Background Paper 6.3 Ischaemic heart disease

Transcription

1 Priority Medicines for Europe and the World "A Public Health Approach to Innovation" Update on 2004 Background Paper Written by Bruce Neal Background Paper 6.3 Ischaemic heart disease By Dr Ruth Webster and Professor Anthony Rodgers The George Institute for Global Health Level 13, 321 Kent St Sydney, NSW 2000, Australia Tel

2 Table of Contents 1. Introduction What is the size and nature of the disease burden? What is the control strategy? Lifestyle intervention Lipid-lowering therapy Blood pressure lowering therapy Evidence on potential benefits of regimen simplification and use of two-drug combination pills Evidence on hypertension combination pills containing more than two medications Anti-platelet therapy Why does the disease burden persist? Non-optimal use of existing effective medications New innovative therapies What can be learnt from past/current research into pharmaceutical interventions for this condition? Previous trials polypill versus placebo or no treatment Summary of TIPS 1 and Summary of Wald and Law trial PILL Collaborative Group Other trials Conclusions from previous trials of polypill versus placebo or no treatment Ongoing trials polypill versus placebo Previous trials polypill versus usual care FP7-funded UMPIRE trial Ongoing trials versus usual care (Annexes 6.3.7) FP7 funded FOCUS trial Kanyini-GAP IMPACT SPACE Collaboration meta-analysis What is the current pipeline of products that are to be used for this particular condition? What are the opportunities for research into new pharmaceutical interventions? What are the gaps between current research and potential research issues which could make a difference are affordable and could be carried out in a) five years or b) in the longer term? Need for large-scale trials among people with established cardiovascular disease and other indications for treatment What are the effects of implementing a polypill strategy on cardiovascular outcomes? Potential benefits of next generation polypills Additional benefits from use of newer agents How many dose versions for each polypill? Low dose or high dose polypill components? Polypill approach in specific patient populations Expanding the polypill concept to acute care

3 9. For which of these gaps are there opportunities for pharmaceutical research? Conclusion Declarations References Annexes Annex 6.3.1: Mortality and burden of disease from IHD per age group and per region Annex 6.3.2: Baseline characteristics of previous randomised controlled trials versus placebo or no treatment Annex 6.3.3: Actual versus expected reductions in systolic blood pressure and LDL-cholesterol in trials of polypills versus placebo or no treatment Annex 6.3.4: Baseline characteristics of UMPIRE Trial Annex 6.3.5: Ongoing randomised controlled trials polypill versus usual care Annex 6.3.6: Ongoing trials of hypertension polypills Annex 6.3.7: Ongoing trials polypill versus placebo or no treatment Annex 6.3.8: Pipeline of polypills

4 1. Introduction In 2004 Warren Kaplan and Richard Laing wrote the Priority Medicines for Europe and the World Report. 1 In this report they placed great emphasis on the background paper written by Bruce Neal titled Secondary Prevention of Cardiovascular Disease: Fixed Dose Combinations. ( doc). In the 2004 report Kaplan and Laing stated The simple solution to this deficiency (in the effective treatment of patients with proven cardiovascular disease) is to develop and test a fixed-dose combination (FDC) product of these proven effective medicines. The research agenda proposed in this section is different to that of the other sections because this approach offers the greatest potential shortto-medium term impact of all of the possible research activities in this Report. (Page 58). This background paper to the 2013 update of the Priority Medicines for Europe and the World reports on the work that has been done since 2004 making the case that what was proposed in 2004 has now been undertaken and that the next stage is to undertake large scale pan European and global clinical trials to understand the place of polypills in the treatment of individuals who have suffered from cardiovascular and/or cerebrovascular events. There have been two large scale clinical trials funded in this area. One of these studies (the UMPIRE trial) has since reported positive results as outlined in detail in this background paper. This report updates the information on this topic. This report updates the potential information on this topic and therefore continues to focus on secondary prevention among patients who have already suffered a cardiovascular event. The majority of such patients have IHD, but a significant minority have cerebrovascular disease or peripheral vascular disease. In addition to secondary prevention with the polypill, a number of other pharmacological approaches to prevention and treatment of IHD will need to be researched in order to provide more effective, safer and individualized intervention strategies. These include the development of new lipid-lowering drugs; pharmacological means to address novel mechanistic concepts of vessel wall damage and protect against conditions such as chronic inflammation and local angiogenesis; and regenerative medicine/cell therapy approaches. Similarly, new pharmacological treatment strategies need to be developed for heart failure and arrhythmias, frequent consequences of IHD. 2. What is the size and nature of the disease burden? Detailed analysis of overall global trends in burden of disease is available in Chapter 5, however a summary of disease burden attributable to cardiovascular disease is included here. Each year about 15.6 million deaths (30% of global mortality) occur from cardiovascular disease (CVD) making it the leading cause of death. 2 Worldwide, ischaemic heart disease (IHD) is ranked as the leading specific cause of death, with 13.3 % of total deaths, followed by cerebrovascular disease (11.1%) (Table 6.3.1).Together IHD and all forms of stroke worldwide killed an estimated 12.9 million people in 2010, a quarter of the global total, an increase from one in five deaths worldwide 20 years earlier

5 Following global trends, the largest single cause of death in the 2010 Global Burden of Disease study in the combined region of Central, Eastern and Western Europe was ischaemic heart disease (26.6% of all deaths), closely followed by cerebrovascular diseases (ischaemic and haemorrhagic and other non-ischaemic stroke) with 11.0% of the total number of deaths (Table 6.3.1). The most common specific cause of cardiovascular death is IHD which accounts for 45% of global cardiovascular deaths and 54.6% of European cardiovascular death. Cerebrovascular diseases account for 37.6% of cardiovascular diseases globally and 31.4% in Europe. Hypertensive heart disease is the third biggest contributor to this group of diseases with 5.6% of global cardiovascular mortality and 3.7% of the total cardiovascular mortality in Europe. Table 6.3.1: DALY and mortality data for the most common cardiovascular diseases, for the European regions and the world. Eastern, Western and Central Europe b World Eastern, Western and Central Europe World DALYs % of total DALYs % of total Mortality (total deaths) % of total Mortality (total deaths) % of total Ischemic heart disease Cerebrovascular disease Hypertensive heart disease Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD 2010) Results by Cause b Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Hungary, Macedonia, the Former Yugoslav Republic of Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, Belarus, Estonia, Latvia, Lithuania, Moldova, Russian Federation, Ukraine, Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom

