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Chapter 6.3: Cardiovascular Disease
Priority Medicines for Europe and the World
"A Public Health Approach to Innovation"
Background Paper
Secondary Prevention of Cardiovascular Disease:
Fixed Dose Combinations
A Research Agenda for the European Union
prepared for the ‘Priority Medicines for Europe and the World’ project
7 October 2004
Prepared by
Associate Professor Bruce Neal
Director, Heart and Vascular Division
George Institute for International Health
PO Box 576
Newtown
Sydney
NSW 2042
Australia
Tel +61 (0)2 9351 0043
Email [email protected]
With advice from Dr Anthony Rodgers and Professor Stephen MacMahon
All correspondence to Associate Professor Bruce Neal
6.3-1
Chapter 6.3: Cardiovascular Disease
Table of Contents
Summary _______________________________________________________________________ 4
The global burden of cardiovascular disease _________________________________________ 6
Cardiovascular disease in the European Union _______________________________________ 7
Cardiovascular disease in the developing world _____________________________________ 8
Current evidence about prevention ________________________________________________ 12
Primary and secondary prevention ________________________________________________ 12
Large high risk patient groups ____________________________________________________ 13
Risk-based prevention strategies __________________________________________________ 15
Proven drug treatments for secondary prevention ___________________________________ 16
Additive treatment effects ________________________________________________________ 20
Fixed dose combination therapy __________________________________________________ 22
Potential health gains from combination therapy ____________________________________ 22
Why fixed-dose combinations? ___________________________________________________ 24
Existing fixed dose combinations__________________________________________________ 26
New fixed dose combinations ____________________________________________________ 27
New pharmaceutical research opportunities ________________________________________ 30
Key issues in drug development __________________________________________________ 31
Clinical research ________________________________________________________________ 33
Development and implementation timeframes ______________________________________ 35
A clear commonality of interest___________________________________________________ 37
Key references __________________________________________________________________ 37
6.3-2
Chapter 6.3: Cardiovascular Disease
Annex and Appendices to Background Chapter 6.3 Cardiovascular
Disease
Annex 6.3.1
153KB]
Top twenty conditions by DALYS and mortality for Europe and the World [word
Appendix 6.3.1 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised
trials of antiplatelet therapy for prevention of death, myocardial infarction and stroke in high risk
pateints. BMJ. 2002;324:71-86.
Appendix 6.3.2(1) (1) Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of
ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of
the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-258. Appendix 6.3.2(2)(2)
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;358:1033-1041.
Appendix 6.3.3 EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a
comparison of EUROASPIRE I and II in nine countries. Lancet. 2001;357:996-1001.
Appendix 6.3.4 Patents relevant to the risk pill [word 101KB]
Appendix 6.3.5 Secondary prevention of noncommunicable diseases [pdf 467KB]
Appendix 6.3.6 Prevention of Recurrent Heart Attacks and Strokes in Low-and Midlle-Income
Populations [pdf 23KB]
Appendix 6.3.7 Crude estimates of effects on cardiovascular events of different levels of use of proven
secondary preventive treatments
Appendix 6.3.8 Concept paper on the development of a committee for medicinal products for human
use (CHMP) -- Note for guidance on the need for regulatory guidance in the evaluation of medicinal
products for the secondary cardiovascular prevention
6.3-3
Chapter 6.3: Cardiovascular Disease
Summary
In June 2003 the British Medical Journal published a research paper entitled ‘A strategy to
reduce cardiovascular disease by more than 80%’1 with the bold claim that the intervention
proposed ‘would have a greater impact on the prevention of disease in the Western world
than any other single intervention’. As the accompanying editorial 2 noted this was not a
‘magic bullet for cancer’ or a ‘radical new gene therapy’ but simply the combination of well
established, widely used therapies into a single medication for the prevention of stroke and
heart attack. With use in all individuals aged 55 years or over and all with existing
cardiovascular disease, the authors argued that it would be possible to avert most strokes
and heart attacks. While much of the subsequent discussion of this paper focussed or
whether doctors and patients are ready to sanction the treatment of everyone over 55 years
with poly-pharmacy, this report served to highlight the as yet unachieved potential of
therapies for the prevention of cardiovascular disease.
Patients with existing vascular disease requiring secondary prevention are a recognised
target for combination therapy addressing multiple facets of risk.3 A key advantage of
secondary prevention, over primary prevention is that it is possible to prevent large numbers
of events while treating only a relatively small number of individuals.4 As a consequence,
the delivery of proven secondary preventive treatments to patients with vascular disease has
been a high clinical priority4,5 to which a substantial portion of recent declines in vascular
death rates are ttributed.6
Fundamental to the success of secondary prevention have been advances in our
understanding of the full effects of two of the chief risk factors for stroke and heart attack,
cholesterol and blood pressure.7,8 For both it is now well established that risks increase
progressively across the full range of the risk factor distributions and that all patients, not
just those above arbitrary cut-off values, benefit from treatment.9-11 The chief consequence of
this has been to greatly increased the number of individuals to whom secondary prevention
is offered with the aversion of additional serious vascular events. A second effect has been
simplification of disease prevention in practice – secondary prevention-based approaches to
treatment can be directed on the basis of an individual reporting a history of a vascular event
making expensive measurement and monitoring of risk factor levels largely redundant.
Unfortunately, despite these advances, the use of proven secondary prevention strategies
remains substantially incomplete and large numbers of patients attending leading hospital
facilities in Europe go without long-term treatment that would significantly reduce their
risks of future heart attack, stroke and death.12 While the reasons for under treatment are not
always clear,13,14 the complexity of preventive therapy is repeatedly identified as a major
issue for both doctors and patients alike.15 Optimum treatment frequently involves three,
four or five separate agents, culminating in regimens that doctors are reluctant to prescribe
and patients unlikely to take. A fixed dose combination ‘polypill’ would be an important
simplification that would positively impact on the practicalities of secondary prevention
resulting in more patients on better treatment for longer.
The core components of secondary prevention for vascular disease are aspirin,16-19 cholesterol
lowering20 and blood pressure lowering,21 and all are underpinned by a comprehensive
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Chapter 6.3: Cardiovascular Disease
evidence base. Furthermore, with clearly additive beneficial effects on the risks of serious
vascular events and death, there is a very strong rationale for the combined use of these three
key interventions. A clinical innovation that resulted in the more appropriate, widespread
and sustained use of these treatments may well be the next great breakthrough in
cardiovascular prevention.2 The last few decades have seen substantial under-investment in
research addressing the more effective translation of research findings into clinical practice
and a major advancement in this field is both overdue and urgently required.12,22,23
Conservative estimates of effect in the secondary prevention setting would be a 20%
reduction in relative risk for antiplatelet therapy, a 25% reduction in relative risk for
cholesterol lowering therapy and a 25% reduction in relative risk for blood pressure
lowering therapy. If incorporated together in a fixed dose combination therapy the net
relative risk reduction would be 55% [100%-(100*0.80*0.75*0.75)]. In terms of the absolute
risk reduction, an individual with established vascular disease and a 10 year risk of a
vascular event of 1 in 4 (25%) would have their 10-year risk reduced to 1 in 9 (11.25%). Over
a 10 year period it would be necessary to treat about 7 individuals with the fixed dose
combination to avert a serious vascular event. By contrast, the risks of a serious complication
from treatment would be very low. Low-dose aspirin would be the main cause of serious
side effects resulting in about one serious (but likely non-fatal) bleed requiring transfusion
among every 83 patients treated for 10 years.
The proposed fixed dose combinations are: First, for patients with established ischaemic
heart disease, aspirin 75mg, simvastatin 40mg, lisinopril 10mg, and atenolol 25mg. Second,
for patients with established ischaemic cerebrovascular disease aspirin 75mg, simvastatin
40mg, lisinopril 10mg, and hydrochlorothiazide 12.5mg. Proving the benefits of these fixed
dose combination therapies would be low-risk and straightforward. Each of the individual
components is already of clearly proven efficacy in the secondary prevention setting and
there is extensive and well documented evidence of the benefits of the individual agents both
when used in isolation and when used in conjunction with each other.
The research program would commence with evaluations of the stability and bioavailability
of the active pharmacological ingredients when provided as a fixed dose combinations rather
than individual moieties. This would be followed by clinical studies designed to establish
the effects on intermediate outcomes such as platelet function, blood pressure and
cholesterol of the fixed dose combinations compared with the four active pharmacological
ingredients provided concommitantly as separate tablets. Once comparable effects have
been established the main goal of the research program, to demonstrate superior adherence
to the fixed dose combination, will commence. Since each of the components of the fixed
dose combination already has a wealth of evidence defining the effects of the agents on
mortality and major morbidity it will not be necessary to conduct new mortality and
morbidity trials. While it may ultimately be possible to define the effects of the fixed dose
combination on these outcomes through the conduct of prospectively designed overviews of
adherence trials conducted in a range of different settings, the focus of research will be on
demonstrating the enhanced adherence of patients to established national and international
guidelines.
6.3-5
Chapter 6.3: Cardiovascular Disease
The rationale for the development and use of the fixed dose combinations in Europe is
evident, but large health gains are also likely in the developing world.2 The great majority of
all cardiovascular disease now occurs in low- and middle-income counties,24 mostly among
individuals with limited access to all but the most basic medical services.25 In this setting, a
new treatment strategy for secondary prevention based on a fixed dose combinations
promises to do for stroke and heart attack what fixed dose combination anti-retroviral
therapy has done for HIV/AIDS.26 With simple management regimens, treatment and
prevention can be done by existing primary care services thereby providing access to care for
many millions of individuals that would otherwise remain untreated. Furthermore, if the
fixed dose combination were based on low cost generic medications then full preventive
therapy might reasonably be offered to very large numbers, at low cost and within existing
resources.27
In summary, Wald and Law’s BMJ paper1 brought the idea of fixed dose combinations for
cardiovascular prevention to the forefront of the world’s attention. Wider and more
complete use of proven preventive therapies in high risk individuals’ requiring secondary
prevention might well be the greatest step forward in disease prevention. Multi-component
fixed dose combinations for the prevention of cardiovascular disease present a major new
opportunity for pharmaceutical research in the European Union and appropriate investment
can ensure that the European pharmaceutical industry takes an early lead in a rapidly
evolving field.
The global burden of cardiovascular disease
Cardiovascular disease is the leading cause of death worldwide and has been so for several
decades. In 2002, cardiovascular disease was estimated to have caused over 15 million
deaths comprising more than a quarter of all deaths that year. 28 About 7.2 million of these
deaths were due to ischaemic heart disease (heart attack) and 5.5 million were due to
cerebrovascular disease (stroke), the two main components of cardiovascular disease. By
2020 it is estimated that there will be 10 million deaths from cardiovascular disease annually
and that these deaths will comprise 37% of all deaths that year. This comprises an additional
9 million cardiovascular deaths each year and a two thirds proportional rise in deaths from
2002 to 2020. The great majority of these additional deaths will be due to stroke and heart
attack. No other diseases currently cause this number of deaths or have such a large
projected increase in the total number of deaths over this time period.
