BMJ  2003;326:1419 (28 June), doi:10.1136/bmj.326.7404.1419

Paper

A strategy to reduce cardiovascular disease by more than 80%

¹ Department of Environmental and Preventive Medicine, Wolfson Institute of Preventive Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London EC1M 6BQ

Abstract

Objectives To determine the combination of drugs and vitamins, and their doses, for use in a single daily pill to achieve a large effect in preventing cardiovascular disease with minimal adverse effects. The strategy was to simultaneously reduce four cardiovascular risk factors (low density lipoprotein cholesterol, blood pressure, serum homocysteine, and platelet function) regardless of pretreatment levels.

Design We quantified the efficacy and adverse effects of the proposed formulation from published meta-analyses of randomised trials and cohort studies and a meta-analysis of 15 trials of low dose (50-125 mg/day) aspirin.

Outcome measures Proportional reduction in ischaemic heart disease (IHD) events and strokes; life years gained; and prevalence of adverse effects.

Results The formulation which met our objectives was: a statin (for example, atorvastatin (daily dose 10 mg) or simvastatin (40 mg)); three blood pressure lowering drugs (for example, a thiazide, a blocker, and an angiotensin converting enzyme inhibitor), each at half standard dose; folic acid (0.8 mg); and aspirin (75 mg). We estimate that the combination (which we call the Polypill) reduces IHD events by 88% (95% confidence interval 84% to 91%) and stroke by 80% (71% to 87%). One third of people taking this pill from age 55 would benefit, gaining on average about 11 years of life free from an IHD event or stroke. Summing the adverse effects of the components observed in randomised trials shows that the Polypill would cause symptoms in 8-15% of people (depending on the precise formulation).

Conclusion The Polypill strategy could largely prevent heart attacks and stroke if taken by everyone aged 55 and older and everyone with existing cardiovascular disease. It would be acceptably safe and with widespread use would have a greater impact on the prevention of disease in the Western world than any other single intervention.

Introduction

Heart attacks, stroke, and other preventable cardiovascular diseases kill or seriously affect half the population of Britain. Randomised trials show that drugs to lower three risk factors—low density lipoprotein (LDL) cholesterol,¹ blood pressure,^2–6 and platelet function (with aspirin)^{7 8}—reduce the incidence of ischaemic heart disease (IHD) events and stroke. Evidence that lowering serum homocysteine (with folic acid) reduces the risk of these diseases is largely observational but still compelling.^{9 10}

Drug treatment to prevent IHD events and stroke has generally been limited to single risk factors, to targeting the minority of patients with values in the tail of the risk factor distribution, and to reducing the risk factors to "average" population values. This policy can achieve only modest reductions in disease.¹¹ A large preventive effect would require intervention in everyone at increased risk irrespective of the risk factor levels; intervention on several reversible causal risk factors together; and reducing these risk factors by as much as possible.¹¹

We describe a strategy to prevent cardiovascular disease based on these three principles¹²: a daily treatment, the Polypill, containing six components, each lowering one of the above four risk factors. We also quantify its overall preventive effect. The pill would be suitable for people with cardiovascular disease and for everyone over a specified age (say 55).

Methods

We identified categories of drugs or vitamins used to modify LDL cholesterol, blood pressure, homocysteine, and platelet function. For LDL cholesterol, statins are the drugs of choice.^{1 13 14} For lowering blood pressure, we considered all five main categories of drugs: thiazides, blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and calcium channel blockers.¹³ Serum homocysteine is most effectively reduced by folic acid.¹⁵ Aspirin is the most widely used and least expensive antiplatelet agent.

The choices of statin and of the categories and doses of blood pressure lowering drugs were determined from the meta-analysis of short term randomised trials in our companion papers.^{1 16} The dose of folic acid was the minimum needed to ensure the maximum reduction in serum homocysteine.^{15 17} The long term effect of a specified absolute reduction in LDL cholesterol, blood pressure, and homocysteine expressed as the proportional reduction in the incidence of IHD events and stroke was based on systematic reviews of cohort studies.^{1 9 14 18} Both cohort studies and trials have shown that a specified reduction in blood pressure or serum cholesterol produces a constant proportional reduction in risk that is independent of the initial value of the risk factor.^{1 3 4 11 14} The average age at which cardiovascular event occurred in the studies was around 60-65 years.

We used direct evidence from randomised trials of the effects of low dose aspirin on disease events. Since the necessary information on stroke and adverse effects was not available from published meta-analyses, we conducted one. We identified trials of ≥ 6 months' duration from previous meta-analyses,^{7 8} from Medline, and the Cochrane Collaboration and Web of Science databases. This yielded 15 trials. We determined the average proportional reduction in IHD events and stroke, and the prevalence and incidence of adverse effects.

We calculated the combined effect of changing the four risk factors (the effect of the Polypill) by multiplying the relative risks associated with each. Using a simple Markov model, we calculated the years of life gained without a heart attack or stroke if people without a previous cardiovascular event used the Polypill from age 55.