6 Figure 6.3.1: Distribution of global and European mortality for cardiovascular and circulatory diseases. Central, Eastern and Western Europe a World 6.9% 2.3% 1.1% 3.7% 31.4% 54.6% 5.6% 37.6% 2.6% 2.2% 7.0% 45.0% Ischemic heart disease cerebrovascular disease (stroke) Hypertensive heart disease Other cardiovascular and circulatory diseases Cardiomyopathy and myocarditis Rheumatic heart disease Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD 2010) Results by Cause a Bosnia and Herzegovina, Bulgaria, Croatia, Czech Republic, Hungary, Macedonia, the Former Yugoslav Republic of Montenegro, Poland, Romania, Serbia, Slovakia, Slovenia, Belarus, Estonia, Latvia, Lithuania, Moldova, Russian Federation, Ukraine, Andorra, Austria, Belgium, Cyprus, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Netherlands, Norway, Portugal, Spain, Sweden, Switzerland, United Kingdom. In addition, cardiovascular disease causes a large non-fatal global disease burden as a consequence of prevalent disease states such as angina. When the non-fatal disease burden is taken in conjunction with the healthy life years lost due to premature death the total overall disease burden attributable to cardiovascular and circulatory diseases accounted for 11.8% of global DALYs (Disability Adjusted Life Years) in The major diseases within this group worldwide are, just as with mortality data, ischaemic heart disease (5.2%), cerebrovascular diseases (4.1%), and hypertensive heart disease (0.6%). In Central, Eastern and Western Europe, 13.8% of the total DALY burden can be attributed to IHD, 7.1% to cerebrovascular disease and 0.8% to hypertensive heart disease (Table 6.3.1). Not only is CVD currently the greatest cause of death and disability worldwide, CVD mortality is predicted to rise to approximately 23.4 million by 2030 with CVD predicted to remain the leading cause of death. 5 Recent data from the Global Burden of Disease study 2010 confirms the likelihood of reaching these predictions. Cardiovascular diseases and more specifically ischaemic heart disease increased by 31.2% and 34.9%, respectively, in terms of absolute deaths in the past two decades. In terms of years of life lost (YLLs), ischaemic heart disease increased in rank from fourth in 1990 to first in 2010, reflecting an increase of 28%. Cerebrovascular disease is currently ranked third globally for YLLs, but in some Asian regions is ranked first. Ischaemic heart disease is ranked first in almost all regions other than Asia. In addition, from 1990 to 2010, both ischaemic heart disease (IHD) and cerebrovascular disease have risen in their position amongst the top 10 causes of DALYs IHD from position number four to number one and stroke from position number five to number three, reflecting increases of 29% and 19% respectively. 4 In Europe, ischaemic heart disease and 6.3-6

7 stroke have maintained their ranking as the leading and second most common causes of death and YLLs over the past 20 years. In central and eastern Europe they have maintained their respective highest and second highest rankings for DALYs also, however in western Europe, low back pain has now emerged as the foremost cause for DALYs in that region. IHD and stroke come in at numbers two and three. 3 Figure shows the amount of absolute disability-adjusted life years (DALYs) caused by ischaemic heart disease (IHD) by age group for the world, Central, Eastern and Western Europe. The highest burden of disease from ischaemic heart disease, amongst the three European regions, is present in Eastern Europe in all age groups, followed by Western Europe. The amount of DALYs caused by ischaemic heart disease peaks at 80 years and above in all four regions. Figure 6.3.3: Absolute deaths caused by ischaemic heart disease by age group and region demonstrates the mortality rates for ischaemic heart disease, in absolute death numbers, by age group and region. 3 As with the DALYs, Eastern Europe has the highest number of deaths from ischaemic heart disease amongst the European regions in all age groups, except for in the over 80 years age group, where Western Europe has slightly higher numbers of deaths due to IHD. This is remarkable since Western Europe has approximately half the number of deaths in the other age groups, compared to Eastern Europe. Furthermore, it s striking that Central Europe has less than half the number of deaths due to IHD than Eastern Europe or Western Europe. More figures for mortality and burden of disease from IHD per region and age group can be found in the annexes of this background paper

8 Figure 6.3.2: Absolute DALYs caused by ischaemic heart disease by age group and region. 3 Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD 2010) Results by Cause Figure 6.3.3: Absolute deaths caused by ischaemic heart disease by age group and region. 3 Source: Institute for Health Metrics and Evaluation (IHME). Global Burden of Disease Study 2010 (GBD 2010) Results by Cause

9 Common interests between Europe and the world Despite the common misperception that CVD is a rich man s disease, 80% of CVD deaths occur in low- or middle-income countries (LMIC). 6 These deaths in LMICs are not only occurring more frequently than in high income countries but are also occurring earlier in life causing a greater social and economic impact in these countries. Many of these countries typically are least equipped to deal with this epidemic of CVD due to inadequate health care systems and significant levels of poverty. The commonality between high income countries and low income countries of risk factors responsible for the identical leading causes of death ensures that any solutions that are found have the potential (within the bounds of adaptation to local conditions) to advantage a broad range of countries across the economic spectrum. Any intervention that has the capacity to affect significant public good in Europe can be applied globally in many different settings. This well documented epidemic of CVD is due to two main factors ageing of the world s population, and epidemiological transition in LMIC leading to global exposure to the key risk factors for CVD. 7 Population Ageing Chapter 5 provides significant detail on global ageing and will not be repeated here. Figures 5.1 and 5.2 in particular show the predicted ageing of the population globally and particularly in the European Region. Such increases in life expectancy, although showing global successes in modernization and improvements in standards of living and health care, mean that more people are living to an age where they are more likely to have a cardiovascular event and if they survive that event, live longer with the disability associated with that event. Risk Factors Risk factors associated with CVD are well established through multiple large epidemiological studies which show that CVD is overwhelming preventable. 8,9 Fifty-seven per cent of CVD deaths (19% of global deaths) can be attributed to just eight risk factors associated with poor diet and low rates of physical activity: high blood pressure, high blood glucose, physical inactivity, being overweight or obese, high cholesterol and low fruit and vegetable intake. 10 The other key risk factor is tobacco use which accounts for nearly 10% of CVD. 10 The 2010 Global Burden of Disease study reported that the two leading risk factors for global disease burden overall were high blood pressure (9.4 million deaths and 7% of global DALYs) and tobacco smoking including second-hand smoke (6.3 million deaths and 6.3% DALYs) both of which are key factors in increasing risk of CVD. The leading risk factor for Europe was also high blood pressure with smoking ranked either second or third (depending on the region of Europe). Detailed proportions of global IHD DALYs attributable to individual risk factors are presented in Table 6.3.2: Proportion of ischaemic heart disease DALYs attributable to individual risk factors, worldwide, These risk factors are all similarly implicated in other atherosclerotic disease such as stroke. Of note is the high proportion of IHD DALYs attributable to excessive alcohol use. Although significant, excessive alcohol use and the consequent disease states, treatment options and recommendations for further research are covered in detail in Chapter 6.14: Alcohol use 6.3-9