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Chapter 6.3: Cardiovascular Disease
Figure 1 Millions of deaths worldwide estimated for
2002 and projected for 2020 attributable to
cardiovascular disease24,29
40,000,000
30,000,000
2020
20,000,000
2002
10,000,000
Cardiovascular diseases
Cardiovascular disease also causes a very large
non-fatal global disease burden as a
consequence of prevalent disease states such as
angina.29 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 ischaemic heart
disease
and
cerebrovascular
disease,
worldwide constitutes 107.5 million disability
adjusted life years (DALYs). This comprised
7.2% of all DALYs in 2002 and was the leading
cause of DALYs from any cause that year. Like
deaths, the total number of DALYs attributable
to cardiovascular disease is anticipated to rise
substantially over the next few decades with
cardiovascular disease anticipated to cause
204.4 million DALYs (10.3% of all DALYs) by
2020.30
Cardiovascular disease in the European Union
There is some evidence that death rates from cardiovascular causes are stabilising in higher
income countries but there is little evidence that the incidence of non-fatal cardiovascular
disease events is falling.31,32 As such, in higher income regions of the world such as the
European Union, the number of DALYs attributable to cardiovascular over the next two
decades is not expected to fall.30 Furthermore, the significance of cardiovascular disease to
the European Union has just risen steeply with the addition of the 10 new member countries.
Cerebrovascular
disease
Ischaem ic heart
disease
Figure 2 Proportion of
all deaths caused by
leading cardiovascular
diseases in Europe,
overall and separately
for the 15 original
member states and the
10
new
member
33
countries
EU10
EU15
EU25
EU10
EU15
EU25
0
5
10
15
20
25
30
In
2002,
EU10
countries experienced
an estimated 281,000 deaths due to ischaemic heart disease or cerebrovascular disease and
these causes of death comprised 38% of all deaths that year. By comparison, deaths from
these causes in the EU15 member states comprised only 28% of all deaths.33 A corresponding
greater proportional contribution of cardiovascular disease to total disease burden was also
seen in these countries in 2002. That year, ischaemic heart disease and cerebrovascular
disease were jointly responsible for 11.8% of all DALYs in the EU 15 member states and
16.2% of all DALYs in the 10 new member countries (See Annex 6.3.1).
Percent
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Chapter 6.3: Cardiovascular Disease
Cardiovascular disease in the developing world
While cardiovascular disease is long-established as the leading cause of death in developed
countries, it is only in recent times that it has emerged as the leading cause of ill health in
economically developing countries.34,35 A very large proportion of the world’s population
lives in developing countries and both the current and projected impact of cardiovascular
disease in these countries are enormous.25 Already more than four fifths of all cardiovascular
deaths occur in developing countries and the great majority of the growth in global
cardiovascular disease burden over the next 20 years will be in these regions.25 Of the
anticipated 10 million additional deaths each year attributable to cardiovascular disease in
2020, about 9 million are expected to occur in low- and middle-income populations.
Figure 3
Numbers of cardiovascular deaths
estimated for 2002 and projected for 2020 in higherincome and lower-income countries 29,36
40,000,000
30,000,000
2020
20,000,000
2002
10,000,000
2002 2020
Low er incom e
Higher incom e
Worsening risk factors
There are a number of well-established
determinants of cardiovascular disease that
have driven this epidemic of ill health in
developed and developing countries
alike.34,35 Adverse changes in population
levels of smoking, blood pressure,
cholesterol, diabetes and obesity are among
the most important causes of heart attack
and stroke and deteriorating levels of these
risk factors appear to account for much of
the past growth in the global burden of
cardiovascular disease.34
An equally
important determinant of the increasing
cardiovascular disease burden has been the
growth in the number of individuals living
until
middle
and old age
when
cardiovascular disease becomes most
prevalent.25
In the last fifty years there has been a striking ageing of the populations of developed regions
such as Europe and North America and this is now being mirrored in developing regions. In
the fifty years between 2000 and 2050 the number of people aged 60 years or over is
anticipated to more than triple from about 600 million to about 2 billion, and by 2050 about
one third of the population of the European Union is anticipated to be aged 60 years of over.
The effects of an ageing population and unchecked deterioration in other risk factors,
particularly in developing regions,29,37 will continue to drive the growth of cardiovascular
disease over the next few decades.
There is a wealth of evidence defining the separate and combined effects of the leading
determinants of cardiovascular risk on ischaemic heart disease and cerebrovascular
disease.8,38-42 Such evidence is now available for populations from many different regions of
the world and clearly demonstrates qualitatively and quantitatively consistent effects of each
6.3-8
Chapter 6.3: Cardiovascular Disease
of the major causes of vascular disease in the diverse populations studied. The 2002 World
Health Report showed that, worldwide, more than three-quarters of all cardiovascular
disease is attributable to established risk factors such as tobacco, blood pressure and
cholesterol.29 While these have traditionally been thought of as ‘Western’ risk factors each
now features prominently among the ten leading causes of total disease burden in middleincome countries and all are beginning to appear among the leading determinants of disease
burden in poorer developing countries.
In making these estimates, the 2002 World Health Report, for the first time, recognised the
full importance of key risk factors such as blood pressure and cholesterol. For both these risk
factors increases in vascular risk are produced across a much broader range of baseline levels
that was previously thought. So, blood pressure is an important determinant of disease
among individuals with average or below average blood pressure levels as well as among
individuals with hypertension (Figure 4).7,8 Indeed, among non-hypertensive individuals with
established vascular disease the importance of blood pressure as a determinant of risk and
the benefits from effective blood pressure lowering appear to be at least as great as for
hypertensive patients without established disease. The same is also true for the effects of
cholesterol on risk and for the benefits from cholesterol lowering. 8,40,43,44 One consequence of
the continuity of these risk factor-disease associations is that preventive therapies targeting
blood pressure and cholesterol can be administered primarily on the basis of an individuals`
risk of experiencing a blood pressure- or cholesterol-related event rather than knowledge of
the level of the risk factor. As such, expensive measurement and monitoring of risk factor
levels becomes largely redundant reducing costs and simplifying treatment protocols for
high risk individuals such as those receiving treatment for secondary prevention.
6.3-9
Chapter 6.3: Cardiovascular Disease
Figure 4 Association of blood pressure with
the risk of recurrent stroke and the effects of
blood pressure lowering on that risk in
hypertensive
and
non-hypertensive
individuals10,45
Economic consequences
Continuous
associations of blood
pressure and risk
across hypertensive
and
nonhypertensive blood
pressure levels
The 2001 report of the World Health
Organisation
Commission
on
46
Macroeconomics and Health spelled out
the inter-dependency of health and
economic development and highlighted the
consequences of inadequate investment in
health - an increasing disease burden and,
in turn, worsening poverty. While that
report applied primarily to communicable
diseases in sub-Saharan Africa it did note
that even in these lowest income regions of
the world there was a large and growing
burden of non-communicable diseases and
that in just a few years all but the most
impoverished countries would have noncommunicable conditions as their leading
causes of disease burden. If they do not
already, most countries will soon have
stroke and heart attack as principal
contributors to the direct and indirect costs
of ill health.
The economic consequences of cardiovascular disease comprise the direct costs attributable
to healthcare delivery and the indirect costs caused by lost productivity in affected
individuals.27 In developed countries the impact of both the direct and indirect costs of
cardiovascular disease are well-recognizedand at least partially quantified. The direct
financial burden attributable to cardiovascular disease has been identified as a leading
consumer of health care resources in every study that has addressed the question. In the
United States in 1995 it was estimated by the American Heart Association that coronary heart
disease and cerebrovascular disease incurred direct costs of US$50.8 billion and US$18.1
billion respectively.47,48 While highly significant in their own right they are almost certainly
only a fraction of the size of the indirect costs. A UK study conducted in 2000, for example,
estimated that the indirect costs of cardiovascular disease were about four times the direct
costs.49 The indirect costs of cardiovascular disease can be reduced by preventive strategies
that decrease rates of cardiovascular disease during economically productive younger years.
Direct costs, on the other hand, appear more difficult to manage since even if disease rates
are reduced at younger ages it appears that increased use of interventions designed to delay
or avert mortality and morbidity offsets any cost savings made by decreasing the resources
required for the management of acute events.50
Information about the financial burden attributable to cardiovascular diseases in lower
income regions is much more sparse although the recently released report, ‘A Race Against
Time - The Challenge of Cardiovascular Disease in Developing Countries’27 does now
provide some quantitative estimates of the likely economic consequences of cardiovascular
disease in developing countries. That report again emphasized the devastating impact on
6.3-10
Chapter 6.3: Cardiovascular Disease
the costs of cardiovascular disease of serious vascular events occurring in people of younger
age. While about three quarters of cardiovascular disease occurs among individuals aged 70
years or over in developed countries, over half of all major cardiovascular events occur
before that age in most developing world settings.24 In addition to the direct financial effects
on household income, cardiovascular disease at a young age may have wider-ranging
implications that could adversely affect the future wellbeing of the family – in one
developing country setting the death of the family breadwinner was observed to increase the
likelihood of death among young children as well as impact negatively on a series of other
outcomes.51 The different average ages at which events occur does not greatly influence the
direct medical management costs of disease but does substantially increase the indirect costs
exacerbating the impact of cardiovascular disease in lower-income settings.
Lost
productivity resulting from cardiovascular disease among younger people is likely much
greater in developing countries leading to larger indirect costs in those countries least well
equipped to deal with it.
The problem of cardiovascular disease at young ages is particularly great for developing
countries in Asia, South America and other regions but is not without consequence for
Europe. Several new member countries are from Eastern Europe where projected
deterioration in the rates of cardiovascular disease are substantial. For example, in the
Formerly Soviet Economies of Europe cardiovascular deaths in the 45-59 year age group in
men are anticipated to rise from about 162,000 in 1990 to 244,000 in 2020.24
In summary, the European Union, like much of the rest of the developed world, is
anticipated to experience continued growth in the direct costs of cardiovascular disease over
the next few decades. For developing countries, expansion in the direct costs of
cardiovascular disease will be accompanied by a spectacular rise in the indirect costs. In all
but the most impoverished countries of sub-Saharan Africa, it is anticipated that
cardiovascular disease will compete only with injury for the dubious distinction of being the
leading cause of lost productivity.27 There is huge potential for macro economic decisions of
governments, the policy decisions of health ministries and the interventions available to
health care providers to impact on the evolution of this cardiovascular disease burden.
6.3-11
Chapter 6.3: Cardiovascular Disease
Figure 5 Numbers of cardiovascular deaths in men
aged 45-59 in the Formerly Soviet Economies of
Europe in 1990 and projected for 202024
300,000
250,000
200,000
New treatment and prevention
strategies that could be made
available at low cost to large
numbers of individuals have
great potential to positively
influence both the direct and the
indirect costs of cardiovascular
disease in Europe and the
world.