Results

Efficacy
Table 1 shows the effects of the individual agents. By use of statins, LDL cholesterol concentration can be reduced by an average of 1.8 mmol/l. Atorvastatin 10 mg taken at any time of day or simvastatin (or lovastatin) 40 mg taken in the evening or 80 mg taken in the morning after about two years of treatment can reduce the incidence of IHD events at age 60 by an estimated 61%.¹ The overall reduction in stroke from an LDL cholesterol reduction of 1.8 mmol/l is about 17%.¹

View this table: [in this window] [in a new window]   Table 1 Effects of the Polypill on the risks of ischaemic heart disease (IHD) and stroke after two years of treatment at age 55-64

 

The five main categories of blood pressure lowering drugs (thiazide, blockers, ACE inhibitors, angiotensin II receptor antagonists, and calcium channel blockers), and the individual drugs within the categories, produce similar reductions in blood pressure, given dose as a ratio of standard dose.¹⁶ A combination of three drugs from different categories in low dose has greater efficacy and fewer adverse effects than using one or two drugs in standard dose.¹⁶ The blood pressure reduction with three drugs in combination at half standard dose is about 11 mm Hg diastolic, reducing the incidence of IHD events by 46% and stroke by 63%.^{16 17}

The maximum effect of folic acid, achieved at a dose of about 0.8 mg/day,^{15 18} lowers serum homocysteine by 3 µmol/l (about 25%) and reduces IHD events by about 16% and stroke by 24%.⁹

Figure 1 shows our meta-analysis of the 15 randomised trials of low dose aspirin (50-125 mg/day). IHD events were reduced by 32% and strokes by 16% (details in web table A).

View larger version (22K): [in this window] [in a new window]   Fig 1 Relative risks (95% confidence intervals) of ischaemic heart disease events and all strokes (fatal and non-fatal) in 15 randomised trials of low dose aspirin

 

Table 1 shows that changing all four risk factors together reduces the risk of IHD events by 88% and stroke by 80%. These results are obtained by multiplying the relative risk estimates relating to the intervention on each risk factor, which is the complement of the proportion of events prevented; thus, preventing, say, 61% is equivalent to a relative risk of 0.39. The following example illustrates the calculation. The relative risks of an IHD event for the four interventions in table 1 are 0.39, 0.54, 0.84, and 0.66, the product of which yields a combined relative risk of 0.12 or an 88% preventive effect (if 100 people who would have had IHD events without intervention were treated, statins would prevent 61 of the 100 events, leaving 39; 46% of these would be prevented with blood pressure lowering drugs, leaving 21; 16% of these would be prevented with folic acid, leaving 18; and 34% of these would be prevented with aspirin, leaving 12; 88% have thus been prevented). Reducing one risk factor has a similar proportional effect on risk irrespective of the level of other risk factors, as confirmed by cohort studies and randomised trials.^19–22 For example, trials of LDL cholesterol reduction show similar proportional reductions in risk in people with high and low blood pressure and in people taking and not taking aspirin.^{20 21}

Other than the statin (in respect of IDH), omitting a single component has a relatively minor impact on the combined effect of the residual components, illustrating the robustness of the Polypill concept. Compared with the reductions in IHD events and stroke of 88% and 80% respectively with all six components, the reductions were 86% and 74% without folic acid, 85% and 73% without one blood pressure lowering drug (two instead of three), and 83% and 77% without aspirin. So, for example, aspirin prevents 32% of IHD events when used alone but prevents only an additional 5% of the original number of expected events when added to the other components in the combination.

Table 2 shows the expected proportion of people who would avoid an IHD event or stroke by taking the Polypill from age 55 and, in those, the average number of event-free life years gained. The estimates take account of deaths from causes other than IHD and stroke. About a third of people taking the Polypill would benefit. On average each will gain 11-12 years of life free from a heart attack or stroke. The gain in life is substantial at all ages.

View this table: [in this window] [in a new window]   Table 2 Expected benefits in 100 men and 100 women without a known vascular disease who start taking the Polypill at age 55. Calculations are based on a Markov model and allow for other causes of death

 

Adverse effects
See bmj.com for a table of the extracranial adverse effects of low dose aspirin from our meta-analysis of 15 randomised trials. Table 3 uses these data together with those published in our companion papers^{1 16} to show the proportions of people reporting symptoms attributable to any of the components of the Polypill (percentage with symptoms in treated groups minus percentage in placebo groups in trials). If we included the three classes of blood pressure lowering drugs with the lowest prevalence of adverse effects (thiazide, angiotensin II receptor antagonist, and calcium channel blocker¹⁶) in a Polypill formulation, 8% would be expected to have symptoms attributable to one or more of the six components of the pill, mostly due to aspirin. If we used the three least expensive blood pressure lowering drugs (a thiazide, a blocker, and an ACE inhibitor) instead, a Polypill including these would cause symptoms in about 15% of people taking the pill.

View this table: [in this window] [in a new window]   Table 3 Prevalence of participants in randomised trials reporting symptoms attributable to the Polypill components (in doses specified in table 1)

 

Of all the components, aspirin has the most serious adverse effects, mainly due to haemorrhage (see tables on bmj.com). In our meta-analysis of the trials of low dose aspirin the increase in haemorrhagic stroke (table A on bmj.com) was exceeded by the reduction in thrombotic strokes, producing an overall 16% reduction in stroke. There was no excess risk of fatal extracranial haemorrhage, with 13 and 15 deaths in the aspirin and placebo groups respectively in about 17 000 people in each (table B on bmj.com), and an excess risk of major non-fatal extracranial haemorrhage (mainly gastric) of 1.2 per 1000 person years (tables on bmj.com).

Discussion

The Polypill strategy, based on a single daily pill containing six components as specified, would prevent 88% of heart attacks and 80% of strokes. About 1 in 3 people would directly benefit, each on average gaining 11-12 years of life without a heart attack or stroke (20 years in those aged 55-64).

We are confident that the estimated effect is accurate. There is substantial evidence on the individual components of the Polypill, both for risk factor reduction and disease reduction. Extensive evidence exists that reducing the four risk factors by any means lowers the risk of cardiovascular disease. The consistency between evidence from observational studies and trials is persuasive.