10 disorders and alcoholic liver disease and the accompanying background paper. Hence, this will not be addressed in this background paper. Table 6.3.2: Proportion of ischaemic heart disease DALYs attributable to individual risk factors, worldwide, Disability adjusted life-years (%) Physiological risk factors High blood pressure 53% High total cholesterol 29% High body-mass index 23% High fasting plasma glucose 16% Alcohol use 33% Tobacco smoking including second-hand 31% smoke Dietary risk factors and physical inactivity Diet low in nuts and seeds 40% Physical inactivity and low physical 31% activity Diet low in fruits 30% Diet low in seafood omega-3 fatty acids 22% Diet low in whole grains 17% Diet high in sodium 17% Diet high in processed meat 13% Diet low in vegetables 12% Diet low in fibre 11% Diet low in polyunsaturated fatty acids 9% Diet high in trans fatty acids 9% Diet high in sugar-sweetened beverages 2% Air pollution Ambient particulate matter pollution 22% Household air pollution from solid fuels 18% Other environmental risks Lead exposure 4% Source: Lim SS et al. Lancet, Summary: From the previously presented data, it is immediately apparent that CVD must be a priority for any attempt to reduce burden of disease at a global level and within Europe. The potential for public health benefit from the development of new or improved medical interventions to address the pandemic of CVD is incontrovertible. Not only would this have a major impact on Europe but would also potentially improve the lives of millions of patients in LMIC as well. The most significant contributors to IHD (and via extrapolation of other CVD) DALYs are amenable to pharmacological intervention i.e. the physiological risk factors and tobacco smoking. Despite much progress in the development of pharmaceutical

11 interventions to prevent CVD, there is significant opportunity to further invest in this area, as will be described in the remainder of this background paper. 3. What is the control strategy? Recommended strategies for prevention of CVD (both primary and secondary) can be categorized into lifestyle versus pharmacological interventions. Most attention in this chapter will focus on pharmaceutical interventions. 3.1 Lifestyle intervention Since most of the major risk factors for CVD are related to lifestyle; advocacy and promotion at the population and patient level to modify poor lifestyle choices will always be an important and critical method to reduce the burden of CVD. When adhered to by patients not only is it cost-effective but will always be more effective that simply directly recommending pharmaceutical therapy. Smoking cessation has been shown to significantly decrease the smoking-attributable risk of disease and CVD risk return to that of a nonsmoker within about five years. 12,13 Intuitively, modification of diet and activity levels will positively benefit an individual s cardiovascular risk factor profile. Physical activity and dietary modification have not only been shown to have a significant favourable effect on other major risk factors (including lipids, blood pressure and insulin resistance) but also to have an independent role in prevention of cardiovascular disease. 14,15,16,17,18 Taken in conjunction, data has shown that adherence to lifestyles guidelines advocating moderate physical activity, cardio-protective diet and abstinence from smoking can reduce the incidence of cardiovascular disease by more than 80% compared to the rest of the population. However, studies have shown that the general population nor (more surprisingly) people with established CVD typically adhere to these recommended guidelines. Recent data from the United States NHANES 2005 to 2010 study 19 showed that 22.6% of respondents were current smokers and 24.1% were former smokers. Thirty-two per cent did not engage in any physical activity with a further 23% only engaging in intermediate activity (better but still not reaching the ideal level of activity). A total of 77.7% of people surveyed scored less than two out of out on a healthy diet score that included consumption of fruit and vegetables, wholegrains, and fish, and limiting sugar and salt intake. These figures have not changed significantly since previous NHANES surveys. 19 It is not only the general population who are failing to follow lifestyle advice. The European Action on Secondary and Primary Prevention by Intervention to Reduce Events (EUROASPIRE) studies have completed three surveys on lifestyle and risk factor management in patients with coronary heart disease (CHD). 20,21,22 Each study recruited consecutive patients with first or recurrent diagnosis or treatment for CHD across multiple hospitals in nine to 22 countries and interviewed between six months and three years later to see how many were adhering to recommended lifestyle and treatment measures. Arguably this population should be the most motivated to apply and adhere to lifestyle guidelines, having already experienced CVD and being at high risk of a recurrent event. In the latest round of surveys in 2006 to 2007, the investigators found that 51.9% of smoking patients persisted after their event and only 51.8% of obese patients had followed dietary

12 recommendations to lose weight, with only 38.2% of obese patients increasing their regular physical activity. 22 Of the overall cohort, only 48% increased their overall physical activity. An impressive 92% of the cohort attempted to change their diet however this subjective reporting is undermined by the objective measures of obesity (35.3%) and central obesity (52.7%). Many of these high risk patients were not taking medicines that have been proven to prevent reoccurrence of cardiac events. The EUROASPIRE investigators also compared the results of the three different surveys to see if any improvements had been made over time. 23 Disappointingly, between the first and third surveys rates of smoking in younger female patients increased (despite an overall decrease in smoking) and prevalence of obesity increased by 13%. Raised blood pressure increased by 3.4% and reporting of diabetes mellitus increased by 9.3%. Full prevalence data for coronary heart disease risk factors in EUROASPIRE III are shown in Table 6.3.3: Prevalence (%) of coronary heart disease risk factors in EUROASPIRE III, by country, age and diagnostic category 22 Table 6.3.3: Prevalence (%) of coronary heart disease risk factors in EUROASPIRE III, by country, age and diagnostic category. Source: Kotseva K et al. Eur J Cardiovasc Prev Rehabil,

