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Rapid Responses: Rapid Responses published:
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Costing the polypill, £60 per year.
- john s ashcroft (27 June 2003)
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More Compelling Evidence
- William E. Osmun (27 June 2003)
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Beware the Epidemiology
- Bruce Bain (27 June 2003)
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Good news: All we need to do now is get people to prescribe it and then take it...
- Alexander M Clark (27 June 2003)
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correction to cost of prescribing polypill
- john s ashcroft (27 June 2003)
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Now who's playing God …
- Steve Taylor, Angela Konings (27 June 2003)
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Pilly Polly Doo Dah all the way
- Malcolm Kendrick (27 June 2003)
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PolyPill may not decrease all-cause mortality
- Eddie Vos (27 June 2003)
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Only 80% reduction? Why not go for 100%?
- Barry A Groves (27 June 2003)
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Whose Life Is It Anyway? The Polypill May Increase Health Inequalities
- Michael A Soljak (27 June 2003)
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Shabby Medical Thinking
- Nicholas M Regush (27 June 2003)
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A gauntlet thrown at drug companies or doctors?
- Richard G Fiddian-Green (28 June 2003)
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The 'Vacca Foeda' PolyPill
- Joseph .C. Obi (28 June 2003)
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Impact of single normal dose blood pressure medications
- Bala Subramanian (28 June 2003)
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Polypill drawbacks and multivitamin as alternative
- BIll Sardi (28 June 2003)
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The Big Issue
- Dan Rutherford (28 June 2003)
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new paradigm
- Martin R Innes (28 June 2003)
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Dumbfounded
- Peter J Hosein (28 June 2003)
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Can anyone afford to live a very long life?
- Mark Hochhauser, Ph.D. (29 June 2003)
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A Sad Day For British Medicine
- Allan Withnell (29 June 2003)
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Also dumbfounded
- Margaret J Tyson (29 June 2003)
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Treat people not populations
- Eugene A. Rybinski (29 June 2003)
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polypill ; for all races, sexes and seasons ?
- Adesuyi Ajayi, Southern Univ. 3100 Cleburne Ave, Houston TX77004 (29 June 2003)
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Old joke and current practice
- Adrian K Midgley (29 June 2003)
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What do we die then?
- Roger Wanner (29 June 2003)
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WHEN?
- Linda L Gimnich (30 June 2003)
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About as believable as the tooth fairy
- Adam Jacobs (30 June 2003)
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A pill a day keeps health away?
- Ewan Hamnett (30 June 2003)
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Shame on you BMJ!!
- Michael C Bunbury, Me (30 June 2003)
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Nearer 66% rather than 88% IHD risk reduction after 2 years?
- Eric S. Kilpatrick (30 June 2003)
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POLYPILL, AN IDEA, PERHAPS A VERY GOOD ONE, BUT NOT A JOKE
- CELIO LEVYMAN,MD,MSc, CEP 06454-030 (30 June 2003)
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Relative risks and meta-analysis
- J Michael Henk (30 June 2003)
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Unbelievable and unachievable
- Mark J Garton (30 June 2003)
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Multiple Polypill Benefits
- Gerard T O'Brien (1 July 2003)
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WHO should convene an aspirin meeting?
- Gareth P Morgan (1 July 2003)
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POLYPILL AGAIN,BUT IN THE THIRD WORLD
- CELIO LEVYMAN,MD,MSc (2 July 2003)
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Patients before populations
- Peter N Trewby, Catherine Trewby (2 July 2003)
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Polypill treatment and the physical properties of blood.
- Leslie.O. Simpson (2 July 2003)
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Re: Shame on you BMJ!!
- Daniel Weyandt (2 July 2003)
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Reality check
- Mike Schachter (2 July 2003)
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Brave New World
- Joachim P Sturmberg (2 July 2003)
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Polypill Choices
- Shah M Tauzeeh (2 July 2003)
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Concept is correct
- Paul W Masters (2 July 2003)
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Logical consequence of current polypharmacy
- Dr. Matthew L Grove (2 July 2003)
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What must be done now.
- William Plummer (2 July 2003)
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Aspastatapril vs Polypill
- Ketan K Dhatariya (2 July 2003)
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Compliance with the Polypill
- Anita Sainsbury (3 July 2003)
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Re: What must be done now - correction.
- William Plummer (3 July 2003)
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Is The Paper a Spoof?
- David A Brodie (3 July 2003)
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Dubious mathematical assumptions
- David M Reith (3 July 2003)
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Total Mortality
- Jeffrey R Johnstone (4 July 2003)
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Modelling and assumptions need clarification
- Tom Fahey, Alan Montgomery, Yoav Ben Shlomo (5 July 2003)
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Polypill Debate
- Stephen J Redmond (5 July 2003)
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Cat amonsgt the pigeons
- Adam L Brown (5 July 2003)
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Eradicating cardiovascular disease with polypharmarcy: Dream or reality ?
- Peter Marckmann (6 July 2003)
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Willing suspense of disbelief
- Elved B Roberts (7 July 2003)
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'Magic pill' approach would shift focus from proven and cost-effective CVD prevention
- Derek Yach, Shanthi Mendis, JoAnne Epping, Ruth Bonita, Amalia Waxman (7 July 2003)
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Salicylate deficiency
- Gareth P Morgan (7 July 2003)
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we should ask patients
- Alejandro F. Luque-Coqui (8 July 2003)
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Reducing cardiovascular disease by taking a "polypill" hope or hype?
- Marcus Flather, Anil. K. Taneja, Diego Perez de Arenaza (9 July 2003)
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The Polypill and prevention of Coronary Heart Disease
- Daan Kromhout, Henry Blackburn, Alessandro Menotti, and Hugo Kesteloot (10 July 2003)
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Re: PolyPill may not decrease all-cause mortality
- Alejandro F. Luque-Coqui (10 July 2003)
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The fundamental principle of western medical science is the principle of scientific testing
- Jeffrey Mann (10 July 2003)
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Polypill for older adults.
- Nandkishor V Athavale (10 July 2003)
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Polypill versus conventional preventive care
- Barry Lewis (11 July 2003)
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Incredulous of middle England !!
- Saul G Myerson (11 July 2003)
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Misplaced notions of simplicity, denial of complexity
- Lawrence J. O'Brien, Arlington, VA 22209 (11 July 2003)
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Re: Re: Shame on you BMJ!!
- Michael Bunbury (12 July 2003)
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Questionable benefit from polypill treatment.
- Uffe Ravnskov (13 July 2003)
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The ‘polypill’: medical myth versus balanced judgement
- Ian F Godsland, Victor Wynn (14 July 2003)
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CARDIOVASCULAR PREVENTION AND THERAPY
- Andrea Alberto Conti, Gian Franco Gensini (15 July 2003)
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Poly-drug to reduce cardiovascular disease
- Dietmar Fuchs, Schroecksnadel Katharina, Frick Barbara (18 July 2003)
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The wonderful poly-pill
- Miguel E. Campos, None (19 July 2003)
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Potential Issues
- Robert Kerr (23 July 2003)
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Concept of Poly-Pill contrary to medical judgement
- Munir E Nassar, M.D., N/A (25 July 2003)
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The Nays Have It
- John A. DePoy, BS, MSc, MBA, Milwaukee, WI 53217 (26 July 2003)
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The “polypill” strategy in high-risk Australian CVD patients
- Christopher M Reid, Sloane Birrell, Melinda D. Rockell (28 July 2003)
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Markov models deserve scientific scrutiny too.
- Christopher J Martin, French J, Vanderpump M (29 July 2003)
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Noncompliance with hypertensives
- Christopher J Squire (30 July 2003)
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Risks with the "Polypill" in the Oldest Old
- Sven E Nilsson, Stig Berg (13 August 2003)
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delay vs prevention
- gerry e burns (15 August 2003)
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Why not Omega-3 fatty acid as part of Polypill ?
- William K Smith M D (17 August 2003)
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Enter...The 'Omnipill'
- Joseph .C. Obi (18 August 2003)
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Omega-3 fatty acids and brown fat.
- Richard G Fiddian-Green (19 August 2003)
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We are headed toward a healthcare crisis fast enough, thank you.
- Philip King, D.Ph. (20 August 2003)
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A natural mini polypill: Potential impact on population cardiovascular risk of a daily drink of milk
- Gary A Wright, Allan D. Struthers (22 August 2003)
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The Polypill and Ayurdeva
- Rajeev Gupta (28 August 2003)
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What's really behind the antagonism for the polypill?
- James G Penston (1 September 2003)
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drug interactions
- Teresa Tarnowski Goodell, RN (18 September 2003)
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Reducing Cardiovascular Disease
- William E. Feeman Jr., William E. Feeman, Jr., M.D. (19 September 2003)
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polypill - why not ? polypharmarcy is practised !
- das sabapathy (4 October 2003)
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Methodological issues remain unanswered
- Tom Fahey, Alan A Montgomery, Yoav Ben-Shlomo (31 October 2003)
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Polypill-Pr, a new formulation for the mature male
- A. Mark Clarfield (30 January 2004)
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Re: Polypill- adding osteporosis treatment restores gender equality at 8 all
- Jeremy G Jones (1 February 2004)
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Methodological issues remain unanswered - Authors' response
- Nicholas J Wald, Malcolm R Law, Joan K Morris (8 March 2004)
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Polypill a life…in
- Guy-André Pelouze (19 March 2004)
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john s ashcroft, general practitioner old station surgery,heanor rd, ilkeston,derbyshire,DE7 8ES
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Wald and colleagues make no attempt at pricing the polypill, or the costs of treating all people in the UK over the age of 55, as they propose. As they point out many of the agents you may wish to use are of patent. With the help of the BNF, and a few helpful internet sites (www.21.cep.com/drug) I have attempted to do this. The BNF price of a bendrofluazide 2.5mg tablet is 2.5p and includes the cost of packaging, calender pack and patient information leaflet. Adding in extra components at there bulk ingredient cost per tablet the beta blocker, bisoprolol, 5mg @ $2,800/kg....0.67p the ACE inhibitor, lisinopril,5mg @ $2,200/kg....0.5p aspirin 75mg adds a suprising 0.5p/tablet, while folic acid 0.8mg, only 0.1p. Simvastatin adds to the bulk of the cost, but as from may 2003 it is off patent and available as generic.In bulk 40mg of simvastatin at $2450/500g adds 12p/tablet, for a grand total for this polypill of 16.4p/day or £60/year. Approximately one third of the UK population is over the age of 55 years,or 20 million people. The polypill as discribed here would cost the NHS approximately £120 million/year. Considering the NHS spent £571 million on lipid lowering drugs alone last year, this should not be a problem, indeed the NHS would save £450 million/year if the polypill was available. However, a note of caution, the price of ingredients has little to do with price the NHS decides to pay, even for of patent drugs, The NHS is still paying £29.69 for 28days of simvastatin at only 20mg, while even the US Millitary pay only pay approximately £7.50 on their contract with Merck & co.(www.pec.ha.osd.mil), and over £25/pack of omeprazole 20mg, even though it has been of patent for more than a year, and parmacists are paying less than a quarter of that price. Competing interests: None declared |
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William E. Osmun, Assistant Professor, University of Western Ontario Mount Brydges, ON N0L 1W0
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I am just wondering if the 'compelling' observational evidence that lowering serum homocysteine reduces heart disease is as 'compelling' as the observational evidence that estrogen did the same thing. Competing interests: None declared |
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Bruce Bain, Senior Medical Officer 8 Wing Medical Squadron, 8 Wing Trenton, Trenton,ON, Canada
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Sir, I read with interest the article by Wald and Law. A fascinating analysis. However, I can't help but think of the statistical data presented to us a few years ago concerning the DEFINITE benefit regarding cardiovascular disease that we could achieve if we put all our post-menopausal female patients on hormone therapy! I believe it is very dangerous to take bits and pieces of research and cobble it together and come up with a major conclusion such as this. Although I agree there are premature deaths due to cardiovascular disease, surely something has to get us in the end! There will always be a "Number One" cause of death; we are not, after all, immortal. I suspect if we could get everyone a bit more active and outlaw smoking, we would see some very dramatic changes. Indeed, cardiovascular disease already seems to be on the wane (according to some other epidemiologists!). However, the authors are probably correct in saying the population at large would probably rather just take a pill, as we do for so many other things these days. I'm sure the drug companies will be ecstatic having all of us taking medication once we hit 55. Shares in Glaxo-Wellcome anyone? Competing interests: None declared |
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Alexander M Clark, Assistant Professor Facult of Nursing, University of Alberta, Edmonton, AB. Canada. T6G 2G3
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The paper by Wald and Law 1 details a creative yet sensible approach to reduce cardiovascular disease. The evidence for the cost-effectiveness of the drugs that are proposed to be included in the Polypill is well established and the idea for general provision to those over 55 years of age well placed. However, to what degree a single pill constitutes a strategy is debatable. Medications for cardiovascular disease that have been known to be effective for some years are often not prescribed 2 nor taken by patients 3. These patterns are identified across all fields 4. Though provision of medication via a single pill is likely to increased compliance, patient beliefs regarding medications exert a very strong influence on whether medications are consumed 4. Further, medications are least likely to be taken if they are preventative as opposed to curative4. Any strategy that aims to reduce cardiovascular disease by 80% therefore requires to address not only medications but health care systems, professionals and patients. Using a approach based on concordance 5 6, professionals need to acknowledge the influence of patients’ beliefs and attempt to come to mutual agreements about medication regimen. 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. British Medical Journal 2003;326:1419. 2. Euroaspire II Study Group. Lifestyle and risk factor management and use of drug therapies in coronary patients from 15 countries. European Heart Journal 2001;22:554-572. 3. World Health Organisation. Adherence to long-term therapies: evidence for action. Geneva: WHO, 2003. 4. Cater S, Taylor D, Levenson R. A question of choice- compliance in medication taking. London: Medicines Partnership, 2003. 5. Mullen PD. Compliance becomes concordance. BMJ 1997;314:691. 6. Royal Pharmaceutical Society of Great Britain. From compliance to concordance : towards shared goals in medicine taking. London: RPS, 1997. Competing interests: None declared |
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john s ashcroft, general practitioner old station surgery,ilkeston,derbyshire,DE723EA
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The cost of prescribing to 20million people a polypill costing £60/year is £1200 million/year. Competing interests: None declared |
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Steve Taylor, GP Auckland, New Zealand, Angela Konings
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The implications of Wald & Law's paper are truly monumental. Whilst scientifically brilliant and Nobel-ian in their relevance, they are simultaneously unsettling and even alarming. The impact of such a low-cost initiative upon individual and population based health parameters is potentially enormous. But having, at a stroke, (to coin a phrase), slashed the risk of cardiovascular disease – what then for humanity? Will everyone be that much healthier, happier and productive in their lives? As GPs we have many patients nowadays whose cardiovascular problems have been managed by control of their blood pressure, reduction of their LDL and the use of aspirin. Yet they continue to get older, and they continue to develop other problems - often of a serious, debilitating, and very long term nature. We can be sure that the pharmaceutical companies, having 'lost' the cardiovascular market to the low-cost generic polypill, will concentrate their efforts on other avenues, so is it only a matter of time before we hear of suggestions to produce 'polypill mark 2'? Perhaps containing glucosamine and chondroiton, a cox-2 inhibitor, a proton pump inhibitor, a calcium homeostatic agent, a memory enhancing agent and others? And, for this part of the world, something to prevent the total failure of the skin induced by UV exposure? And how long will it before the polypill becomes a part of veterinary science? We're all still mortal and perhaps as clinicians this is the most important message for us all to remember. Which is more important: quality or quantity of life? Or how do we achieve a balance in that? Because it's not science that poses the hardest questions, it's the ethics and morality of what we are doing. Doctors used to be accused of 'playing God', although for a generation or more society has done its reasonable best to knock that out of us. But, perhaps its time has come again? Competing interests: None declared |
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Malcolm Kendrick, Medical Director Adelphi Lifelong Learning Adelphi Mill, Bollington, Macclesfield, Cheshire SK10 2TH
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It is almost impossible to know where to start in responding to this article. I will restrict myself to one part of their polypill concept, namely the benefits of blood pressure reduction. I will quote, highlights, from the European Heart Journal. 'Stamler stated 'the relation of SBP to risk of death is continuous, graded and strong, and there is no evidence of a threshold... The formulation of this 'lower the better' principle, in terms of the linear logistic model is the paradigm for the relationship of all cardiovascular risks to blood pressure and forms the foundation for the current guidelines for hypertension... Twenty years ago Keys, using simple graphical methods, concluded that the linear model, in terms of the relationship of overall and coronary heart disease death to blood pressure was unjustified. Could Keys be correct? To see, we reexamined data from the Framingham Heart Study. That carefully conducted and most widely cited study played a seminal role in firmly entrenching the current linear thinking on blood pressure.... We limited our analysis to the 18 year follow-up data. The use of the full (34 year) data would have introduced serious confounding in the natural relationship of cardiovascular risk to blood pressure, which was our primary interest. Shockingly, we have found that the Framingham data in no way supported the current paradigm to which they gave birth. In fact, these data actually statistically rejected the linear model. This fact has major consequences. Statistical theory now tells us that the paradigm MUST be false for the target population of the study.' Port S et al 'There is a non-linear relationship between mortality and blood pressure' European Heart Journal (2000) 21 1635 - 1638 In the area of blood pressure reduction Law and Wald are using a model of blood pressure reduction that is almost certainly wrong. I believe that their other models are also wrong, but this is a rapid response, not a PhD thesis. Yet, on the basis of a horribly flawed analysis Law and Wald recommend that everyone in the Western World should be taking six different drugs for the rest of their lives. Any moment now I am expecting an article to appear in the BMJ written by the Red Queen, entitled 'Everyone is ill, and all shall have medication.' Competing interests: None declared |
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Eddie Vos, maintains http://www.health-heart.org Sutton (Qc) Canada J0E 2K0
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While folic acid [with vitamins B2, B6 and B12] lowers homocysteine which well may be causal to athero-sclerosis, non of the other ingredients of PolyPill [aspirin, statin, blood pressure drugs] deal with underlying root causes of vascular disease. Even in "high risk" populations, statins failed to reduce OVERALL mortality in ALLHAT, PROSPER and ASCOT while numbers needed to treat for 1 year to postpone one death in HPS was about 300. These are the last 12 months of statin trials. The concept of all-cause mortality is glaringly missing in the Law/Wald analysis. Maybe, Editor Smith's editorial idea is a good one: adding red wine in a pub would raise HDL-cholesterol. Let me propose that jogging from pub to pub would add another HDL raising exercise component while avoiding the danger of driving on heart-healthy alcohol, but not that of liver toxicity and addiction for some. In any approach, from statin via alcohol to aspirin, the focus should be on overall health, overall mortality and safety, and only the multivitamin/folic acid approach is totally safe while dealing with underlying processes, in part or largely through proven homocysteine reduction. Competing interests: None declared |