The percentage reduction in stroke will be greater for non-fatal than fatal events (about 82% and about 75%, respectively) because statins and aspirin have different effects on thrombotic and haemorrhagic stroke and haemorrhagic strokes are more often fatal.

Who should take the Polypill
In people with a previous heart attack or a stroke, without any treatment, cardiovascular disease mortality is about 5% per year for life.²³ About half of all cardiovascular deaths occur in individuals with a previous myocardial infarction or cerebral thrombosis. All such individuals should be offered treatment to reduce the reversible risk factors and would benefit from taking the Polypill. Patients with angina pectoris, transient ischaemic attacks, peripheral arterial disease, and diabetes mellitus should also consider taking the Polypill.

Among people without existing disease, the most discriminatory screening factor is age. As 96% of deaths from ischaemic heart disease or stroke occur in people aged 55 and over, treating everyone in this group would prevent nearly all such deaths. Using different age cut-offs for men and women, or smokers and non-smokers, or combining several risk factor values with age and sex to produce individual estimates of overall risk would add little discrimination and would probably not justify the added complexity and cost.^{11 24 25} These factors, though aetiologically important, are poor predictors of future cardiovascular disease events (see bmj.com for a figure illustrating this with serum cholesterol, blood pressure, and serum homocysteine). There is little separation between the distributions of the risk factors in people who over a specified period do or do not have a disease event. Cut-off levels that identify the 5% of the unaffected population who have the most extreme values of the risk factors identify only about 15% of the disease events (24% for blood pressure and stroke). The screening performance of cardiovascular risk factors in combination is little better.²²

The best approach is therefore to treat people with known occlusive vascular disease and everyone aged 55 and over. There is no need to measure the four risk factors before starting treatment, because intervention is effective whatever the initial levels of the risk factors,¹¹ nor to monitor the effect of the treatment, because fluctuations within individuals tend to mask variations between individuals in the systematic effects of the interventions.

Adverse effects
The Polypill may not be suitable for some people. blockers are unsuitable for people with asthma, and some people are intolerant of aspirin. Monitoring to prevent rare serious adverse effects of treatment might be considered, measuring serum creatine kinase and transaminase (for rhabdomolysis and hepatitis caused by statins), and serum potassium and creatinine (for acute renal failure caused by ACE inhibitors and angiotensin II receptor antagonists). However, the value of such monitoring is uncertain. The complications are rare, it is not known whether monitoring will avoid them, and the tests lack specificity, so the increased risk of cardiovascular disease after stopping the drug in people positive on monitoring may outweigh any benefit.

Cost and acceptability
A low cost Polypill could use generic components that are not subject to patent protection (simvastatin (from mid-2003), hydrochlorothiazide, atenolol, enalapril, folic acid, and aspirin). This formulation does not have the lowest rate of adverse effects, but even if about 10% of people were intolerant of the formulation it would still have considerable public health merit. Those found to be intolerant could be prescribed alternatives to avoid the side effects. Controlled trials of different formulations of the Polypill would provide direct estimates of acceptability.

What is already known on this topic Four risk factors (LDL cholesterol, blood pressure, homocysteine, and platelet function) that can be reduced by drugs or vitamins account for most cardiovascular disease Apart from aspirin, the use of such agents has focused on people with high levels of the risk factor What this study adds Intervening on all four risk factors reduces heart attacks and strokes by over 80% To achieve this large effect in a population requires a combination treatment taken by everyone above a specified age (say 55) and younger people with a clinical history of occlusive arterial disease A combination pill containing six active components could be widely used Each component has been used in medical practice for more than 10 years with substantial evidence on safety and efficacy

Conclusions
The preventive strategy outlined is radical. But a formulation that prevented all cancer and was safe would undoubtedly be widely used, and one that prevented more than 80% of cardiovascular disease would be even more important, because such deaths are more common than cancer deaths. It is time to discard the view that risk factors need to be measured and treated individually if found to be "abnormal." Instead it should be recognised that in Western society the risk factors are high in us all, so everyone is at risk; that the diseases they cause are common and often fatal; and that there is much to gain and little to lose by the widespread use of these drugs.

---

This is an abridged version; the full version is on bmj.com

Editorial by Rodgers

Further tables appear on bmj.com

We thank Joan Morris and Alicja Rudnicka for statistical help, and Leo Kinlen, Jeffrey Aronson, Mark Caulfield, David Collier, James Haddow, and Frank Speizer for their helpful comments on drafts of this paper. This paper is based on a lecture given by Nicholas Wald on 18 September 2000 at a meeting in Israel of the Israel National Institute for Health Services Policy and Health Services Research.

Contributors: See bmj.com.

Funding: None.

Competing interests: The authors have filed a patent application on the formulation of the combined pill described here (application Nos GB 0100548.7 and GB 008791.6, priority date 10 April 2000) and a trademark application for the name Polypill.