13 These data indicate that, despite public awareness campaigns and educational efforts, population based lifestyle change is not happening. Into this evidence-practice gap fits the opportunity for modification of CVD risk with pharmacological management. The role of cholesterol lowering therapy, blood pressure lowering therapy and anti-platelet therapy is now incontrovertible having been proven effective in large meta-analyses in all three medication categories. 3.2 Lipid-lowering therapy The role of lipids as a major risk factor for cardiovascular disease has been well established and has been estimated to cause approximately a third of global ischaemic heart disease. 24 Furthermore, the relationship between serum cholesterol and the risk of cardiovascular disease has been shown to be continuous 25,26 with no defined level below which a person can be considered to be at low risk. The discovery of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) has dramatically impacted the treatment of cardiovascular risk. Ongoing individual patient data meta-analyses by the Cholesterol Treatment Trialists (CTT) Collaboration of large scale clinical trials of statins have shown with standard statin regimes a consistent reduction in major vascular events over five years of around 20% per 1 mmol/l decrease in LDL regardless of baseline lipid levels or other patient characteristics. 27 This benefit is seen even in those at lowest baseline risk with demonstrated reduction in events greatly exceeding any known hazard of statin therapy. 28 This raises the possibility that indications for treatment, which are currently aimed at patients at high risk should possibly be widened to include those at 5 to 10% absolute cardiovascular risk over five years. 28 No level has been demonstrated below which reduction in LDL produces an increase in adverse events, demonstrating an acceptable safety profile for intensive treatment regimes capable of further LDL reductions. 29 The observed benefit from statins improves with the length of time taken with only a 10% decrease in events seen in the first year but up to 28% reduction in events by the third or fourth year. These estimates of benefit are in fact likely to be an underestimate of the true effect of long term benefit from statin therapy due to the problem of long term nonadherence by patients. Full compliance would achieve larger overall reductions in LDL, up to mmol/l predicted in some cases 30,31 which would result in closer to a one third reduction in vascular events overall. 27 In addition to statins role in reducing LDL cholesterol, fibrates (agonists of the peroxisome proliferator receptors selective for the α receptors - PPAR) have a clear role in raising HDL cholesterol and reducing triglyceride concentrations 32 and consequently have recently been shown in meta-analysis to be effective in reducing cardiovascular events in their own right primarily by preventing coronary events. 33 The relative risk reductions shown for fibrates (10% for major cardiovascular events, 13% for coronary events, no effect on stroke) are much less than for statins, however offer the potential for additive effects in risk reduction due to targeting of different cholesterol sub fractions and hence addressing the residual risk remaining after treatment with statins particularly those patients with combined dyslipidemia. Despite this, the potential for increased risk of side effects, in particular muscle damage (myopathy) when taken together with statins has somewhat limited concurrent use of these drugs together, in particular gemfibrozil

14 Ezetimibe is a newer lipid-lowering agent which inhibits cholesterol absorption from the gut available as monotherapy as well as combination therapy with simvastatin. Although shown to be effective in significantly lowering LDL cholesterol (including an extra 12 to 19% when coadministered with a statin 35,36 ), there is still controversy about its use with three separate trials showing paradoxical results in effect on carotid-artery intima-media thickness and also superficial femoral artery atherosclerosis. 37,38,39 Results from the ongoing IMPROVE-IT trial ( are required to determine the true value of ezetimibe in CVD prevention. Two other products of note are niacin and omega-3 fatty acids. Despite marketing approval for nicotinic acid/laropiprant (niacin) being granted in 2008 by the European Medicines Agency to treat adults with dyslipidemia, this approval was suspended in January, following the preliminary reporting of the HPS2-THRIVE study s ( primary outcome and safety data which showed no advantage of niacin in addition to statins on the outcome of CVD events and an increase in non-fatal but serious side effects. Omega-3 fatty acids have received widespread publicity and now represent a multi-million dollar industry due to positive findings in prevention of CVD in early trials. Later trials however produced conflicting results. A recent systematic review and meta-analysis 41 did find a significant effect of omega-3 fatty acids on vascular death (RR 0.86, ) however no significant effect on all other outcomes studied (it was noted that there was significant heterogeneity between the trials which may have impacted the overall results). The authors concluded that although there does seem to be a positive effect on some cardiovascular outcomes, perhaps the public and physician s expectations of the true benefit should be lowered somewhat. 3.3 Blood pressure lowering therapy Suboptimal blood pressure (systolic >115 mmhg) has been estimated to account for about 62% of global cerebrovascular disease and 49% of ischaemic heart disease globally. 42 The majority of adult blood pressures are this category, and only about half of the attributable burden occurs among those with hypertension. This is true for both developing and developed countries although in developed regions blood pressure levels are particularly high. 11 Major prospective observational studies have shown conclusively that blood pressure (both diastolic and systolic) has a continuous, independent relationship with the risk of cardiovascular disease. 43,44,45 Evidence for the effectiveness of blood pressure lowering therapies 43,46,47 has led to a plethora of such drugs in multiple classes. All commonly used regimens (including ACE inhibitors, calcium channel antagonists, diuretics and beta blockers) have been shown to reduce cardiovascular risk similarly with larger reductions in blood pressure producing larger reductions in risk. 46 As is the case for cholesterol lowering, an approximately consistent proportional difference in CV risk (35 to 40% for stroke and 20 to 25% coronary heart disease) is associated with each given absolute reduction in blood pressure (5-6 mmhg of diastolic blood pressure) regardless of the BP at baseline. 43 It follows then that if the size of the absolute risk reduction is related to baseline untreated risk, then the greatest risk reductions occur in those whose baseline risk is highest. 47 In Europe, although no particular medication class is recommended for treatment of uncomplicated high blood pressure, certain classes have been recommended in certain clinical conditions (Table 6.3.4) 48 and new guidelines are in development