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Barry A Groves, Independent researcher OX7 6LP
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I have read some rubbish in my time, but this just about takes the biscuit. Let’s take this to its logical conclusion and put every drug known to medical science in the water supply. That way we will prevent and cure every disease Man is subject to. And we can all live happily ever after. Diseases will be abolished overnight; doctors will all be redundant; the NHS will no longer need vast sums of money, and we will all be, not only healthier, but wealthier. Or, of course, we could cut mortality by 100% by preventing the most important “risk factor” of them all – being born. Competing interests: None declared |
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Michael A Soljak, Consultant in Public Health Medicine North West London Strategic Health Authority
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Assuming that the strategy advocated by Wald and Law in their paper in this week's BMJ (1) is cost-effective, a major concern is that its implementation may further increase socieoeconomic inequalities in health. Two small surveys have investigated the absolute benefits of treatment different groups would require before starting treatment themselves. A survey in Norwich showed that the threshold for numbers needed to treat chosen by consultant physicians was twice that chosen by general practitioners and three times that chosen by nurses and the public (2). In a survey in London general practices, doctors and other health professionals chose treatment for smaller absolute benefits than patient groups; patients from an inner city practice chose higher benefits than patients from a suburban practice, and homeless people chose the highest absolute benefits (3). It is likely that these differences are a result of confounding with socioeconomic class. A recent review of patient involvement in decision- making noted that research in this area has underemphasised the effects of social structure in the construction of health beliefs and subsequent behaviour, as well as the effects of sociodemographic characteristics, social circumstances, and group influences (4). In their review of the relation between income and health, Marmot and Wilkinson show that a consistent finding of analyses of how subjective well-being varies with income is that richer people are, on average, more satisfied with their lives than their poorer contemporaries (5). It seems plausible that patients "quality adjust" the predicted benefits of preventative healthcare on the basis of their personal expectations of the life years to be gained. Wald's and Law's proposal therefore has major political and ethical implications which should be widely debated. In the absence of a radical improvement in the expectations of the relatively poor, is saving a wealthy life year more valuable? Or should NHS resources be directed at reducing inequity in life expectancy by persuasion if necessary? 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-0. 2. Steel S. Thresholds for taking antihypertensive drugs in different professional and lay groups: questionnaire survey. BMJ 2000;320:1446-1447. 3. Lewis DK, Barton S. Who decides when to start preventive treatment? A questionnaire survey to compare the views of different population subgroups. J Epidemiol Comm Health 2003;57:241-242. 4. Bowling A, Ebrahim S. Measuring patients' preferences for treatment and perceptions of risk. Quality in Health Care 2001;10:i2-i8. 5. Marmot M, Wilkinson RG. Psychosocial and material pathways in the relation between income and health: a response to Lynch et al. BMJ 2001;322:1233-1236. Competing interests: None declared |
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Nicholas M Regush, Editor, redflagsdaily.com Montreal, Canada H3G 1Z9
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What is this wonder pill all about? It's a combination pill that everyone over the age of 55 (or younger) would take – and could reduce the incidence of cardiovascular disease by over 80%. Really? Is there actual direct data for this humdinger? No, there is not. The authors propose this idea based on a review of other studies, and strangely believe that the indirect data all could add up to a huge reduction in the incidence of cardiovascular disease. This has got to be one the most egregious presentations that I have ever come across in all my years as a health reporter, both in the print world and at ABC News in New York. That the authors actually appear to have the support of the editor of the British Medical Journal is truly amazing – and dangerous. All these so-called health professionals actually have convinced themselves that if you put six different drugs together, they will all add up to one big cure of sorts. This is not only junk science at its worst, but reveals the sloppy intellectual processes going on these days in medical science, in focusing attention on such complex issues (and controversial ones, I might add) surrounding cardiovascular disease. Furthermore, to assume that each and every one of these drugs used for different strategic purposes in the battle against heart disease is, for one thing, the best approach in providing treatment for heart trouble, and then to assume that you can batch them, on the basis of what they appear to be doing on their own, is Fool’s Gold. Can we please have some real science conducted, preferably research that deals with safety and efficacy before we become enchanted with a polypill idea? Any serious discussion about incorporating a variety of theories about cardiovascular disease into one product package, which is what this entire issue amounts to, reveals a total disregard for scientific principles and for the human condition, which is far more complex than these authors seem to think. Competing interests: None declared |
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Richard G Fiddian-Green, None None
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The Polypill is an appealing idea but specifically addresses risk factors for cardiovascular diseases to the exlusion of other diseases notably cancers. Furthermore whilst not specific for statins per se there was a trend (p=0.06)towards an increase in suicides, accidents, and trauma in a meta-analysis of the effects of cholesterol reduction on mortality from all causes(1). There are rational reasons, inhibition of coenzyme Q synthesis, for believing that there may well be an increased risk in suicides, accidents, and trauma and other causes of mortality associated with statin usage (2,3). The longer the usage the greater the risks, and it is early days yet in the statin trials. There may also be a risk of developing chronic diseases such as heart failure, that is echocardiographic evidence of altered myocardial size and function. The authors acknowledge that they are treating risk factors, which might be effects which may well be secondary causes, rather than the primary cause of the cediovascular diseases. Anytime one treats an effect rather than a cause there is a risk of unintended consequences, such as an increase in suicides, accidents and trauma. Until the primary cause or causes of all diseases is defined, and that could be closer to reality than commonly supposed, the sooner doctors will stop flying by the seat of our pants as they have done since antiquity. I would not bet on this issue being the most important issue of the BMJ in decades unless the Polypill has been proposed with the specific intent of provoking a legal confrontation with the drug industry. It is not the drug companies that are at fault. It is us, the doctors. 1. Cholesterol reduction and non-illness mortality: meta-analysis of randomised clinical trials Matthew F Muldoon, Stephen B Manuck, Aaron B Mendelsohn, Jay R Kaplan, and Steven H Belle BMJ 2001; 322: 11-15. 2. UPDATE: Statins Lack Mortality Benefit Eddie Vos bmj.com/cgi/eletters/321/7267/983#29001, 22 Jan 2003 3. Re: update on statins and mortality Richard G Fiddian-Green bmj.com/cgi/eletters/321/7267/983#29013, 22 Jan 2003 Competing interests: None declared |
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Joseph .C. Obi, Chief Consultant WellnessClinics.co.uk
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10.1mg of Common Sense 22.5mg of Epidemiology 15.6mg of Critical Appraisal 49.5mg of Biostatistics 77.2mg of Pharmacology 94.8mg of Remorse Dosage: One wee little capsule daily. Swallowed whole. Duration : For Life Indication: 'Tiresome' and 'Under-employed' Editors Competing interests: Dr Joseph Chikelue Obi MBBS MD MPH DSc FRIPH is also the Chairman of the General Wellness Assembly (GWA); an International Professional Body for Independent Wellness Consultants |
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Bala Subramanian, Consultant cardiologist(Retired) Harrow HA3 9XE
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I have been advocating and using a combination of statins, folic acid, aspirin and a blood pressure lowering drug such as beta blockers, calcium channel blockers or ace inhibitors if indicated for over 8 years. I normally use full dose antihypertensive medication usually in combination therapy in hypertensives, ACE inhibitors in heart failure and beta blockers to control synptoms of Ischaemia.
Such strategies in non surgical management of Ischaemic heart disease over the last 10 years have yielded extremely favourable results in my patients and I have advised a company to market a polypill with 4 components named 4URHEART which is commercially available.
A question to the authors:How is the risk modified by use of either one or two drug antihypertensive treatment in hypertensives and what is the risk factor reduction if any in normotensives?
What are the side effects in persons with low blood pressure?
The authors have come to a conclusion that use of three antihypertensive medications in lower than normal therapeutc doses has the same effect as full dose of a single drug. This is an important statement and would encourage the widespread use of these drugs as indicated in the article.
I congratulate the authors for an extremely important and practical contribution.
Bala Subramanian
Competing interests: None declared |
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BIll Sardi, President, Knowledge of Health, Inc. 457 W. Allen Ave. #117 San Dimas, CA 91773 USA
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The originators of the polypill (5 drugs + 1 vitamin) concept have launched a rather admirable and bold attempt to prevent rather than just detect and treat cardiovascular disease. Yet, according to the Drug- Induced Nutrient Depletion Handbook, 2nd edition (2001, Lexi-Comp), some of the ingredients in the polypill could induce shortages of nutrients essential for cardiovascular health. Examples are statin drugs which deplete coenzyme Q10, diuretics which deplete electrolytes (magnesium and potassium), aspirin which depletes folic acid, potassium and vitamin C. The projected 80 percent reduction figure in cardiovascular risk needs to be clarified since the studies cited to substantiate the polypill used relative reduced risk data rather than hard numbers. Out of 100 users of polypill, how many could be expected to benefit (alleged 11-years of added life)? -- Bill Sardi Competing interests: No direct competing financial interests (write and sell books on nutrition) |
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Dan Rutherford, GP & MD of www.netdoctor.co.uk St Andrews, Fife, KY16 8LP
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No government, or doctor, has to my knowledge ever received a mandate from the public to restrict medical care based on the principle of treating the most 'at risk' first (this is never more than a smoke screen for inadequate resources). It's therefore to the good that Wald & Law propose a risk reduction treatment across the board, subject only to clinically sensible restrictions on who should get it. One thing worries me though. Why have they patented this idea? I'll be suitably impressed if it's to prevent Big Pharma from doing the same thing and profiting from something that potentially should be cheap and very widely affordable. Of course that'll also mean that they hand over the patent to the World Heath Organisation or the like who can administer it for the public good. Competing interests: None declared |
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Martin R Innes, GP-Principal Ravenswood Surgery Johnstone PA5 8SO
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I was under the impression that "new paradigm" thinking involved "mind/body/spirit" approaches . Indeed the BMJ of Christmas 2002 stated if we did not address spiritual issues concerning our patients , we were missing the boat.The Japanese are classified as the healthiest nation-can we find anything in their philosophy that entertains polypills-I think not.Are we not to learn from those that are successful? And what happened to the notion of encouraging the body's own natural healing responses? It is one of the tenets of complementary medicine-and the public do seem to be responsible for a significant rise in it's popularity(they seem to know what the like).Or are we to stick with the same old Cartesian model .I ,for one , will stick with trying to assist the body in helping itself . Competing interests: None declared |
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Peter J Hosein, SHO Trinidad, West Indies.
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I would like to add my voice to those who are truly dumbfounded that an article like this could find its way into the pages of the BMJ, with the whole hearted support of the Editor. I first learnt of the Polypill while watching CNN over breakfast this week and I scurried over to the BMJ's website, expecting to find a well designed prospective trial evaluating this wonder pill...only find a series of meta-meta-analyses and promises of theoretical benefit for a combination drug that has not yet been formulated. If this is the most important BMJ issue for 50 years then I'm glad that I never had a subscription. I will save my enthusiasm for the day when the evidence for efficacy and safety of the Polypill is published. Competing interests: None declared |
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Mark Hochhauser, Ph.D., Readability Consltant Golden Valley, MN USA 55422
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The Polypill, if successful, may add decades to a patient's life. While this may be a desirable end medically, a relatively rapid extension of everyone's lifespan has monumental societal consequences. If this pill extended the average lifespan to 100, people would spend about 35 years in retirement--but can people save enough money during 45 years of work to pay for 35 years of retirement? The US Congress is debating ways to pay for prescription drugs for Medicare patients, many of whom are spending a large percentage of their income on prescriptions. Will patients be able to pay prescription drugs costs for the one-third of their life they'll be retired? If people live to be 100, it won't be unusual to have two (or even three) retired generations in the same family. Will employees be able to pay the huge payroll taxes needed for Social Security and Medicare benefits for their retired parents and grandparents? Will employers be able to offer employee health benefits after retirement if such benefits continue for 35 years? An effective Polypill will have consequences for families, communities, health care systems, social service agencies, businesses and goverment programs, impacting virtually every part of society in ways that have not yet been identified or addressed. Competing interests: None declared |
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Allan Withnell, Retired Compton Court, Compton Green, Gloucester. GL19 3JB
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EDITOR-Your editorial marks a sad day for British Medicine(1 We shall never reduce the increasing costs of the NHS unless we encourage people to take more responsibility for their own health. Nathan Pritikin and others have shown that it is possible to prevent and cure coronary heart disease and other degenerative diseases by diet and exercise alone. The reasons with references are set out in my recent paper(2). (1)Editoral. BMJ 28 June 2003. (2)Withnell,A.(2003). The Natural Cure of Coronary Heart Disease. Nutrition and Health, Vol.17, pp.55-60. Competing interests: None declared |
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Margaret J Tyson, Director The Orchard, Woodseats Lane, Charlesworth, Glossop SK13 5DP
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I would like to say that I couldn’t agree with “Dumbfounded” more! Without a full trial how can the claim be made that cardiovascular risk is reduced by 80% by the “Polypill”. Haven’t the authors heard of synergistic and antagonistic effects? Secondly, if the Polypill were brought into existence people would feel free to eat what they felt like, lower exercise levels and forget all previous advice. This would lead to an increase in obesity and more particularly of Diabetes II with all its effects. We would therefore see an increase in limb loss, blindness, kidney problems etc. This could lead to a cancelling out of any benefits of the Polypill. The Polypill is a recipe to increase patients’ dependence on the NHS when a preventive lifestyle should be hammered home so that people take responsibility for their own lives. And where this is unsuccessful what’s wrong with diagnosing and prescribing medications for individual lifestyle problems? Isn’t the NHS supposed to be about treating the individual? Competing interests: None declared |
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Eugene A. Rybinski, General Practitioner Burncross Surgery,Sheffield,S35 1RN
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Wald and Law's 'polypill' is an intriguing proposition.Their calculations are based on pooled data in large populations. While it may be true that age is the single most predictive factor for the development of cardiovascular disease,within group variation is likely to be large.Where it may not be possible to separate populations on the basis of multivariant analysis, individuals with low and higher abolute risk can be identified. As epidemiologists Wald and Law do not have to concern themselves with the difficult matter of dealing with individual patients,some of whom are well informed and may pose searching questions.I suspect that most subjects would not be interested in taking a 'polypill' in order to reduce the population burden of disease.People are more likely to be concerned with their own individual absolute risk of disease,the treatments which may safely reduce that risk and the burden of costs they have to incur in order to obtain the benefit. If all those over 55years are treated then a large number with low absolute risk will incur no benefit.I propose that the well informed customer would prefer to go for individual risk analysis,a policy that may thwart well intentioned epidemiologists. Competing interests: None declared |
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Adesuyi Ajayi, Adjunct Professor of Medicine/ Sr Scientist Ctr for CardiovascularDiseases, Texas, Southern Univ. 3100 Cleburne Ave, Houston TX77004
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Drs Wald and Law are to commended for the rare insight and ingenuity, in the advocacy of polypill to prevent and treat cardiovascular diseases. There are however, unanswered questions regarding the global applicability of their proposed pill , by ethnicity and gender. There are established racial differences in the monotherapeutic response to ACE inhibitors and beta -blockersin hypertension. Blacks respond poorly and the Chinese respond perhaps too well. Whites are intermediate. Aspirin efficacy may be gender dependent, since TXA2 receptors is under androgenic regulation and also exhibits a pharmacogenetic polymorphic response. Aspirin may also negate the beneficial actions of ACE inhibitors. Moreover, the benefit estimated at 80% reduction in cardiovascular end points may be an overestimation, because drugs such as aspirin and statins and ACE inhibitors may diminish platelet aggregation and thrombosis through Nitric oxide production as the final common path. Redundancy, may thus cause a less than additive beneficial cumulative effect. In blacks other risk factors are not factored in , such as the sickle cell trait [ hemoglobin genotype AS ] which acts as a subliminal accelerator of vascular disease and organ damage. I therefore strongly opine, that large multi-centered clinical trials in all races, gender should be conducted before the quantification of the benefits of this fixed drug combination can be known. It may be that many variants [ containing different doses of same constituents ]of the polypill may be the final answer to cardiovascular disease scourge in the 21st century. Prof AA Leslie Ajayi MD, Ph.D. Competing interests: None declared |
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Adrian K Midgley, GP Exeter EX1 2QS
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There has always been an element of truth in the old and slightly cynical description of "Gerifix" and "Gerifix Forte" - the common collection of medicines that many elderly medical patients find themselves on in and after hospital. Outside hospitals, in the effort to achive reductions in premature or avoidable cardiovascular death and disability we find there are many people who are actually taking all or most of the components of the "Polypill", and we have reasonable grounds to believe deriving benefit at least in the mass from doing so. Incredulous SHOs may yet hear of all these things, and may also learn that meta-analysis is commonly more reliable than inspecting the results of a single trial, particularly if its power is low. Good paper. There are a lot more bits of wisdom camouflaged as cynicism in the profession, and subjecting these "folk-stories" to scientific analysis is at least entertaining. Competing interests: None declared |
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Roger Wanner, student Switzerland
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Before the time of polypill cardiovascular events killed 50 percent of britains citizens. So what will be the causes of death in the next century? Diing of Polypills intoxication? Competing interests: None declared |
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Linda L Gimnich, Principal, TMNG 75243
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Please advise WHEN this would be available in the US OR could be purchased elsewhere. Being OVER 55, we do not want to waste any time, and take any more chances than necessary. Already have a high blood pressure problem & cholesterol, we REALLY want and need this....along with the rest of the population! THE WORLD REALLY NEEDS THIS.........NOW! Competing interests: None declared |
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Adam Jacobs, Director Dianthus Medical Limited, London SW19 3TZ
