

1 BP drug 266 (26.5%) 225 (22.5%)

≥2 BP drugs 660 (65.9%) 711 (71.0%)

Statin 882 (88.0%) 878 (87.6%)

Anti-platelet drug 920 (91.8%) 912 (91.0%)

Indicated medications1 598 (59.7%) 635 (63.4%)

Data not shown as n (%) are mean (SD).

1 Indicated medications = statin + anti-platelet + ≥2 anti-hypertensive drugs.

FDC = fixed dose combination.


6.3-55

Annex 6.3.5: Ongoing randomised controlled trials – polypill versus usual care

Study Study population

characteristics

N Regions ‘Polypill’ contents (dose); Comparison; Duration of

follow-up

Expected results Outcomes

Kanyini-GAP Established CVD or

CVD risk of >15%

over five years

623 Australia RHP version 1c:

aspirin 75 mg

lisinopril 10 mg

simvastatin 40 mg

atenolol 50 mg

RHP version 2c:

aspirin 75 mg

lisinopril 10 mg

simvastatin 40 mg

hydrochlorothiazide 12.5

mg

Usual care Minimum 12

months

Q2 2013 Adherence,

SBP, total

cholesterol

IMPACT Established CVD or

CVD risk of >15%

over five years

513 New Zealand RHP version 1c:

aspirin 75 mg

lisinopril 10 mg

simvastatin 40 mg

atenolol 50 mg

RHP version 2c:

aspirin 75 mg

lisinopril 10 mg

simvastatin 40 mg

hydrochlorothiazide 12.5

mg

Usual care Minimum 12

months

Q4 2013 Adherence,

SBP, LDL

cholesterol

FOCUS Post-myocardial

infarction

Phase 1

– 4 000

Phase 2

– 1 340

Argentina,

France, Italy,

Spain,

Switzerland

Aspirin 100 mg

Simvastatin 40 mg

Ramipril (2.5, 5, 10 mg)

Usual care 9 months ? Adherence, BP,

LDL

cholesterol,

safety, cost

effectiveness


6.3-56

Annex 6.3.6: Ongoing trials of “hypertension polypills”

Trial Aims Patient population Comparisons Follow-up Outcomes

TRIUMPH To assess role of a low-dose

triple antihypertensive

compared to usual care

Newly diagnosed patients

with persistent hypertension

despite adequate lifestyle

advice and/or changes;

and/or single drug therapy

for BP lowering

India

Triple pill versus usual care.

Triple pill is Telmisartan 20 mg, Amlodipine 2.5 mg,

Hydrochlorothiazide 6.25 mg or option with double

doses

Usual care: separate BP lowering medication

prescribed completely at the discretion of the

treating doctor

Six months Primary outcome: %

achieving target BP at

six months;

Secondary outcomes:

% with BP control at

six and 12 weeks;

change in BP;

tolerance to

treatment; use of

health care services;

self-reported BP

lowering medication

use; quality of life.

TIPS 4 To assess the incremental BP

lowering by full doses of

- two 3-BP lowering drugs

compared to

- three 2-BP lowering drugs

combinations.

• To assess the impact of

adding a statin on lipids to

the BP lowering drug

combinations

Men or women aged 30

years or older,

With SBP 150 to 180 mmHg

N= 825

India, Canada, Italy

1. HCTZ (25 mg) + Amlodipine (10 mg)

2. HCTZ (25 mg) + Atenolol (100 mg)

3. HCTZ (25 mg) + Ramipril (10 mg)

4. Low doses: – HCTZ 12.5 mg + rami 5 mg +

aten 50 mg or Amlodipine 5mg

5. Full doses: – HCTZ 25 mg + ramipril 10 mg +

atenolol 100 mg or Amlodipine 10mg

6 Simvastatin 40 mg

7. Atorvastatin 20 mg

Two weeks

run-in, eight

weeks

follow-up


6.3-57

Annex 6.3.7: Ongoing trials – polypill versus placebo or no treatment

Trial N Population Intervention Countries and Sponsors Outcomes Status

Indian Polycap Trial –

TIPS3

5 000 – 2x2x2

factorial

Men ≥55 and women

≥60 years with:

– an INTERHEART risk

score of ≥10,

– no known vascular

disease and

– no clear clinical

indication or

contraindication

for treatments

Polycap DS (thiazide

25 mg, atenolol 100

mg, ramipril 10 mg,

simvastatin 40 mg) -

daily +/- aspirin EC

75 g +/- vit D 60 000

IU monthly versus

control

China and India

Cadila Pharmaceuticals

Wellcome Trust

Canadian Institutes of Health

Research (CIHR)

Heart and Stroke Foundation

of Ontario

Major CVD events,

neurocognitive function

Enrolment started

Heart Outcomes

Protection (HOPE) 3

12 500- 2x2

factorial

Primary prevention in

men >55 years and

women >65 years with

at least one risk factor

and women aged >60

years with at least two

risk factors

Rosuvastatin 10 mg,

candesartan 16

mg/HCTZ 12.5 mg

factorial

22 countries

CIHR and Astra Zeneca

Major CVD events,

neurocognitive function,

renal function

Follow-up

complete 2015

Poly-Iran 7 000 Men and women

between 50 and 79

years old

Aspirin 81 mg,

enalapril 5 mg (or

valsartan 40 mg),

atorvastatin 20 mg

and

hydrochlorothiazide

12.5 mg

Iran

Tehran University of Medical

Sciences

CVD events, blood

sugar, cholesterol, BP,

compliance, tolerability

Enrolment started


6.3-58

Annex 6.3.8: Pipeline of polypills

Company Name Active Components Clinical trial status

In development

Alborz Darou (Iran) Polyiran 1 Aspirin 81 mg, Atorvastatin 20 mg, Enalapril 5 mg,

hydrochlorothiazide 25 mg

Pilot studies conducted and published

Polyiran 2 Aspirin 81 mg, Atorvastatin 20 mg, Valsartan 40 mg,

hydrochlorothiazide 25 mg

Pilot studies conducted and published

Cadila (India) Ramitorva Aspirin 100 mg, simvastatin 20 mg, ramipril 5 mg, atenolol

50 mg, hydrochlorothiazide 12.5 mg

TIPS program published; FDA application in process

Cardio-Pharm (USA) CardiaPill BP lowering, statin and aspirin 3 components – specifics

undisclosed

Uncertain

CNIC-Ferrer (Spain) Trinomia Secondary prevention Aspirin 100 mg, simvastatin 40 mg, ramipril 2.5/5/10 mg 100 patients in trial in Spain; PD studies done in USA

and Spain

Large FOCUS trial underway in Italy, Spain, South

America; First patient randomized Nov 2011

Already available in Guatemala, and in registration

process in Latam

Dr Reddy’s (India)* Red Heart Pill (RHP) 1 Aspirin 75 mg, Lisinopril 10 mg, Simvastatin 20 mg (40 mg),

Atenolol 50 mg

SPACE trials underway, UMPIRE completed

Red Heart Pill (RHP) 2 Aspirin 75 mg, Lisinopril 10 mg, Simvastatin 20 mg (40 mg),

hydrochlorothiazide 12.5 mg

PILL trial published; SPACE trials underway, UMPIRE

completed

Polypill Company (United

Kingdom)

Polypill Simvastatin 20 mg; bendroflumethiazide 1.25 mg; losartan 25

mg ; amlodipine 2.5 mg

Uncertain

PolypillRx.com (USA) Customized production of different drugs into a single

capsule through registered pharmacies. Not actually a new

pill

None

On the market**

TajPharma (India) Multiple pill combinations Atorvastatin 10 mg, aspirin 75 mg, ramipril 5 mg

Atorvastatin 10 mg, aspirin 75 mg, ramipril 5 mg; metoprolol

50 mg (co-packaged),

Atorvastatin 10 mg, aspirin 150 mg, clopidogrel 75 mg

Torrent (India) CVPill Polytorva®. plus co-packaged metoprolol

Surien (India) Polytorva®. Atorvastatin 10 mg, Ramipril 5 mg, and enteric-coated

Aspirin 75 mg

Marketed by USV Ltd. In India only

Zyduscadila (India) Zycad – secondary prevention Atorvastatin 10 mg, ramipril 5 mg, Aspirin 75 mg

metoprolol 50 mg

*TGIGH has license –see Declarations ** Not developed to GMP standards, registered only on home country and not able to be exported. Only a selection of products shown here

Documents

Background Paper 6.3 Ischaemic heart disease