15 Table 6.3.4: Position statement: Antihypertensive treatment: Preferred drugs. European Society of Hypertension and European Society of Cardiology. Subclinical organ damage Preferred drugs LVH ACEI, CA, ARB Asymptomatic atherosclerosis CA, ACEI Microalbuminuria ACEI, ARB Renal dysfunction ACEI, ARB Clinical event Previous stroke any BP lowering agent Previous MI BB, ACEI, ARB Angina pectoris BB, CA Heart failure diuretics, BB, ACEI, ARB, antialdosterone agents Atrial fibrillation Recurrent ARB, ACEI Permanent BB, non-dihydropiridine CA ESRD/proteinuria ACEI, ARB, loop diuretics Peripheral artery disease CA Condition ISH (elderly) diuretics, CA Metabolic syndrome ACEI, ARB, CA Diabetes mellitus ACEI, ARB Pregnancy CA, methyldopa, BB Blacks diuretics, CA Abbreviations: LVH: left ventricular hypertrophy; ISH: isolated systolic hypertension; ESRD: renal failure; ACEI: ACE inhibitors; ARB: angiotensin receptor antagonists; CA: calcium antagonists; BB: β-blockers Source: Mancia G, et al. J Hypertens, Combination therapy for lowering blood pressure Hypertension management strategies, such as those endorsed by most practice guidelines including the European Society of Hypertension 49 have traditionally focussed on tailored therapy and stepped-care approaches. These tend to be time consuming for doctor and patient, only cautiously recognise that contemporary BP targets almost always necessitate additional medication and ignore the auto-regulatory mechanisms that limit responsiveness to a single drug administered alone Evidence on potential benefits of regimen simplification and use of twodrug combination pills Most patients with hypertension require BP lowering medication from two or more classes to achieve adequate control. 50 The need for titration of medication and addition of multiple classes of drug requires multiple physician visits and this in itself triggers poor adherence to prescribed medication and poor attendance at scheduled visits. 51 The requirement to take multiple medications in complex regimes also results in poor adherence. 52 For physicians, the need for repeated up-titrating or adding extra medications can lead to inertia and complicit

16 acceptance of inadequate BP control. 53,54 Dual combination BP lowering medication has been shown to improve achieved BP reductions as well as cardiovascular event rates. 55 Initiating anti-hypertensive treatment with dual combination therapy not only accelerates the time taken to achieve control but also attains a lower final target. 56,57 For the patient, improved adherence has also been demonstrated without adversely affecting the side effect profile Further benefits in BP control are also available via simplifying up-titration regimes Evidence on hypertension combination pills containing more than two medications There are sound pharmacological principles to expect the maximum benefit to side effect ratio from low-dose triple combinations. 59,60,61 In short, benefits of each component are additive, and low doses typically avoid most side effects while achieving most blood pressure reduction. Thus for example, three half-dose medications would typically lower blood pressure about as much as two full-dose medications, but with fewer side effects. 59 A number of important questions however remain to be answered. The triple BP lowering pills that have recently become available in western countries, have focussed exclusively on severe hypertension that remains uncontrolled with full dose dual combination therapy. Furthermore, previous trials have been within the mode of traditional stepped care, and have not tested the integration of a low-dose triple combination within a simplified regimen. For example, the recent trial of Exforge 62 involved patients with baseline BP of mmhg, randomised to receive five weeks of treatment with amlodipine valsartan HCTZ mg or one of the three dual therapies indicated previously herein. Perhaps unsurprisingly, this trial showed that patients on triple therapy achieved better BP reductions than patients on dual combination therapy. To date no clinical trial has tested the benefits or cost-effectiveness of combination therapy with three, low dose BP lowering drugs in hypertension. One such trial, the TRIUMPH (TRIple Pill versus Usual care Management for Patients with mild-to-moderate Hypertension) study ( a 700 patient randomised controlled trial of a triple low dose blood pressure lowering pill versus usual care is currently starting up in India with the aim of answering these questions. 3.4 Anti-platelet therapy A meta-analysis by the Antithrombotic Trialists Collaboration in showed that use of antiplatelet agents (primarily aspirin) in patients at high risk due to a pre-existing occlusion or predisposing condition, decreased the occurrence of serious vascular events by one quarter, with a third reduction in non-fatal myocardial infarction (MI) and a quarter reduction in non-fatal stroke. Vascular mortality overall was decreased by one sixth. They concluded that the absolute benefits of antiplatelet therapy substantially outweighed the absolute risks of major extra-cranial bleeding in patients with vascular disease. The balance of benefits and risks is less clear in lower risk populations, and conclusions have been hampered by not recognising the heterogeneity of this primary prevention population. A more detailed meta-analysis by the Antithrombotic Trialists Collaboration stratified results by estimated cardiovascular risk, and showed that even in medium risk population the number of excess haemorrhagic events (mostly gastrointestinal) was broadly similar to the

17 number of major vascular events prevented. 64 However, further modelling and research is required to determine appropriate patient populations, given the emerging evidence showing that aspirin reduces the risk of several major cancers, 65 and the changing background rates of gastrointestinal haemorrhage and vascular events. Clopidogrel is the next most commonly used anti-platelet agent, and has similar efficacy to aspirin. 63 Clopidogrel confers additional benefit when added to aspirin treatment in ST elevation myocardial infarction (RRR 9%, 3-14) 66, non-st elevation myocardial infarction (RRR 20%, 10 28) 67 and long-term following percutaneous coronary intervention (RRR 26.9%, ). 68 Prior to coming off patent in May 2012, opinions varied as to the costeffectiveness of clopidogrel compared to aspirin, 69,70 and LMIC cost almost certainly would have limited its use significantly. However, now that generic clopidogrel is becoming available, its use in prevention of CVD is likely to increase. 4. Why does the disease burden persist? 4.1 Non-optimal use of existing effective medications Despite large-scale clinical trial/meta-analyses having demonstrated substantial reductions in the risks of cardiovascular events with antiplatelet, 63 blood pressure lowering 46 and cholesterol lowering therapy 71 in patients with established CVD and those at high calculated risk of CVD current treatment gaps among this patient group are very large. Despite the majority of people with established CVD in high income countries being started on recommended medications, significant numbers of people in high income countries 23,72,73 and even larger numbers in low and lower middle income countries do not either receive or remain adherent to these treatments long-term. 74,75,76 (Figure 6.3.4) Within Europe, the EUROASPIRE III study 22 showed that the majority of coronary patients that required BP lowering and lipid lowering medications were not receiving them on a long-term basis and if patients were receiving them, they were not reaching their BP and lipid targets (Table 6.3.5) suggesting either poor adherence by the patient or insufficient titration by physicians