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It almost seems unnecessary to read any further than the title of Wald and Law’s paper to realise that it must be deeply flawed. The maxim ‘If it seems too good to be true, then it probably is’ tells us that anything claiming to reduce cardiovascular disease by more than 80% is unlikely to stand up to scrutiny. First, we are expected to believe that the relative risks of the separate ingredients are multiplicative. What is the evidence for this? It seems to rely on a failure to find modification of the effect of reducing one risk factor by the level of other risk factors. However, detecting such a difference (a statistical interaction term) usually requires greater statistical power than detecting a main effect. Were the trials Wald and Law cite in support of their claim adequately powered to detect the interactions? I doubt it. Looking closely at their suggestion that a statin can reduce IHD events by 61% shows more flaws. This seems to be based on the reduction expected on the basis of cohort studies if the reduction in LDL cholesterol of 1.8 mmol/l were achieved. First, the figure of 1.8 mmol/l is based on reductions achieved in patients with high LDL cholesterol, but we are told the Polypill is suitable for everyone irrespective of their cholesterol. And why look at cohort studies, with all their inherent biases and confounding, when we could look at randomised trials? In their subsequent paper, Wald and Law present the much less impressive data from randomised trials, which shows reductions in IHD events of about 20–30%. Only in a subset of trials selected on the basis of showing a large treatment effect did the reduction in IHD risk reach 50%. And does the claim of a 46% reduction in IHD from the antihypertensive components of the pill stand up to scrutiny? Well, no. It assumes that the antihypertensive effects of the three drugs are additive. In their third paper, Wald and Law present data showing that combinations of two drugs are additive (although not convincingly so), and then go on to make the untested assumption that combinations of three drugs would also be additive. And again, the expected reduction in blood pressure is based on patients with high blood pressure at baseline, and reductions in event rates are based on cohort studies, not on randomised trials. All this makes me wonder whether this paper was ever meant to be taken seriously. Perhaps it was simply part of an elaborate experiment designed to discover what the reaction of the journal’s readership and the popular media would be if a respectable medical journal published a load of complete bollocks. Competing interests: None declared |
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Ewan Hamnett, GP Principal Lordswood Medical Practice,54 Lordswood Road ,Birmingham ,B17 9DB
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If we were guaranteed never to have an accident or get caught for speeding would we drive slower? If I could print unlimited money in my attic would I spend less? If a pill is produced to reduce heart attacks by 80% will we excercise more and eat less? Richard Smith says this is a memorable BMJ.He may be right.This may be the day that the medical profession joins forces with the car and video game manufacturers to create a truly sedentary society! Competing interests: None declared |
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Michael C Bunbury, GP St Vincent, Me
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I am truly surprised that evidenced based medicine has taken such a strong grip on medical intelligence that even the editor of the BMJ could sanction a conclusion that defies even common sense. 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. So the message is "carry on smoking , grow fat on carbohydrates and hydrogenated fats and take a pill and you will live a normal healthy life?" Competing interests: None declared |
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Eric S. Kilpatrick, Consultant in Chemical Pathology Department of Clinical Biochemistry, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ, UK
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The main study finding of the paper by Wald et al(1) is shown in their table 1, where it is stated that 88% of IHD events and 80% of strokes can be avoided after 2 years of ‘Polypill’ treatment at age 55-64. I cannot help but question the validity of this assertion, both on statistical and evidence-based grounds. To use IHD risk as an example, Table 2 of the authors’ own subsequent lipid paper (2) suggests that only half of the ultimate IHD risk reduction in LDL lowering is present within the first 2 years. So rather than a 61% reduction by 2 years treatment, it will be nearer 30%. To justify the IHD risk reduction that triple therapy with antihypertensive drugs may bring, the authors, in their hypertension paper,(3) extrapolate from the Prospective Studies Collaboration. However, in this instance no attempt is made to estimate over what period of time (if ever) the treatment will have to be continued before this theoretical reduction in risk is met. Inclusion of homocysteine at all in the analysis seems premature due to the lack of evidence that lowering concentrations is of any benefit in primary prevention of IHD. We have learnt from recent definitive studies investigating antioxidant vitamins and hormone replacement that hypothetical reasons for treatment are not always a guarantee of benefit for real patients. At least the existing evidence for aspirin presented is more compelling, and suggests that the effect on risk reduction is rapid after commencing treatment. Overall, if antihypertensives are assumed to reduce risk at the same rate as statins, and homocysteine is removed from the model due to paucity of evidence, then the reduction in IHD risk after 2 years on the ‘Polypill’ falls from 88% to nearer 66%. Still impressive, admittedly, but if public health policy is to be changed on the basis of this evidence then, in view of this and other errors noted, we need to be sure that this is not only one of the most important papers published by the BMJ in the last 50 years, but also one of the most accurate. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419 2. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423 3. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003; 326: 1427 Competing interests: None declared |
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CELIO LEVYMAN,MD,MSc, Staff Neurologist Hospital Israelita Albert Einstein,Unidade Avançada Alphaville,Alameda Purus,105,São Paulo,SP,Brasil, CEP 06454-030
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Polypill, as Wald and Law propose in BMJ, sounds like an esoteric or miraculous marvel of the so-called “alternative” world, and most of us look at this kind of things with skepticism. However, although many rapid responses related to this despise the idea and even mock the subject, it has a strong point assured in the Editorial: the undeveloped countries. I live and work in one of these countries, and a very strange one: Brazil in a large amount of South America, with enormous very poor areas and, in Sao Paulo, my city, and in the Albert Einstein Hospital, my place of work, we have the best of the developed world – is the financial,cultural,research and technological center of all Latin America. However,even in the same city,there are blocks regarding New York City or London, and other like African countries… This is the “beauty” of globalization. But diseases, and cardio and cerebrovascular ones, don’t pay attention to these details, and we have a lot of people with overweight, smoking problems, cholesterol, blood pressure, etc., etc.The academic, evidence-based medicine is offered with primary and secondary prevention interventions, with gold standards, state-of-the art diagnostic and therapeutic weapons – but this is limited to Sao Paulo, Rio de Janeiro and other big cities middle to higher class citizens, with good health plans. The other millions of Brazilians have the public system to take care of them, named here as SUS, and I believe that I don’t have necessity to explain how bad it works. Even in a strange form, a unique pill, resemble such homeopath conducts, without all the absolute result of all investigations, low BP, use statins and aspirin there are not more in the center of the arena, right ?Perhaps folic acid. It is easy to make jokes or very rigid guidelines in relation to “polypill” in UK, USA, Canada, Europe and so. But here, in my real world, there is a lot of practical evidence to support these kinds of ideas. Of course, there are some problems to be solved, like hepatic function and statin, aspirin without gastric protection, interaction of drugs, bioavailability and so on. And the crucial point is one only pill for all kinds of people – but the paper is very important to very countries in the world, and these questions could be answered in a brief time. First world colleagues: do not work like in your countries, be more flexible and please, erase the yellow smile in your faces when someone talk or write about “polypill” or other similar ideas: in my country things could be very sad. Competing interests: None declared |
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J Michael Henk, Hon consultant clinical oncologist Royal Marsden Hospital, Downs Rd Sutton Surrey SM2 5PT
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EDITOR - The outcomes of clinical trials may look impressive when presented as relative risks, but less so when presented as absolute percentages or "numbers required to treat". Would Wald and Law be prepared to present their meta-analyses and estimates of the putative benefit of the combined pill in the latter manner, so that readers can estimate their individual chance of benefitting from taking it? Competing interests: None declared |
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Mark J Garton, Consultant Physician Perth Royal Infirmary, Perth, Scotland PH1 1NX
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EDITOR-Over a conference dinner last week, a respected professor confided that he found the quality of BMJ articles increasingly poor. As an avid reader and occasional contributor I felt obliged to defend the prestigious journal. Sadly the latest issue (28 June 2003) does appear to have wandered into tabloid-style medical journalism, and strays far from its self-declared aim to ‘publish rigorous, accessible and entertaining material that will help doctors and medical students in their daily practice, lifelong learning and career development’. The culprit article is perhaps entertaining but certainly not rigorous. Wald and Law make the spectacular claim that a suitably formulated ‘polypill’ would reduce cardiovascular disease by more than 80%.1 However they fail to take account of several important variables that would significantly degrade the alleged benefits of universal and long-term prescription of their wonder pill. Even if one generously agrees with the authors estimate that 88% of ischaemic heart disease events would be avoided (in reality deferred), the population burden would reduced by a much lesser proportion determined by completeness of healthcare registration,2 the likely response to an invitation to attend a clinic, and longer term issues of adherence and persistence with therapy. Assuming rates of 90%, 80% and 50% for these parameters, the projected benefits would be reduced by about two-thirds. It is also counterintuitive that the entire population should need pharmacological treatment to remain healthy. If the population exposure to cardiovascular risk factors is so grave then this is surely a mandate for action to reverse the trend. A robust food policy could encourage consumption of cardio-protective foods such as oily fish, nuts and berries, whilst reducing permissible levels of salt 3 and saturated fats in processed foods. Additional benefits would accrue from banning the sale of tobacco, clear guidance on the certain risks and doubtful benefits of alcohol consumption, and encouragement at all ages of increased physical activity. When describing strategies to prevent another public health problem (osteoporosis and hip fracture), 4 Wald et al., rejected the notion of universal treatment (with hormone replacement therapy) not on the grounds of efficacy, but rather potential cost and the need for life-long treatment. Instead they recommended cessation of smoking and regular physical exercise, ironically noting that such an approach would also protect against ischaemic heart disease. The authors might want to reflect on their previous advice before advocating universal pharmaco- therapy for cardiovascular disease prevention. Meanwhile the BMJ editorial team should consider how well they are meeting the journal’s own mission statement. 1. Law MR, Wald NJ. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003:326;1419-23. 2. Garton MJ, Abdalla M, Reid DM, Russell IT. Estimating the point accuracy of patient registers using capture-recapture analysis in Scotland. Journal of Epidemiology and Community Health 1996;50:99-110. 3. Selmer RM, Kristiansen IS, Haglerod A, Graff-Iversen S, Larsen HK, Meyer HE, Bonaa KH, Thelle DS. Cost and health consequences of reducing the population intake of salt. Journal of Epidemiology and Community Health 2000;54:697-702. 4. Law MR, Wald NJ, Meade TW. Strategies for prevention of osteoporosis and hip fracture. BMJ 1991;303: 453-9. Competing interests: None declared |
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Gerard T O'Brien, General Practitioner 38 Cecil St, Limerick ,Ireland
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The potential land-mark report by Wald and Law (1) based on meta- analysis, proposing a Polypill (or should that be 'multi-pill'?), represents a logical, relatively safe, effective treatment for prevention of cardio-vascular disease. The good cost-benefit ratio, and the fact that this is a 'first' should help its widespread uptake. Existing drug combinations include thiazides with beta-blockers, angiotension receptor blockers and ACE inhibitors- this pill would maximise the synergism involved with the latter two drug types. Already in Diabetes and many Cardiac disorders such multiple treatments are used, often in higher doses. The conclusions about relative safety of smaller doses of these medications represent what Doctors in Primary Care often empirically employ- ie half doses at least at first to ensure compliance, limiting side-effects. The safety of these agents are well established and the Statins in particular have now been shown to have broad indications far beyond dyslipidemias solely. (2). Indeed the Polypill emphasises the broad etiologies and therefore treatments needed- to the general public. Obvious contraindications as mentioned those with Asthma because of Beta-blockers and also the 10% of whom are allergic to Aspirin , also haemorrhagic disorders etc. Angioedema because of ACE inhibitors especially should be forewarned about and further mention of the fact that this can arise even after years of therapy should be made. In addition to the suggested labs, a serum B 12 level might be indicated given that Subacute Combined Degeneration of the Cord can be triggered in the undiagnosed case of Pernicious Anemia, while rare, by the use of Folate solely. Also Creatinine, Urea 2 weeks after starting the Polypill to exclude Renal Artery Stenosis. (because of ACE inhibitors). Dry cough might be a common finding in the population concerned given the ACEI though an ARB agent would lessen this significantly. Another treatment at least partially effective for this is the use of an Intal inhaler, given the histamine mechanism involved. (3) Other possible additives might include plant sterols -to further decrease cholesterol, plavix instead of/ or with aspirin, and for the obese patient Xenical-possibly in low dose. Timing for the pill? Might be an issue in that Statins are better taken at night while Aspirin and Anti-hypertensives are generally best taken in the morning. Long acting Statins such as Lipitor might be one solution. And for those trying to recall its constituents, an easy mnemonic abcdef would help. a for Aspirin, b for Beta-blocker, c for cholesterol -Statin , d for diuretic- thiazide , e for enzyme-ACE inhibitor, f for folate. In addition to less need for Cardiac Physicians and Surgeons, how about Neurologists (Stroke, possible Alzheimers, Multi-infarct Dementia etc) , Nephrologists (due to ACE inhibitors and better hypertensive management), Endocrinologists (possible lower DM incidence with ACEI), even Oncologists (possibly lower Cancer incidence with Statins. reference 4). Also psychiatrists (better overall health and less Cerebro-vascular disease), Orthopedists (less falls and fractures from reduced CVAs). Sales of Viagra might decline but with a greater older population who knows? One area of increased need, happily, would be Geriatrics. References 1. Wald NJ Law MR Strategy to reduce CardioVascular disease by more than 80%. BMJ 2003; 326: 1419-23. 2. Heart Protection Study Lancet 2002 July 6 360:7-22 and Lancet 2003; 2000-2001, 2005-2016. 3. Hardreaves MR Benson MK Intal Inhaler in ACE Inhibitor Cough Lancet 1995; 345: 13-6 4. Matthijs Graaf, University of Amsterdam. Lowered Kidney, Prostate Cancer with Statins. American Society of Clinical Oncology Annual Meeting 2 June 2003. Competing interests: None declared |
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Gareth P Morgan, Public Health Officer National Public Health Service for Wales, 36 Orchard Street, Swansea, SA1 5AQ.
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Aspirin reduces cardiovascular disease risk and is showing promise in reducing the risk of certain forms of cancer (1). Taking a low-dose aspirin (75-150 mg) with a bedtime drink from the age of 50 years (2,3) may have benefits similar to taking the ‘polypill’ from the age of 55 years. Furthermore, the former approach would be less expensive and have fewer undesirable effects than the latter. I believe that the disease reduction potential of aspirin needs to be raised. Perhaps the World Health Organisation should convene an international scientific meeting on aspirin without delay (4). References 1. Vainio H, Morgan G, Elwood P. The public health potential of aspirin. Pharmacol Toxicol 2002; 91(2): 49-50. 2. Morgan G. A quantitative illustration of the public health potential of aspirin. Med Hypoth 2003; 60(6): 900-902. 3. Hermida RC, Ayala DE, Calvo C, et al. Administration time- dependent effects of aspirin on blood pressure in untreated hypertensive patients. Hypertension 2003; 41(6): 1259-1267. 4. Morgan G. An international scientific meeting on aspirin is needed. J Epidemiol Community Health 2003; 57(5): 314. Competing interests: None declared |
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CELIO LEVYMAN,MD,MSc, Staff Neurologist Advanced Alphaville Unit,Albert Einsteom Jewish Hospital,Sao Paulo,Brazil
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Reading the other rapid responses about polypill, I want to make new comments. Of course, I agree in regard to many other responses, such as the polypill is one prevention measure to many different people; a journal like BMJ publish a paper without evidence-based approach; the problems that could appear when someone prescribe one pill to many different conditions, like type II diabetes, the statins collateral effects,etc.This is crystal clear in the mind of all good doctors.However,I claim again to the issue pointed in the Editorial and the comment I have made in a previous rapid response: these points,relatated by various physicians, are correct in all ways. But the question of undeveloped countries is very important: other prevention measures, like reduction of overweight, control of BP and a many other things occur only in developed areas of countries like Brazil. In my city and my place of work, I repeat, the Albert Einstein Hospital in Sao Paulo, we can apply all good points in Medicine. Einstein Hospital is accredited by the Joint Commission International, and our patients are in the high economical profile. In that cases, we use all international guidelines, and we have all diagnostic tools, from lab examinations to RM,PET,molecular measures, genetic approachs,etc.But in other places of the large country that is Brazil, are many regions without permanent doctors, and none diagnostic tools at all, including blood examinations, parasitological examination, and simple RX. Campaigns are a very difficult issue, because there are many illiterate citizens, and they use popular medicine and herbs, for example, to treat everything, and they don’t believe in a doctor when one appears. In the large forest rain region, the Amazonas state, are people that never have seen a physician in their life: perhaps twice in their lifespan, when the Army make a military operation and the military physician pay some attention to that people. A few medical schools have programs to that regions, like advanced campi, and in that cases the good Medicine can be used. By the majority of these people, I repeat, don’t have medical attention, but they could have disease like everyone, including the vascular ones. There are a lot of measures in progress by the new federal administration, from a left-wing political branch, and perhaps the social programs in the future could be a reality; however, in the meantime, we must think in other emergencial measures, and the “polypill” is one of those procedures in the present moment. Responses that say “a bad day to British medicine”, many critical letters to BMJ and more responses look to the UK point of view, the developed world reality. And I must repeat: I agree with all the comments, that are very solid in my Hospital and City; but the other great regions of Brazil, and certainly other countries, could have a benefit with strange things like “polypill”:with some corrections, the pill could be very useful in these cases. And I appeal to my British colleagues: be more complacent in regard to the undeveloped countries. In my world, I repeat, I could use the gold standard approach to all diseases, like in USA and UK.But these don’t occur in the rest of Brazil, and the new social vision of the politicians I believe that they will occur and work, but in a long time in the future. At the moment, we can’t close our eyes to people that die for famine, simple diseases and the vascular ones: that is the place of the “polypill” in the present. Like hungry people, we must adopt emergency measures, and wait the result of the long time ones. Competing interests: None declared |
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Peter N Trewby, Consultant Physician Darlington Memorial Hospital DL3 6HX, Catherine Trewby
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EDITOR - Wald and Laws’ provocative paper and your accompanying editorial on the Polypill disappointed us enormously (1,2). By focussing only on the advantage to the population, both articles ignore completely the individual’s views of the benefit they would wish to see from taking preventive drugs. If presented in patient-focussed terms, the median threshold of absolute risk reduction (ARR) below which patients would not wish to take a preventive drug may be as high as 30% over 5 years. This is far higher than the benefit of the Poypill which offers a meagre 7% ARR over 10 years if started at age 55 (3). In our study we found this benefit would only be acceptable to 1 in 10 healthy indivduals (3). If only 1 in 10 take the Polypill the effect on the population will be negligible. It all comes down to accurate numerical presentation and framing of the benefits of drugs to patients. As the patient’s treatment broker we are duty bound to inform our healthy 55 year old that if he or she takes the Polypill for the next 10 years there will be less than 1% chance per year of benefit and a 6% overall chance of side effects, some of which (e.g. aspirin related GI haemorrhage) may be life threatening (1). Furthermore if the Polypill is successful, our patient’s chance of dying from cancer, trauma and degenerative brain disease will increase pari passu with the effectiveness of the Polypill, as sadly even on the Polypill mortality will remain stubbornly around the 100% mark. Some patients will do anything to prevent a heart attack or stroke. Some will take any treatment if their doctor recommends it. In the modern health service where increasingly the focus is on health promotion rather than disease treatment it is more important than ever for doctors to be numerically well informed and to present to our patients figures on drug effectiveness which are relevant to them as an individual. Journal editors have a tremendous responsibility to support us in this task by insisting that authors emphasise ARR figures. Given the ARR figures for the Polypill, most doctors and patients will be considerately less enthusiastic than the authors of your paper and editorial (1,2). Peter Trewby Catherine Trewby Competing Interests: none. 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326;1419-23. 2. Rodgers A. A cure for cardiovascular disease. BMJ 2003;326:1407- 08. 3. Trewby PN, Reddy AV, Trewby CS, Ashton VJ, Brennan G, Inglis J. Are preventive drugs preventive enough? A study of patients' expectation of benefit from preventive drugs. Clinical Medicine 2002;2:527-533. Competing interests: None declared |
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Leslie.O. Simpson, director Red Blood Cell Research Limited, 31 Bath Street, Dunedin, New Zealand, 9001
