Rapid Responses to:

FEATURE: Geoff Watts What happened to the polypill? BMJ 2008; 337: a1822 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Add vitamin D to the polypill.

John H Livesey   (30 September 2008)

Why is there more heat than light concerning the polypill?

Anthony Rodgers, Associate Professor Anushka Patel   (1 October 2008)

The death of the polypill

Eddie Vos Vos   (4 October 2008)

News of the Polypill

Tom Marshall, Fatemeh Malekzadeh, Akram Pourshams , Mina Gharravi , Afshin Aslani, Alireza Nateghi , Mansoor Rastegarpanah, Masoud Khoshnia, G. Neil Thomas Bagher Larijani , Reza Malekzadeh, KK Cheng.   (10 October 2008)

Polypill: for Polyanna

J.David Spence   (31 October 2008)

Add vitamin D to the polypill. 30 September 2008
John H Livesey, Hospital Scientific Officer Christchurch Hospital, New Zealand 8140 Send response to journal: Re: Add vitamin D to the polypill.	Vitamin D deficiency and insufficiency are very common in non- tropical climates and probably contribute to the risk of many chronic diseases(1). A serum concentration of 25-hydroxy vitamin D of at least 75 nmol/L is desirable for optimal health(1) and this could be achieved for most people by adding 2000 IU of cholecalciferol to the daily polypill (2). 1. Holick MF. Deficiency of sunlight and vitamin D. BMJ 2008;336:1318 -9. 2. Livesey JH, Elder P, Ellis MJ, McKenzie R, Liley B, Florkowski C. Seasonal variation in vitamin D in the Canterbury New Zealand population in relation to available UV radiation. New Zealand Medical Journal 21 September 2007, Vol 120 No 1262. (http://www.nzma.org.nz/journal/120- 1262/2733/). Competing interests: None declared
Why is there more heat than light concerning the polypill? 1 October 2008
Anthony Rodgers, Professor School of Population Health, University of Auckland, PB92019, Auckland, NZ, Associate Professor Anushka Patel Send response to journal: Re: Why is there more heat than light concerning the polypill?	Geoff Watts asks a very reasonable question - why are there still so few polypill trials? In 2001 Richard Peto, one of the worlds most influential epidemiologists, facilitated a meeting between WHO and the Wellcome Trust to discuss development of fixed dose combination products in secondary prevention of cardiovascular disease.[1] Salim Yusuf noted the potential for a combination treatment to reduce cardiovascular risk by three- quarters in the Lancet in 2002.[2] Wald and Law brilliantly summarised the evidence and proposed the polypill concept, including widespread use for primary prevention, in the widely cited BMJ papers in 2003.[3] Yet in late 2008 there are only a few trials, all in early stages. Hence, discourse in the area is still dominated by opinion rather than evidence, and registered products are still a long way off. How could this be? The big issue is not the finer points of the initial target population, the pill components, or professional opinion on the right balance between the perfect and the possible. The big issue is the huge gap in funding for research and development of affordable "applied innovations". Formulation, manufacture, testing and clinical trials of a polypill to EMEA and FDA requirements will cost well over ten million pounds. Big pharma won't develop a pill that could be available for a few pence a day. Generics pharma are geared to high-volume, low-margin products, but these margins typically can't support substantial R&D. No other sector has yet "stepped up to the plate" to address this funding gap. As well as changing the ecomonic incentives for industry, we need large scale, co-ordinated public funding to address this funding gap. There is a compelling equity motive for such funding for conditions that primarily affect low and middle income countries.[4] There is also a compelling economic motive for conditions with global impact such as cardiovascular disease, given vast current expenditure[5] and vast undertreatment.[6-8] Filling this R&D gap is a major challenge for translational research. We must recognise the great opportunities for innovation after the bench-to-bedside stage and also that patient benefits only accrue once effective interventions are brought to scale. The other major issue also brought to the fore by the polypill is the strange reticence about preventing cardiovascular disease. Can one imagine such delay if leading scientists proposed a credible solution to preventing most cancer? ______________________________________________________________________________________ 1. World Health Organization. Secondary prevention of non- communicable disease in low and middle income countries through community- based and health service interventions. World Health Organization - Wellcome Trust meeting report 1 - 3 August 2001, Geneva. 2002. 2. Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002;360:2-3. 3. Wald N, Law M. A strategy to reduce cardiovascular disease by more than 80%. British Medical Journal 2003;326:1419-1424. 4. Widdus R. Public-private partnerships for health: their main targets, their diversity, and their future directions. Bulletin of the World Health Organization 2001;79(8):713-720. 5. Dickson M, Jacobzone S. Pharmaceutical Use and Expenditure for Cardiovascular Disease and Stroke: A Study of 12 OECD Countries. OECD Health Working Papers, 2003. 6. EUROASPIRE I and II Group. Clinical reality of coronary prevention guidelines: a comparison of EUROASPIRE I and II in nine countries. Lancet 2001;357(9261):995-1001. 7. Mendis S, Abegunde D, Yusuf S, Ebrahim S, Shaper G, Ghannem H, et al. WHO study on Prevention of REcurrences of Myocardial Infarction and StrokE (WHO-PREMISE). Bulletin of the World Health Organization 2005;83(11):820- 8. 8. Rafter N, Connor J, Hall J, Jackson R, Martin I, Parag V, et al. Cardiovascular medications in primary care: treatment gaps and targeting by absolute risk. New Zealand Medical Journal 2005;118(1223). Competing interests: The authors are involved in raising funding for research on affordable medicines