18 Figure 6.3.4: PURE study: Number of drugs taken by individuals with established cardiovascular or cerebrovascular disease by country economic status. Source: Yusuf S, et al. Lancet For coronary heart disease (A), drugs counted were aspirin, β blockers, ACE inhibitors or ARBs, or statins. For stroke (B), drugs counted were aspirin, statins, ACE inhibitors or ARBs, or other bloodpressure-lowering drugs (e.g., β blockers, diuretics, and calcium-channel blockers). ACE=angiotensinconverting enzyme. ARB=angiotensin-receptor blocker. 76 Table 6.3.5: Percentage of patients reaching BP and lipid targets in EUROASPIRE III Reaching Target (%) On BP lowering medication 43.9 Not on BP lowering medication 48.3 On lipid lowering medication 55.0 Not on lipid lowering medication 25.4 Source: Kotseva K et al. Eur J Cardiovasc Prev Rehabil, Various factors may underlie the suboptimal treatment of high risk patients, such as the need to navigate complex guidelines by doctors, low continuation rates by patients, inequities in health care and resistance to costs by both doctors and patients. Non-adherence to therapy is one of the main obstacles for the unsatisfactory reduction of risk factors, particularly in developed countries. It is characterized by the premature cessation of treatment together with suboptimal use of medication, and is correlated with an increased risk of mortality. 77 Non-adherence is especially relevant in chronic, asymptomatic diseases as cessation of treatment does not lead to symptoms in patients but they remain at high risk of serious micro- and macrovascular complications in the case of atherosclerotic cardiovascular diseases. Patients often do not understand the importance of taking long-term medication for chronic diseases, particularly those that are generally symptom-free. Reported long-term adherence is low with only 70% adherence to aspirin therapy and only 45% to lipid- and BP

19 lowering therapy after 12 months. 78 The main determinants of non-adherence are multiple medications with complex dosing regimens, inadequate knowledge about the medications and cost. 79,80,81,82,83 Increasing age, established cardiovascular disease and/or type 2 diabetes usually indicate the usage of more than five drugs per day (polypharmacy). 84 Treating high risk patients often requires polypharmacy even though this is known to be associated with patients non-adherence, inadequate prescription of medication by doctors and drug interactions. Therefore the complexity of the prevention of cardiovascular diseases requires simplicity. The lack of affordability of therapy largely affects treatment gaps in developing countries since in developing countries most healthcare services are paid for out-of-pocket with little or no subsidy through health insurance or the government. The economic burden of secondary prevention of cardiovascular diseases is enormous, especially among the rural and urban citizens. As a month s treatment costs ranges from 1 to 18 days wages of government workers, preventive drugs are unaffordable for the majority of individuals in developing countries. 85,86 Patients can delay or omit drug doses and not fill prescriptions as strategies for cost reduction. Though the efficacy of preventive strategies may be proven and recognized at a high level, supply and access at the population level remains the major challenge. Practical and affordable approaches to closing these treatment gaps are required. Combination pills or polypills may play a role in closing these treatment gaps in ischaemic and cerebrovascular disease, and their use has been advocated for almost a decade. 87,88,89 Reducing the complexity, number and costs of medication regimens with a polypill containing off patent generic medicines will potentially improve adherence and hence reduce cardiovascular events. 4.2 New innovative therapies Further research into new, innovative therapies for the prevention and treatment of CVD is ongoing particularly amongst the larger pharmaceutical companies. Advancements in the knowledge of the pathophysiology and underlying determinants of the various types of CVD (including advances in genomics and targeted population groups) are constantly opening up new lines of enquiry into the possibility for a newer drug that may perhaps target a more specific mechanism or a targeted clinical population which, when added to the currently available medication options, may offer increased prevention or treatment for CVD. There is clearly a need for development of new medication types as even if all of the previously mentioned available therapies are utilized maximally, patients still have a residual risk of CVD. The reality though is that development of a new drug costs well over a billion US dollars. This scope of research is well outside any publically funded research scheme and therefore will not be addressed in this background paper. Although new innovative therapies are potentially worthwhile, the most cost-effective measure for preventing CVD currently is improving access and adherence to currently available, generic medications

20 5. What can be learnt from past/current research into pharmaceutical interventions for this condition? Research over the last half century involving hundreds of thousands of patients in clinical trials has provided an enormous body of evidence on the efficacy and safety of different blood pressure lowering, statin and antiplatelet agents in the control of cardiovascular disease. 88,89 The large majority of these trials were designed to assess the effects of individual medicines given the understandable clinical, regulatory and commercial requirements to assess the benefits and risks of specific drugs before access and uptake in the market. Hence trials typically involved randomization of a single agent versus placebo, on top of a background of usual care treatments at that time. Systematic reviews of these trials reveal an overall finding of broad relevance to clinical and public health practice, and to development of polypills: an approximate constancy of relative risk reduction (i.e. lack of interaction or effect modification) of each modality (BP lowering, cholesterol lowering and anti-platelet effect), irrespective of whether the other modality is present or absent. 31,90,91 More specifically, these systematic reviews of clinical trials have shown that proportional reductions in causespecific outcomes (such as CVD mortality) are closely similar across a wide range of patient populations, with no major differences between agents (after accounting for the extent of risk factor reduction for SBP and LDL) and even when event rates vary tenfold or more.for example, aspirin produces a one-fifth reduction in CHD and ischaemic stroke risk in primary and secondary prevention, even though event rates differ by an order of magnitude. There is clear evidence that the proportional reductions in major outcomes achieved with each treatment modality are approximately the same in the presence or absence of other interventions and across a range of risk factor levels which is expected given the lack of interaction between treatments in terms of risk factor reduction and the epidemiology of blood pressure and cholesterol joint effects this is outlined in Figures and Given this consistency in proportional reductions, it is an expectation that combination therapy will have beneficial effects. More specifically, the combined effects are best estimated by multiplying relative risks together, after adjusting for the size of SBP and LDL-cholesterol reductions

21 Figure 6.3.5: Reduction in vascular events with a statin in the Heart Protection Study 92 and reduction in stroke events with blood pressure lowering in the PROGRESS study 93 by concomitant treatments and other factors Source: Heart Protection Study Collaborative Group. Lancet, 2002 Progress Collaborative Group. Lancet, 2001 Figure 6.3.6: Reduction of serious vascular events with aspirin, by blood pressure and cholesterol levels Source: Baigent C et al. Lancet,