References

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• Bulugahapitiya, U, Siyambalapitiya, S, Sithole, J, Fernando, D J, Idris, I (2008). Age threshold for vascular prophylaxis by aspirin in patients without diabetes. Heart 94: 1429-1432 [Abstract] [Full text]  
• Bhattacharyya, O. K. MD PhD, Shah, B. R. MD PhD, Booth, G. L. MD MSc (2008). Management of cardiovascular disease in patients with diabetes: the 2008 Canadian Diabetes Association guidelines. CMAJ 179: 920-926 [Full text]  
• Marshall, T., on behalf of Fatemeh Malekzadeh, Akram Pourshams,, (2008). News of the polypill. BMJ 337: a2160-a2160 [Full text]  
• Rodgers, A., Patel, A. (2008). Why is there more heat than light concerning the polypill?. BMJ 337: a2162-a2162 [Full text]  
• Watts, G. (2008). What happened to the polypill?. BMJ 337: a1822-a1822 [Full text]  
• Jackson, R., Wells, S., Rodgers, A. (2008). Will screening individuals at high risk of cardiovascular events deliver large benefits? Yes. BMJ 337: a1371-a1371 [Full text]  
• Egan, B. M., Nesbitt, S. D., Julius, S. (2008). Review: Prehypertension: should we be treating with pharmacologic therapy?. Ther Adv Cardiovasc Dis 2: 305-314 [Abstract]  
• Lonn, E. (2008). Homocysteine-Lowering B Vitamin Therapy in Cardiovascular Prevention--Wrong Again?. JAMA 299: 2086-2087 [Full text]  
• Dubel, G. J, Murphy, T. P (2008). The role of percutaneous revascularization for renal artery stenosis. Vasc Med 13: 141-156 [Abstract]  
• Rizza, R., Eddy, D., Kahn, R. (2008). Cure, Care, and Commitment: What Can We Look Forward To?. Diabetes Care 31: 1051-1059 [Full text]  
• Sabroe, I, Parker, L C, Calverley, P M A, Dower, S K, Whyte, M K B (2008). Pathological networking: a new approach to understanding COPD. Postgrad. Med. J. 84: 259-264 [Abstract] [Full text]  
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• Choudhry, N. K., Patrick, A. R., Antman, E. M., Avorn, J., Shrank, W. H. (2008). Cost-Effectiveness of Providing Full Drug Coverage to Increase Medication Adherence in Post-Myocardial Infarction Medicare Beneficiaries. Circulation 117: 1261-1268 [Abstract] [Full text]  
• Bakris, G. L., Berkwits, M. (2008). Trials That Matter: The Effect of a Fixed-Dose Combination of an Angiotensin-Converting Enzyme Inhibitor and a Diuretic on the Complications of Type 2 Diabetes. ANN INTERN MED 148: 400-401 [Full text]  
• Badger, S. A., Soong, C. V., Lee, B., Swain, G. R., McGuigan, K. E. (2008). Prescribing Practice of General Practitioners in Northern Ireland for Peripheral Arterial Disease. ANGIOLOGY 59: 57-63 [Abstract]  
• Wienbergen, H., Senges, J., Gitt, A. K. (2008). Should We Prescribe Statin and Aspirin for Every Diabetic Patient?: Is it time for a polypill?. Diabetes Care 31: S222-S225 [Full text]  
• Stirban, A. O., Tschoepe, D. (2008). Should We Be More Aggressive in the Therapy Against Cardiovascular Risk Factors?: Should we prescribe statin and aspirin for every diabetic patient, or is it time for a polypill?. Diabetes Care 31: S226-S228 [Abstract] [Full text]  
• Grundy, S. M. (2008). Promise of Low-Density Lipoprotein-Lowering Therapy for Primary and Secondary Prevention. Circulation 117: 569-573 [Full text]  
• Capewell, S, O'Flaherty, M (2008). Maximising secondary prevention therapies in patients with coronary heart disease. Heart 94: 8-9 [Full text]  
• DeWilde, S, Carey, I M, Richards, N, Whincup, P H, Cook, D G (2008). Trends in secondary prevention of ischaemic heart disease in the UK 1994 2005: use of individual and combination treatment. Heart 94: 83-88 [Abstract] [Full text]  
• Karthikeyan, G., Xavier, D., Prabhakaran, D., Pais, P. (2007). Perspectives on the management of coronary artery disease in India. Heart 93: 1334-1338 [Abstract] [Full text]  
• Loscalzo, J. (2007). Association Studies in an Era of Too Much Information: Clinical Analysis of New Biomarker and Genetic Data. Circulation 116: 1866-1870 [Full text]  
• Huang, E. S., Brown, S. E.S., Ewigman, B. G., Foley, E. C., Meltzer, D. O. (2007). Patient Perceptions of Quality of Life With Diabetes-Related Complications and Treatments. Diabetes Care 30: 2478-2483 [Abstract] [Full text]  
• van der Elst, M. E, Bouvy, M. L, de Blaey, C. J, de Boer, A. (2007). Effect of drug combinations on admission for recurrent myocardial infarction. Heart 93: 1226-1230 [Abstract] [Full text]  
• Wald, D. S, Morton, G., Walker, K., Iosson, N., Curzen, N. P (2007). Long-Term Continuation on Cardiovascular Drug Treatment in Patients with Coronary Heart Disease. The Annals of Pharmacotherapy 41: 1644-1647 [Abstract] [Full text]  
• Chow, C K, Pell, A C H, Walker, A, O'Dowd, C, Dominiczak, A F, Pell, J P (2007). Families of patients with premature coronary heart disease: an obvious but neglected target for primary prevention. BMJ 335: 481-485 [Full text]  