150,000
100,000
50,000
0
1990
2020
Current evidence about prevention
There are many proven interventions for the primary and secondary prevention of
cardiovascular disease and a wealth of information is available documenting the effects of
preventive strategies in different patient groups.3,22,52-56 Prevention options for cardiovascular
disease range from population wide macro-economic and policy initiatives such as the
Framework Convention on Tobacco Control57 through to drug treatment regimens tailored to
the individual patient.3,19,21 In terms of policy-based approaches, there is little doubt about
the merits of tobacco control but while the potential for benefit from policy-based
interventions targeting other determinants of cardiovascular disease is enormous,
confirmation of the efficacy of such strategies is more limited. At the clinical end of the
spectrum there is, however, definitive evidence that interventions targeted at individual
patients can produce profound benefits.19,21,58 It has been estimated that about half of the
decline in age-adjusted cardiovascular disease rates observed in higher-income countries can
be attributed to improvements in clinical care.6 Among these clinical interventions some of
the largest benefits have been those produced by agents that reduce cholesterol levels,58
agents that reduce blood pressure levels21 and agents that decrease platelet activity.19 It is a
novel strategy for achieving the full potential of these agents that forms the basis of the
research agenda proposed in this paper.
(See Appendix 6.3.6)
Primary and secondary prevention
In broad terms the prevention of vascular disease is considered as ‘primary’ among patients
with no documented evidence of vascular disease and ‘secondary’ among patients with a
history of vascular disease established on a prior occasion. The population health gains
achieved by the two approaches are approximately additive in any given community but the
decision to focus health care resources on one or the other may be influenced by several
6.3-12
Chapter 6.3: Cardiovascular Disease
factors. One key practical consideration in such decisions is the difference in the level of risk
between patients with and without existing vascular disease and the implications that this
has for the implementation of any prevention program. Specifically, the risk of disease
among patients targeted with primary prevention strategies is usually much lower than the
risk of disease in patients with existing disease and as a consequence, primary prevention
strategies must treat many more individuals to prevent the same number of events. By way
of an example, cholesterol lowering reduces the proportional risk of heart attack by about
one quarter in both primary and secondary prevention settings. If used for primary
prevention the population group treated might have an overall four year risk of heart attack
of about 4% (1% per annum) and in this situation it would be necessary to treat 100 patients
for four years to prevent one heart attack. In the secondary prevention scenario, the risk of
heart attack is likely to be about 5 times higher because individuals that have already had
one heart attack are much more likely to have another one. The overall four year risk in this
patient group would be about 20% (5% per annum) and because the proportional risk
reduction achieved in secondary prevention is the same as for primary prevention (one
quarter) it would be necessary to treat only 20 patients to prevent one event over the same
time period. So, in this setting, a secondary prevention strategy averts events for about one
fifth the resource required for primary prevention. While secondary prevention can only
prevent events in patients already known to be at high risk, this comprises a substantial
proportion of all vascular events in many populations.6,29 In conjunction with effective
population-wide policy-based public health interventions such as tobacco control secondary
prevention appears to be among the most cost-effective strategies for the control of
cardiovascular disease.29 (See Appendix 6.3.7)
Large high risk patient groups
Much of the current cardiovascular disease burden occurs among people with easily
identifiable risk factors known to significantly elevate the risk of heart attack and stroke.
Individuals with established cardiovascular disease manifest by existing ischemic heart
disease or cerebrovascular disease are a group at particularly high risk of future
events.9,10,29,43,44,59-62 Worldwide, there are currently an estimated 50 million people with
established cerebrovascular disease10 and at least as many more with existing ischaemic heart
disease.29 Many tens of millions live in Europe. Among such individuals the 10-year risk of
suffering a further serious vascular event is at least 1 in 429,63 and the potential benefits from
comprehensive risk reduction are enormous. The combined effects of cholesterol lowering,
blood pressure lowering and antiplatelet therapy will reduce the risks of heart attack and
stroke by at least a half in these patients.1 Furthermore, identification of a large proportion of
patients that have a history of stroke or heart attack can be achieved with simple questioning
only and without the need for sophisticated or expensive investigations.64-66
6.3-13
Chapter 6.3: Cardiovascular Disease
Figure 6 Map illustrating the global distribution of individuals with a risk of vascular
disease of 25% or greater over the next 10 years
36 m
46 m
38 m
18 m
50 m
16 m
5m
5m
45 m
12 m
7m
1m
19 m
4m
>275 million people at 25%+
risk of a major CV event,
about half of whom are likely
to have established vascular
disease
In addition to patients with established vascular disease, combinations of risk factors in
patients that have not yet suffered a first stroke or heart attack can result in similarly high
chances of a major vascular event. There are thought to be at least 275 million individuals
worldwide with this level of cardiovascular risk.29 In total, including patients with and
without a disease history, there are an estimated 50 million people living in Europe with a 10
year vascular risk of 1 in 4 or above. The highest rates in Europe are found among member
states in the East of the European Union33 and the largest numbers worldwide are in India
and the Peoples Republic of China.29 The reliable identification of high-risk individuals
without a history of vascular disease is less straightforward but it is likely that simple
algorithms suitable for use in both developed and developing settings could be developed to
achieve more systematic and reliable detection of these patients.
6.3-14
Chapter 6.3: Cardiovascular Disease
Risk-based prevention strategies
The last decade has seen a shift in the management of cardiovascular risk from approaches
based on the measurement and management of individual risk factors such as blood
pressure67 or cholesterol53 to the evaluation and management of global cardiovascular risk
simultaneously addressing multiple disease determinants.22,56 This change in approach has
been driven by a better understanding of the additive effects of vascular disease
determinants41 and recognition of the impact that these determinants have across a broad
range of risk factor levels.68,69 It is clear that cholesterol, blood pressure and smoking, three
of the chief determinants of cardiovascular risk combine to produce progressively higher
levels of risk (Figure). Furthermore, each appears to have a dose response type effect on risk
such that progressively higher levels are associated with progressively higher risks across
the full range of the risk factor distribution. For example, observational studies show that
each 1mmol/l higher level of cholesterol is associated with an approximate one quarter
greater risk of coronary heart disease and this is true across a broad range of low, moderate
and high cholesterol levels.69 So, the proportional risk of a heart attack is 25% higher among
patients with a cholesterol level of 5mmol/l compared to patients with a cholesterol level of
4mmol/l, and likewise for patients with cholesterol levels of 7mmol/l compared to patients
with a cholesterol level of 6mmol/l.70 The same is also true for blood pressure another key
determinant of cardiovascular disease and a leading target for preventive strategies. 68
Figure 7 The combined effects of systolic blood pressure, cholesterol and smoking on the
risks of coronary heart disease death rates in the Multiple Risk Factor Intervention Trial41
Smokers
Non-smokers
70
70
60
60
50
50
40
40
30
30
20
20
10
142+
132-141
125-131
118-124
<118
0
<4.7
4.7-5.2 5.2-5.7
Total
(mmol/l)
5.7-6.3
6.3+
cholesterol
10
142+
132-141
125-131
118-124
<118
0
<4.7
SBP
(mmHg)
4.7-5.2
5.2-5.7
Total
(mmol/l)
5.7-6.3
6.3+
cholesterol
SBP
(mmHg)
The continuous nature of the association of blood pressure and cholesterol with
cardiovascular risk has a key implication for preventions based on lowering blood pressure
and lowering cholesterol. Because each of the risk factors is associated with risk across the
full range of the risk factor distribution and does not just produce harmful effects above a
threshold level, it would be expected that reducing blood pressure and cholesterol would
6.3-15
Chapter 6.3: Cardiovascular Disease
provide protection to all individuals except those at the very lowest end of the risk factor
distribution. So, just as having a cholesterol level of 5mmol/l incurs a 25% greater
proportional risk of heart attack than a cholesterol level of 4mmol/l so too would lowering a
cholesterol level of 5mmol/l to 4mmol/l be expected to produce a 25% reduction in risk.
Furthermore, lowering of ‘normal’ cholesterol levels among high risk individuals (such as
those with established cardiovascular disease requiring secondary prevention) might
reasonably be expected to avert more events than lowering high cholesterol levels in
individuals who are otherwise well.
Proven drug treatments for secondary prevention
On the basis of existing evidence, there are three types of agents suitable for inclusion in a
fixed dose combination therapy for the secondary prevention of cardiovascular disease. 71
These are anti-platelet therapy,19 blood pressure lowering therapy9,10 and cholesterol
lowering therapy.11 Each has a low rate of serious side effects and a very high benefit to risk
ratio in the secondary prevention setting. Several others types of treatment are also of
known efficacy for secondary prevention72-74 but are either indicated for treatment in only
particular subsets of patients or unsuitable for inclusion in a once daily fixed dose
combination for other reasons.
Antiplatelet therapy
Systematic overviews of randomised trials provide clear evidence that aspirin or another oral
antiplatelet drug is protective in most types of patients at increased risk of occlusive vascular
events.75 (See Appendix 6.3.1) Patient groups with established vascular disease for which
there is clear evidence of benefit include those with acute myocardial infarction, acute
ischaemic cerebrovascular disease as well as those with non-acute presentations of ischaemic
heart disease, ischaemia cerebrovascular disease or peripheral vascular disease. Low dose
aspirin (75-150mg) is an effective regimen for long-term secondary prevention with a low
risk of serious side effects. The addition of a second anti-platelet agent may produce some
additional benefit in selected clinical circumstances but the balance of costs, risks and
benefits of combination antiplatelet therapy is not well established for most populations
requiring long-term secondary prevention. There appears to be no strong rationale for
selecting an agent other than aspirin, at a dose of 75mg, as first line therapy. The
proportional risk reduction for the secondary prevention of heart attack and stroke achieved
with long-term low-dose aspirin therapy is about 22% and appears to be broadly consistent
across the principal patient
Patient group
Reduction
groups.
Prior MI
Acute MI
Prior stroke/TIA
Acute stroke
Other high risk
Coronary disease
Embolic risk
Peripheral arterial
Other
All trials
0.0
25%±4
30%±4
22%±4
11%±3
37%±5
26%±7
23%±8
13%±7
6.3-16
22%±2
0.5
1.0
1.5
2.0
Figure 8
Effects of
antiplatelet
therapy
on
major vascular events in
high-risk patients19
In addition to the clear
protection afforded against
Chapter 6.3: Cardiovascular Disease
ischaemic events, there is a proportionate increase in the risk of major bleeding of about one
half. The two principal types of serious bleeding complications may be divided into
intracranial (mainly haemorrhagic stroke) and extracranial (mainly gastro-intestinal) bleeds.
Overall in randomised trials conducted among patients treated long-term for secondary
prevention there was a net proportional reduction in stroke risk of about 22%19 which
translated over the average two year follow-into absolute reductions in stroke risk of 7 per
thousand for patients with established cardiac disease and 27 per thousand for patients with
prior cerebrovascular disease. By contrast, low-dose aspirin causes serious bleeding
complications requiring transfusion in about 0.1% of patients treated each year translating
into about 2 per thousand over two years. It is also of note that in the largest overview
completed to date there were no fatal extra-cranial bleeding events caused by low-dose
aspirin.1 As such, patients treated with low dose aspirin experience benefits that greatly
outweigh the risks so long as patients are at high absolute risk of ischaemic events and low
absolute risk of haemorrhagic events. This is the case for the vast majority of patients
requiring treatment for secondary prevention. For occasional patients at high risk of both
bleeding and ischaemic events (for example haemodialysis patients with a history of
vascular disease) the overall balance of benefits and risks remains somewhat unclear but
fortunately such patients comprise only a small majority of individuals eligible for secondary
preventive therapy with aspirin.