22 The concept of combining multiple classes of cardiovascular medications into a single pill also has a long history for example, the term asp-olol was coined for an aspirin and atenolol combination in the 1970 s. Patents claiming rights over combinations of various cardiovascular medications had been filed since the late 1990s (for example 94,95,96 ). The first major scientific meeting on the concept of a fixed dose combination pill for CVD prevention was held in 2001, when the World Health Organization and the Wellcome Trust convened a meeting of experts to discuss evidence-based and affordable interventions for noncommunicable diseases. 87 A major impetus for the meeting was the potential for fixed-dose combination pills containing aspirin, statin, and BP-lowering agents, noting the use of a single pill could well encourage patients to adhere to treatment as well as seriously reduce the cost of the drugs. In the medical literature, the concept of a fixed-dosed combination pill was discussed by Yusuf in a Lancet editorial in and effectiveness and cost-effectiveness analyses were conducted in the 2002 World Health Report. 97 The term polypill itself was introduced with the publication of the Wald and Law s seminal paper in Wald and Law estimated that the use of a single pill (containing aspirin, a statin, three BP-lowering drugs, and folic acid) in all people aged over 55 years would reduce cardiovascular disease by more than 80%. Over the ensuing decade several clinical trials in the area of fixed dose combination pills have been conducted. These trials can be broadly grouped into two main areas: - Comparisons of polypill versus usual care - in patient populations with established indications for all the component medications e.g. previous coronary disease - Comparisons of polypill versus placebo/no treatment - in patient populations with established indications for none of the component medications e.g. those without hypertension, dyslipidaemia or vascular disease but who are nonetheless at raised cardiovascular risk The 2004 Priority Medicines for Europe and the World Report 1 and its recommendation to prioritize research into fixed dose combinations for the secondary prevention of CVD led to the European Commission funding of the largest Request for Proposal in this area, and hence two of the largest polypill trials: the Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial 98 and the Fixed Dose Combination Drug for secondary Cardiovascular prevention (FOCUS) trial 99 and these will be discussed following a review of other trials. While many of the patients involved in these trials suffered from IHD, some of the patients included were suffering from cerebrovascular disease. 5.1 Previous trials polypill versus placebo or no treatment These trials are summarized in Annex and main outcomes in Annex Summary of TIPS 1 and 2 The Indian Polycap Study (TIPS) 100 was a randomised, partial factorial design trial of Polycap versus eight other medication combinations including aspirin alone, simvastatin alone and different combinations of hydrochlorothiazide, ramipril, and atenolol (see reference 100) for details of various combinations). Over two-thousand participants with at least one risk factor for CVD (such as hypertension, diabetes, current smoker, raised lipids or raised waist: hip ratio) were randomly allocated to one of the nine groups and followed up for 12 weeks. Outcomes included effect on blood pressure, heart rate, lipids and urine

23 thromboxane B2 as well as safety and tolerability. The study showed that the BP lowering effect of the Polycap was comparable to the additive effects of each of the three component BP lowering drugs. A lesser effect on LDL cholesterol than simvastatin alone was noted (0.13 mmol/l) which was significant. Mean changes in blood pressure and LDL are shown in Figure below. Figure 6.3.7: Mean changes in blood pressure and LDL in the TIPS study Source: The Indian Polycap Study (TIPS). Lancet, 2009 Error bars indicate 95% CI. Mean changes from baseline in the nine groups in the TIPS trial, and the effects of no blood-pressure-lowering drugs (As, S), one blood-pressure-lowering drug (T), two bloodpressure-lowering drugs (T+R, T+At, or R+At), or three blood-pressure-lowering drugs (T+R+At, T+R+At+S), or the Polycap (P) Summary of Wald and Law trial Wald and Law 101 conducted a randomised, double-blind, cross-over trial of the polypill studied containing three half-dose BP lowering medications and a statin in 86 participants over the age of 50 with no history of CVD. Each participant took placebo or polypill for 12 weeks sequentially. Mean systolic blood pressure was reduced by 17.9 mmhg (95% CI, ) on a polypill, diastolic blood pressure by 9.8 mmhg ( ), and LDL cholesterol by 1.4 mmol/l ( ), reductions of 12%, 11%, and 39% respectively (Figure 6.3.8). These results were almost identical to those predicted from previous trials of individual components. This trial is in effect a large Phase 1 study of the polypills efficacy in patients without cardiovascular disease

24 Figure 6.3.8: Observed and expected reduction of blood pressure and LDL-cholesterol in a 2x12 week crossover trial. 101 Source: Wald DS, et al. PLoS ONE, PILL Collaborative Group The Pill Pilot study 102 was a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated five year cardiovascular disease risk over 7.5%. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmhg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/l

25 LDL (mmol/l) Blood pressure (mmhg) Update on 2004 Background Paper, BP 6.3 Cardiovascular Disease Figure 6.3.9: Change in BP and LDL cholesterol at 12 weeks in the Pill Pilot study ΔSBP 9.9 mmhg ( ) ΔDBP 5.3 mmhg ( ) Follow-up (weeks) ΔLDL-cholesterol 0.8 mmol/l ( ) Follow-up (weeks) Source: Pill Collaborative Group, Rodgers A, et al. PloS one, Other trials Two other trials have been conducted however have significant issues associated with them meaning that their results must be interpreted very cautiously. Malekzadeh et al 103 conducted a double-blind randomized, placebo controlled trial in Iran in 475 participants over 50 years without CVD. They found a small but significant different in SBP at 12 months (4.5/1.6 mmhg) as well as LDL cholesterol (0.46 mol/l) however a significant difference of 6 mmhg of SBP at baseline between the two groups infers failure of the randomization process. Furthermore, the less than expected effects of the polypill on their outcomes raises concern about the reliability of reported compliance with medication. Soliman et al 104 reported on an open-label, randomized controlled trial of a polypill versus usual care in 216 patients without CVD. No significant difference was found in SBP or total cholesterol after three months which was presumed by the authors to be due to the usual care arm receiving a higher than usual standard of care during the trial than would occur in usual practice. Further, larger than expected reductions in risk factors (e.g. for SBP a decrease