The death of the polypill 4 October 2008
Eddie Vos Vos, Maintains health-heart.org Sutton (Qc) J0E 2K0 Canada Send response to journal: Re: The death of the polypill	Geoff Watts asks what became of polypill, the 'single pill to prevent cardiovascular disease' . He cites some planned trials but the folate component to lower homocysteine is dropped from further work. That leaves 3 kinds of biochemical inhibitors (statin, aspirin, blood pressure drugs) that, at least in women, have never shown to extend life vs. placebo. The absence of these drugs is not the underlying cause of arterial disease. Homocysteine, however, is an amino acid that is toxic to arterial proteins and enzymes. It can be reduced by higher than common intakes of several B-vitamins, and in homocysteine, there is consensus that lower is better. No researcher would do studies in animals that are sub-optimally supplied in micronutrients thereby introducing known confounders, yet all human cardiovascular studies are done in that context, i.e. with homocysteine above minimal amounts. With research in the polypill apparently moving to the developing world, that situation may well be worse. Vascular disease is rarely reported in free roaming animals, or in humans with homocysteine levels <7 micromol/L. Significantly, the HOPE-2 study found that B-vitamins reduced stroke, a finding supported for folate by the impressive drops in heart and stroke deaths in the U.S. following the low level folate fortification of grain products. Homocysteine is proposed to be a life-long artery corrosive and lowering it from early age with an over the counter multivitamin, a 'polyvit' so to speak, should underlie prevention and polypill studies everywhere. It may surprise Europeans that $38/year high dose multivitamins such as this one [trade names removed] are available by mail in the U.S. at amounts sure to correct many known common deficiencies and genetic impediments, apart from lowering homocysteine as well as the vitamin amounts used in most trials. The safety of the illustrated no-iron ' polyvit ' is illustrated by the fact that a 6 month supply comes in a bottle without the FDA requiring a child proof cap. People may have an understandable aversion to drugs but micronutrients are not drugs. Increasing public awareness that food processing and socioeconomic conditions have reduced the micronutrients in our diets from the levels our genome developed on should reduce professional resistance to effective fortification strategies while the use of a ' polyvit ' is clearly indicated, logical, evidence based and should accompany, in fact precede polypill trials. Competing interests: None declared
News of the Polypill 10 October 2008
Tom Marshall, Senior Lecturer in Public Health University of Birmingham, B15 2TT, Fatemeh Malekzadeh, Akram Pourshams , Mina Gharravi , Afshin Aslani, Alireza Nateghi , Mansoor Rastegarpanah, Masoud Khoshnia, G. Neil Thomas Bagher Larijani , Reza Malekzadeh, KK Cheng. Send response to journal: Re: News of the Polypill	Geoff Watts asks what happened to the Polypill for primary prevention of cardiovascular disease. We can provide an answer. The University of Birmingham and Tehran University of Medical Sciences have completed a randomised controlled trial of a four component polypill in approximately 500 men aged 50 to 79 and women aged 55 to 79. This is a pilot study, with the aim of starting a fully powered clinical trial if this is successful. The polypill consists of aspirin, a statin, an angiotensin converting enzyme inhibitor and a thiazide diuretic. The trial is registered with www.controlled-trials.com. [2] We aim to determine the effects of treatment on blood pressure and lipid levels. Recruitment began in 2006 in Golestan (North East Iran) and follow up was completed earlier this year. We are currently analysing data. Our pilot study keeps close to the original spirit of the polypill proposed by Professor Wald by including only persons who were not currently eligible for antihypertensives and not currently eligible for lipid lowering therapy. Furthermore, we have located our trial in a developing country where uptake of preventive treatments is far from ideal. Ours is probably the first clinical trial of a polypill. It is very likely to be the first trial to include patients defined by their age. We await results of analysis and look forward to a fully powered trial. We suspect others may be equally interested in our results. Yours sincerely Tom Marshall 1. Watts G. What happened to the polypill? BMJ 2008: 337 ;786. 2. www.controlled-trials.com/ISRCTN43076122/ [Accessed 25th January 2007] Competing interests: None declared