Blood pressure lowering
Systematic overviews of randomised trials provide clear evidence that blood pressure
lowering is protective in patients at increased risk of vascular events.21 Patient groups with
established vascular disease for which there is clear evidence of benefit from a blood
pressure lowering regimen include those with acute myocardial infarction and those with
non-acute manifestations of ischaemic heart disease or cerebrovascular disease (See
appendices 6.3.2(1) and 6.3.2(2)). For each of these groups beneficial effects of blood pressure
lowering regimens are accrued irrespective of whether patients have a prior history of
hypertension.9,10 There is also an increasing body of evidence that the magnitude of the
benefit is directly proportional to the size of the blood pressure reduction achieved
suggesting that blood pressure lowering is of paramount importance and providing
considerable support for the use of combinations of blood pressure lowering agents. 21 By
contrast, data to support the choice of particular classes of agent on the basis of blood
pressure independent effects of regimens are few.21,76 While special beneficial effects
independent of blood pressure reduction have been postulated for selected agents9,77,78 in
particular clinical settings there is little evidence for large special benefits.21,76 So, while antiarrhythmic effects of beta-blockade and antagonism of the renin angiotensin system may still
provide some benefits beyond blood pressure lowering the magnitude of such effects appear
to be less than initially postulated and small compared to the role of blood pressure
reduction itself.
6.3-17
Chapter 6.3: Cardiovascular Disease
Figure 9 Effects of blood pressure lowering on the risk of vascular events in hypertensive
and non-hypertensive patients with established cerebrovascular diseases9,10
Many patients report side effects
from blood pressure lowering
medication but the proportion
with side effects sufficient to
cause treatment discontinuation
is much lower and the occurrence
of serious side effects is unusual.
On average, compared to placebo
about 15% more patients treated
with blood pressure lowering
agents in the doses proposed for
the fixed dose combination
therapy described here would be
expected to develop side effects
sufficient to require discontinuation of treatment.1 The principal reason for discontinuation
would be cough attributable to the ACE inhibitor component. Angioedema, the most severe
side effect attributable to a blood pressure lowering agent is also caused primarily by ACE
inhibitors. Angioedema occurs once in about every 100 patients commenced on ACE
inhibitor therapy but is life-threatening in many fewer.79 While a potentially serious
complication, angioedema is a risk widely accepted in clinical practice because of the very
substantial net benefits associated with ACE inhibitor treatment for the secondary
prevention of vascular disease.9,10,80 The proportion likely to discontinue treatment because
of side effects attributable to the blood pressure lowering component could be substantially
reduced by substituting an angiotensin receptor blocker for the ACE inhibitor. In this case
discontinuation would be reduced to less than 5%. While the risk of cough and angioedema
attributable to ACE inhibitors does not appear to be reduced by using lower doses, the risks
of symptoms sufficient to cause discontinuation from thiazides, beta-blockers, and calcium
channel blockers are all strongly dose related.81 It is of note that if two blood pressure
lowering drug classes are used in combination the occurrence of side effects is typically less
than additive while the blood pressure lowering effect is that of the two agents combined.81
Reduction of vascular events with statin therapy
in the Heart Protection Study
Active better
Placebo better
Figure 10 Reduction of vascular events with statin
therapy in the Heart Protection Study11
Treated hypertension
Yes
Cholesterol lowering
No
Systematic overviews and individual randomised
trials provide definitive evidence of the value of
cholesterol lowering in a broad range of high-risk
patients and there is clear evidence that cholesterol
lowering reduces the risks of both ischaemic heart
disease and ischaemic stroke when used for
secondary prevention.82 In the Heart Protection
Study which comprised a high risk population with
Aspirin
Yes
No
ACE inhibitor
Yes
No
Beta -blocker
Yes
No
Calcium antagonist
Yes
No
6.3-18
ALL PATIENTS
24% SE 3
reduction
(2P<0.00001)
0.4
0.6
0.8
1.0
1.2
Rate ratio & 95% CI
1.4
Chapter 6.3: Cardiovascular Disease
diabetes or existing vascular disease cholesterol lowering with simvastatin resulted in a 25%
proportional reduction in the risk of stroke, a 27% proportional reduction in the risk of
ischaemic heart disease and a 24% proportional reduction in the overall risk of
cardiovascular events. The effects of cholesterol lowering on haemorrhagic stroke remain
uncertain but appear likely to be neutral rather than strongly protective or strongly harmful.
There is definitive evidence for secondary prevention among patients with existing coronary
heart disease, cerebrovascular disease or peripheral vascular disease. As for blood pressure
lowering there are convincing data showing that greater benefits accrue with greater
reductions in the risk factor level. There is also clear evidence of benefits from cholesterol
lowering for high risk patient groups with average, above average and below average
cholesterol levels. These data pertain primarily to statin therapy and comparable evidence to
support the alternate or combined use of a fibrate or other cholesterol-lowering regimen is
not available.
Side effects of cholesterol lowering therapy are few and rarely serious. The best estimates of
the side effects attributable to statin therapy come from large-scale randomised trials such as
the Heart Protection Study.11 While discontinuation rates are typically quite high in such
trials, not least because randomised treatment becomes indicated for a substantial proportion
of patients during the course of the study, the differences between discontinuation rates in
the active and placebo groups are frequently small. In the Heart Protection Study for
example, 17% of patients on simvastatin and 15% of patients on placebo discontinued
therapy prior to their completion of study follow-up indicating that only about 2% of
patients suffer side effects of a severity sufficient to require discontinuation. The absolute
rates of serious side effects with statin therapy are very low and in the Heart Protection
Study persistent serious liver enzyme abnormalities (0.09% simvastatin vs. 0.04% placebo),
persistent serious muscle enzyme abnormalities (0.07% vs. 0.01%) and myopathy (one case in
each group) were very infrequent. When compared against the beneficial effects of
simvastatin on the risk of a major vascular event (19.8% simvastatin vs. 25.2% placebo) it can
be seen that the fraction of a percentage point increase in the risk of a persistent muscle
enzyme abnormality (less than 0.2% for muscle and liver enzymes combined) is outweighed
more than thirty fold by the 5.4% decreased absolute risk of a life-threatening vascular
complication.
Glucose lowering for diabetes
Diabetes is a contributor to cardiovascular risk that is of rapidly expanding global
significance. Worldwide, there were estimated to be 171 million individuals with diabetes in
2000, about 44 million in the Established Market Economies and 127 million elsewhere.83
These figures are anticipated to grow to 68 million and 298 million respectively by 2030
fuelled in large part by the global epidemic of obesity. Among patients with diabetes
elevated glucose levels are associated with increased risks of both microvascular and
macrovascular events and for the former, at least, there is good evidence that glucose
lowering provides protection.84,85 However, at least as important for cardiovascular
prevention among patients with diabetes are cholesterol lowering11 and blood pressure
lowering.86,87 For each of these two treatments standard daily treatment doses administered
for secondary prevention provide protection at least comparable in magnitude to that
achieved in patients identified on the basis of existing vascular disease. There are also likely
6.3-19
Chapter 6.3: Cardiovascular Disease
to be substantial benefits from aspirin therapy among patients with diabetes and while the
evidence is less comprehensive for patients with uncomplicated diabetes, the benefits among
patients with diabetes and existing vascular disease are likely to be comparable to those
achieved for secondary prevention in other patient groups.19 Accordingly, a fixed dose
combination including these agents would be of great value in patients with diabetes and
could be administered on top of any concurrently administered glucose lowering regimen.
Including agents for glucose control in the fixed dose combination would, however, present
considerable challenges. While once daily glucose lowering regimens are available,88,89 good
glucose control frequently requires tailoring of therapy to individual patient needs. This
may include titration of the total dose administered, the use of multiple concurrent
hypoglycaemic agents and division of drug doses throughout the day. While all of these
could be achieved if a comprehensive range of fixed dose combinations were made available
the simplicity central to the development, testing and implementation of the fixed dose
combinations proposed here would be lost.
Other interventions
There are a number of other intervention strategies that have either been proved effective for
secondary prevention or suggested for inclusion in fixed dose combinations for patients with
existing vascular disease that are not included in the formulations proposed here. For some,
such as anti-coagulant therapy among patients with atrial fibrillation, the reason that the
intervention is not included in the fixed dose combinations proposed is that it would be
applicable to only a small proportion of all patients with established vascular disease.73,90 For
others, such as fish oil,74 it is because the intervention is required in large doses and would be
difficult to include in the formulation. And for others still it is because there is either as yet
no definitive evidence that treatment is effective (homocysteine lowering) 91,92 or else clear
evidence that treatment is ineffective (hormone replacement therapy). 93 In summary, the
current evidence base and considerations relating to practicalities of administration and
formulation make the proposed combination of blood pressure lowering, cholesterol
lowering and antiplatelet therapy the most rational components for a fixed dose
combination. Future development in the field might of course lead to the development of
future fixed dose combinations of expanded or otherwise modified composition.
Additive treatment effects
The data summarised above provide clear evidence from robust subgroup analyses of
randomised trials and overviews of trials that the effects of antiplatelet therapy, blood
pressure lowering therapy and cholesterol lowering therapy are achieved independent of
each other and result in additive reductions in the risks of serious vascular complications
when used for secondary prevention. There is clear evidence that the risk reductions
produced by cholesterol lowering therapy are achieved on top of background use of
antiplatelet therapy and blood pressure lowering,82 the risk reductions achieved with blood
pressure lowering are achieved on top of background antiplatelet therapy10 and cholesterol
lowering9 and the benefits of antiplatelet therapy are achieved against a background of blood
pressure lowering.94 Furthermore, there are clearly additive effects of different classes of
blood pressure lowering agents81 and the inclusion of several different classes of blood
pressure lowering agent would be anticipated to produce yet further reductions in risk. In
6.3-20
Chapter 6.3: Cardiovascular Disease
terms of the three main classes of treatment, conservative estimates of effect in the secondary
prevention setting would be a 20% reduction in relative risk for antiplatelet therapy, a 25%
reduction in relative risk for cholesterol lowering therapy and a 25% reduction in relative
risk for blood pressure lowering therapy. If each of these three risk reductions are achieved
together then the overall reduction in the relative risk of major cardiovascular events would
be 55%
[100%-(100*0.75*0.75*0.80)] (Figure 11). In terms of the absolute risk reduction, an individual
with established vascular disease and a 10 year risk of a vascular event of 1 in 4 (25%) would
have their 10-year risk reduced by over one half [25%*(1-0.55)] to 1 in 9 (11.25%). Over a 10
year period it would be necessary to treat about 7 individuals to avert a serious vascular
event (stroke or heart attack).