• Sabroe, I., Parker, L. C, Calverley, P. M A, Dower, S. K, Whyte, M. K B (2007). Pathological networking: a new approach to understanding COPD. Thorax 62: 733-738 [Abstract] [Full text]  
• Bonneux, L. (2007). Cardiovascular risk models. BMJ 335: 107-108 [Full text]  
• Matfin, G. (2007). Aspects of drug development and clinical trials -- Part 2. British Journal of Diabetes & Vascular Disease 7: 149-150  
• Matfin, G. (2007). Review: Challenges in developing therapies for the metabolic syndrome. British Journal of Diabetes & Vascular Disease 7: 152-156 [Abstract]  
• Authors/Task Force Members:, , Mancia, G., De Backer, G., Dominiczak, A., Cifkova, R., Fagard, R., Germano, G., Grassi, G., Heagerty, A. M., Kjeldsen, S. E., Laurent, S., Narkiewicz, K., Ruilope, L., Rynkiewicz, A., Schmieder, R. E., Struijker Boudier, H. A.J., Zanchetti, A., ESC Committee for Practice Guidelines (CPG):, , Vahanian, A., Camm, J., De Caterina, R., Dean, V., Dickstein, K., Filippatos, G., Funck-Brentano, C., Hellemans, I., Kristensen, S. D., McGregor, K., Sechtem, U., Silber, S., Tendera, M., Widimsky, P., Zamorano, J. L., ESH Scientific Council:, , Kjeldsen, S. E., Erdine, S., Narkiewicz, K., Kiowski, W., Agabiti-Rosei, E., Ambrosioni, E., Cifkova, R., Dominiczak, A., Fagard, R., Heagerty, A. M., Laurent, S., Lindholm, L. H., Mancia, G., Manolis, A., Nilsson, P. M., Redon, J., Schmieder, R. E., Struijker-Boudier, H. A.J., Viigimaa, M., Document Reviewers:, , Filippatos, G., Adamopoulos, S., Agabiti-Rosei, E., Ambrosioni, E., Bertomeu, V., Clement, D., Erdine, S., Farsang, C., Gaita, D., Kiowski, W., Lip, G., Mallion, J.-M., Manolis, A. J., Nilsson, P. M., O'Brien, E., Ponikowski, P., Redon, J., Ruschitzka, F., Tamargo, J., van Zwieten, P., Viigimaa, M., Waeber, B., Williams, B., Zamorano, J. L. (2007). 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 0: ehm236v1-75 [Full text]  
• Schiff, E., Gurgevich, S., Caspi, O. (2007). Potential Synergism between Hypnosis and Acupuncture--Is the Whole More Than the Sum of Its Parts?. Evid Based Complement Alternat Med 4: 233-240 [Abstract] [Full text]  
• Hackam, D. G., Spence, J. D. (2007). Combining Multiple Approaches for the Secondary Prevention of Vascular Events After Stroke: A Quantitative Modeling Study. Stroke 38: 1881-1885 [Abstract] [Full text]  
• James, P. D, Wilkins, R., Detsky, A. S, Tugwell, P., Manuel, D. G (2007). Avoidable mortality by neighbourhood income in Canada: 25 years after the establishment of universal health insurance. J. Epidemiol. Community Health 61: 287-296 [Abstract] [Full text]  
• Reid, J. L. (2007). Fall and Rise of Polypharmacy?. Hypertension 49: 266-267 [Full text]  
• Reddy, K. S. (2007). The Preventive Polypill -- Much Promise, Insufficient Evidence. NEJM 356: 212-212 [Full text]  
• Gaziano, T. A. (2007). Reducing The Growing Burden Of Cardiovascular Disease In The Developing World. Health Aff (Millwood) 26: 13-24 [Abstract] [Full text]  
• Mensah, G. A., Brown, D. W. (2007). An Overview Of Cardiovascular Disease Burden In The United States. Health Aff (Millwood) 26: 38-48 [Abstract] [Full text]  
• Pearson, T. A. (2007). The Prevention Of Cardiovascular Disease: Have We Really Made Progress?. Health Aff (Millwood) 26: 49-60 [Abstract] [Full text]  
• Choudhry, N. K., Avorn, J., Antman, E. M., Schneeweiss, S., Shrank, W. H. (2007). Should Patients Receive Secondary Prevention Medications For Free After A Myocardial Infarction? An Economic Analysis. Health Aff (Millwood) 26: 186-194 [Abstract] [Full text]  
• Marshall, T, Bryan, S, Gill, P, Greenfield, S, Gutridge, K, Birmingham Patient Preferences Group, (2006). Predictors of patients' preferences for treatments to prevent heart disease. Heart 92: 1651-1655 [Abstract] [Full text]  
• Franco, O. H, Steyerberg, E. W, Peeters, A., Bonneux, L. (2006). Effectiveness calculation in economic analysis: the case of statins for cardiovascular disease prevention.. J. Epidemiol. Community Health 60: 839-845 [Abstract] [Full text]  
• O'Connor, P. J. (2006). Improving medication adherence: challenges for physicians, payers, and policy makers.. Arch Intern Med 166: 1802-1804 [Full text]  
• O'Kennedy, N., Crosbie, L., Whelan, S., Luther, V., Horgan, G., Broom, J. I, Webb, D. J, Duttaroy, A. K (2006). Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans.. Am. J. Clin. Nutr. 84: 561-569 [Abstract] [Full text]  
• Hammerman-Rozenberg, R., Jacobs, J. M., Azoulay, D., Stessman, J. (2006). Aspirin prophylaxis and the prevalence of anaemia. Age Ageing 35: 514-517 [Abstract] [Full text]  
• Bucci, K. K., Possidente, C. J. (2006). Combination-drug products: Benefit or burden to patients?. Am J Health Syst Pharm 63: 1654-1655 [Full text]  
• Colagiuri, R., Colagiuri, S., Yach, D., Pramming, S. (2006). The Answer to Diabetes Prevention: Science, Surgery, Service Delivery, or Social Policy?. AJPH 96: 1562-1569 [Abstract] [Full text]  