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The proposal for mass medication by a polypill has generated much interest. As it will absolve sedentary and overweight individuals from the need for personal responsibility for health care, it will be greeted with enthusiasm. However, it is strange that neither the authors of the original report and the editorial writers nor the contributors of rapid responses have given any consideration to the possibility that changes in the blood may have pathogenic potential. The viscosity of blood and how this is influenced by the thixotropic nature of whole blood, is a major determinant of peripheral resistance and thus of blood pressure. In 1930 a paper recording the relationship between blood viscosity and blood pressure referred to earlier work in the field (1). Letcher et al (2) reported a direct relationship between blood viscosity and blood pressure in both normal and hypertensive subjects. But neither study noted that in situations where the rate of blood flow was reduced there would be a thixotropic amplification of blood viscosity. The proponents of the polypill suggest that the use of 3 antihypertensive agents will exert a preventative influence against high blood pressure and coronary heart disease, but those agents will not influence blood rheology. The effects on blood viscosity of lowering blood pressure were discussed in 1987 (3). Floras (4) drew attention to the importance of the sleep-related fall in blood pressure which occurs between 0200 and 0400. The extent of this drop in blood pressure was such that a significant thixotropic amplification of blood viscosity could be expected. Without any recognition of this possibility Floras noted " Nocturnal hypoperfusion could contribute to an excess cardiac morbidity and mortality if the blood pressure of these patients is lowered too quickly or too far." In 1991 the implications of of lowered blood pressure in myocardial infarction was discussed (5). Because the polypill medication was aimed at those aged 55 years and older it needs to be recognised that biological aging is different from chronological aging. An unpublished study showed that the blood of subjects 60 years of age and older was more viscous and less filterable than that of people 59 years and younger. However, the results of some samples from people in their 40s suggested early biological aging manifested as altered blood rheology. Those early observations are in accord with a recent review of blood rheology during aging, from the NIH Institute of Aging (6). It seems likely that the changes in blood rheology reported in that review could relate to the changes in red cell shape populations which were found in blood samples from subjects who were 60 years of age and older (7). These findings controvert the basis for mass medication with a polypill and draw attention to other options. At all age levels healthy nutrition and regular physical activity should be encouraged. There is a significant literature which suggests that the blood flow problems which develop during biological aging might be counteracted by a sufficient intake of a fish oil rich in omega-3 fatty acids. References. 1.Harris I, McLoughlin G. The viscosity of the blood in high blood pressure. Quart J Med 1930;23:451-464. 2.Letcher RL, Chien S, Piickering TG, Sealey JE, Laragh JH. Direct relationship between blood pressure and blood viscosity in normal and hypertensive subjects:role of fibrinogen and concentration. Am J Med 1981;70:1195-1202. 3.Simpson LO. Blood viscosity and lowering blood pressure (letter). Lancet 1987;2:580. 4.Floras JS. Antihypertensive treatment,myocardial infarction, and nocturnal myocardial ischaemia. Lancet 1988;2:994-996. 5.Simpson LO. Blood pressure and myocardial infarction (letter). Br Med J 1991;303:924. 6.Ajmani RS, Rifkind JM. Hemorheological changes during human aging. Gerontology 1998;44:111-120. 7.Simpson LO, O'Neill DJ. Red cell shape changes in the blood of people 60 years of age and older imply a role for blood rheology in the aging process. Gerontology 2003; in presss. Competing interests: There are no competing interests |
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Daniel Weyandt, Anaesthetist, Wanganui Wanganui 5005, NZ
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Sorry, but I really can't see where the cited conclusion "defies common sense" as Michael C Bunbury asserts. Nowhere does it say, that because of the polypill, if it became available, people should "carry on smoking , grow fat on carbohydrates...". It's just that if the estimated magnitude of the polypill effect was true, then it would probably be more effective than just giving up hydrogenated fats for example. That doesn't invalidate a healthy lifestyle as such which has other benefits in subjective well being for example. Competing interests: None declared |
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Mike Schachter, Senior Lecturer in Clinical Pharmacology Imperial College, St Mary's Hospital, London, W2 1NY
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Epidemiologists are primarily concerned with populations. Most no longer prescribe for individual patients and some never have. With great respect for the eminent proposers of the Polypill, it oftens shows all too clearly. Leaving aside the questions about the medicalisation of cardiovascular prevention and about the precision of the authors' calculation of benefit, there is the small problem of practicality. As others have pointed out foxed-dose combination are increasingly popular in hypertension. However, they only include two drugs and it is not too difficult to keep track of the contraindications and adverse effects. here we have five, six if we include folic acid. All of these--including folic acid if you believe in the vitamin B12 deficiency story--have relative and absolute contra-indications which are generally additive, so we will or should exclude large numbers of people at the outset. the side-effects are also drug specific: if our 55-year-old man develops a cough on his ACE inhibitor, or becomes tired due to the beta-blocker or gets gout or impotence because of his thiazide he will stop the the medication. What will we do then? What we should normally do, which is to tailor the therapy to the patient as an individual. This proposal could lead to potential harm to many patients adn ultimately more not less work for health professionals. It is the sort of idea people discuss in the pub (shame!) at the end of a long day at a cardiovascular meeting. It should not have emerged from the saloon bar. Competing interests: None declared |
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Joachim P Sturmberg, A/Prof of General Practice Wamberal, NSW - Australia
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This paper is further evidence of the crisis in medicine1. The power of medicine – in a healing sense – lies in the doctor- patient relationship. Non-medical practitioners, in particular policy makers and bureaucrats as well as some public health specialists and epidemiologists have a psychological envy of the primacy and privacy of this unique relationship. Knowing little about clinical decision-making these groups attack clinicians on the grounds of lack of evidence2. Wald and Law may not believe in the concepts of patient-centred care, let them be assured, patients are not interested in eternity, rather they are interested in quality of life and a “quick end” when their time is up – and many frankly state that “a heart attack in my sleep will just be fine”. Most patients for whom Wald and Law suggest the polypill are mature enough to accept that “life is a deadly enterprise”. Their greatest fear is being caught up in the modern game called MORBIDITY & MORTALITY SUBSTITUTION, where heroic institutionalised interventions cause lots of suffering for all involved, and “good old care” is long forgotten. This is not the way forward for a brave new world! [1] Sturmberg JP. Preparing Doctors For The “Post-Science” Medical Era – Focusing Back On The Patient. Asia Pacific Family Medicine 2002;1(2- 3): 63-66 [2] Ellyard P. Ideas for the New Millenium. 2nd ed. Melbourne: Melbourne University Press, 2001. Competing interests: None declared |
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Shah M Tauzeeh, Staff Grade Physician London N12 OJE
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I am in a rush. I would like to be at the Patent Office before any one can get there.I am about to introduce wider choices and varieties of Polypills as listed below: 1. Polypill A- for Asians. Original 6 + Metformin. 2. Polypill B- For Blacks. ACE inhibitor excluded from the Original 6. 3. Polypill C-for people sensitive to Aspirin.Substitute Aspirin for Clopidogrel. 4. Polyill D- for diabetics other than Asians containing a combination of different oral hypoglycaemic agents. 5.Polypill E- for people with erectile dysfunction. Original 6+ Viagra. 6. Polypill F-for postmenopausal women. Original6 + HRT 7. Polypill O - for sexually active women. Original six + oral contraceptive. 7. Super Polypill- details not for disclosure at the moment. First two can be sold at super markets and corner shops, rest through the pharmacies. I am trying to get in to Sir Richard Branson's diary to allure him to the pharmaceutical industry.I think he is still a virgin in this area. Competing interests: Investment in Schroders Medical Discovery Fund |
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Paul W Masters, Consultant Chemical Pathologist Chesterfield Royal Hospital, S42 6PZ
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Whilst the size of the benefit may be debatable, in the absence of direct trial evidence, the concept of the Polypill is surely correct. The burden of cardiovascular disease in the UK is explained by the high prevalence of traditional risk factors, which do not differ between those who succumb and those who don't. Lifetime exposure to small excesses of multiple risk factors is the problem and intervention across the whole population is the solution. Of course, this could consist of us all eating fish, riding bicycles and giving up tobacco, cars, salt and junk food. But get real. What's easier: reversing societal trends of the last 50 years or popping a cheap once-daily pill that let's you have your cake and eat it (literally)? Wald and Law might consider the benefit of adding metformin to their pill in order to help offset the rise in type 2 diabetes, which will inevitably follow. Competing interests: None declared |
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Dr. Matthew L Grove, Consultant Physician / Rheumatologist NTGH NE29 8NH
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I greatly enjoyed Wald and Law's paper. I'm not sure how seriously they intended it - some of the responses above clearly take it very seriously - but it is provocative and, I suspect, indicative of where cardiovascular prevention is heading.
It's not proven that all of the proposed ingredients synergise in the manner assumed by Wald and Law. But this is what is assumed in the current management of cardiovascular disease: I completed my stint in medical admissions last week, and every middle-aged diabetic I saw with chest pain was on aspirin and a statin; most were on a beta-blocker, ACE inhibitor and a thiazide too (if they weren't we wanted to know why not, and doled out ATII antagonists and clopidogrel instead). Folic acid seems to have passed us by; I clearly need to read up on this in a bit more detail. Last time I checked it was safe and cheap though; if there's added benefit, why not throw it in the cocktail? I don't agree a polypill should be standard therapy for otherwise fit 55yr olds (as side effects likely to considerably outweigh benefits, as shown above by the Trewbys). But we are already using this combination or one very like it in high risk patients, and there are very many of those. A single pill to replace the six or seven drugs some of our patients are on would doubtless improve compliance, which offers cost savings in itself. It could be taken first thing in the morning; unlike Dr. O'Brien, I don't beleive in Cholesterol Fairies (see (1)). Because patients would doubtless need the combination modifying due to intolerance to individual components, I have no doubt that we will need a range of polypills - as Dr Tauzeeh humorously suggests above (although post-WHI, I doubt polypill F will get off the ground; and there is unlikely to be much demand for polypill O). The proposal clearly has it's problems - and should not be advocated as a universal panacea without one's tongue firmly in cheek - but, with minor changes, might well be the face of secondary prevention to come...
(1)"The Fat Police and the Cholesterol Fairy" Bandolier 86 (follow up Bandolier 88). Available on line at:
Competing interests: None declared |
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William Plummer, Consutant Psychiatrist St Martin's Hospital, Canterbury, Kent CT1 1AZ
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Sir, Before Wald and Law's recommendations for a 'poly-pill' to reduce deaths from heart disease can be accepted, research needs to be done to answer a number of questions. Firstly, is the effect of each element of the poly-pill independent of the effect of other elements (in a logistic regression model), leading to a multiplicative model as claimed? The papers quoted by the authors do not support this assertion. In particular, showing the effect of one element is the same for different levels of another element does not give information on its effect compared with the absence of the other element and does not take account of non-linear dose related effects. Studies need to be carried out to demonstrate that the effects of each element of the polypill is indeed multiplicative with other elements. As pointed out by Adams (responses above)these need to have sufficient power to detect interaction effects. Secondly, the study does not estimate overall mortality. If a person does not die of cardiovascular disease they may die soon from some other cause, especially if elderly. Thus, the overall mortality from treatment may be reduced far less than expected. As in the case of statins, the poly -pill might actually increase mortality from other causes. Studies on overall mortality need to be carried out for any final formulation of the poly-pill. Finally, it is not clear that taking the poly-pill will be of benefit to people in the general population. I presume that many of the studies which went into the meta-analysis were performed on patients who were in high risk groups (high blood pressure, high cholesterol etc.) Even if the elements of the pill save lives in these high risk groups, what proportion of cardiovascular deaths would this represent? The low risk population may have lower event rates but still contribute to a fair proportion of deaths and there is no logical reason to suppose that the pill will reduce risk in this group. The pill needs to be tested in the general population to determine its efficacy (and safety). The practicality of the pill is also questionable. It is most unlikely that people will be fully compliant in taking it. Even if its efficacy were demonstrated, its effectiveness would have to be demonstrated in clinical settings, as well as a cost-benefit analysis. Perhaps in ten or twenty years(or fifty years?), when this programme of research has been completed, we will be in a better position to judge how important is the concept of the poly-pill. Competing interests: None declared |
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Ketan K Dhatariya, Research Fellow in Endocrinology Mayo Clinic
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It is gratifing to see the recognition for morbidity and mortality due to cardiovascular disease being given such a high priority in the BMJ. Most major news organisations carried this story and it may have done more to promote cardiovascular risk reduction than most government sponsored initiatives. However, I have reservations about the intent of the article. For several years I have been promoting the use of 'Aspastatapril', a combination of aspirin, a statin and an ACE inhibitor for use in people with diabetes who have any risk factor at all. There is, in my opinion, sufficient evidence to support the use of these drugs in this clinical situation. Indeed, the BMJ rejected an editorial about this possible combination in early 2003. An updated synopsis of this evidence is currently in press in the Journal of the Royal Society of Medicine (Type 2 diabetes is a cardiovascular disease. Dhatariya K). The suggestion that everyone over the age of 55 shoudl be on the polypill is blunderbuss medicine. This policy, will only lead to the shareholders of the pharmaceutical companies lining their pockets, at the expense of the inevitable morbidity and mortality that would be associated with such blanket coverage. However, it is much more responsible to target selected at groups who are at higher rsik of developing cardiovascular disease. For the rest of the population, the better approach would be to lobby the food industry to add less sugar and less salt in processed food. This would lead to similar reductions in cardiovascular disease as those proposed by the 'polypill' with less expense to the governments subsidising prescription charges. Reported in the past few days is that Kraft foods, the second largest food manufacturer in the world, is to reduce it's portion sizes in an effrt to try and reduce obesity. This represents a major step by to tackle the underlying causes of cardiovascular disease Competing interests: I have promoted 'Aspastatapril' to GP's and other interested individuals at pharmaceutical sponsored meetings |
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Anita Sainsbury, SpR Elderly Care St James's University Hospital, Leeds, Yorkshire, LS9 7TF
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Compliance with the polypill in elderly people will be problematic as intolerance to 1 component will mean that patients stop taking the entire combination, thereby missing out on the beneficial effects of all the other components. Side-effects such as iatrogenic impotence will not be tolerated by the public, particularly in primary prevention. The polypill will never reduce cardiovascular disease by at least 80%, mainly because people won't take it. Competing interests: None declared |
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William Plummer, Consultant Psychiatrist St Martin's Hospital, Canterbury, Kent. CT1 1AZ
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There is a correction to my previous posting in this correspondence. When I said that Wald and Law have not estimated total mortality this is not correct. They made an adjustment for mortality from other causes in their model. I meant to say that they have assumed that age related mortality from causes other than cardiovascular disease will remain constant in those patients who would otherwise have suffered a cardiovascular event. This assumption is highly dubious and needs to be supported by experimental evidence. It is very likely that age related mortality from other causes will rise significantly if there is a reduction in cardiovascular deaths. This may well reduce the expected benefits of the poly-pill according to Wald and Law's model. In addition to this, the components of the poly-pill may themselves have adverse effects, raising mortality from other causes. The point I am making is that the statistical model used by Wald and Law depends upon these assumptions, but any mathematical model must be tested against the real world. The only way to know if the assumptions are correct is to carry out large scale clinical trials. Competing interests: None declared |
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David A Brodie, GP Cambridge CB4 1NQ
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Most BMJ papers have a date of acceptance below the referances. This paper does not. The two other papers by Law and Wald in this issue of the BMJ have a date of acceptance 8 April 2003. Was this paper accepted a week earlier? Competing interests: None declared |
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David M Reith, Senior Lecturer Dunedin School of Medicine, University of Otago, Dunedin, New Zealand
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The approach taken by Wald and Law assumes that the effects of the various treatments proposed are additive, yet there is little evidence presented that this is, in fact, the case. Without this assumption it is not valid to multiply the relative risks of the various treatment strategies in order to determine the overall effect of the combined treatments. There may be interactions between the treatments, whereby one treatment may negate the effect of one or more of the other treatments. This could only be determined if comparative trials, with combined treatment arms, had been performed. Hence, the authors have proposed an interesting hypothesis that deserves to be tested, but they have not provided convincing evidence that their proposed combination of treatments should be adopted into clinical practice. Competing interests: None declared |
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Jeffrey R Johnstone, self-employed 7 Bruce St, Nedlands 6009, Western Australia
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The three papers by Wald and Law et al show several odd features. The first follows from their opening sentence: "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." So their aim is to find a multifactorial preventive for cardiovascular disease. Yet as they state elsewhere, only single factor trials are to be considered and not multifactorial preventive trials. Such trials, which they ignore, do not support their case. Second, even with their restrictive criteria there seems to be some selectivity in their choice of data. In Table B (http://bmj.com/cgi/content/full/326/7404/1423/DC1) they give the results of the Coronary Drug Project for clofibrate and niacin. But that trial included three other groups: low dose oestrogen, high dose oestrogen and dextrothyroxine. All three were abandoned prematurely because of alarming side-effects, one after only 1.5 years instead of the proposed 5. The New York Anti-Coronary Club Program is missing.(Reference is given in a link at my home page http://members.iinet.net.au/~ray/ or by emailing me.) In this trial 814 men were placed on a diet high in polyunsaturated fats. They were to be compared with a similar group of 463 men who formed a control group. After 4 years there was a large drop in their cholesterol levels but this was associated with a significant 153% increase in mortality in the low-cholesterol group as compared to high- cholesterol. There were 9 coronary heart disease deaths in the test group and none in the unhealthy control group. Third, Wald and Law largely neglect total mortality. There is little point in reducing cardiovascular mortality if total mortality is increased. The reader can be seriously misled because of this omission. For example, in Table B, some of the results of the WHO clofibrate trial are presented. but not the fact that total mortality was significantly raised in the test, low cholesterol group. Again in Table B, for subjects in the Sydney Diet-Heart Study the death rate in the test group was 49% higher than in the control group. With the publication of any intervention study or analysis of them, total death rates should always be given. Competing interests: None declared |
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Tom Fahey, Professor of Primary Care Medicine Tayside Centre for General Practice, University of Dundee, DD2 4AD, Alan Montgomery, Yoav Ben Shlomo
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Wald and Law propose an innovative strategy to prevent cardiovascular disease.1 They have used a Markov model to estimate the years of life gained without a heart attack or stroke. Surprisingly, no confidence intervals are presented around their estimates. They do not report whether the probabilities for each of the proposed treatments in the model were point estimates or drawn from a distribution. This uncertainty should be investigated using sensitivity analyses. Whilst they state “the gain in life is substantial at all ages”, they do not present data to show average life expectancy gain in age and sex strata; these should be presented. In our own Markov model,2 life expectancy gains were not substantial. For example, a male at high risk of cardiovascular disease age 30, 50 and 70 gains on average 2.3 years, 1 year and 3 months of life. We found that absolute risk is a critical determinant of cost-effectiveness of treatment, even within the same age and sex strata2 whilst they dismiss this as unnecessary.