Figure 11 The joint effects of blood pressure lowering, cholesterol lowering and
antiplatelet therapy on risk
10 year cardiovascular risk
By comparison, the risk of a severe side effect from treatment would be low. While the
proportional increase in risk would be about one half, the absolute risk of serious
complications in this group is very low1 and this would translate into only one serious
complication being caused among about every 83 patients treated for ten years. The
complications caused would be
30%
almost entirely extra-cerebral
bleeding events due to low25%
dose aspirin. In the largest
overview of the effects of low20%
dose aspirin completed to date,
there was no excess of fatal
15%
bleeding complications caused
10%
by aspirin with all such events
being
non-fatal
bleeds
5%
requiring transfusion.1
0%
Baseline
w ith aspirin
(20% relative
risk reduction)
w ith aspirin
w ith aspirin,
and blood
blood
pressure
pressure and
low ering (40% cholesterol
relative risk low ering (55%
reduction)
relative risk
reduction)
6.3-21
Chapter 6.3: Cardiovascular Disease
Fixed dose combination therapy
Potential health gains from combination therapy
Individuals with established vascular disease are at very high risk and it is clear that this risk
is a consequence of multiple interacting risk factors.41 Correspondingly, maximum benefit
from secondary prevention is anticipated from a multi-factorial intervention targeting many
determinants of disease simultaneously. Current guidelines for the secondary prevention of
cardiovascular disease now recommend multiple drug therapies for these patient groups
(See Appendix 6.3.).3,43,44,59,61,62,67,95
Unfortunately,
many
Table 1 Prevalence of major risks and use of patients
with
existing
recommended preventive interventions in 3379 patients cardiovascular
disease
with established coronary disease in Europe in 200012
receive
substantially
incomplete
preventive
Intervention
Percent on
12
therapy.
In 1999-2000 a
treatment or
survey of several thousand
achieving goal
patients at about 50 leading
Treatments used
hospitals around Europe
Antiplatelet therapy
84%
identified continued major
Beta-blockers
66%
shortfalls in the secondary
ACE-inhibitors
43%
preventive care provided to
Cholesterol lowering therapy
63%
patients who had been
admitted with ischaemic
Persisting risks
heart
disease
(Table).
Diabetes
22%
Ideally
each
of
the
Remain obese
33%
treatments should have
Continue smoking
21%
been used in all patients
Cholesterol level above goal
59%
and each of the risks should
Blood pressure above goal
54%
have been present in none.
Well under half of all patients were receiving all recommended treatments and even fewer
received all treatments and achieved blood pressure and cholesterol goals. While full
adherence in the secondary prevention setting is clearly implausible substantial
improvements in drug use and treatment goals should be easily achievable. Another
concerning feature of the data was that there was only very limited evidence of improvement
in the use of pharmaco-therapy in comparison with a comparable survey completed a few
years earlier. This reinforces the need for novel strategies that will give physicians new ways
of bridging the large gaps between defined optimal care and actual clinical practice. The
importance of full use of proven drug based regimens was further highlighted by the very
poor record achieved for behavioural and lifestyle interventions - twenty one percent
continued to smoke, 33% remained obese and 48% remained overweight. Furthermore, for
some behavioural characteristics the proportion of patients achieving goals had not just
failed to improve but had actually deteriorated over the 4 years between surveys. It is of
note that this study was conducted mainly in tertiary institutions where it might reasonably
be expected that patient care, and adherence of individuals to prescribed therapies would be
superior to that achieved in most other health care facilities. It is also of note that
6.3-22
Chapter 6.3: Cardiovascular Disease
comparable surveys conducted in the UK and Spain a few years earlier had identified similar
failures in preventive care.
For developing countries there are few data about the uptake of secondary preventive
strategies although a recent review of health care facilities conducted by the World Health
Organisation in 10 low- and middle income country settings suggests that the situation is
considerably worse in such regions. In that study, among patients eligible for secondary
prevention of coronary heart disease the use of aspirin was 81%, beta-blockers 48%, ACE
inhibitors 40% and statins 30%. For cerebrovascular disease the figures were aspirin was
71%, beta-blockers 23%, ACE inhibitors 38% and statins 14% (Personal Communication S
Mendis, World health Organisation). Even these are, however, likely to be substantial
overestimates since the patients attending the health care facilities involved are unlikely to
apply to representative of all individuals living in low- and middle-income settings. The
proportion of patients receiving full secondary preventive therapy in most low- and middle
income countries is likely to be only a fraction of that achieved in Europe providing huge
opportunity for improvement. In this situation, the potential health gains from a low-cost,
easily administered fixed dose combination therapy for the secondary prevention of
cardiovascular disease would likely be particularly large.
Using existing evidence about risk levels among patients with cardiovascular disease and the
known effects of treatments on these risks it is possible to make estimates of the likely
consequences of incomplete use of proven therapies for secondary prevention. For example,
if there were 40 million individuals in Europe with a 10 year risk of 25% or greater caused by
established vascular disease24,29 there will, in the absence of treatment, be a total of about 1
million strokes and heart attacks each year. If all 40 million of these individuals received
combination therapy with aspirin, blood pressure lowering and cholesterol lowering the
average risk of a major vascular event in each individual would be reduced by 55% and the
actual number of events occurring each year would be 0.45 million. 0.55 million of the
anticipated 1 million events would have been averted by complete use of these three proven
therapies. If Europe-wide treatment were actually about that observed in EUROASPIRE12
(antiplatelet therapy in most and blood pressure lowering and cholesterol lowering in about
two-thirds each) then the average risk reduction being achieved would be about 43% instead
of 55%. (See Appendix 6.3.3) This would mean that there would be about 0.57 million
strokes and heart attacks each year, abut 0.12 million of which might have been averted with
full use of treatment. If the actual use of treatments Europe-wide is instead assumed to be
somewhat worse than that observed in EUROASPIRE12 (say aspirin use in four fifths and
cholesterol lowering and blood pressure lowering in one half each) then the actual risk
reduction being achieved is 36%, the number of events occurring is 0.65 million and the
shortfall compared to full use of the three therapies is about 0.39 million events. In the world
as a whole, where there are an estimated 100 million individuals with a history of heart
disease or cerebrovascular disease eligible for secondary prevention24,29 among whom about
2.5 million strokes and heart attacks would be anticipated each year. At least half of these
individuals are likely to be living in low- and middle-income settings where only a fraction
of those patients with established vascular disease are identified. The secondary preventive
therapies received by these individuals are likely to be very substantially incomplete with
the potential for full preventive therapy to avert large numbers of events worldwide .
6.3-23
Chapter 6.3: Cardiovascular Disease
Why fixed-dose combinations?
Fixed dose combination therapies are a well established treatment modality for a range of
different diseases. Most recently global interest in fixed dose combinations has focused on
the epidemics of infectious disease caused by HIV/AIDS, tuberculosis and malaria although
fixed dose combinations have been widely used to improve blood pressure control for many
years.96,97 The merits of fixed dose combination regimens are well established in these
settings14 and fixed dose combinations are increasingly viewed as optimal treatment.98,99 The
reasons for the use of fixed dose combinations in communicable diseases are multiple and
many are of direct relevance to the proposed use of fixed dose combinations for the
secondary prevention of cardiovascular disease.14,99 So, while arguments based on slowing
the development of drug resistant organisms are clearly not applicable to the secondary
prevention of cardiovascular disease, others based upon improved clinical outcomes,
simplification of logistics and better patient adherence are all underpinned by the same
rationale that supports their use for communicable diseases. As for tuberculosis,100 fixed
dose combination therapies based on generic drugs would also be the lowest cost option for
disease management.
Improved adherence
Fixed dose combinations can greatly reduce the complexity of dosing regimens, a key
therapy-related factor influencing adherence.14,15 For HIV/AIDS and tuberculosis fixed dose
combinations reduce both the number of tablets and the frequency of dosing, greatly
simplifying otherwise very complicated treatment regimens.101 In other situations, including
the management of blood pressure, fixed dose combinations can also enhance adherence by
reducing side effects - low doses of two different classes of blood pressure lowering agents in
a fixed dose combination can produce better blood pressure control than regimens based on
full doses of individual agents.81 Clearly, fixed dose combinations address only one aspect of
adherence which is a complex behavioral phenomenon but as a simple, low cost strategy for
which there is reasonable evidence of benefit, fixed dose combinations have much to
recommend them in this regard alone. In conjunction with other strategies to enhance
adherence, the proposed fixed dose combinations for the secondary prevention of
cardiovascular disease seem very likely to importantly enhance adherence, although formal
evaluation would be required.
Reduced costs
The potential to reduce the direct and indirect costs of medical care with an intervention that
reduces the risk of major cardiovascular events is clear.27,50 However, even if fixed dose
combinations resulted in only the same risk reductions as can be achieved with individual
medications it is likely that the use of fixed dose combinations would result in long-term cost
reductions in several sectors.102 First, a fixed dose combination would be anticipated to
produce savings from reduced expenditure in the packaging of medications by the
pharmaceutical company - packaging will be required for only one medication instead of
three or four. Second, storage, handling and distribution costs will be for a single agent only
and third, there will be savings to the health care systems providing the treatment to the
patient since treatment will involve only one prescription and a corresponding single
episode of dispensing.
6.3-24
Chapter 6.3: Cardiovascular Disease
Perhaps the greatest saving will however be in drug costs - all of the components required
for the proposed fixed dose combinations are available as low cost generic formulations. A
simple to administer fixed dose combination for the secondary prevention of cardiovascular
disease is likely to be widely prescribed by physicians and much sought after by patients.
Patients commenced on the proposed fixed dose combinations will generally be required to
discontinue their use of more expensive individual on-patent treatments and while fixed
dose combinations are anticipated to result in more patients on more treatments for more of
the time there may well still be substantial net savings because of the large differences in the
prices of generic and on-patent treatments. For example, daily treatment with some onpatent medications for blood pressure lowering (such as angiotensin receptor blockers) can
cost many many times more than off-patent treatments of similar efficacy (such as
diuretics).21,76,103 It is anticipated that the fixed dose combinations proposed here could
eventually be produced by a generic manufacturer for less than a dollar a week (personal
communication A Rodgers). The potential for generic medications to deliver cost effective
global health solutions has been well recognised and economic analyses reported by the
World Health Organisation have previously indicated that broader use of individual generic
drug treatments among high risk individuals would be the next most cost-effective use of
resources for many countries after population-wide measures such as tobacco control or
restriction of dietary sodium.104 The use of fixed dose combinations for treatment of other
diseases has also resulted in substantial reductions in the cost of treatment, approximately
halving the cost of providing four-drug therapy for tuberculosis.102
Improved access and equity
The use of fixed dose combinations in infectious diseases has significantly decreased the
complexity of treatment administration and broadened options for treatment delivery.105 For
example, by enabling a range of care providers including non-physician health workers to
provide treatment, fixed dose combinations for the management of HIV/AIDS have allowed
treatment programs to be expanded to cover many more patients. This has profound
implications for equity of access to health care, particularly in resource poor settings where
physician-based care is beyond the reach of many.27 As for HIV/AIDS, the development of
simplified treatment regimens for the secondary prevention of cardiovascular disease would
be expected to greatly increase access to effective treatment.2 The proposed fixed dose
combinations could easily be provided through existing non-physician medical services that
are already widely available for the management of communicable diseases. Only minimal
re-training of staff would be required - the very high chance of benefit and the very low risk
of harm associated with these fixed dose combinations means that occasional inappropriate
treatment of individuals without cardiovascular disease can be tolerated since it would be
very unlikely to result in harm.
