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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 NealDirector, Heart and Vascular DivisionGeorge Institute for International HealthPO Box 576NewtownSydneyNSW 2042AustraliaTel +61 (0)2 9351 0043Email [email protected]

With advice from Dr Anthony Rodgers and Professor Stephen MacMahonAll correspondence to Associate Professor Bruce Neal

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Table of Contents

Summary______________________________________________________________________4The global burden of cardiovascular disease_______________________________6Cardiovascular disease in the European Union__________________________________7Cardiovascular disease in the developing world_________________________________8Current evidence about prevention____________________________________________12Primary and secondary prevention_____________________________________________12Large high risk patient groups_________________________________________________13Risk-based prevention strategies______________________________________________15Proven drug treatments for secondary prevention_____________________________16Additive treatment effects_____________________________________________________20Fixed dose combination therapy____________________________________________22Potential health gains from combination therapy______________________________22Why fixed-dose combinations?_________________________________________________24Existing fixed dose combinations______________________________________________26New fixed dose combinations__________________________________________________27New pharmaceutical research opportunities______________________________30Key issues in drug development_______________________________________________31Clinical research_______________________________________________________________33Development and implementation timeframes_________________________________35A clear commonality of interest____________________________________________37Key references_________________________________________________________________37

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Annex and Appendices to Background Chapter 6.3 Cardiovascular DiseaseAnnex 6.3.1 Top twenty conditions by DALYS and mortality for Europe and the World [word 153KB] 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

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SummaryIn 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 editorial2 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 evidence base. Furthermore, with clearly additive

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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.

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

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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 diseaseCardiovascular 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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Figure 1 Millions of deaths worldwide estimated for 2002 and projected for 2020 attributable to cardiovascular disease24,29

Cardiovascular disease in the European UnionThere 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.

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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


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 countries33

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).

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 higher-income and lower-income countries 29,36

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

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Worsening risk factorsThere 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


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 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 middle-income 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.

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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 consequencesThe 2001 report of the World Health Organisation Commission on Macroeconomics and Health46 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 non-communicable 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

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Continuous associations of blood pressure and risk across hypertensive and non-hypertensive blood pressure


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 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.

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Figure 5 Numbers of cardiovascular deaths in men aged 45-59 in the Formerly Soviet Economies of Europe in 1990 and projected for 202024

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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.

Current evidence about preventionThere 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 factors. One

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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

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Figure 6 Map illustrating the global distribution of individuals with a risk of vascular disease of 25% or greater over the next 10 years

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.

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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

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 provide protection to all

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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 therapySystematic 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 groups.

Figure 8 Effects of antiplatelet therapy on major vascular events in high-risk patients19

In addition to the clear protection afforded against ischaemic events, there is a proportionate increase in the risk of major bleeding of about one half. The two

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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 loweringSystematic 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 anti-arrhythmic 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.

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24% SE 3reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

AspirinYesNo

ACE inhibitorYesNo

Beta -blockerYesNo

Calcium antagonistYesNo

ALL PATIENTS

Treated hypertension

Yes

No

24% SE 3reduction(2P<0.00001)

0.4 0.6 0.8 1.0 1.2 1.4

Rate ratio & 95% CI

Active better Placebo better

AspirinYesNo

ACE inhibitorYesNo

Beta -blockerYesNo

Calcium antagonistYesNo

ALL PATIENTS

Treated hypertension

Yes

No

Reduction of vascular events with statin therapy in the Heart Protection Study


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

Figure 10 Reduction of vascular events with statin therapy in the Heart Protection Study11

Cholesterol loweringSystematic 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

6.3-18


secondary prevention.82 In the Heart Protection Study which comprised a high risk population with 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 diabetesDiabetes 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 to be substantial benefits from aspirin therapy among patients with diabetes and

6.3-19


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 interventionsThere 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 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

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0%

5%

10%

15%

20%

25%

30%

Baseline w ith aspirin(20% relativerisk reduction)

w ith aspirinand bloodpressure

low ering (40%relative riskreduction)

w ith aspirin,blood

pressure andcholesterol

low ering (55%relative riskreduction)

10 y

ear c

ardi

ovas

cula

r ris

k


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 riskBy 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 almost entirely extra-cerebral bleeding events due to low-dose aspirin. In the largest overview of the effects of low-dose aspirin completed to date, there was no excess of fatal

bleeding complications caused by aspirin with all such events being non-fatal bleeds requiring transfusion.1

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Fixed dose combination therapyPotential health gains from combination therapyIndividuals 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 patients with existing cardiovascular disease receive substantially incomplete preventive therapy.12 In 1999-2000 a survey of several thousand patients at about 50 leading hospitals around Europe identified continued major shortfalls in the secondary preventive care provided to patients who had been admitted with ischaemic heart disease (Table). Ideally each of the treatments should have been used in all patients and each of the risks should 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 comparable surveys conducted in the UK and Spain a few years earlier had identified similar failures in preventive care.

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Table 1 Prevalence of major risks and use of recommended preventive interventions in 3379 patients with established coronary disease in Europe in 200012

Intervention Percent on treatment or

achieving goal

Treatments usedAntiplatelet therapy 84%Beta-blockers 66%ACE-inhibitors 43%Cholesterol lowering therapy 63%

Persisting risksDiabetes 22%Remain obese 33%Continue smoking 21%Cholesterol level above goal 59%Blood pressure above goal 54%


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 .

Why fixed-dose combinations?

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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 adherenceFixed 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 costsThe 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.

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

6.3-24


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 on-patent 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 equityThe 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 errorsIn 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 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.

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Co-blistered combinationsCo-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 long-term 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

IssuesThere 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 two-component 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 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

6.3-26


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 diseaseFor 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 year11,113 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.

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

6.3-27


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 diseaseFor 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 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.

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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 haemorrhage19

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 rate119 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 preventionIschaemic 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 pressure122 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 combinationsThe 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 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

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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 levels11 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 case21,76,123 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 opportunitiesMulti-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.

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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.

FormulationA 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 propertyA 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.

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RegulationThe 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 multi-component 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 assuranceThe 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 stabilitySince 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-kineticsThe 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 be to demonstrate comparability of the pharmaco-dynamics and pharmaco-kinetics for each of the active pharmaceutical ingredients when administered as the fixed

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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 tolerabilityThe 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 guidelinesThe 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 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

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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 countriesThe ‘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 morbidityDefinitive 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 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

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meta-analyses 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 termThe 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-termOnce 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 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

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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 on-patent 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 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.

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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 interestFor 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.

Key references

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