Their estimate of relative risk reduction of the Polypill is based on the assumption that benefit of each component are independent of each other, yet the pleiotropic effects of statins mean this may not be the case.3 Furthermore, assumptions about the relative benefits of lowering serum homocysteine are based on observational studies. No RCTs have examined the combined effects of the four drugs on morbidity and mortality. The assumptions about the relative benefits from blood pressure lowering (taken from their own systematic review) may be too optimistic, being based on RCTs using blood pressure as a surrogate endpoint and not on cardiovascular morbidity and mortality.4 Adherence to medication is known to be highly variable and effects recurrence of myocardial infarction and all cause mortality.5 No sensitivity analyses are presented to account for varying levels of adherence. We accept that de facto, secondary prevention and treatment of high risk individuals now means that many patients are routinely prescribed aspirin, a statin and blood pressure lowering drugs. Wald and Law’s suggestion of combining the efficacy of these ingredients into a single drug may be valuable. However, their assumptions and incomplete modelling make it likely that the true benefits are less impressive. Before medicalising every adult over 55 years of age, we need a greater appreciation of potential benefits and harms for overall quality of life, disease morbidity and mortality. References 1. Wald NJ,.Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419. 2. Montgomery AA, Fahey T, Harding J, Ben-Shlomo Y. The influence of absolute cardiovascular risk, patient utilities and costs on the decision to treat hypertension: A Markov Decision Analysis. Journal of Hypertension 2003;In press. 3. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering – are they clinically relevant? European Heart Journal 2003;24:225-248. 4. Hansson L, Zanchetti A, Carruthers S, Dahlof B, Elmfeldt D, Julius S et al. Effects of intensive blood pressure lowering and low dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1999;351:1755-62. 5. Jackevicius C,.Mamdani M. Adherence with statin therapy in elderly patients with and without acute coronary syndromes.JAMA 2002;288:462-7. Competing interests: None declared |
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Stephen J Redmond, GP Liverpool Ellergreen Medical Centre L11 2YA
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Dear Editor, I dispute the claim that the Polypill concept outlined in your last issue constitutes the most important paper you've published in 50 years and do so for a variety of reasons. Firstly such axtion depends on an abnegation of personal responsibility and as such represents a dangerous precedent for a 'Big Brother' state which dictatesthe actions of its citizenry.This attitude disempowers individuals and leads them to collude with an apparently all powerful medicine in believing it can rescue them from the consequences of their actions- medical technology can pluck them from the brink. Conversely being inevitably labelled at 55 as at risk could have adverse psychological consequences. The shift from well to ill is a more significant threshold than is often believed. Secondly, compliance is a problem even in the most cut and dried medical scenarios and there seems often to be an inverse care law that applies- those most likely to benefit are those least likely to take advantage of an offer What then? Coercion? Thirdly, the entire exercise shows a focus on a population whose benefit is an abstuse and artificial concept at the best of times, rather than on athe traditional focus of medical care, an individual. Primum non nocere- even on their own figures two thirds of the people taking this medication will derive no benefit whatsoever. For the rest, the risk is not uniform- a person at high risk has the most to gain ,as with the individual risk factors, yet the risk of adverse events is the same- hence for a lot of people the risk outweighs the potential benefit and the equation only sorts out for a whole population rather than for the individual. Fourthly, there is a problem with the nature of the evidence. This is skewed as the people funding the majority of research have a vested interest in increasing our consumption of pharmaceuticals. A common mistake seems to be to equate a lack of evidence regarding an intervention with the existence of evidence that the intervention is without benefit. This is false. Research is begging an answer and I am especially skeptical given that the people promoting this policy are the patent holders for this new wonder drug. Their promotion of it seems a bit less than disinterested. Fifthly, the view proposed is monoptic, viewing the interventions applying to one disease overall and doing so in isolation.The extra gains to be made from addressing the alternatives are ignored and the underlying causes, while acknowledged in the article,are not tackled. Folic acid in the Polypill will reduce your incidence of cardiovascular disease but not of colon cancer, whereas increasing your consumption of fruit and vegetables will.Taking a statin may attentuate the disadvantages of smoking on your blood vessels but will not stop your lungs from succumbing.Interventions that address the aspects of the Western lifestyle that put us at high risk would benefit our population and the individuals that constitute it to a far greater extent than will miracle drugs addressing single disease entities. What next? Another polypill for cancer rather than action to tackle smoking, diet and so on? Yours sincerely S J Redmond Competing interests: None declared |
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Adam L Brown, SpR Derriford Hospital PL6 8DH
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It is good to see Wald & Law once again setting the cat amongnst the pigeons. As I see it, the intention of this paper is to get people thinking. Sure, they haven't ended up with the final ingredients for the global panacea, but they have set the ball in motion. They have helped move medicine on from "wouldn't it great to have a pill to cure all heart disease" to "well, we could have a cure for heart disease with a little more work". Competing interests: None declared |
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Peter Marckmann, Senior registrar, MD, DMSc Medical Department, Roskilde Hospital, DK-4000 Roskilde, Denmark
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It is indeed a radical and thought-provoking paper that Wald and Law presented (BMJ 2003;326:149). Is it really possible to almost eradicate IHD and stroke from our societies with a polypill combining a statin, antihypertensives, ASA, and folic acid ? According to the very beautiful statistical analyses by Wald and Law the answer is yes. However, I am in serious doubt whether the hypothetical calculations will hold true in reality and also have at least one major concern about the proposed strategy. Regarding the statistical analyses, I wonder how Wald and Law can totally neglect the possible existence of interactions between the individual pharmacological agents. I consider it very likely that e.g. effective cholesterol-lowering will reduce the clincal benefit of e.g. antihypertensives, not only in absolute, but also in relative terms. In clinical practice, high risk individuals such as diabetics are already in polypharmacological treatment very similar to the treatment proposed by Wald and Law, but still experience a rather high incidence of IHD events and stroke which seems to disprove that 80-90% can be prevented. Even if medical treatment is optimized and combined with some sort of life-style changes the risk of diabetic patients seems only to be halved (1). Compliance with the Polypill is another aspect that Wald and Law did not touch upon in their paper. What level of compliance could be expected ? In Denmark, I think that large parts of the population would react strongly against being treated with drugs if they don’t have any symptoms of disease. A compliance rate of more than 30% would surprise me, which would mean that the overall benefit of the Polypill would be strongly reduced. My primary concern is that telling people that polypharmacy will rescue you from cardiovascular disease will remove the motive for quitting smoking, increasing the physical activity level, and improving the diet for many individuals. As a result, the Polypill might lead to many more lung cancers, much more obesity, and many more type 2 diabetic patients. These possible side effects would seriously counteract any benefits won by the Polypill strategy. I think all of the aspects mentioned in this comment should be discussed before anyone chooses to recommend Polypills to everyone above 55 years. Ref 1: Gæde P, Vedel P, Larsen N, et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med 2003;348:383-93. Competing interests: None declared |
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Elved B Roberts, SpR Cardiology Mid Cheshire Hospital Trust CW1 4QJ
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EDITOR-I was a week late reading the now infamous issue of the BMJ published on the 28th of June 2003, but I was disappointed in the end. I am very surprised that Wald and Law assume deriving the product of relative risk scores for separate therapies results in an accurate relative risk score for combined therapy. Interactions, synergy, antagonism, and tolerability on a pharmacological level will result in distortion of the mathematical model such that a much more biololgically plausible relative risk score is reached. This is likely to be less spectacular than that claimed by the authors. To quote the example of two statin trials as evidence of relative risk reduction in treatment groups, irrespective of baseline Blood Pressure and Aspirin therapy, is insufficient - extrapolation of such an effect to pharmacotherapy in general, even for the six agents suggested, is unwise. In addition, the authors have fallen into the trap of stating that disease can be prevented in all those comprising the population to which the stated relative risk reduction applies. This is incorrect. Such diseases might be prevented in some, deferred in others, while being replaced by other diseases (eg Cancer) in the remainder of treated the population. A willing suspension of disbelief is required to accept the stated figures at face value, although the concept of a Polypill is neat, albeit unoriginal! Yours Sincerely, Dr Elved Roberts, Cardiology Specialist Registrar, Mid Cheshire Hospital Trust. Ref: Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-1423. Competing interests: None declared |
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Derek Yach, Executive Director, Noncommunicable Diseases & Mental HEalth World Health Organization, Geneva 27, Switzerland, Shanthi Mendis, JoAnne Epping, Ruth Bonita, Amalia Waxman
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Dear Sir, In BMJ 28 June, 2003 (1) Wald and Law suggest that intervening on the four risk factors (LDL cholesterol, blood pressure, homocysteine and platelet function ) with a “polypill” containing six active components, would prevent more than 80% of cardiovascular disease (CVD). They argue that the best approach is to treat everyone aged about 55 or over, in addition to people with known occlusive vascular disease. In the accompanying editorial, Rodgers proposes that realising the enormous potential of this approach “should be a major goal, especially for developing countries.” We strongly disagree. Notwithstanding our serious methodological concerns concerning Wald and Law's analytic approach, we acknowledge the proposed polypill may have a specific, although limited, scope for secondary prevention. But only once clinical trials have assessed its bioavailability, effect on intermediate end points, safety, tolerability and adherence, all of which will take many years. (2) Following this “magic” pill approach could shift the focus and needed resources away from proven and cost-effective CVD prevention strategies, and could well have adverse consequences, especially for developing countries. We know the major risk factors for CVD: high blood pressure, cholesterol, raised BMI, unhealthy diet, physical inactivity and tobacco use explain over 75% of new CVD events in developing countries. (3) We also know that a small shift in population-wide consumption levels of saturated fats and salt, tobacco cessation and increased physical activity, can result in major changes in CVD incidence. (4) Some of these shifts would also lead to less cancers, diabetes and chronic respiratory disease. With adoption by WHO’s 192 member states of the Framework Convention on Tobacco Control in May 2003, more aggressive action to reduce smoking at the country level is already underway. An equally significant shift is likely to occur when WHO member states next year adopt a Global Strategy on Diet, Physical Activity and Health. The process for developing this strategy has involved wide-ranging consultations. (5) And it has contributed to changes in attitudes by both the food industry and the public towards the production, marketing and consumption of foods high in saturated fats, sugar and salt. Recent announcements by food companies are a significant precursor of likely industry-wide shifts. (6) Some of these strategic changes follow key recommendations in the recent publication of a joint WHO-Food and Agriculture Organization expert consultation report. (7) The potential long-term gains for health of these preventive approaches are enormous. (8) To propose, as an alternative, that the world’s over-55 and CVD-at risk population should be medicated, ignores some practical realities, especially in developing countries. First, adherence to long-term therapies is at best around 50%. (9) Second, the authors appear to disregard the complexities of delivering health interventions, and the overall state of health systems, particularly in the developing world. This oversimplified “quick fix” approach is unlikely to provide a comprehensive strategy for prevention and control of the CVD epidemic. The most sustainable way forward for prevention and control of the CVD epidemic in developing countries is to scale-up secondary prevention of those with established CVD (2) and target those at high risk with cost- effective population-based interventions. (10) This includes shifting health care towards proactive systems, which emphasize health across a lifetime, and introducing self-management and prevention support as core components of clinical care. These strategies should be complemented with bold upstream policy measures, which have a population-wide impact on the risk factors of major NCD. We do not believe the strategy proposed by Wald and Law is an adequate response to the growing global burden of chronic diseases. Sincerely, Dr Derek Yach, Executive Director, Noncommunicable Diseases & Mental Health, WHO; Dr Shanthi Mendis, Coordinator, CVD; Dr JoAnne Epping- Jordan Coordinator, Health Care for Chronic Conditions; Dr Ruth Bonita, Director, Surveillance, Ms Amalia Waxman, Project Manager, Global Strategy on Diet, Physical Activity and Health, WHO. References: (1) Wald.N.J. & Law M.R. A strategy to reduce cardiovascular disease by more than 80%. BMJ Vol. 326, 28 June 2003. Rodgers.A.A cure for cardiovascular disease? Editorial. BMJ, Vol, 326, 28 June 2003. (2) Secondary Prevention of noncommunicable diseases in low and middle income countries through community based and health service interventions. World Health Organization -Wellcome Trust meeting report 1- 3 August 2001 (3)Magnus. P, Beaglehole R. The real contribution of the major risk factors to the coronary epidemics. Arch Intern Med 2001; 161:2657-60 (4)World Health Report 2002: reducing risks, promoting healthy life. Geneva, World Health Organization, 2002. (5)See www.who.int/hpr/global.strategy.shtml (6)See : www.mcdonalds.com/countries/usa/whatsnew/pressrelease/2003/0362003/index.html and http://www.kraft.com/newsroom/07012003.html (7)Diet, Nutrition and the Prevention of chronic diseases. TRS916. World Health Organization. (8)Yach D. Unleashing the power of prevention to achieve global health-gains. Lancet 2002 360:1343-4. (9)Adherence to long-term therapies: Evidence for action. World Health Organization, 2003. (10)Integrated Management of Cardiovascular-Risk. World Health Organization, 2002. Competing interests: None declared |
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Gareth P Morgan, Public Health Officer National Public Health Service for Wales, 36 Orchard Street, Swansea, SA1 5AQ.
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I have followed the ‘Rapid responses’ with interest. It appears that the majority of these, including mine on July 1st, have highlighted problems with the ‘polypill’. I have suggested that WHO should convene an international scientific meeting on aspirin (acetylsalicylate) without delay. There is a related dimension that should be considered at the meeting, namely salicylate deficiency. The main risk factor for the deficiency is a low intake of fruits and vegetables. I am drawn to a hypothesis that humans need to be exposed to sufficient level of salicylate throughout their entire life in order to maintain good health status (1,2). This hypothesis could generate lines of research that eventually have more public health benefit than the 'polypill'. References 1. Coomarasamy A, Honest H, Papaioannou S, et al. Aspirin for prevention of preeclampsia in women with historical risk factors: A systematic review. Obstet Gynecol 2003; 101: 1319-32. 2. Morgan G. ‘Salicylic acid deficiency’ has important public health implications. Eur J Pub Health (in press). Competing interests: None declared |
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Alejandro F. Luque-Coqui, Aldama No. 240 Celaya Gto Mexico Centro Diagnostico Integral 38000 Mexico
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The only advantage I can see with this strategy is, taking only one pill instead six components, and only in high risk patients that they usually take polypharmacy and it is mandatory to ask patients if they wish to take this "bomb" or the six components separated.
Competing interests: None declared |
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Marcus Flather, Director , Clinical Trials and Evaluation Unit Royal Bromton Hospital , Sydney Street, London SW3 6NP, Anil. K. Taneja, Diego Perez de Arenaza
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Reply to Wald NJ, Law MR. “A strategy to reduce cardiovascular disease by more than 80%. British Medical Journal 2003; 326:1419” In the 28th June issue of BMJ, Wald and Law tell us about a huge breakthrough in the prevention and treatment of cardiovascular disease [1], a claim heralded in the media at around the same time. They provide analyses of cholesterol and blood pressure lowering studies with summaries of the benefit provided by these strategies [2,3]. We were also interested to learn that they had filed a patent for the Polypill. So what does all this tell us? First we already know that multiple risk factor modification in patients at high risk of cardiovascular events lead to substantial benefits, This approach is recommended in all recent guidelines and should be routine practice [4]. Second most patients with established vascular disease should be on a combination of antiplatelet, statin, beta-blocker and ACE-inhibitor based on the available evidence. Third many combination pills are already available or in development, although these contain 2 or 3 agents at most. Fourth they are advising that everyone over the age of 55 years or those with established vascular disease take untested doses of drugs in untested combinations. Fifth for researchers with an apparent regard for evidence-based practice they advise including folic acid in the Polypill that as yet has no supportive clinical trials evidence [5]. Finally the estimates of benefits with the polypill are derived in an untested model taking the product of relative risks from the four major risk categories, and take no account of the probable small reductions in absolute risk for the majority of healthy people. For people at low to moderate risk of cardiovascular events the role of exercise, healthy diet, stopping smoking, decreasing obesity and lowering blood sugar may be at least as effective the polypill. The cost implications for primary prevention in the major population group formed by > 55 years is another aspect not considered. There are also practical issues to be addressed. The combination of drugs in the polypill may make it difficult to work out the cause side effects. If the polypill had to be discontinued for intolerance, the composite drugs will each have to be started individually which is a drawback. The potential adverse effects of the polypill need to be carefully assessed in the elderly since they may have different rates of absorption, metabolism and excretion of the drugs. We advise that a randomized trial of the Polypill against effective lifestyle modifications in people at low to moderate risk of cardiovascular disease be carried out before Wald and Law’s proposal can be put into practice. The Polypill is an interesting concept with potential health benefits but let us subject it to the same rigorous scrutiny as other treatments before embracing it with fanfare. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. British Medical Journal 2003; 326:1419 2. Wald NJ, Law MR, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials British Medical Journal 2003; 326:1427 3. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease and stroke: systemic review and meta-analysis. BMJ 2003 Jun 28; 326(7404): 1423 4. Gibbons RJ etal. American College of cardiology/American Heart Association Task Force on practice guidelines (Committee on the management of patients with chronic stable angina). Circulation 2003 Jan 7; 107(1): 149-58. 5. Morris CD, Carson S. Routine supplementation to prevent cardiovascular disease: a summary of the evidence for the US Preventive Services Task Force. Ann Intern Med 2003 jul1; 139(1): 56-70. Competing interests: None declared |
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Daan Kromhout, Director Director Nutrition and Consumer Safety Division , P.O. Box 1, 3720 BA Bilthoven, The Netherlands, Henry Blackburn, Alessandro Menotti, and Hugo Kesteloot
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The Polypill and prevention of Coronary Heart Disease In the British Medical Journal of June 28 Wald and Law advocated the use of a Polypill by everyone aged 55 and older and everyone with existing cardiovascular disease (1). They estimated that this Polypill would reduce coronary heart disease (CHD) events by 88%. They concluded that no other preventive method would have so great an impact on public health in the Western world. The main question is whether the use of a Polypill is the most effective strategy for CHD prevention. A prospective cohort study showed that 82% of the occurrence of CHD can theoretically be prevented by a healthy diet and lifestyle e.g. non-smoking, regular physical active and moderate alcohol consumption (2). Even in non-smokers 74% of the occurrence of CHD may be prevented by a healthy diet, regular physical activity and moderate alcohol consumption. This is in accord with findings of the Seven Countries Study showing after 25 years of follow-up a six- fold difference in CHD mortality between rural cohorts from Finland and Crete (3). Also all-causes mortality differed by a factor of 2 (60% vs 30%) (4). In 1960 57% of the Cretan farmers were smokers, if they would not have smoked cigarettes their all-causes mortality would have been even lower. These results clearly show that a healthy diet and lifestyle are a natural alternative to a Polypill. The long-term mortality experience of the Cretan cohort of the Seven Countries Study points the way to an attractive way of living as an alternative to Polypill taking for which compliance will always be a major problem. A pill does not a healthy diet and lifestyle make or a healthy population make. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419-23. 2. Stamper MJ, Hu FB, Manson JE, Rimm EB, Willett WC. Primary prevention on coronary heart disease in women through diet and lifestyle. N Engl J Med 2000;343:16-22. 3. Kromhout D, Menotti A, Bloemberg B, Aravanis C, Blackburn H, Buzina R, et al. Dietary saturated and trans fatty acids, cholesterol and 25-year mortality from coronary heart disease. The Seven Countries Study. Prev Med 1995;24:308-15. 4. Kromhout D, Bloemberg B, Feskens E, Menotti A, Nissinen A for the Seven Countries Study Group. Saturated fat, vitamin C and smoking predict long- term all cause mortality rates in the Seven Countries Study. Int J Epidemiol 2000;29:260-5. Daan Kromhout1, Henry Blackburn2, Alessandro Menotti3, Hugo Kesteloot4 1.National Institute of Public Health and the Environment, Bilthoven,
The Netherlands
Competing interests: None declared |
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Alejandro F. Luque-Coqui, Private Cardiologist Aldama No. 240 Celaya Mexico
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According to my own calculations about HPS trial de NNT for five years in order to prevent one death for any cause was 57, and we need also to calculate the risk on our own patient por example in the Framingham nomogram if our patient´s risk is 2.5% for one year the NNT using the HPS data on any death is NNT 34 for one year not 300. If you take the numbers of ASCOT trial NNT was 95 in primary point nonfatal MI + fatal CHD during one year of follow-up and once again in a patient with 2.5% of yearly risk NNT would be just 11. Otherwise in ALLHAT the lipid branch really had a serious flawed because 40 mg of pravastatin was compared with the "ususal care" that also included a statin.