Less medication errors
In addition to facilitating access to preventive cardiovascular therapies, the simplification of
treatment regimens possible with fixed dose combinations should also greatly reduce the
number of medication errors made by prescribers, dispensers and patients.106 The delivery of
quality preventive care should also be possible with shorter consultation times since the use
of the fixed dose combination treatments will be much more straightforward to explain than
6.3-25
Chapter 6.3: Cardiovascular Disease
the use of multiple individual therapies. Finally, monitoring of all aspects of the treatment
delivery process should be simplified with significant resource savings in audit activities.
Co-blistered combinations
Co-blistered combinations, whereby multiple tablets or capsules are blistered together, are
an alternate to single tablet/capsule fixed dose combinations.14 In general, co-blistered
combinations are a second choice when a fixed dose combination is not available or not
possible. While both co-blistered combinations and fixed dose combinations should enhance
the likelihood that all the active ingredients required for effective treatment travel together
from the producer, through the supply chain, to the prescriber, the dispenser and the patient,
co-blistered combinations do not have all the advantages of fixed dose combinations.
Specifically, while the complexity of the dosing regimen can be simplified the pill burden is
not reduced and there is still the potential for errors in pill consumption by patients. In
terms of cost, co-blistering is likely to provide short term cost advantages since the research
required to develop quality co-blistering should be less then the costs required for the
development of a physical combination of several active ingredients. However, in the longterm co-blistered combinations are unlikely to provide the clinical benefits of fixed dose
combinations, and the ongoing costs of the more sophisticated packaging process required
for co-blistering are likely to outweigh any short-term cost savings.101
Issues
There are many likely advantages of fixed dose combinations but there are also a number of
established drawbacks to their use. First, there is reduced capacity to tailor therapy and
adjust doses to meet individual patient needs. Tailoring of therapy is a tenet of most medical
training courses and reducing the capacity of physicians to individualize therapy is likely to
be met with concern unless the advantage of fixed dose combinations are clear for doctors
and patients alike. Second, side effects of one treatment in a fixed dose combination might
lead to discontinuation of all therapies. To some extent this might be overcome by providing
a range of fixed dose combinations including different combinations of two-three or four
agents but simplicity of use would be impacted accordingly. For the fixed dose
combinations proposed, the rates of discontinuation due to side effects are likely to be low
and most patients are likely to tolerate them well. Nonetheless, continued use of multiple
individual treatments will be required for a minority of patients reporting intolerance and
for clinicians unwilling to change their prescribing patterns. Several other complexities of
fixed dose combinations encountered in their development for communicable diseases will
not be an issue for cardiovascular disease – specifically paediatric dosing regimens will not
be required and the development and distribution of starter packs containing different doses
will not be necessary.
Existing fixed dose combinations
Fixed dose combinations are by no means a new idea for cardiovascular prevention and twocomponent combination regimens have been developed and are widely used.107 The
pharmaceutical, academic and public health sectors alike are, however, now advocating the
expansion of the concept to include multi-component fixed dose combinations targeting
multiple risk factors.108 (See Appendix 6.3.5) To date, much of the activity in the field has
6.3-26
Chapter 6.3: Cardiovascular Disease
been directed towards two-component fixed dose combinations for the management of
blood pressure79 although this has recently expanded to include a two-component fixed dose
combinations for cholesterol lowering109 and the first fixed dose combinations targeting
different risk factors.110,111 The latter of these now include a two-component fixed dose
combination of a cholesterol lowering agent and an antiplatelet agent in a co-blistered
format111 and another single tablet fixed dose combination of a blood pressure lowering
agent and a cholesterol lowering agent.112
New fixed dose combinations
As has been highlighted above, most fixed dose combinations for cardiovascular prevention
have been designed for the management of individual risk factors. Current guidelines for
cardiovascular prevention have, however, progressively shifted away from the management
of individual risk factors and now recommend combination therapy with at least three
different classes of agent targeting multiple facets of cardiovascular risk.3 As a consequence,
new fixed dose combinations including each of the main preventive therapies are a focus of
interest and an urgently required tool for effective secondary prevention. 1,2 There are three
main classes of agent that should be included in new fixed dose combinations for the
secondary prevention of cardiovascular disease: antiplatelet therapy, cholesterol lowering
therapy and blood pressure lowering therapy. On the basis of current evidence two
formulations would be most appropriate - one for use among patients with established
ischaemic heart disease and one for use among patients with established ischaemic
cerebrovascular disease.
Patients with ischaemic heart disease
For patients with established ischaemic heart disease there is clear evidence of the long-term
efficacy and safety of aspirin, statins, angiotensin converting enzyme (ACE) inhibitors and
beta-blockers. Current guidelines recommend the use of all of these agents in combination
among this patient group. All of these agents are available in generic formulations and fixed
combination therapy would comprise, a once daily preparation containing:




Low-dose antiplatelet therapy (for example aspirin 75mg),
A statin (for example simvastatin 40mg),
An angiotensin converting enzyme inhibitor (for example lisinopril 10mg), and
Low dose of a beta-blocker (for example atenolol 25mg)
Serious side effects of this fixed dose combination would be rare and almost entirely due to
low-dose aspirin which would be expected to cause a serious bleeding complication
requiring transfusion in about every one thousandth patient treated each year.1 Serious side
effects from statin therapy and blood pressure lowering therapy would be anticipated to
occur in less than one in every five thousand patients treated each year 11,113 although less
severe side effects such as abnormalities of liver enzymes and non-life threatening
manifestations of angioedema would be more common. By contrast in a patient group with
existing ischaemic heart disease and a 25% or greater 10 year risk the fixed dose combination
would be expected to prevent a minimum of one serious vascular complication in every 70
patients treated each year.
6.3-27
Chapter 6.3: Cardiovascular Disease
Less serious side effects would be more common and would result in some treatment
discontinuation. The principal cause of treatment discontinuation would be cough
attributable to the angiotensin converting enzyme inhibitor.114 The problem of cough could
be greatly reduced by using an angiotensin receptor blocker such as losartan or irbesartan
and discontinuation rates would then be brought down to just a few percent.1,81
Overall, among patients with established ischaemic heart disease, it is likely that only about
15% of patients would develop side effects to the components of the proposed fixed dose
combination that would be sufficiently severe to require discontinuation (and probably less
than 5% if an angiotensin receptor blocker was substituted for the ACE inhibitor). Treatment
rates of 85% or above for four proven therapies would constitute a substantial improvement
upon existing practice patterns12 and would avert large numbers of serious vascular events
each year, worldwide.
Patients with ischaemic cerebrovascular disease
For patients with established ischaemic cerebrovascular disease there is clear evidence of the
long-term efficacy and safety of aspirin, statins, angiotensin converting enzyme inhibitors
and diuretics.3,115 All of these agents are, once again, available in generic formulations and a
fixed dose combination therapy could comprise a once daily preparation containing:




Low-dose antiplatelet therapy (for example aspirin 75mg),
A statin (for example simvastatin 40mg),
An angiotensin converting enzyme inhibitor (for example lisinopril 10mg), and
Low dose of a diuretic (for example hydrochlorothiazide 12.5mg)
The rates of serious side effects attributable to statin therapy and ACE inhibition would be
low and directly comparable to those reported above for patients with ischaemic heart
disease. It is also likely that the risks of serious extracranial bleeding complications with
low-dose aspirin would also be comparable to those for patients with ischaemic heart
disease. It is theoretically possible that the risk of intra-cerebral haemorrhage might be
increased in patients with cerebrovascular disease - cases of cerebrovascular disease caused
by intra-cerebral haemorrhage might be misdiagnosed as ischaemic in origin and such
patients would be at increased risk of further bleeds if antiplatelet therapy were instituted in
error. There is however little evidence to support this possibility and it is very unlikely that
beneficial effects of combination treatment resulting in the avoidance of at least one serious
ischaemic event among every 70 patients treated each year1 would be offset by an increased
rate of serious bleeding complications that would be unlikely to result in more than one
additional haemorrhagic stroke caused among every few thousand patients treated each
year.19
In terms of less severe side effects, the anticipated discontinuation rates would again be
comparable to those for patients with ischaemic heart disease and there would be a similar
rationale for the substitution of the ACE inhibitor with an angiotensin receptor blocker. Low
dose diuretic therapy is as well tolerated as low-dose beta-blocker therapy and would not be
expected to importantly increase discontinuation rates.81 It worth noting here that low dose
diuretic therapy is very well established for the prevention of vascular disease with efficacy
6.3-28
Chapter 6.3: Cardiovascular Disease
at least as good21 (and possibly better)116 than that observed for newer agents such as ACE
inhibitors. Concerns about adverse effects on metabolic indicators such as lipid levels,
glucose levels and new diabetes do not appear to translate into important effects on risk in
the short to medium term.
Patients with cerebrovascular disease of haemorrhagic aetiology would not be suitable for
treatment with this fixed dose combination since long-term aspirin therapy would be
anticipated to increase the risk of recurrent haemorrhage 19 and cholesterol lowering therapy
does not appear to influence the risk of haemorrhagic stroke.11,40 Bedside differentiation of
ischaemic and haemorrhagic stroke is difficult but diagnosis can usually be made using
computerised tomography (CT) scanning or magnetic resonance imaging (MRI) which is
available at most hospitals in Europe. In addition, since 80% or more of strokes in high
income countries are ischaemic in origin the risk associated with inappropriate use of this
fixed dose combination is low.117,118 In lower-income settings the proportion of strokes
caused by haemorrhage is higher40 and the chance of misdiagnosis and commencement of
inappropriate therapy is therefore also higher. In part this problem will be alleviated by the
severity of haemorrhagic stroke which has a much higher case fatality rate 119 but in some
settings where haemorrhagic stroke is known to predominate a fixed dose combination
without aspirin might be of use.
Other patient groups for secondary prevention
Ischaemic heart disease and cerebrovascular disease are the two most common presentations
of vascular disease but there are other high risk patient groups that present with
manifestations such as atrial fibrillation120,121 and peripheral vascular disease.3 There is not
separately definitive evidence for each of these groups for every one of the components of
the fixed dose combinations proposed here and beta-blocker therapy would probably be
contra-indicated among patients with peripheral vascular disease and might or might not be
useful among patients with atrial fibrillation. However, both these patient groups clearly do
benefit from preventive therapies72,73,90 and would probably achieve further decreases in risk
from more effective risk factor control using a fixed dose combination of the type proposed
for patients with cerebrovascular disease. Patients with diabetes are another high-risk group
that while not strictly fitting into the secondary prevention category, would likely gain from
more effective risk factor control. Use of aspirin for primary prevention in this group is not
proven but there is now a strong rationale for the use of aggressive blood pressure 122 and
cholesterol lowering therapy11 in all but the lowest risk patients. Once again, fixed dose
combinations of the composition planned here, perhaps without the aspirin component until
more comprehensive data become available, would be likely to significantly add to current
treatment options.