• Asia Pacific Cohort Studies Collaboration, (2006). The impact of cardiovascular risk factors on the age-related excess risk of coronary heart disease. Int J Epidemiol 35: 1025-1033 [Abstract] [Full text]  
• Sleight, P., Pouleur, H., Zannad, F. (2006). Benefits, challenges, and registerability of the polypill. Eur Heart J 27: 1651-1656 [Abstract] [Full text]  
• Yusuf, S. (2006). Preventing Vascular Events Due to Elevated Blood Pressure. Circulation 113: 2166-2168 [Full text]  
• Sambu, N, Wald, D S, Seddon, M, Simpson, I A (2006). Undertreatment of coronary heart disease in patients undergoing coronary artery bypass surgery.. Heart 92: 697-698 [Full text]  
• Falk, E. (2006). Pathogenesis of atherosclerosis.. J Am Coll Cardiol 47: C7-C12 [Abstract] [Full text]  
• Bonaa, K. H., Njolstad, I., Ueland, P. M., Schirmer, H., Tverdal, A., Steigen, T., Wang, H., Nordrehaug, J. E., Arnesen, E., Rasmussen, K., the NORVIT Trial Investigators, (2006). Homocysteine Lowering and Cardiovascular Events after Acute Myocardial Infarction. NEJM 354: 1578-1588 [Abstract] [Full text]  
• Jackson, R., Lynch, J., Harper, S. (2006). Preventing coronary heart disease.. BMJ 332: 617-618 [Full text]  
• Manuel, D. G, Lim, J., Tanuseputro, P., Anderson, G. M, Alter, D. A, Laupacis, A., Mustard, C. A (2006). Revisiting Rose: strategies for reducing coronary heart disease.. BMJ 332: 659-662 [Full text]  
• Franco, O. H, Steyerberg, E. W, de Laet, C. (2006). The polypill: at what price would it become cost effective?. J. Epidemiol. Community Health 60: 213-217 [Abstract] [Full text]  
• Ramsay, S. E, Whincup, P. H, Lawlor, D. A, Papacosta, O., Lennon, L. T, Thomas, M. C, Ebrahim, S., Morris, R. W (2006). Secondary prevention of coronary heart disease in older patients after the national service framework: population based study. BMJ 332: 144-145 [Abstract] [Full text]  
• Marks, J. B. (2006). Metabolic Syndrome: To Be or Not To Be?. Clin. Diabetes 24: 3-4 [Full text]  
• Kaplan, N. M. (2006). Treatment of Hypertension: Remaining Issues After the Anglo-Scandinavian Cardiac Outcomes Trial. Hypertension 47: 10-13 [Full text]  
• Koh, K. K., Han, S. H., Quon, M. J. (2005). Inflammatory Markers and the Metabolic Syndrome: Insights From Therapeutic Interventions. J Am Coll Cardiol 46: 1978-1985 [Abstract] [Full text]  
• Choi, B. C K, Hunter, D. J, Tsou, W., Sainsbury, P. (2005). Diseases of comfort: primary cause of death in the 22nd century. J. Epidemiol. Community Health 59: 1030-1034 [Abstract] [Full text]  
• Lewington, S., Clarke, R. (2005). Combined Effects of Systolic Blood Pressure and Total Cholesterol on Cardiovascular Disease Risk. Circulation 112: 3373-3374 [Full text]  
• Asia Pacific Cohort Studies Collaboration, (2005). Joint Effects of Systolic Blood Pressure and Serum Cholesterol on Cardiovascular Disease in the Asia Pacific Region. Circulation 112: 3384-3390 [Abstract] [Full text]  
• Lewis, S. J, Ebrahim, S., Davey Smith, G. (2005). Meta-analysis of MTHFR 677C->T polymorphism and coronary heart disease: does totality of evidence support causal role for homocysteine and preventive potential of folate?. BMJ 331: 1053- [Abstract] [Full text]  
• Sud, A., Kline-Rogers, E. M, Eagle, K. A, Fang, J., Armstrong, D. F, Rangarajan, K., Otten, R. F, Stafkey-Mailey, D. R, Taylor, S. D, Erickson, S. R (2005). Adherence to Medications by Patients After Acute Coronary Syndromes. The Annals of Pharmacotherapy 39: 1792-1797 [Abstract] [Full text]  
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• Fosslien, E. (2005). Cardiovascular Complications of Non-Steroidal Anti-Inflammatory Drugs. Annals of Clinical & Laboratory Science 35: 347-385 [Abstract] [Full text]  
• Ebrahim, S., Smeeth, L. (2005). Non-communicable diseases in low and middle-income countries: a priority or a distraction?. Int J Epidemiol 34: 961-966 [Full text]  
• Paraskevas, K. I., Daskalopoulou, S. S., Daskalopoulos, M. E., Liapis, C. D. (2005). Secondary Prevention of Ischemic Cerebrovascular Disease. What Is the Evidence?. ANGIOLOGY 56: 539-552 [Abstract]  
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• Norris, J. W. (2005). Antiplatelet Agents in Secondary Prevention of Stroke: A Perspective. Stroke 36: 2034-2036 [Abstract] [Full text]  
• Williams, M. T., Hord, N. G. (2005). The Role of Dietary Factors in Cancer Prevention: Beyond Fruits and Vegetables. Nutr Clin Pract 20: 451-459 [Abstract] [Full text]  
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• Hanson, M, Gluckman, P (2005). Endothelial dysfunction and cardiovascular disease: the role of predictive adaptive responses. Heart 91: 864-866 [Full text]  
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Rapid Responses:

Read all Rapid Responses

Costing the polypill, £60 per year.

john s ashcroft
bmj.com, 27 Jun 2003 [Full text]

More Compelling Evidence

William E. Osmun
bmj.com, 27 Jun 2003 [Full text]

Beware the Epidemiology

Bruce Bain
bmj.com, 27 Jun 2003 [Full text]

Good news: All we need to do now is get people to prescribe it and then take it...

Alexander M Clark
bmj.com, 27 Jun 2003 [Full text]

correction to cost of prescribing polypill

john s ashcroft
bmj.com, 27 Jun 2003 [Full text]

Now who's playing God …

Steve Taylor, et al.
bmj.com, 27 Jun 2003 [Full text]

Pilly Polly Doo Dah all the way

Malcolm Kendrick
bmj.com, 27 Jun 2003 [Full text]

PolyPill may not decrease all-cause mortality

Eddie Vos
bmj.com, 27 Jun 2003 [Full text]

Only 80% reduction? Why not go for 100%?

Barry A Groves
bmj.com, 27 Jun 2003 [Full text]

Whose Life Is It Anyway? The Polypill May Increase Health Inequalities

Michael A Soljak
bmj.com, 27 Jun 2003 [Full text]

Shabby Medical Thinking

Nicholas M Regush
bmj.com, 27 Jun 2003 [Full text]

A gauntlet thrown at drug companies or doctors?

Richard G Fiddian-Green
bmj.com, 28 Jun 2003 [Full text]

The 'Vacca Foeda' PolyPill

Joseph .C. Obi
bmj.com, 28 Jun 2003 [Full text]

Impact of single normal dose blood pressure medications

Bala Subramanian
bmj.com, 28 Jun 2003 [Full text]

Polypill drawbacks and multivitamin as alternative

BIll Sardi
bmj.com, 28 Jun 2003 [Full text]

The Big Issue

Dan Rutherford
bmj.com, 28 Jun 2003 [Full text]

new paradigm

Martin R Innes
bmj.com, 28 Jun 2003 [Full text]

Dumbfounded

Peter J Hosein
bmj.com, 28 Jun 2003 [Full text]

Also dumbfounded

Margaret J Tyson
bmj.com, 29 Jun 2003 [Full text]

Can anyone afford to live a very long life?

Mark Hochhauser, Ph.D.
bmj.com, 29 Jun 2003 [Full text]

A Sad Day For British Medicine

Allan Withnell
bmj.com, 29 Jun 2003 [Full text]

Treat people not populations

Eugene A. Rybinski
bmj.com, 29 Jun 2003 [Full text]

polypill ; for all races, sexes and seasons ?

Adesuyi Ajayi, et al.
bmj.com, 29 Jun 2003 [Full text]

Old joke and current practice

Adrian K Midgley
bmj.com, 29 Jun 2003 [Full text]

What do we die then?

Roger Wanner
bmj.com, 29 Jun 2003 [Full text]

POLYPILL, AN IDEA, PERHAPS A VERY GOOD ONE, BUT NOT A JOKE

CELIO LEVYMAN,MD,MSc, et al.
bmj.com, 30 Jun 2003 [Full text]

WHEN?

Linda L Gimnich
bmj.com, 30 Jun 2003 [Full text]

About as believable as the tooth fairy

Adam Jacobs
bmj.com, 30 Jun 2003 [Full text]

A pill a day keeps health away?

Ewan Hamnett
bmj.com, 30 Jun 2003 [Full text]

Shame on you BMJ!!

Michael C Bunbury, et al.
bmj.com, 30 Jun 2003 [Full text]

Nearer 66% rather than 88% IHD risk reduction after 2 years?

Eric S. Kilpatrick
bmj.com, 30 Jun 2003 [Full text]

Relative risks and meta-analysis

J Michael Henk
bmj.com, 30 Jun 2003 [Full text]

Unbelievable and unachievable

Mark J Garton
bmj.com, 30 Jun 2003 [Full text]

Multiple Polypill Benefits

Gerard T O'Brien
bmj.com, 1 Jul 2003 [Full text]

WHO should convene an aspirin meeting?

Gareth P Morgan
bmj.com, 1 Jul 2003 [Full text]

POLYPILL AGAIN,BUT IN THE THIRD WORLD

CELIO LEVYMAN,MD,MSc
bmj.com, 2 Jul 2003 [Full text]

Patients before populations

Peter N Trewby, et al.
bmj.com, 2 Jul 2003 [Full text]

Polypill treatment and the physical properties of blood.

Leslie.O. Simpson
bmj.com, 2 Jul 2003 [Full text]

Re: Shame on you BMJ!!

Daniel Weyandt
bmj.com, 2 Jul 2003 [Full text]

Reality check

Mike Schachter
bmj.com, 2 Jul 2003 [Full text]

Brave New World

Joachim P Sturmberg
bmj.com, 2 Jul 2003 [Full text]

Polypill Choices

Shah M Tauzeeh
bmj.com, 2 Jul 2003 [Full text]

Concept is correct

Paul W Masters
bmj.com, 2 Jul 2003 [Full text]

Logical consequence of current polypharmacy

Dr. Matthew L Grove
bmj.com, 2 Jul 2003 [Full text]

What must be done now.

William Plummer
bmj.com, 2 Jul 2003 [Full text]

Aspastatapril vs Polypill

Ketan K Dhatariya
bmj.com, 2 Jul 2003 [Full text]

Compliance with the Polypill

Anita Sainsbury
bmj.com, 3 Jul 2003 [Full text]

Re: What must be done now - correction.

William Plummer
bmj.com, 3 Jul 2003 [Full text]

Is The Paper a Spoof?

David A Brodie
bmj.com, 3 Jul 2003 [Full text]

Dubious mathematical assumptions

David M Reith
bmj.com, 3 Jul 2003 [Full text]

Total Mortality

Jeffrey R Johnstone
bmj.com, 4 Jul 2003 [Full text]

Modelling and assumptions need clarification

Tom Fahey, et al.
bmj.com, 5 Jul 2003 [Full text]

Polypill Debate

Stephen J Redmond
bmj.com, 5 Jul 2003 [Full text]

Cat amonsgt the pigeons

Adam L Brown
bmj.com, 5 Jul 2003 [Full text]

Eradicating cardiovascular disease with polypharmarcy: Dream or reality ?