So I disagree with the statement "statins failed to reduce mortality for all-causes" the real benefit of statins is well established, but we can get lost with this aparently small amounts, in absolute risk reductions and just a few physicians translate trial´s data in a real NNT in accordance to our individual patient on risk. Competing interests: None declared |
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Jeffrey Mann, Retired physician Salt Lake City, UT 84103
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I have read the many rapid response letters written in response to the Wald and Law article with great interest. I am surprised that no correspondent has brought up the fact that the authors' efficacy projections are seemingly based on their theory that the RRR of statins (and the other therapeutic agents in the Polypill) are going to be the same for all levels of cardiovascular risk and that there is no risk threshold below which the drugs lose their therapeutic efficacy. I have read their article on risk factor thresholds [1] and it not clear to me that their interesting theory is scientifically valid. I would like to see more clinical trial evidence to support the theory that all the therapeutic agents used in the Polypill are going to produce the same RRR for an asymptomatic 55 year old patient who is at low risk of adverse cardiovascular events (AMI or stroke or CV death) compared to an asymptomatic 55 year old patient who is at high risk of an adverse CV event. I would especially like to review the trial evidence that demonstrates that three antihypertensive agents used in combination at half-dose strength would be equally effective in patients with normal blood pressure compared to patients with high blood pressure. I would also like to see much more detail on how the authors' determined the absolute degree of benefit for the 10 year period -- age 55 years to 65 years -- and how they would precisely calculate the ARR and NNT for three different types of 55 year old patient:- 1) an asymptomatic 55 year old patient with normal serum cholesterol and normal blood pressure, 2) an asymptomatic 55 year old patient with high serum cholesterol and high blood pressure, 3) and a 55 year old patient with known CV disease. I would also like to see more scientific evidence that could support the viewpoint that any adverse CV event prevented during the first 10 year period (age 55 years - age 65 years) would be absolutely prevented, and not merely delayed. I would also like to learn how the authors know that overall mortality would be proportionately reduced if CV mortality is significantly reduced, and how they can accuratedly establish that other causes of death would not become more common if patients were relatively free of adverse cardiac events for a 30 year time period (age 55 years - 85 years). Many correspondents have brought up the fact that there is little clinical trial evidence to support the theory that the RRR of all the therapeutic components of the Polypill are simply additive, and they question the hypothesis that the projected efficacy of the Polypill can be accuratedly determined by simply multiplying the RR figures of all those components. I agree! Surely, a clinical trial is mandatory to determine whether reality will confirm (or refute) the authors' Polypill hypothesis. The fundamental basis of Western medical science is the principle of scientific testing, which is the keystone of Karl Popper's philosophy of science belief that a scientific hypothesis is only true if it cannot be falsified (by rigorous scientific testing). The idea of prescribing the Polypill (based on theoretical projections of efficacy) prior to actually testing its efficacy in a clinical trial is totally contrary to this most basic principle of medical science. I believe that the Polypill should first be tested against a placebo in a RCT, and not against other therapies (eg. dietary and/or other lifestyle changes). We first need to know whether the Polypill will be clinically efficacious in a clinical trial, before we compare it to alternative therapies to determine its relative clinical effectiveness. Other considerations such as the projected "real life" effectiveness of the Polypill that are based on hypothetical "guesstimations" as to whether asymptomatic patients would take the Polypill regularly over the long-term (patient compliance factor), the effects on society of the "medicalization" of health care that would follow the utilization of an universal preventive drug strategy for all asymptomatic middle-aged/elderly citizens, and the long-term social effects that would occur if CV deaths were significantly reduced and people actually lived longer are only really relevant if scientific testing actually proves that the Polypill is truly highly-efficacious. References: 1. Risk factor thresholds: their existence under scrutiny M R Law and N J Wald BMJ 2002; 324: 1570-1576. Competing interests: None declared |
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Nandkishor V Athavale, Specialist Registrar Department of Health Care for older adults, Northern General Hospital, Sheffield S5 7AU.
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POLYPILL FOR OLDER ADULTS Sir, Wald and Law (1) have come up with a novel and fascinating concept of Polypill trying to persuade the readers with staggering 80% reduction in cardiovascular events. In an era of increasing cardiovascular morbidity a concept like this is most welcome as it is challenging and thought provoking. Many issues have already been discussed in BMJ’s rapid responses (2). I will restrict myself to its implications to my specialty of geriatric medicine. Good old medicine discourages generalised use of combination medications except in certain situations (3). Poor compliance to medication as seen in the older population (4) is one of them. And with increasing number of secondary prevention strategies a patient leaving the hospital after a cardiac event finds himself on 3-4 new medications. A Polypill will be a welcome relief for them. Whether this improves the compliance needs to be tested in a clinical trial setting. Secondly, side effects of the pill would be problematic which are more common in the elderly. Though different modifications of the pill can be suggested for known side effects (e.g.- a pill without ACE inhibitor in worsening renal impairment), side effects like rashes, anaphylaxis would pose a problem regarding which component could be causative. Thirdly, many older people have other comorbidities like airways disease, renal disease, severe peripheral vascular disease making one or more of the components of the pill contraindicated. Finally, total mortality and absolute risk reduction which are more relevant to this population are not included in the paper. Though there may be a case for such a pill for secondary prevention in selected adults, its use as a blanket primary prevention strategy for adults over 55 would need rigorous clinical evidence. There are many other controversial issues such as statistical model used, inclusion of folic acid, etc (2). One must congratulate Wald and Law for provoking the debate and giving food for thought. The epidemiologists have done their job and onus is on clinicians to test the theory in randomised trials. BMJ has kept up with the newly embraced policy of controversial articles (recent one on passive smoking). It is too early to decide if this is the most important issue in last 50 years as Editor R Smith claims (5). I think we will get the answer 50 years down the line. References: - 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419-23. 2. Rapid responses. http://bmj.com/cgi/eletters/326/7404/1419. (accessed 7 July 2003). 3. Lawrence DR, Bennett PN, Brown MJ. Clinical pharmacology. 8th Edition, Churchill Livingstone, New York, 1997, p 106-7. 4. Bloom BS. Daily regimen and compliance with treatment. BMJ 2001; 323: 647. 5. Smith R. the most important BMJ for 50 years? http://bmj.com/cgi/content/full/326/7404/0-f (accessed 9th July 2003). Competing interests: None declared |
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Barry Lewis, Emeritus Professor, Consultant Physician 14 Wimpole Street, London W1G 9SX
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Sir, In 35 years of treating hyperlipidaemia I have often regretted undertreating patients, through underestimating their cardiovascular risk, or lack of effective drugs; but I have yet to regret treating it actively. This is in conformity with the emphasis, in Wald and Law’s papers (BMJ, June 27 2003; 326: 1419-23), their earlier review1 and in the Heart Protection Study2 on the non-threshold, continuous distribution of risk. The bold proposal by Wald and Law and colleagues to reduce cardiovascular disease (CVD) profoundly, by widespread use of a fixed-dose 6-drug ‘Polypill’ to lower risk factor levels, derives from a wealth of clinical trial analysis; it merits serious attention. It is a radical departure from the long-accepted dual preventive strategy of public education in health-oriented living habits plus medical recognition of and management of individuals at increased risk, with a view to minimizing such risk. The latter strategy has, with a lesser contribution from reduced case fatality, proved impressively successful, reducing coronary heart disease (CHD) and stroke deaths by 40-60% in many countries in the past 35 years. Their and others’2 criticism of the use of risk factor thresholds, as guides to the use of risk-reducing drugs such as statins, is sound: there is a continuous graded relation between risk factor levels and CVD incidence. Thresholds were introduced to promote a level of treatment proportionate to risk, but they are indeed a blunt instrument. In common with all current guidelines Wald and Law advocate basing treatment decisions on global CVD or CHD risk; but risk too is continuous: choice of cut-off points is arbitrary, ranging in recent guidelines from 10-year rates of 15 to 30%. The answer is surely that management of risk factors is also necessarily graded: diet alone, or diet plus medication at appropriate dosage, using one or more drugs. I take issue however with their statements that treatment ‘has generally been limited to single risk factors’ and to ‘reducing risk factors to “average” population levels’. All clinical guidelines for risk reduction, including those I have co-authored, have for years emphasized the need to deal with all modifiable risk factors; thresholds and targets were not based on population distributions, but were derived from prospective epidemiology, as guidelines to be applied as informed by clinical judgement. 2 Several considerations have bearing on the new proposal: [1] Although the average lowering of plasma cholesterol, homocysteine, and blood pressure by the components of the ‘Polypill’ predicts excellent CVD reduction, individual variation in responsiveness to treatment is pronounced. In the strategy outlined above, risk factor reduction is clinically monitored, and treatment is adjusted as needed to maximize benefit. Mass medication without clinical care would be insufficient for some at high risk, and would offer little to those at low risk. [2] It is proposed that the ‘Polypill’ be taken by all with CVD and by asymptomatic people aged over 55. Granted that 96% of CVD deaths occur after this age, nonfatal and fatal events affecting younger people are not negligible and represent a disproportionate loss to family and to productivity. Detection of high risk is thus needed early in adult life. Several major genetic hyperlipidaemias require flexible, often high dosage of one or more lipid-lowering drugs, two-drug treatment having the advantage over high-dose statins that the latter have somewhat flat dose- response curves. Such disorders are not uncommon, e.g. familial hypercholesterolaemia affects one person in 500 in the UK; unless detected early and effectively treated it often leads to CHD before age 50. [3] Among the population unaffected by genetic hyperlipidaemias, cholesterol and triglyceride levels can be reduced in many, and (importantly) HDL cholesterol increased, by the triple approach of weight control, dietary change and exercise. Since CHD is in significant part a nutritional disease, an initial trial of these approaches is surely appropriate. Compliance is difficult to maintain in dietary trials and in practice, but when it is achieved cholesterol lowering can be substantial and sustained 3,4,5. [4] Trial-based estimates of the incidence of serious drug-related side effects from the ‘Polypill’ are reassuring. But trials of lipid- lowering drugs have missed significant side effects; impotence, a recognized side effect of fibrates, was unrecorded in some large end-point trials. Furthermore, patients complain of and stop treatment because of symptoms that may not be drug-related, e.g. muscle pain with normal creatine kinase, a common symptom during statin treatment. There is a vast need for wider, and better, application of public health measures and of clinically-based strategies for detecting and treating individuals at high risk. To proceed to mass polypharmacy would indicate that clinicians and public health doctors have been derelict in applying well-tried preventive methods. Yours sincerely Barry Lewis 3 1. Law MR, Wald NJ. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2002; 324: 1570-6. 2. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high- risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360: 7-22. 3. Hjermann I, Velve Byre K, Holme I, Leren P. Effect of diet and smoking intervention on the incidence of coronary heart disease. Lancet 1981; ii: 1303-10. 4. Watts GF, Lewis B, Brunt JNH, Lewis ES, Coltart DJ, Smith LDR, Mann JI, Swan AV. Effects on coronary artery disease of lipid-lowering diet, or diet plus cholestyramine, in the St Thomas’ Atherosclerosis Regression Study (STARS). Lancet 1992; 339: 563-9. 5. Schaefer EJ, Lichtenstein AH, Lamon-Fava S, Contois JH et al. Efficacy of a National Cholesterol Education Program step 2 diet in normolipidemic and hypercholesterolemic middle-aged and elderly men and women. Arterioscler Thromb Vasc Biol 1995; 15: 1079-85. Competing interests: None declared |
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Saul G Myerson, Clinical lecturer Oxford University, John Radcliffe Hospital, Oxford OX3 9DU
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I have read some rubbish in medical journals in my time, but none as appallingly bad as this. I am astonished that the BMJ endorses it both in editorial form and from the editor himself. The fundamental statistical and scientific flaws have been expanded on above and I find it incredulous that this paper passed peer review - or did it? The only reason I can see for publication is to increase the BMJ's press coverage - an underhand and worrying trend for a journal that would like to think of itself as serious. I suggest Richard Smith should seek work with the News Of The World - some of their stories are at least based loosely on fact. If the article was intended to stimulate debate, then it should have appeared as an opinion piece, not a paper. This is all the more disappointing as the principle of a 'polypill' for primary/secondary prevention is a worthy one for debate with many merits. Had the authors applied the concept with more rigour, we might have had a reasonable debate. Instead, it is lost already. Competing interests: None declared |
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Lawrence J. O'Brien, retired 1200 N. Nash Street #535, Arlington, VA 22209
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The meta-analysis that has resulted in the conclusion that a poly- pill might be concocted that would reduce cardiovascular disease in persons over age 55 by more than 80 percent is flawed because the randomized controlled clinical trials (RCCTs) that the analysis and conclusion have been based upon were fundamentally flawed. Undoubtedly, many of the RCCTs included in the meta-analysis were conducted in the United States. In a 1997 paper, Theodore Pincus, MD, professor of medicine in the Division of Rheumatology and Immunology at Vanderbilt University School of Medicine, commented as follows on the degree to which some physicians have been cowed by the "evidence" issuing from the contemporary explosion of RCCTs: [C]linical communities in standard and alternative medicine have come to rely on randomized controlled clinical trials as the only method to document the effectiveness of an intervention. ...I have heard at least two lecturers dismiss their own clinical experiences because they were at variance with data from randomized controlled clinical trials. ...In this milieu, many professionals, in both the conventional and alternative communities, have developed a type of ¡§helplessness¡¨ (Seligman 1975) that the randomized controlled clinical trial is the only method to evaluate therapies, including their own. [It is] a sense of "helplessness" to systematically monitor long-term outcomes in their own patients. The sense of helplessness among clinicians that Pincus points to is no more, and no less, than another concrete manifestation of the systematic undermining of professional respect for the content and the significance of clinical observation at the point of first contact, i.e., for the cumulative clinical experience physicians engaged in primary care. Professor Pincus sums up the current situation in the few sentences following: [C]ontrary to current beliefs, data from clinical observational studies--not trials-- may, in certain instances, depict outcomes in chronic diseases more accurately than do data from clinical trials. (Pincus & Stein 1995; Pincus & Wolfe 1992). Data from formal randomized trials can result in directives that compromise and even detract from optimal patient care. ...Yet most health professionals do not attempt to evaluate formally the success or failure of most interventions used in their care of individual patients. They may refer to published data, including randomized controlled clinical trials, or say that a clinical trial is needed, but data from their own experiences usually are not available. ...It seems fair to say that although thousands of health professionals may enhance the lives of millions of people with chronic diseases each day, in general they have little data to document the effectiveness of most interventions for their individual patients. As for the treatment records that are being kept by physicians in clinical practice, Pincus has this to say: Medical records and charts have evolved primarily as medico-legal, rather than scientific instruments, and are designed to document the actions of professionals but not necessarily whether those actions were effective or even harmful. ...These limitations may be traced in part to evolution of the medical record under the "biomedical model," the fundamental paradigm of twentieth-century medicine (Engel 1977, Holman 1976, Sagan 1987). In this model, the patient history is regarded as "subjective" information that serves primarily to identify appropriate laboratory tests, radiographs, and other high-technology data required for effective diagnosis and treatment. Patient information described in the medical record is viewed as "subjective" and "nonscientific"...in contrast to laboratory and other high-technology data, which are regarded as "objective" data, [derived from tests] conducted according to strict "scientific" standards. From this perspective, information provided by patients is regarded as largely irrelevant to outcomes; only "objective" data compiled by professionals are considered of value to predict and monitor disease. Further, the goal of interventions in the biomedical model is ¡§cure,¡¨ and documenting the effectiveness of measures to reduce pain, fatigue, psychological distress, and/or other symptoms, is regarded as relatively unimportant. (Emphasis is in the original). Pincus has employed information resulting from his own clinical observations as a rheumatologist to powerfully illustrate the fact that patient-provided "subjective" data can be of far greater clinical and predictive value than information obtained from an RCCT. For example, in an RCCT designed to test the efficacy of the beta-blocker propranolol against a placebo in preventing a second heart attack in patients who have had a recent heart attack, the trial succeeded in establishing its intended point -- propranolol had greater efficacy than the placebo in forestalling a second attack. However, there was more to the story. Pincus has commented as follows on the outcomes from this trial: [F]urther analysis of data in this trial indicated that mortality according to level of education differed more than according to whether patients received propranolol or placebo. ...In other words, what might loosely be termed "mind-body" variables had a stronger effect on outcomes of patients under study than did the randomization group. (Analyz. p.15). The leaders of the American medical establishment are unlikely to readily admit the serious limitations that are intrinsic to its highly touted "gold standard of scientific proof," the RCCT, preferring instead to conceal the awkward facts and to preach their totally unbelievable gospel, which is that these clinical trials do in fact identify a specific therapy, most often a single synthetic pharmaceutical agent, that will prove to be optimal for the majority of individual patients who present with symptoms of the specific disease under investigation in a given clinical trial. Pincus has made the following observations on this subject: The tendency to interpret trials to mean that one drug will invariably be more efficacious than another may stem from the prototypical clinical trials, which were performed to analyze the activity of antibiotics in retarding the growth of or destroying infectious bacteria. Bacteria are single cell simple organisms, and the purpose of antibiotics is to eliminate these nonhuman cells from the body. In these trials, a single optimal drug might be relatively easily identified for all patients. The treatment of multicellular, multiorgan human patients presents a more complex challenge. Variation in responses to a drug, or to any treatment, would be expected in therapies designed to reduce overproduction of gastric acid, blood pressure, pain, or depression. Nonetheless, most clinical trials are reported as though they identify the "best" therapy for all patients. (Emphasis is in original). The work that Pincus and his colleagues have done throws copious amounts of cold water on the claims of efficacy for many if not most of the "gold standard" clinical trials. From the vantage point of a recognition that these trials must inevitably involve great complexity, given the fact that idiosyncratic human organisms constitute their subject matter, it ought to be clear that these clinical trials usually cannot produce unquestionable "scientific proof" that some proposed intervention will produce optimal medical benefits for a majority of patients who present with similar symptoms. The recognition of the inevitable complexity of such human experiments also makes it clear and distinct that many of the RCCTs, as currently designed and conducted, rest on flawed Enlightenment-era underpinnings--including Descartes' erroneous mechanistic and dualistic calculus and logic, and Newton's reductionistic and linear notions in physics. These seventeenth century schemes of thought are always inappropriate when they are applied to the study of a subject matter of admittedly great complexity, which must surely be the condition for the large majority of RCCTs, however skillfully they may have been designed. The following words of Robert Rosen are extremely relevant to the point at issue here: If somatically an organism is a machine to be understood in purely syntactic, reductionistic terms, then life is only a matter of putting its fractions back together. But as we all know, it is literally not that simple. ...No (finite) concatenation of syntactic models of an organism yields something which must be an organism. ...Organisms are not in this class of systems. Just as we cannot concatenate syntactic models to obtain an organism, we cannot, for that same reason, concatenate reductionistic fractions to get an organism. ...Something else is needed to characterize what is alive from what is complex. Rachevsky provided this in his idea that biology was relational, and that relational meant (as we stated it) throwing away the physics and keeping the organization. ¡KOrganization in its turn inherently involves functions and their interrelations; the abandonment of fractionability, however, means that there is no kind of 1 to 1 relationship between such relational, functional organizations and the structures that realize them. These are the basic differences between organisms and mechanisms or machines. (Emphasis is not in original). Analyzed from the vantage point of Rosen's trenchant observations, most RCCTs can be understood as requiring the reversal of the analog suggested by Rosen: i.e., throwing away the organization and keeping the reductionistic physics--as the only means possible to coax a 1 to 1 relationship out of the complex set of conditions under which such a relationship will only rarely prove to be scientifically justifiable. From this angle of vision, many if not most of conventional medicine's "gold standard" clinical trials can be seen to be fundamentally fantastic adventures, the outcomes of which cannot be reasonably accepted as being scientific. Medicine's prevailing reductionistic and mechanistic metaphor for dealing with the complex biological life of idiosyncratic human organisms must certainly be rejected as being an inadequate and insufficient analog for comprehending much of anything about these organisms, at least anything that could meet the requirements of scientific method. Perhaps the ultimate fantasy for conventional medicine is the loony idea of assembling results drawn from the science-fiction world of contemporary RCCTs into a poly-pill to be prescribed for everyone over the age of 55 as a benefit to their health. The randomized controlled clinical trials that now provide the underpinning for "evidence-based" medicine in the United States include many more limitations than the ones already identified in the foregoing paragraphs. Included among these additional "intrinsic limitations" of conventional RCCTs are the following: Many therapies "proven" to be effective in an RCCT have ended up by producing poor outcomes for the patient over periods of time longer than the term of the trial itself. Pincus has made the following observations on the actual outcomes from an RCCT that involved 297 patients with rheumatoid arthritis: ¡§[M]ost patients experienced poor long-term outcomes, with progressive incapacity and shortened survival. ...