Other possible combinations
The two fixed dose combinations recommended above would constitute optimal therapy for
the vast majority of patients with established vascular disease. There will however be some
individuals for whom these two combinations of treatment are not appropriate and a range
of different fixed dose combinations would provide scope for tailoring of therapy to
individual patients needs. While the availability of many different fixed dose combinations
would offer some advantages, there is the danger that wide availability of 2- or 3-component
fixed dose combinations, or fixed dose combinations with reduced doses of selected
6.3-29
Chapter 6.3: Cardiovascular Disease
components would result in sub-optimal treatment regimens for large numbers of
individuals.
In addition to fixed dose combinations with fewer components, an argument might also be
made for fixed dose combinations that include agents additional to the two fixed dose
combinations proposed here. There s good evidence, for example, that the use of three blood
pressure lowering drugs at half dose would produce greater blood pressure reductions and
less side effects less than either one or two agents used at higher doses. 81 It is also clear that
the epidemiological associations of blood pressure and cholesterol with the risks of stroke
and heart attack are both continuous with no lower level of either blood pressure or
cholesterol identified below which the risks do not continue to decline. 8,39,40 These
epidemiological observations lead to two principal conclusions. The first is that blood
pressure lowering and cholesterol lowering agents should reduce risk irrespective of the
baseline level of cholesterol or blood pressure. Large-scale randomised trials have clearly
demonstrated that patients with existing vascular disease achieve substantial benefits from
both these treatment modalities even if they have normal cholesterol levels 11 and normal
blood pressure levels9,10 thereby providing the rationale for the blanket treatment of these
patient groups. The second conclusion is that greater reductions in blood pressure and
cholesterol should produce greater reductions in risk. Large scale randomised trials have
also demonstrated that this is quite clearly the case 21,76,123 and optimal preventive therapy for
patients with existing vascular disease should therefore probably comprise more than one
blood pressure lowering agent and more than one cholesterol lowering agent. It is also
possible that the next decade will see new treatment modalities, such as folic acid, 124
identified as providing benefit in patients with existing vascular disease. Additional fixed
dose combinations with components targeting new means of prevention or seeking to
achieve greater benefits through established modes of protection might reasonably be
developed but in the meantime the focus of attention should be on establishing the benefits
of the two formulations proposed here.
New pharmaceutical research opportunities
Multi-component fixed dose combinations for the prevention of cardiovascular disease
present a major new opportunity for pharmaceutical research. Many pharmaceutical
companies already have or are developing two-component fixed dose cardiovascular
preventive therapies but there appears to be little current investment in multi-component
fixed dose combinations. There is, however, a clear scientific and public health rationale for
the development of multi-component combinations1,108 and a clear opportunity for the
European Union to stimulate this work. With appropriate investment the European
pharmaceutical industry could take an early lead in a field that will evolve rapidly over the
next decade. The opportunity may be particularly great for the European generics industry
since the strongest scientific rationale and the greatest potential for public health gain
appears likely to result from the development of high volume, low cost products based on
proven off-patent generic agents.
6.3-30
Chapter 6.3: Cardiovascular Disease
Key issues in drug development
The fixed dose combinations proposed here are comprised of active pharmaceutical agents
for which there is already a comprehensive evidence base supporting all stages of drug
development, manufacture and prescribing. Accordingly, many of the most expensive, high
risk and time consuming aspects of product development can be circumvented and there is a
reasonable expectation that it will be possible to bring the proposed fixed dose combinations
to market in a much shorter time frame (two or three years after program commencement)
than would be possible for a completely novel agent. There are, however, a number of
research issues unique to the development of fixed dose combinations that will need to be
addressed and the research agenda required to answer these forms the basis for investment
by the European Union proposed here. There are also several longer-term objectives that
will require ongoing research into fixed dose combinations for cardiovascular prevention
providing for a sustained and dynamic research agenda for at least a decade to come.
Formulation
A broad range of different formulations for fixed dose combinations for the secondary
prevention of cardiovascular disease is theoretically possible and there would be substantial
benefit for clinical practice if an array of different fixed dose combinations were available. 1,81
However, the initial focus of development should be on the two formulations proposed here
since they comprise the combinations of active pharmaceutical ingredients with the soundest
evidence base and the greatest potential for public health gain in Europe and the World.
Clinical acceptance of new fixed dose combinations for secondary prevention will be vital for
success and this will require initial conservatism in the selection of agents widely recognized
to produce maximum benefit at minimum risk. On this basis the two formulations proposed
will each include an antiplatelet agent, two blood pressure lowering agents and a cholesterol
lowering agent each of which has a major body of evidence demonstrating clinical efficacy.
While the addition or substitution of other agents might reasonably be expected to produce
additional benefits either the absence of a comprehensive evidence base or the additional
costs associated with including on-patent treatments will preclude most other combinations
at this time. However, as currently on-patent agents become available in generic
formulations there will be the opportunity to enhance the properties of the two initial fixed
dose combinations providing for ongoing research and development.
Intellectual property
A key advantage to the fixed dose combinations proposed here is that all of the individual
active pharmaceutical ingredients are available off-patent at low cost. There are, however, a
number of patents relating to fixed dose combinations (See Appendix 6.3.4) and these may
impede the development of generic fixed dose combinations by complicating issues relating
to intellectual property rights and licensing. Depending upon the local regulatory setting,
companies may therefore find themselves limited by the drug classes within their own
portfolio or requirements for complex intellectual property negotiations. This would be an
early area for further research but after an initial review it appears reasonable to expect that
intellectual property issues related to the two fixed dose combinations proposed could be
resolved reasonably rapidly for selected regions where the product could be brought to
market, at low cost, in just a few years.
6.3-31
Chapter 6.3: Cardiovascular Disease
Regulation
The development of multi-component fixed doses combinations for cardiovascular disease
could be achieved with existing European Union regulatory mechanisms. (See Appendix
6.3.8) High quality, safe and efficacious products would be assured by compliance of the
research and development process with established regulatory practices and quality
assurance processes. The pharmaceutical industry and regulatory bodies alike will be able to
draw on the experience gained in the development of multi-component fixed dose
combinations for HIV/AIDS, tuberculosis and malaria. Disease specific expertise acquired in
the development and licensing of established two-component fixed dose combinations for
cardiovascular disease will also facilitate the rapid and efficient approval of multicomponent fixed dose combinations for use in the cardiovascular field. There is, however,
clearly some opportunity for streamlining of the regulatory processes related to products
such as those proposed here. Given the wealth of information available about each of the
individual components of the proposed fixed dose combinations and their current
widespread concurrent usage it appears that aspects of the approval process might be
circumvented without risk.
Manufacture and quality assurance
The manufacture of fixed dose combinations is more technically demanding than the
manufacture of single agents and requires an additional scientific base for production.
However, compliance with existing regulations for good manufacturing practice will ensure
that high quality product is delivered to the market place and that appropriate monitoring is
in place to ensure that the quality of products is sustained. Once again, prior successes of
pharmaceutical companies and regulatory agencies in bringing to market two-component
fixed dose combinations for cardiovascular prevention provide practical evidence of
feasibility. Furthermore, several of the two-component fixed dose combinations in the
marketplace already include one or more of the active pharmaceutical ingredients planned
for the multi-component fixed dose combinations planned pointing towards the high
likelihood of success for the research agenda proposed.
Bioequivalence and stability
Since each of the individual active pharmaceutical ingredients has previously completed
comprehensive pre-clinical research programs elements of the pre-clinical research program
mandated for completely novel agents will be uncessary. The focus of this phase of the
research would be evaluation of the stability of the active pharmaceutical ingredients in a
single formulation and the development of a manufacturing and quality control process that
will ensure the delivery of high quality product.
Pharmaco-dynamics and pharmaco-kinetics
The in vivo research program would commence with small-scale evaluations designed to
establish the pharmaco-dynamics and pharmaco-kinetics of each of the active
pharmaceutical ingredients when administered in the form of fixed dose combinations.
While the active pharmaceutical ingredients included in the fixed dose combinations
proposed are already routinely administered in conjunction with each other the findings of
these studies would be a required regulatory step and would provide clinicians with
reassurance that the fixed dose combination approach is an appropriate one. The goal would
6.3-32
Chapter 6.3: Cardiovascular Disease
be to demonstrate comparability of the pharmaco-dynamics and pharmaco-kinetics for each
of the active pharmaceutical ingredients when administered as the fixed dose combination
and when administered as four separate agents. The results would also provide further
indirect evidence of product stability for the fixed dose combinations. Separate randomised
trials would be conducted for each of the two proposed fixed dose combinations in patients
with established ischaemic heart disease and in patients with established cerebrovascular
disease. Each study would involve less than one hundred individuals with follow-up
planned for just a few weeks duration.
Clinical research
Clinical research will hold the key to the success of the planned fixed dose combinations. A
first goal of the clinical research program will be to provide the evidence required to meet
the regulatory requirements of national and international agencies for the purposes of
registration. However, at least as important as this first goal will be the design and
implementation of studies that will persuade clinicians of the safety and efficacy of the new
fixed dose combinations. Only with clear evidence of the advantages to be had from these
new treatments will fixed dose combinations become widely incorporated into clinical
practice.
Effects on blood pressure, cholesterol and platelet function and tolerability
The first phase of the program would be to establish the effectiveness of the fixed dose
combinations on the intermediate outcomes of blood pressure, cholesterol and platelet
function. The goal would be to confirm that the administration of the active pharmaceutical
ingredients in fixed dose combinations modifies each of these outcomes to at least the same
extent as the four different agents administered separately. Tolerability of the fixed dose
combinations compared to the four individual components would also be evaluated in these
trials. Two randomised trials would again be conducted, one for each of the proposed fixed
dose combinations used in their respective patient groups. Each study would involve a few
hundred individuals followed for a few months duration.
Enhanced adherence to guidelines
The evidence provided by the preceding studies of physiological efficacy and tolerability
would be used to underpin pivotal trials demonstrating the capacity of the fixed dose
combinations to enhance the number of individuals that adhere long-term to established
treatment guidelines. These studies would comprise open, randomised, multi-centre, clinical
trials, one conducted in patients with established ischaemic heart disease and the other
among patients with established ischaemic cerebrovascular disease. Aside from the
difference in inclusion criteria the trials of the two fixed dose combinations would be
otherwise similar. In each trial, eligible participants will be individuals for whom there is no
known contra-indication to any of the components of the fixed dose combinations.