Peter Marckmann
bmj.com, 6 Jul 2003 [Full text]

Willing suspense of disbelief

Elved B Roberts
bmj.com, 7 Jul 2003 [Full text]

'Magic pill' approach would shift focus from proven and cost-effective CVD prevention

Derek Yach, et al.
bmj.com, 7 Jul 2003 [Full text]

Salicylate deficiency

Gareth P Morgan
bmj.com, 7 Jul 2003 [Full text]

we should ask patients

Alejandro F. Luque-Coqui
bmj.com, 8 Jul 2003 [Full text]

Reducing cardiovascular disease by taking a "polypill" hope or hype?

Marcus Flather, et al.
bmj.com, 9 Jul 2003 [Full text]

The Polypill and prevention of Coronary Heart Disease

Daan Kromhout, et al.
bmj.com, 10 Jul 2003 [Full text]

Re: PolyPill may not decrease all-cause mortality

Alejandro F. Luque-Coqui
bmj.com, 10 Jul 2003 [Full text]

The fundamental principle of western medical science is the principle of scientific testing

Jeffrey Mann
bmj.com, 10 Jul 2003 [Full text]

Polypill for older adults.

Nandkishor V Athavale
bmj.com, 10 Jul 2003 [Full text]

Polypill versus conventional preventive care

Barry Lewis
bmj.com, 11 Jul 2003 [Full text]

Misplaced notions of simplicity, denial of complexity

Lawrence J. O'Brien, et al.
bmj.com, 11 Jul 2003 [Full text]

Incredulous of middle England !!

Saul G Myerson
bmj.com, 11 Jul 2003 [Full text]

Re: Re: Shame on you BMJ!!

Michael Bunbury
bmj.com, 12 Jul 2003 [Full text]

Questionable benefit from polypill treatment.

Uffe Ravnskov
bmj.com, 13 Jul 2003 [Full text]

The ‘polypill’: medical myth versus balanced judgement

Ian F Godsland, et al.
bmj.com, 14 Jul 2003 [Full text]

CARDIOVASCULAR PREVENTION AND THERAPY

Andrea Alberto Conti, et al.
bmj.com, 15 Jul 2003 [Full text]

Poly-drug to reduce cardiovascular disease

Dietmar Fuchs, et al.
bmj.com, 18 Jul 2003 [Full text]

The wonderful poly-pill

Miguel E. Campos, et al.
bmj.com, 19 Jul 2003 [Full text]

Potential Issues

Robert Kerr
bmj.com, 23 Jul 2003 [Full text]

Concept of Poly-Pill contrary to medical judgement

Munir E Nassar, M.D., et al.
bmj.com, 25 Jul 2003 [Full text]

The Nays Have It

John A. DePoy, BS, MSc, MBA, et al.
bmj.com, 26 Jul 2003 [Full text]

The “polypill” strategy in high-risk Australian CVD patients

Christopher M Reid, et al.
bmj.com, 28 Jul 2003 [Full text]

Markov models deserve scientific scrutiny too.

Christopher J Martin, et al.
bmj.com, 29 Jul 2003 [Full text]

Noncompliance with hypertensives

Christopher J Squire
bmj.com, 30 Jul 2003 [Full text]

Risks with the "Polypill" in the Oldest Old

Sven E Nilsson, et al.
bmj.com, 13 Aug 2003 [Full text]

delay vs prevention

gerry e burns
bmj.com, 15 Aug 2003 [Full text]

Why not Omega-3 fatty acid as part of Polypill ?

William K Smith M D
bmj.com, 17 Aug 2003 [Full text]

Enter...The 'Omnipill'

Joseph .C. Obi
bmj.com, 18 Aug 2003 [Full text]

Omega-3 fatty acids and brown fat.

Richard G Fiddian-Green
bmj.com, 19 Aug 2003 [Full text]

We are headed toward a healthcare crisis fast enough, thank you.

Philip King, D.Ph.
bmj.com, 20 Aug 2003 [Full text]

A natural mini polypill: Potential impact on population cardiovascular risk of a daily drink of milk

Gary A Wright, et al.
bmj.com, 22 Aug 2003 [Full text]

The Polypill and Ayurdeva

Rajeev Gupta
bmj.com, 28 Aug 2003 [Full text]

What's really behind the antagonism for the polypill?

James G Penston
bmj.com, 1 Sep 2003 [Full text]

drug interactions

Teresa Tarnowski Goodell, RN
bmj.com, 18 Sep 2003 [Full text]

Reducing Cardiovascular Disease

William E. Feeman Jr., et al.
bmj.com, 19 Sep 2003 [Full text]

polypill - why not ? polypharmarcy is practised !

das sabapathy
bmj.com, 4 Oct 2003 [Full text]

Methodological issues remain unanswered

Tom Fahey, et al.
bmj.com, 31 Oct 2003 [Full text]

Polypill-Pr, a new formulation for the mature male

A. Mark Clarfield
bmj.com, 30 Jan 2004 [Full text]

Re: Polypill- adding osteporosis treatment restores gender equality at 8 all

Jeremy G Jones
bmj.com, 1 Feb 2004 [Full text]

Methodological issues remain unanswered - Authors' response

Nicholas J Wald, et al.
bmj.com, 8 Mar 2004 [Full text]

Polypill a life…in

Guy-André Pelouze
bmj.com, 19 Mar 2004 [Full text]

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