[P]oor outcomes could be predicted and documented most effectively according to the patients¡¦ responses to simple questions, rather than from high-technology measures such as laboratory tests and radiographs. The evidence that patient data were more predictive than high-technology data was clearly outside the traditional biomedical model, but has been confirmed in many subsequent studies by ourselves and others.¡¨ The designers of RCCTs have biases coming in, and in an age when huge pharmaceutical conglomerates have major financial stakes invested in achieving a specific result for a given trial, these entering biases simply cannot be overcome, despite the presence of a "control group." Pincus has remarked as follows about the influence of design on RCCT results: ¡§[U]nless the trial includes all consecutive patients with a given disease over many years (which has not occurred to date), biases inevitably enter into the design of the trial itself, and these may strongly influence the results in favor of or against a particular conclusion. ...[T]he design of a clinical trial can greatly ¡¥tilt¡¦ the probability that an intervention will or will not appear to be more efficacious than a placebo.¡¨ The "scientifically proven" findings of RCCTs are reported only for the group of trial subjects as a whole, ignoring the inevitable individual variation that will always be an outcome of these experiments. Pincus has commented as follows: ¡§[A] typical clinical trial [is one] in which 60 percent of individuals respond more favorably to drug A than to drug B, 20 percent respond more favorably to drug B than to drug A, and 20 percent find drug A and drug B of equal efficacy. Although an accurate interpretation of the data might be that drug A is better for certain individuals and drug B is better for others, the usual interpretation of the data is that drug A is superior to drug B for all patients.¡¨ Because the medical profession has such great difficulty coping with the unsettling reality of adverse side effects, a reality that was recently underlined by the National Institute of Medicine's documentation of nearly 100,000 deaths resulting annually from such side effects, it should be no surprise that RCCTs have routinely failed to standardize the interpretation of the side effects evident in the clinical trials, much less bring these side effects to public notice. Pincus comments as follows: ¡§A clinical trial implies a ¡¥black and white¡¦ choice, while the actual results suggest ¡¥shades of gray,¡¦ particularly in assessing side effects. This aspect of analyzing the results of clinical trials must be recognized to include an interpretation with attendant biases, which may help explain some contentious disagreement within FDA advisory groups concerning approval of certain new drugs.¡¨ Because RCCTs are frequently structured to include a control or "placebo" group, all subjects must be informed that they will be randomly assigned to one of these two groups. All subjects are therefore under the impression that they may be in a group that will receive the "best" and the "latest" experimental intervention known to medical science, or they will receive no treatment. This trial format guarantees that a "placebo effect" that might otherwise be present will be interfered with in unfathomable ways by the knowledge that some subjects will get the "best" therapy, and the rest will receive no help at all. Pincus comments as follows: ¡§The placebo effect is obviously distorted when a health professional invites a patient to participate in a ¡¥scientific experiment¡¦ to determine the best therapy, in which the patient is told that he or she may either receive a therapy or serve as a control. ...[M]uch of the therapeutic benefit that results from patients being told that they are being given an optimal therapy may be lost in a clinical trial.¡¨ There is also the issue of whether it is ethical to utilize a placebo group in a randomized trial to evaluate a drug unless there is no other drug in the medical formulary to treat the condition in question. If another drug is available to treat the problem under clinical investigation, then the new synthetic chemical agent should only be tested against the existing medication, and not against a placebo. This has been the law in most industrialized countries except for the United States. In international medical circles, the United States is considered to be a rogue nation in terms of its loose ethics in testing drugs vs. placebos. One can only imagine how the rest of the world will perceive the radicalism of the poly-pill being proposed by Wald and Law, the marketing of which is to be aimed principally at the peoples of the "developing" nations. A stronger term than "rogue nation" will undoubtedly emerge to describe both the US and the UK if this fantastic poly-pill should ever become a reality. Competing interests: None declared |
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Michael Bunbury, GP St Vincent
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I don't wish to be sarcastic but "common sense" tells me that something is amiss. Professor Wald concludes in his last sentance that " No other preventive method would have so great an impact on public health in the Western world." I propose that that one other intervention should be considered and that is to give up smoking. Since the reduction in risk factors is additive ( although this may have been taken into account) one might expect a further 34% reduction in mortality from IHD making a total reduction in IHD of 114%. I may not be very good at statistics which is why I am a GP and rely on a degree of common sense. I am surprised that Professor Wald forgot this point as he wrote it in an article printed in the BMJ on the 28th June 1997 Ref:Prospective study of effect of switching from cigarettes to pipes or cigars on mortality from three smoking related diseases N J Wald and H C Watt BMJ 1997; 314: 1860. Competing interests: None declared |
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Uffe Ravnskov, Independent researcher Magle Stora Kyrkogata 9, S-22350 Lund, Sweden
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The idea proposed by Wald and Law1
to treat all human beings above age 55 with a six-drug pill for the rest of
their life is fundamentally flawed. According to the authors this treatment
should reduce cardiovascular disease by more than 80% corresponding to 11-12
more years free of ischemic heart disease event or stroke. Apparently, Wald and
Law have little clinical experience. They would else have known that many
unpredictable problems associated with multidrug treatment with all certainty
may reduce the alleged benefit.
Worse is that they have not included the risk of
dying in their calculations. This objection to their papers presented in “the
most important BMJ for 50 years” is most relevant because in many of the
studies included in their trial analyses total mortality was either unchanged or
higher after treatment. For instance, in a meta-analysis of the cholesterol
lowering trials performed before the appearance of the statin drugs, coronary
mortality was unchanged and total mortality increased by ten percent.2
In the three statin trials that included healthy people only, total mortality
was increased in one3 and unchanged in two,4,5 and in a
recent trial that included high-risk individuals only, the benefit from a
decreased cardiovascular mortality was neutralised by an increased mortality
from cancer.6
Also, in most of the controlled, randomised trials
included in a meta-analysis of antihypertensive drug treatments,7
total mortality was not lowered significantly. This discrepancy between
cardiovascular and total mortality may be due to side effects of the treatments
or to the possibility that some of the deceased participants died from a
cardiovascular disease but had another diagnosis on their death certificate.
Whatever the cause may be, I am confident that few people are interested in
avoiding a heart attack by life-long polymedication if their risk of dying, in
particular from another disease, is unchanged or higher, considering the many
nasty alternative ways of dying. References
Competing interests: None declared |
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Ian F Godsland, Wynn Reader in Human Metabolism Endocrinology and Metabolic Medicine, Imperial College London, St Mary's Hospital, London W2 1NY, Victor Wynn
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The possibility of a ‘polypill’ (BMJ, June 27), able to reduce coronary heart disease by 80%, activates a perennial medical myth - much loved by the media - namely ‘the magic bullet’, a regular shot of which will cure whatever ill it is we most fear. This calls to mind another combination of potent pharmacological agents – the oral contraceptive pill – which was to dispel all fear of pregnancy and was also to be available over the counter for all-comers. Forty years on and the ‘pill’ remains a useful option in the array of contraceptive choices, but one that experience has shown is best prescribed only after careful evaluation of its pros and cons for the particular individual concerned. Unfortunately, this pragmatic approach has had to be achieved under heavy fire, with the magic bullet of the ‘pill’, ricocheting dangerously between over-stated scare and over-stated reassurance. It is unfortunate that the ‘polypill’ has been fired off in a way that looks set to replicate the same destructive cycle. Claims have been made and headlines printed that lay the foundation for another spurious drama in which the hopes generated by the myth of a cure-all are played off against the fears engendered when the inevitable side-effects start to be reported. Meanwhile, the unfortunate public is left trying to keep out of the firing line, whilst still trying to pick a constructive path to better health. In fact, the ‘polypill’ will most likely turn out to be a useful option in the array of choices available to any individual wishing to minimise their risks of developing coronary heart disease or stroke. Just how useful will require extensive testing, if indeed a sponsor can be found to manufacture the potion. It is to be hoped that one will, because a tremendous amount of evidence has been marshalled to suggest that further reductions in heart disease risk may be possible. It is unfortunate though that it is the headlines of medical myth that are already setting the agenda, rather than cautious optimism, extensive testing, clinical experience, a secure evidence base and balanced judgement. Competing interests: None declared |
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Andrea Alberto Conti, University Researcher Dept. of Critical Care Medicine and Surgery, University of Florence, Italy, Gian Franco Gensini
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Sir A paper by NJ Wald and MR Law (1) recently published in the British Medical Journal claiming to propose a new strategy to reduce cardiovascular disease has appeared to us as a midsummer nightmare, rather than a midsummer night’s dream. In effect, the proposition of the so- called “Polypill”, a super pill containing six components such as aspirin, a statin, three blood pressure lowering drugs and folic acid, targeted to global cardiovascular prevention and therapy, even if it is the result of a “simulation”, contains potential relevant risks. The underlying concept does not seem much different from that of many currently available integrators (that is “take everything that could be good for you, at worst it will do no harm”); as is well known, such compounds are largely used, we should say overused and, what is worse, useless. The additional problem with the Polypill is that it appears to us even harmful to propose a super pill “useful for everyone”, such as that proposed by the Authors. In effect there is currently a strong trend to shift from “simple” evidence-based medicine to patient tailored evidence- based treatment, and this magic bullet is the most alien thing one can imagine from individually tailored treatment. Physicians may think that a “simple” pill may solve every health care issue, since the efficacy of the treatment should already be established, since the compliance of the patient should improve, and since it “would be acceptably safe”, as Wald and Law state in their paper. Patients may believe that the same “simple” pill may solve all their health problems, perhaps putting in a corner attention to lifestyle habits. We do not consider it at all appropriate at all to discuss the composition and the relative dosage of the different components of the proposed Polypill, simply because we do not believe it methodologically correct to propose, to everyone aged 55 and older and to everyone with existing cardiovascular disease, exactly the same treatment, irrespectively of the preferences, values and needs of the single persons, rather than patients. The editorialist Anthony Rodgers (2) asks himself if Wald and Law’s bold claim is justified, and replies that it is quite possible. We ask ourselves what a person/patient who will not tolerate well the astonishing Polypill will do: will he/she take half the pill? Perhaps a quarter? And what about a person/patient going on smoking while assuming the super pill? Will he/she double the dose, since two super pills could be better than one? Best available research evidence improves clinical reality, and promises wonderful dreams, if and when correctly implemented. Please do not turn our dreams, yet only midsummer ones, into a permanent nightmare. 1) Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419-23. 2) Rodgers A. A cure for cardiovascular disease? BMJ 2003; 326: 1407-8. ________________________________________________ Competing interests: None declared |
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Dietmar Fuchs, Institute of Medical Chemistry and Biochemistry A-6020 Innsbruck, Austria, Schroecksnadel Katharina, Frick Barbara
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We read with interest the article by Wald and Law (1) proposing a “poly-pill” to reduce cardiovascular risk by more than 80%. Although it is attempting to promote the preventive administration of such a drug to everyone above 55 years, this is a rather speculative approach: To conclude from data of different meta-analyses and of single medications is not an appropriate way to estimate the effectiveness of a combination of several drugs. The estimated benefit of the proposed combination of statins, a blood pressure lowering drug, folic acid and aspirin certainly is too optimistic. The simple addition of individual risk reductions derived from meta-analyses for each of the four medications is very questionable. This would at least require that risk factors are independent and that there is no common background of risk factors. By contrast, risk factors treated by the suggested poly-pill are far from being independent. Hyperlipidaemia, hypertension, hyperhomocysteinaemia and inflammation may all result from immune activation, which appears to be deeply involved in atherogenesis. E.g., the extent of carotid atherosclerosis was found to correlate with neopterin concentrations (2), the latter indicating activated macrophages. Immune activation and cytokine production may on the one hand feed inflammation, on the other hand, immune activation is accompanied by enhanced formation of reactive oxygen species (ROI). ROI are capable of, e.g., oxidizing vasodilator nitric oxide to peroxynitrite, another strongly oxidizing derivative (3), and may thus contribute to hypertension. On the other hand, ROI and other oxidizing species do destroy antioxidants including vitamins, which - in case when folate levels are diminished - gives rise to moderate hyperhomocysteinaemia. ROI also cause peroxidation of lipids, a chemical reaction which is also supported by moderate hyperhomocysteinaemia. So it seems that all the four drugs recommended are treating symptoms which can be referred to immune activation and oxidative stress. In patients, immune activation does not only show a relationship with disturbed fat metabolism and lipid peroxidation, it is also associated with increased homocysteine accumulation and enhanced consumption of antioxidants and vitamins (4). Chronic activation of the immune system may provide the “missing” link between the different risk factors, and the extent of activation may have the most predictive value in risk estimation of patients. In consequence, down-regulation of immune stimulation may be more effective than treatment of individual risk factors in patients at risk. Interestingly not only aspirin but also some of the statins, in addition to their effect on HMG- reductase, possess immunosuppressive properties (5). Thus, even if the strategy presented by Wald and Law might have sense, the expected reduction of cardiovascular disease by more than 80% is kind of misinterpretation. Schroecksnadel Katharina, Frick Barbara, Dietmar Fuchs
1.Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419. 2.Weiss G, Willeit J, Kiechl S, Fuchs D, Jarosch E, Oberhollenzer F et al. Increased concentrations of neopterin in carotid atherosclerosis. Atherosclerosis 1994;106:263-71. 3.Squadrito GL, Pryor WA. Oxidative chemistry of nitric oxide: the roles of superoxide, peroxynitrite, and carbon dioxide. Free Radic Biol Med 1998;25:392-403. 4.Widner B, Enzinger C, Laich A, Wirleitner B, Fuchs D. Hyperhomocysteinemia, pteridines and oxidative stress. Curr Drug Metab 2002;3:225-32. 5.Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med 2000;6:1399-402. Competing interests: None declared |
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Miguel E. Campos, Auxiliary Professor Peruvian University Cayetano Heredia, None
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Lima, July 18, 2003 We enjoyed the excellent comments of Dr. A. Roggers about the interesting article of Drs NJ wald & Mr Law, where they pose the possibility of having a "poly-pill" that would conquer the cardiovascular diseases. I will pose to you some possible drawbacks to this wonder therapy: 1.- The poly-pill probably will work only in younger and "healthy" populations (who are not taking medications ), and I am afraid it will not be tolerated by our elderly populations. When we care for them (in the real world of everyday practice) we always have to take in consideration other (negative) factors that commonly complicate their treatments, such as the so called "the 3 P´s": the Polypharmacy, Poly-morbidities and Poly -professionals. Elder Pts always have some other active pathologies (besides their cardiovascular problems), and for them they take a good number of other medications. And as it always happen, our patients do not have the possibility to count with a permanent primary Physician, and they are usually seen for new and different Doctors, that keep prescribing them with more and more medications . 2.- When we treat elderly patients (for well established indications) , with 2 or 3 of the drugs-components of the poly-pill ( and in full doses), they are not well tolerated. For example the Rx of severe systolic Hypertension usually require the use of 2 or 3 medications -and in higher doses (and as everybody knows, more than 40 % of the elderly do not tolerate the ACE-Inhibitors and develop cough ). Another example is the Rx of hypercholesterolemia with Statins (and nowadays, our Cardiologists are pushing for the use of statins in maximal doses, for everybody ! ) and a good percentage of our Pts develop myositis or hepatic toxicity. In the Elderly, all these drugs could reach dangerous levels in serum, due to their expected changes in their Pharmacokinetics and Pharmacodynamics reactions ( that handle poorly all the drugs ingested ), and the common occurrences in them of Drug interactions (because they are also taking at the same time, several other medications ) . In summary, it seems to me that the poly pill-will be most useful for younger persons ( between the ages of 30 to 50 years of age), and perhaps, it will postpone in them, the expected negative changes that will ensue as we age (the so called the "shift to the rigth" of the morbidities).This therapy could be equated to the use of Hormone replacement therapy in women, from the 50 to the 60 years, a period when they are probably more useful. Miguel E. Campos MD, FACP Lima, Peru Competing interests: None declared |
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Robert Kerr, Annuity Pricing Actuary, Norwich Union Annuity, UK York, England
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As an actuary I do not have any medical background, however as a profession we are very interested in understanding improvements to mortality. So I read this article with interest. However I have several issues that make me concerned theat the 80% reduction is heavily overstated. 1. The paper assumes that each factor is independant and this is not necessarily true. 2. The paper appears to assume that the reduction observed in the age 55- 64 group is applicable to other age groups and most notably the very old, I suspect that this may not be the case. 3. The paper assumes that the state of lives who survive are unchanged, because it assumes a constant proportional impact, whilst this treatment may simply delay the period until a heart attack and strokes, as lives gradually become worse. 4 There is an issue over how many deaths are already reduced by taking these pills already, either in whole or in part, and so are we already part way down this 80%. 5 For very old ages cause of death is difficult and as an autopsy is not usually performed, the cause of death may not be the underlying cause. So a life stated as dying from a heart attack or stroke may be due to die from some other disease, which unless the doctor knew of, would not be recorded. 6. There would clearly be concern about the proportion of people who actually stick to the drugs and this is likely to be less in practice than any trial. Subject to these comments, a polypill does sound reasonable subject to full trials verfiying benefits, over and above current medical practices. This may however prove more beneficial in countries where the access to medicine and current drugs is limited. Robert Competing interests: None declared |
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Munir E Nassar, M.D., N/A 17 Cobblefield Way, Pittsford, NY USA 14534, N/A