26 of 28.8 mmhg versus 26.9 mmhg in usual care) also raised concerns about standardization of measurement of risk factors. For the above mentioned reasons, these two studies are not generally considered to be reliable representations of the true effect of polypill care Conclusions from previous trials of polypill versus placebo or no treatment The key conclusions from the previous trials of polypill versus placebo/no treatment are that short term risk factor reductions are of approximately the size expected from individual agents, after taking into account loss to follow-up and non-adherence. The size of the underestimation due to loss to follow-up and non-adherence was very small in some trials (Wald et al, Pill Collaborative Group) and very large in others (Iranian Trial, Sri Lanka trial), with consequent differences in the observed to expected risk factor reductions. The trials provided relatively few data on side effects and tolerability but overall these were consistent with effects known from the separate medications. There were no reliable data on long-term risk factor reductions or cardiovascular outcomes though these would not be expected in such short term small studies. 5.2 Ongoing trials polypill versus placebo Several large scale randomized trials have commenced (Annex 6.3.7) which aim to address the question of the effect of a polypill on CVD outcomes (in particular CVD events) in primary prevention. This is a patient population in which perhaps use of a polypill may be considered more controversial as some may argue that the benefits of treatment may not outweigh the risks of treating such patients (particularly in relation to the use of aspirin). Three trials are recruiting/following-up patients who are at moderate risk of CVD in large scale, long-term trials which are powered to assess the risk-benefit ratio of polypills in primary prevention and particularly the effect on CVD events. The results of these trials will also give an indication of the effect of a polypill on adherence over time in a group of patients who, being asymptomatic without a diagnosis of CVD, may well be less inclined to be adherent to preventive medication. 5.3 Previous trials polypill versus usual care FP7-funded UMPIRE trial The Use of a Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial aimed to assess whether a polypill-based strategy for delivery of medications (aspirin, statin and two blood pressure lowering agents) compared to usual care would improve long-term adherence to guideline-indicated therapy, systolic blood pressure (SBP) and low density lipoprotein (LDL)-cholesterol in people with CVD or at similarly high risk. The trial was a prospective, randomized, open-label, blinded-endpoint (PROBE) clinical trial among 2004 participants from India and Europe. The main eligibility criteria were established CVD or an estimated five-year CVD risk of 15%. Participants were randomly assigned (1:1) to a fixeddose combination POLYPILL-based strategy or usual care. In the POLYPILL group, physicians could use a POLYPILL that contained aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and atenolol 50 mg or one containing aspirin 75 mg, simvastatin 40 mg, lisinopril 10 mg and hydrochlorothiazide 12.5 mg. In the usual care group, treatment continued

27 A n t i p l a t e l e t d r u g ( % ) 2 o r m o r e B P - l o w e r i n g d r u g s ( % ) I n d i c a t e d m e d i c a t i o n s ( % S t a t i n ( % ) Update on 2004 Background Paper, BP 6.3 Cardiovascular Disease according to physician discretion. Adherence to medication (defined as self-reported use of antiplatelet, statin and 2 BP-lowering medications) and changes in SBP and LDL-cholesterol from baseline were the main outcomes. At baseline, mean blood pressure was 137/78 mmhg, LDL-cholesterol was 91.5 mg/dl and 1233/2004 (61.5%) participants reported use of antiplatelet, statin and 2 BP lowering medications. Full baseline characteristics are provided in Annex Median follow-up was 15 months. Allocation to the POLYPILL group improved adherence by one-third (RR 1.33, [95% CI 1.26, 1.41] p<0.0001), with reductions in SBP (-2.6 mmhg [95% CI -4.0, -1.1] p=0.0005) and LDL-cholesterol (-0.11 mmol/l [95% CI -0.17, -0.05] p=0.0005) that which corresponds to 4.6 patients needing to be treated with the polypill in order to gain one additional adherent patient. These results are shown in Figure Figure 6.3.9: Adherence to indicated medications by treatment group over follow-up in the FP7-funded UMPIRE trial F D C 1 0 U s u a l c a r e ( 9 5 % C I ; ), p < B a s e lin e M6 M 1 2 M 1 8 M / / / / / / / / / / F D C U s u a l c a r e 0 B a s e lin e M6 M 1 2 M 1 8 M / / / / / / / / / / F D C U s u a l c a r e F D C U s u a l c a r e 0 B a s e lin e M6 M 1 2 M 1 8 M / / / / / / / / / /3 6 0 B a s e lin e M6 M 1 2 M 1 8 M / / / / / / / / / /3 6 Source: personal communication, S Thom Legend: Figure shows overall adherence (panel A), statin (panel B), antiplatelet drug (panel C), and 2 BP lowering drugs (panel D) by follow-up time in the POLYPILL and usual care groups. M6-M24 are visits at months six to

28 Figure : Systolic blood pressure and LDL-cholesterol by treatment group over follow-up in the FP7-funded UMPIRE trial Source: personal communication, S Thom Legend: Systolic blood pressure (panel A) and LDL-cholesterol (panel B) values shown at baseline, during follow-up and at end of study (EOS) in the polypill and usual care groups. There was broad consistency of effects across pre-defined subgroups including cardiovascular history, gender, smoking status, diabetic status, region (Western Europe versus India) and choice of POLYPILL. In addition, there was consistent evidence of larger benefits among patients with lower adherence at baseline i.e. those who were not already receiving antiplatelet, statin and two blood pressure drugs at baseline (Table 6.3.6). It should be noted that the adherence rates of the non POLYPILL control patients was high as compared to the results of normal care as reported in the EUROASPIRE studies described above. Table 6.3.6: Primary outcomes in UMPIRE trial, according to baseline adherence Outcome Mean difference and 95% CI, polypill versus usual care Adherent* at Not adherent* at baseline baseline p-value for heterogeneity Adherence* (relative risk) 1.04 (1.01,1.08) 3.35 (2.74, 4.09) <0.001 Systolic BP (mmhg) -1.0 (-2.9, 0.8) -4.9 (-7.3,-2.6) 0.01 LDL cholesterol (mmol/l) (-0.15, 0.01) (-0.27, -0.07) 0.1 Source: personal communication, S Thom * defined as taking statin, antiplatelet and two or more blood pressure lowering agents