Participants would be randomly allocated to receive the fixed dose combination or to
continue usual care. Usual care would be defined as usual treatment according to the
practices of the clinicians’ responsible for the patients and would comprise continuation of
the preventive treatments already prescribed at the time of screening. In these studies all
medications included in the fixed dose combination would be available free of charge to both
6.3-33
Chapter 6.3: Cardiovascular Disease
the usual care group and the intervention group. The primary outcome would be long-term
adherence to the four drug classes (antiplatelet therapy, two blood pressure lowering agents
and cholesterol lowering therapy). Secondary outcomes would be differences in blood
pressure and cholesterol levels between groups and there will be a formal economic
evaluation of the two strategies. Each of the two randomised trials would be conducted in
about 1000 participants with follow-up continued for about two years.
Developing countries
The ‘enhanced adherence to guidelines’ studies described above would address the key
opportunity for the use of fixed dose combinations in developed country settings where
there is reasonable access to medical care and the primary goal is to address incomplete
treatment among patients that are already identified but receiving only partial preventive
therapy. In part this would be achieved through simplification of the prescription process
for physicians but in large part the advantage of fixed dose combinations would be from
enhanced adherence achieved through simplification of the treatment regimen for patients.
By contrast, in many developing countries the primary problem to be addressed with fixed
dose combinations does not concern incomplete treatment among identified patients but
rather no treatment among patients unknown to the health care system. In this setting it is
anticipated that the benefits of fixed dose combinations would be derived primarily from
simplification of the process by which patients suitable for treatment are identified and
provided with treatment.
To demonstrate these benefits would require a different type of study focussed on not just
the fixed dose combinations but incorporating broader issues relating to health care delivery
systems in low-income communities. A cluster randomised design evaluating the effects of
an intervention package comprising simple algorithms directing the opportunistic
identification and management of patients with established vascular disease would best
address the potential of fixed dose combinations in developing country settings. The
algorithms supporting the delivery of the fixed dose combinations would be designed for
use by physician or non-physician health workers since the latter are the sole health care
providers for much of the developing world. Health care providers and their communities
would then be assigned at random to receive either the intervention package or continued
usual care. The health care providers in the intervention group communities would be
trained and provided with supplies of treatment accordingly. Evaluation of the effectiveness
of the fixed dose combination-based intervention package would be done by comparing the
proportion of individuals with established vascular disease identified and treated in the
intervention compared to control communities. A number of studies of this type would be
required reflecting the different levels of sophistication of the health care services available to
different parts of the developing world. Each study would require randomisation of 50 or
more communities of village size with before and after surveys of a few hundred
participants in each to reliably establish the most plausible benefits of the fixed dose
combinations.
Effects on mortality and morbidity
Definitive evidence that fixed dose combinations provided benefits in terms of mortality and
morbidity would provide a very powerful argument for their more widespread use. An
individual large-scale trial could address this question but would require a single very
6.3-34
Chapter 6.3: Cardiovascular Disease
substantial investment that may not be immediately forthcoming. Since a series of smaller
trials evaluating the effects of fixed dose combinations on intermediate outcomes are likely
to be required to address questions about fixed dose combinations in different countries and
different health care settings an alternative approach would be to design prospective metaanalyses of these studies. Several trials of a few thousand individuals followed for a year or
more and designed primarily to address questions about enhancing adherence to guidelines
would in combination provide reasonable power to detect effects on mortality and major
morbidity.
Likewise, meta-analyses of a series of cluster randomised community
intervention studies would provide a good opportunity to show the effects of fixed dose
combinations on these outcomes. For the latter, statistical power would be particularly good
because event rates would likely be high and the differences in treatment levels between
intervention and control communities would probably be large. Meta-analyses would also
provide an opportunity to explore factors influencing the effectiveness of the fixed dose
combinations in different settings.
Development and implementation timeframes
Short and medium term
The fixed dose combinations proposed here are based on generic medications each with a
proven record of efficacy and a substantial evidence base. As such, compared to completely
novel agents, the research and development program could be substantially abbreviated and
the products made available to the market in a short time frame. With adequate investment
the existing European generics industry could bring the multi-component fixed dose
combinations proposed here to market within just a few years – in the most optimistic
scenario, about twelve months would be required for development to the stage where the
products would be available to commence the clinical research program and another two
years after that would be needed to accumulate the evidence required to fulfill the regulatory
requirements for product registration. Thereafter the clinical research program would be
focused on phase three and four studies designed to expand the market for the products by
demonstrating the value of the fixed dose combinations in a range of clinical and geographic
settings.
Longer-term
Once the benefits of the two fixed dose combinations proposed here are clearly established
there will be opportunities for pharmaceutical and academic organisations alike to explore
ways of enhancing the products available. This is likely to involve modifications to the
formulations that are designed either to enhance the effectiveness of the existing treatment
modalities or to add new treatment modalities. A number of possibilities for longer-term
research initiatives are outlined below.
Greater reductions in cholesterol would be expected to produce greater reductions in risk40 and
might be achieved either through including another cholesterol lowering agent in the
formulation109 or substituting the statin proposed (simvastatin) with another more potent
agent.20,123 In terms of other cholesterol lowering agents the most plausible additions would
be either a fibrate or ezetimibe.109 There is some concern about the risk of increased side
effects with the combination of statins and fibrates125 although this may be restricted to
particular agents. Ezetimibe on the other hand is a promising potential addition but
6.3-35
Chapter 6.3: Cardiovascular Disease
definitive evidence of efficacy is still some way off and the agent retains a substantial patent
life. Perhaps more plausible will be the substitution of simvastatin with a later generation
statin such as atorvastatin or rosuvastatin.20 These latter two statins are significantly more
potent in terms of the cholesterol reduction achieved and should produce significantly
greater reductions in risk. Data about the effects of these agents on mortality and morbidity
is now becoming available and is likely to soon provide a strong rationale for their inclusion
in fixed dose combinations for cardiovascular prevention. Both are, however, currently
considerably more costly than simvastatin which is available off-patent. It is however of
note that atorvastatin is already marketed in a two-component fixed dose combination with
the blood pressure lowering agent amlodipine.112
Greater reductions in blood pressure could be achieved with the addition of other
antihypertensive drug classes.81 There is already considerable evidence for the additive
effects of different classes of blood pressure lowering agents and multi-agent combination
therapy is routinely recommended for the management of blood pressure in treatment
resistant patients.67,79 In addition, there is good evidence that low dose combinations of
agents can achieve blood pressure reductions at least comparable to those achieved with full
doses of single agents but with a lower incidence of side effects.81 Since epidemiological
studies demonstrate no lower levels of blood pressure below which risks of disease do not
continue to decline8,39,68 then future fixed dose combinations might reasonably explore the
benefits of adding other blood pressure agents to the fixed dose combinations proposed here.
Reduced side effects from blood pressure lowering could be achieved by using an
angiotensin receptor blocker instead of an ACE inhibitor. These agents do not cause cough
and have side effect profiles approximately equivalent to placebo. Furthermore, the first
agents in this class will come off patent shortly. However, while likely to be as effective as
angiotensin converting enzyme inhibitors for cardiovascular prevention, the evidence to
support the use of angiotensin receptor blockers in this patient group is less robust. 21
Ongoing trials will however address this question and if proven comparably effective then a
standard dose of an angiotensin receptor blocker would be a better choice for the fixed dose
combination than the ACE inhibitor. It is also possible that ongoing studies will demonstrate
that angiotensin receptor blockers provide benefit additional to that of ACE inhibitors in
which case one version of the fixed dose combination with an angiotensin receptor blocker
alone and another with an angiotensin receptor blocker and an ACE inhibitor might be a
possibility.
Additional antiplatelet activity could also be achieved with the addition of a second agent.19
There is some evidence to support the combined use of aspirin and clopidogrel for secondary
prevention although the additional benefits, while outweighing the increased risk of serious
bleeding complications, are fairly small. Among patients with existing vascular disease in
whom the risk of thrombotic events is very high the net balance of benefits and risk would
be likely to favour the addition of clopidogrel although clopidogrel currently remains onpatent and expensive.
Other components could be added to new fixed dose combinations once evidence of efficacy
becomes available or technical issues are overcome. Fish oils74 are already of proven benefit
but require large doses typically comprising multiple capsules and recommended regimens
6.3-36
Chapter 6.3: Cardiovascular Disease
could not currently be included in a single tablet fixed dose combination. Folic acid,
proposed for inclusion by Wald and Law in the 2003 BMJ publication,1,124 currently has
insufficient data to support its inclusion but should definitive evidence become available
from trials that are currently ongoing it would be reasonably straightforward to incorporate
it at a later date.
Other high-risk primary prevention groups would be suitable for treatment with the proposed
fixed dose combinations and comprise a substantial opportunity to expand the market for
these products. Worldwide, there are estimated to be almost as many individuals with a
25% 10 year cardiovascular risk without a history of cardiovascular disease as there are with
a history of cardiovascular disease.29 Such individuals are somewhat more difficult to
identify than patients with a prior history of stroke or heart attack but have equally as much
to gain from the comprehensive control of risk factors as their counterparts with established
disease.
A clear commonality of interest
For the European Union and the World Health Organisation, there exists a substantial
commonality of interest in the investment of research into new low-cost strategies for the
prevention of cardiovascular disease. In addition to being the leading cause of death in
Europe, cardiovascular disease is also the leading cause of death in the majority of World
Health Organisation member states. Furthermore, while the burden of disease attributable
to cardiovascular causes is anticipated to expand substantially in the European Union over
the next few decades, the growth in the burden of cardiovascular disease in low- and
middle-income regions of the world is anticipated to grow far more dramatically. Fixed dose
combinations for the prevention of cardiovascular disease in high-risk individuals provide a
unique opportunity for the European Union to invest in a research agenda that will benefit
both its own member states and those lower-income regions of the world most urgently in
need of health gains. The advances in the management of cardiovascular disease anticipated
from this work will bring about very substantial health benefits to both Europe and the
World and likely comprise the greatest advancement in the management of cardiovascular
disease since the discovery of statins some three decades previously.
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1.
Wald N, Law M. A strategy to reduce cardiovascular disease by more than 80%. BMJ.
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2.
Rodgers A. A cure for cardiovascular disease? BMJ. 2003;326:1407-1408.
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Task Force Report. Prevention of coronary heart disease in clinical practice.
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Murray C, Lauer J, et al. Reducing the risk of cardiovascular disease: effectiveness and costs of
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Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:2-3.
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Hunink M, Goldman L, et al. The recent decline in mortality from coronary heart disease,
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Chapter 6.3: Cardiovascular Disease
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Prospective Studies Collaboration. Cholesterol, diastolic blood pressure, and stroke: 13,000
strokes in 450,000 people in 45 prospective cohorts. Lancet. 1995;346:1647-1653.
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HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-258.
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Heart Protection Study. Results of the Heart Protection Study. Lancet. 2002;360:7-22.
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EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison
of EUROASPIRE I and II in nine countries. Lancet. 2001;357:996-1001.
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Macaulay A, Commanda L, Freeman W, Gibson N, McCabe M, Robbins C, Twohig P.
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