Polypill: for Polyanna 31 October 2008
J.David Spence, Professor of Neurology and Clinical Pharmacology Robarts Research Institute, University of Western Ontario, London, Canada, N6G 2V2 Send response to journal: Re: Polypill: for Polyanna	There are fundamental problems with the concept of the polypill, and severe problems with the details. Clinical Pharmacology is about the right medication for the right patient in the right dose at the right time: in other words, individualized therapy. Assuming that one pill is right for all patients runs into insurmountable problems. For example, patients with hypertension do not all have the same cause, and therefore do not all respond to the same therapy. What is needed in resistant hypertension is profiling with plasma renin and aldosterone to identify the appropriate therapy for the patient(1;2). There are problems with "folate" therapy: folate fortification of the grain supply is already in place in North America, and high doses of folate have been implicated in colonic cancer. The more important problem is B12 deficiency, which is far commoner than most doctors think: 20% of patients over age 65 have metabolic B12 deficiency, and many of these have a "normal" serum B12 level(3). Metabolic B12 deficiency is defined by an elevated level of methylmalonic acid, with a serum B12 <258 pmol/L – but recently authorities in this area consider a serum B12 level above 350pmol/L to be adequate (Dr. Sally Stabler, personal communication, October 2008). In folate-replete subjects, an elevated plasma homocysteine also serves to diagnose metabolic B12 deficiency(4). Likely choices for the statin and beta blocker have major problems: simvastatin, because it is 95% metabolized during absorption by CYP3A4, is only 5% bioavailable. It is therefore subject to huge drug interactions. Increases of blood levels by 15-fold, with risk of rhabdomyolysis(5), occur with grapefruit juice(6), erythromycin(7;8), clarithromycin(9;10), itraconazole(8), ketaconazole(11), etc, etc. Metoprolol is subject to huge inter-individual variations in metabolism because of copy number variants of CYP2D6. The range of blood levels achieved with a given dose is 150-fold(12); thus it is impossible to pick a dose. Furthermore, it is very short-acting, requiring twice daily dosing, and has a high risk of rebound hypertension, tachycardia and myocardial ischemia. A much better beta-blocker, for several reasons, would be pindolol - but 7% of the population could not take it because of asthma. ACE inhibitors cause cough in ~8% of patients, and angioedema in fewer, but it can be a big problem for those patients. ARB's would be better, but still inappropriate for patients with low-renin hypertension. Similarly, not all patients can take aspirin: those with GI bleeding, allergic reactions to ASA, or asthma/nasal polyps should avoid it. The polypill is thus inappropriate in concept, and fatally flawed in the details. What we really need is a machine that would allow us to dial up a single pill that is appropriate to each patient. All of this is detailed in my recent paper(13). <P> Reference List (1) Spence JD. Individualized therapy for hypertension. Hypertension 2006 March;47(3):e11. (2) Spence JD. Physiologic tailoring of therapy for resistant hypertension: 20 years' experience with stimulated renin profiling. Am J Hypertens 1999;12:1077-83. (3) Andres E, Loukili NH, Noel E, Kaltenbach G, Abdelgheni MB, Perrin AE et al. Vitamin B12 (cobalamin) deficiency in elderly patients. CMAJ 2004 August 3;171(3):251-9. (4) Spence JD. Nutrition and stroke prevention. Stroke 2006 September;37(9):2430-5. (5) Dreier JP, Endres M. Statin-associated rhabdomyolysis triggered by grapefruit consumption. Neurology 2004 February 24;62(4):670. (6) Lilja JJ, Kivisto KT, Neuvonen PJ. Grapefruit juice-simvastatin interaction: effect on serum concentrations of simvastatin, simvastatin acid, and HMG-CoA reductase inhibitors. Clin Pharmacol Ther 1998 November;64(5):477-83. (7) Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin and simvastatin acid concentrations. Clin Pharmacol Ther 1998 August;64(2):177-82. (8) Bailey DG, Bend JR, Arnold JM, Tran LT, Spence JD. Erythromycin- felodipine interaction: magnitude, mechanism, and comparison with grapefruit juice. Clin Pharmacol Ther 1996 July;60(1):25-33. (9) Molden E, Andersson KS. Simvastatin-associated rhabdomyolysis after coadministration of macrolide antibiotics in two patients. Pharmacotherapy 2007 April;27(4):603-7. (10) Trieu J, Emmett L, Perera C, Thanakrishnan K, Van Der WH. Rhabdomyolysis resulting from interaction of simvastatin and clarithromycin demonstrated by Tc-99m MDP scintigraphy. Clin Nucl Med 2004 December;29(12):803-4. (11) Dresser GK, Spence JD, Bailey DG. Pharmacokinetic- pharmacodynamic consequences and clinical relevance of cytochrome P450 3A4 inhibition. Clin Pharmacokinet 2000 January;38(1):41-57. (12) Fux R, Morike K, Prohmer AM, Delabar U, Schwab M, Schaeffeler E et al. Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study. Clin Pharmacol Ther 2005 October;78(4):378-87. (13) Spence JD. Polypill:for Polyanna. Intl J Stroke 2008;3(2):92-7. Competing interests: None declared