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The medical education of physicians fine tunes the physicians' medical judgement against sweeping, untested medical generalizations which the paper of Wald and Law indicates for prevention of cardiovascular disease(1) My objection to such a Poly-Pill approach when the physician is confronted with 55 year olds and over with hypertensive cardiovascular disease, is that the physician usually and wisely treats the hypertension with one pill and if the blood pressure (BP) is not controlled adds another etc, a sort of graded approach (aspirin, statin and folate are given). Since many patients respond to one antihypertensive medication there is no rational to adding two other medications. Also many such patients have responded without BP medications by changes in their life style: regular moderate exercise, vegetarian diet and weight reduction to an ideal weight status, so where does the poly-pill fit here? African Americans with hypertension do not respond well to beta blockers, hence the poly-pill with its ingredient beta blocker will not help. Similarly in the Dysmetabolic Syndrome X, clearly the hypertension in such patients is related to overweight associated with insulin resistance and its relation to elevated BP and again the treating physician would do well to treat the underlying problems of obesity and diabetes type 2 rather than a poly-pill. Finally, although diastolic hypertension with normal systolic BP is of lesser importance than systolic hypertension, the Poly-pill approach has no place in the treatment of such a condition. Medical judgement and individualization of each patient medical problem separately is the best approach. Munir E Nassar, M.D. Ref: 1- Wald NJ, Law MR: A Study to Reduce Cardiovascular Disease by more than 80%. BMJ 2003;326: 1419-0 Competing interests: None declared |
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John A. DePoy, BS, MSc, MBA, Consultant to the Pharmaceutical Industry 5346 North Berkeley Blvd, Milwaukee, WI 53217
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I have read the rapid responses above and conclude that the weight of opinion seems to be negative: we should not pursue this novel concept. To save people time, I try to summarize and organize the arguments against the polypill below: 1. Taking a pill to prevent heart disease and strokes is immoral. People should exercise and eat well, even if it kills them. 2. A one-size-fits-all approach is wrong (except for the diet and exercise approach mentioned above). Furthermore, the trend is toward individualized medicine. We should not deviate from the trend, even if if there is potential to save lives. 3. Patients will never comply with a daily pill, so what is the point? (The real answer is to get them to spend an hour a day exercising.) 4. The conclusions are based on meta-data. There is no place in medicine for hypothesis. This proposal should be disregarded for lack of clinical data. 5. Other promising proposals (like estrogen) have not lived-up to initial claims, it follows that the polypill will not either and no further consideration should be given. 6. Death is inevitable and we should not postpone the inevitable. Furthermore, people can not afford to live longer. 7. This may benefit the population as a whole, but individual patients will be worse off on average. I hope this was helpful. Competing interests: None declared |
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Christopher M Reid, Head, CVD Prevention Unit Baker Heart Research Institute, Victoria, Australia, 3004, Sloane Birrell, Melinda D. Rockell
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Wald and Law propose a strategy that they suggest could prevent the majority of cardiovascular events if taken by all people aged 55 years plus, and everyone with existing cardiovascular disease. Their plan suggests combining drugs targeted at LDL-Cholesterol, blood pressure, homocysteine and platelet function to form the “polypill”. The strategy advocates pharmacological intervention in people at increased risk, regardless of risk factor levels. We are intrigued by this approach, and examined the potential of a “polypill”-ingredient combination therapy (with the exception of folic acid) in a large ongoing prospective cohort study of 9,671 Australian patients (aged 55+), with cardiovascular disease, being managed by their general practitioner. Despite current Australian evidence-base guidelines recommending wider use of combination treatments in high-risk patients (48%, n=4601), only 3.5% (n=337) of the cohort were taking the “polypill” prescription of statin, aspirin, and the three blood pressure lowering drugs: beta- blocker, ACE inhibitor and diuretic. This data suggests that current approaches are not inducing Australian general practitioners to prescribe 5 agent combination therapies. While no significant differences in age or gender were found between “polypill” patients (n=337) and non-“polypill” patients (n=9334), those receiving multi-combination therapy were more likely to have experienced a myocardial infarction (66% vs 51%, p<0.0001), stable angina (53% vs 48%, p=0.035) or unstable angina (17% vs 12%, p=0.005), but less likely to have had a stroke (15% vs 28%, p<0.0001). The “polypill” group were less likely to have asthma (9% vs 14%, p=0.006), but more likely to have hypertension (79% vs 60%, p<0.0001), renovascular disease (7% vs 4%, p=0.039), gout (19% vs 13%, p=0.002) or diabetes (39% vs 22%, p<0.0001). 23% (n=2,253) of the cohort were not eligible for “polypill” treatment due to contra-indications to aspirin, statin, beta-blocker, ACE- inhibitor, or having concomitant asthma. Thus, the proportion of the cohort that would have been expected to experience adverse effects of “polypill” combination-treatment in this population appears to have been underestimated by Wald & Law’s prediction. The potential for a "polypill" approach to the management of secondary prevention has not yet been realised in Australian general practice. Current therapeutic management seems focussed on treatment of individual risk factors, rather than directed towards the combined impact on overall cardiovascular risk. Competing interests: The Sentinel Program was funded by an unrestricted educational grant from Bristol-Myers Squibb Australia. |
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Christopher J Martin, Lead Researcher, GP principal Laindon Health Centre Primary Care Research Team, French J, Vanderpump M
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Editor- Wald and Law should be congratulated on their analysis of the prevention of cardiovascular disease using the ‘Polypill’ concept.(1) It was an interesting, and valuable contribution to the literature on this topic. It has usefully presented one synthesis of the evidence and presented a radical view on its application. This has stimulated a healthy debate on the relevant issues, not just epidemiological or pharmacological, but also philosophical and ethical. Quite rightly, a number of assumptions they have made have been challenged and discussed, in particular the assumption of independence of effect of the combined use of the component agents; their relative risk reduction estimates; and the equating of the risk reduction from antihypertensives with the difference in risk between similar untreated individuals with a difference in blood pressure equal to the expected reduction with treatment. A further assumption seems to be left unchallenged – that their Markov model accurately predicts the effects of their proposed interventions. The same scientific scrutiny needs to be applied to the construction of a mathematical model and the assumptions used in it, as it does to the construction of the intervention and the assumptions used when estimating its effect. The Laindon Model of survival given cardiovascular disease risk factors and UK mortality data for non-cardiovascular death, predicted the 20 year mortality of an English cohort (Whickham study(2)) to within 1.5% for men, women, smokers, non-smokers, those aged 35-50 years old and 51- 65.(3) Using this model and a relative risk reduction of 88% for both ischaemic heart disease (IHD) and stroke, an ‘average’ non-smoking man of 55 with a systolic blood pressure of 139 mmHg and a total cholesterol / HDL cholesterol ratio of 4.5 would gain 4.1 years of life free from an IHD event or stroke, and would live almost one year longer. Ward and Law’s model estimated a gain of 11 years of life free from an IHD event or stroke. Using the Laindon Model, to achieve this gain would require a population of smoking, 55 year old men with diabetes, left ventricular hypertrophy, a systolic blood pressure of 165 mmHg and a TC/HDL cholesterol ration of 9. Competing interests: None declared |
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Christopher J Squire, Clinical audit officer Royal College of Radiologists, London W1B 1JQ, UK
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Will people actually take the Poly-pill? A report in the current Bandolier [1] suggests not; it is based on a recent US study of 1000 patients with diagnosed hypertension [2]; mean compliance was c. 48 %. The compliance of ordinary members of the general public like myself, who may well not accept that they have been forcibly reclassified as 'patients', will be much lower. So unless some way is found of incorporating the poly- pill into food and drink, this scheme is impractical. 1. Noncompliance with hypertensives. http://www.jr2.ox.ac.uk/bandolier/band112/b112-4.html; accessed 24.07.03 2. PS Wang et al. How well do patients report noncompliance with antihypertensive medications?: a comparison of self-report versus filled prescriptions. Pharmacoepidemiology and Drug Safety. 2003. Published Online: 28 Feb 2003 DOI 10.1002/pds.819 Competing interests: None declared |
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Sven E Nilsson, MD, Ph D, Associate Professor Jonkoping University, Institute of Gerontology, Box 1026, S-551 11 Jonkoping, Sweden, Stig Berg
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To the Editor The proposal of Wald and Law in BMJ (1) about a polypill for prevention of cardiovascular morbidity is of great interest. That type of inexpensive generalised prevention is appealing not only to prevent cardiac and cerebrovascular lesions but also for other expressions of ageing such as cognitive decline. In western society there might be consensus that a shorter life with intact cognitive function is more desirable than a longer life with gravely disturbed brain function. Taking national and cultural variation into account, goals and common rules for co-ordinate prophylactic trials need to be defined. In our studies of some Swedish samples of elderly we find a significant positive correlation between systolic blood-pressure and Mini Mental State Examination (MMSE) scores (OCTO-Twin (2), 599 twins, age ¡Ý80, r = 0,163 p= 0,000; OCTO (3) 277 non-twins, age ¡Ý85, r = 0,175 p= 0,003. In multivariate analyses a significant association is retained after correction for age, gender, congestive heart failure, and a clinical diagnosis of arterial hypertension. Considering these observations, we find it appropriate to avoid lowering blood-pressure without specific indications, at least for the age-group over 80. In a recent study (4) it is concluded that aspirin should be given in anti-inflammatory dosage for protection against cognitive decline and dementia, which may need combination with an antacid drug. Folate and cobalamin (B12) are of importance for the methionine-homocysteine cycle since methyl transferring is vital to nervous function. A malfunction in this process will be expressed by increasing plasma homocysteine. Medication with merely folate may hide a devastating B12 insufficiency. Further, for the oldest old it should be observed that declining cholesterol indicates a shorter time to death (5). The protective effect of statin for the vascular system may be mediated by complex mechanisms including an anti-inflammatory quality of the drug, similar to that of aspirin. For the higher age groups in focus, inclusion of statins is probably unnecessary as the effect of lowering cholesterol may be dubious. In conclusion, a pill containing aspirin >250mg (if needed together with an antacid), folate, and B12 will protect both brain and heart in the ageing population, if taken 2-3 times a week. There are few contraindications for a common prophylaxis after 55 of this low cost remedy. One should, however, be cautious to lower blood pressure after 80 years of age. Plasma level of homocysteine should be controlled yearly for estimating adherence to the treatment. References 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease to more than 80%. BMJ 2003;326:1419-23. 2. McClearn GE, Johansson B, Berg S, Pedersen NL, Ahern F, Petrill SA, Plomin R. Substantial genetic influence on cognitive abilities in twins 80 or more years old. Science 1997;276:1560-63. 3. Zarit S, Johansson B, Malmberg B. Changes in functional competence in the oldest old. J Aging Health 1995;7:3-23. 4. Nilsson SE, Johansson B, Takkinen S, Berg S, Zarit S, McClearn G, Melander A. Does aspirin protect against Alzheimer¡¯s dementia? A study in a Swedish population-based sample aged ¡Ý 80 years. Eur J Clin Pharmacology 2003, in press. 5. Nilsson SE, Evrin PE, Tryding N, Berg S, McClearn G, Johansson B. Biochemical values in persons older than 82 years of age: report from a population-based study of twins. Scand J Clin Lab Invest 2003;63:1-14. Competing interests: None declared |
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gerry e burns, GP principal 165 duncairn gdns belfast bt15 2ge
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Wald and Law state there is a potential for the polypill to greatly reduce cardiovascular disease maybe as much as by 80%. They seem to have missed the point, as others do,with a lot of this research, in that different therapies do not so much as prevent, as delay disease as we all have to die of something (as well as paying taxes). It has been shown in cancer epidemiology that if cancer was cured tomorrow the average lifespan only increases by 3 years. One could assume that this will be the case with the polypill also. gerry burns Competing interests: None declared |
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William K Smith M D, chief radiologist Miami OKLA USA 74355
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An Italian study of more than 11,000 heart attack patients who consumed 850 milligrams omega-3 fatty acids vs. controls had a 21% decrease in total mortality and a 45% decrease in sudden cardiac death. Appears to be more effective than folic acid or asprin,inexpensive and no side effects. Competing interests: None declared |
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Joseph .C. Obi, Chief Consultant WellnessClinics.co.uk
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Sincere apologies for my brief absence (of late). I have just come up with a very simple 'Over-The-Counter' (OTC) strategy , which may possibly reduce the risk of developing Ischaemic Heart Disease (in most human beings)...by up to 39%. The beauty of this particular 'Wellness Approach' is that it goes 'hand-in-hand' with healthy lifestyle patterns... does not require a Medical Doctor to prescribe it...and costs only US$11 per person per year. As it is my personal wish that the capsule will eventually be cheaply available to all, I have warmly decided to christen it the 'Omnipill'; and may soon be sending the 'full innings' of my humble research to various journals ; for appropriate Peer Review. Watch this space... Competing interests: Dr Joseph Chikelue Obi MBBS MD MPH DSc FRIPH is also the Chairman of the General Wellness Assembly (GWA); an International Professional Body for Independent Wellness Consultants. |
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Richard G Fiddian-Green, None None
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In the discussion of cachexia in a textbook Cancer Medicine (1) from the MD Anderson in Texas published in 2003 two observations caught my attention. The first was that in patients with cachexia the proportion of peradrenal fat that was brown fat was 80% relative to 15% in controls. The second was that the administration of omega -3 fatty acids were said to exert a "potent" anti-cachexia effect. There was no accompanying data or references to support these most provocative claims. Brown fat is found in large amounts in hibernating bears. It is the sole site of action of endogenous uncoupling proteins which increase the generation of heat desirable in hibernating bears, relative to the resynthesis of ATP from fatty acid metabolism by glycolysis and oxidative phosphorylation. The endogenous uncoupling proteins cause in effect an anaerobic shift increasing the dependence of ATP resynthesis upon glycolysis alone. This should cause a profound loss in weight for some 18 to 20 times more fat needs to be metabolised to resynthesis one mole ATP by glycolysis alone than that needed to resynthesise one mole by glycolysis and oxidative phosphorylation. The development of cachexia in cancer patients will often precede any reduction in nutrient intake and may even occur before the cancer is any greater than the size of a "pinhead". [This raises the possiblity that whatever causes cachexia, and by inference the increase in proportion of brown fat, might cause cancer]. The cachexia is accompanied by an increase in glycolytic turnover from an increased dependence upon gluconeogenesis with glycerol, formed by the hydrolysis of triglycerdide, as its substrate. [Glycerol enters the glycolytic pathway after the phosphofructokinase step and in so doing doubles the net yield of ATP in glycolysis from 2 moles when glucose is the substate, released from glycogen stores, to 4 moles]. Might the increase in dependence upon gluconeogenesis in cachexia be due to an increase in exposure to those stimuli promoting uncoupling, such as a fall in tissue pH, rise in [Ca++], increase in free radical release, or to an increase in the release of the endogenous uncoupling protein? If so what induces these changes? An increase in permeability of cellular and especially mitochondrial membranes? Changes in the composition and amount of fat in the diet? An increase in omega-3 fatty acid intake changes the fluidity of these membranes (2) and might exert in part its apparently "potent" anti-cachexia effects in this manner. We know very little about the regulation of cellular and mitochondrial membrane fluidity and the degree of uncoupling in mitochondria in general and in brown fat in particular. Studies of those factors influencing the degree of uncoupling and the proportion of brown fat in patients might be fruitful areas for further research in obesity, type 2 diabetes (3), carcinogeneis and cachexia. 1. Cancer medicine. Holland, Frei et al eds. BC Decker Inc, Hamilton, London, 2003 2. Hochachka PA, Somero GW. Biochemical adaptation. Oxford University Press, New York, NY, 2002. 3. Why not Omega-3 fatty acid as part of Polypill ? William K Smith M D (17 August 2003) Competing interests: None declared |
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Philip King, D.Ph., Director of Pharmacy BCMC, Shelbyville, TN 37160
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I congratulate the BMJ for initiating such a spirited debate on an intriguing topic. I'm beginning to think that maybe medicine should strive to find the one perfect pill that would treat all of the ills of all of mankind. Nothing wrong with that goal and nothing wrong with discussing it. However, this is not the pill, and this is not the time. While I have many concerns about the formulation as presented by Wald and Law, one that I have not seen discussed is the increased risk of Diabetes Mellitus when using thiazide diuretics or beta-blockers. I have no doubt that the Polypill would reduce overall cardiovascular disease in people aged 55 and over. I also have no doubt that we would see a dramatic increase in the number of patients that present to us with Metabolic Syndrome and with Diabetes. As we look at the upward trending of these cases, and as "baby boomers" continue to age, this may well be the healthcare crisis that bankrupts the healthcare system. We don't need to do anything to hasten that day, it is coming fast enough. Competing interests: None declared |
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Gary A Wright, Clinical Research Fellow Ninewells Hospital, Dundee, DD1 9SY, Allan D. Struthers
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Editor-Wald and Law’s paper on the use of a polypill containing six components to reduce four risk factors for coronary artery disease is intriguing (1). However, many doctors would be hesitant about taking such a leap into the unknown and applying such relatively ‘untargeted’ polypharmacy with so many different synthetic compounds. There is an alternative to the polypill which follows the same idea but is less daunting. Milk derived peptides have been shown to reduce both blood pressure (by 11/7mmHg) and Cholesterol (by 13%) and as a third mechanism they have aspirin-like properties in that they reduce platelet aggregation (2-4). The effect on cardiovascular risk can be illustrated as below. A 60 year old male with a blood pressure of 139/89mmHg, total cholesterol of 5.8, HDL of 1.2 who doesn’t smoke and has no history of diabetes has a 10year cardiovascular risk of 13%. If he were to drink hydrolysed milk protein daily and reduce his blood pressure by 11/7mmHg and total cholesterol by 13% he would decrease his 10 year risk to 8%. The advantages of milk peptides over the polypill are twofold. Firstly, they are natural substances and as such have fewer side effects. Secondly, they attack a fewer number of risk factors and, as such, are a lesser leap into the unknown than is the polypill. Doctors and the public may feel that such a milk peptide approach is a more acceptable first step to take towards changing population risk factors. Although these products are commercially available as flavoured drinks or yoghurts in Japan (Calpis), Finland (Evolus) and the US (Biozate), very few in the UK are aware even of their existence. The precise mechanism for the above effects are unknown but one possible explanation is that the partial proteolysis of milk (by fermentation or commercial hydrolyses) leads to the liberation of peptides which have ACE inhibitory activity with a predilection for vascular ACE. This might even mean that they would produce further health benefit in that their ACE-inhibitory effects might reduce the future incidence of diabetes as was found in the HOPE study for ramipril.5 By using milk peptides we may be able to produce a large reduction in future cardiovascular events and even possibly new diabetes with a natural approach which would be more acceptable to both the medical profession and the public. It is astonishing that very few doctors are aware of such a potentially important and natural alternative to the polypill. i.e. a natural ‘mini-polypill’. 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419—1425 . 2. Kawase M, Hashimoto H, Hosoda M, Morita H, Hosono A.Effect of administration of fermented milk containing whey protein concentrate to rats and healthy men on serum lipids and blood pressure. J Dairy Sci 1999;83:255-63. 3. Pins JJ, Keenan JM. The antihypertensive effects of a hydrolysed whey protein isolate supplement (Biozate 1): A pilot study. The FASEB Journal 2003;17:A11110 4. Seppo L, Jauhainen T, Poussa T, Korpella R. A fermented milk high in bioactive peptides has a blood pressure-lowering effect in hypertensive subjects. Am J Clin Nutr 2003;77:326-30 5. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel HFR, Zinman B. Ramipril and the Development of Diabetes. JAMA 2001;286:1882- 1885. Competing interests: None declared |
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Rajeev Gupta, Consultant Physician and Professor of Medicine Monilek Hospital and Mahatma Gandhi National Institute of Medical Sciences, Jaipur 302004 India
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Sir: Professors Wald and Law suggest a polypill- a mixture of six different pharmacological agents- to prevent cardiovascular disease and promote healthy life.1 This suggestion is reminiscent of ancient Indian science of ayurveda wherein a mixture of herbs was advocated to prevent various disorders.2 Indeed, ayurvedic pharmacopoeias mention different herbal mixtures and concoctions for prevention and treatment of different types of diseases ranging from arthritis, dementia, debility, heart weakness, insanity, and sexual weakness. More important than the individual components of such a potion was the careful technique used in preparations of such a mixture. There is mention of specific seasons when the herbs could be picked, type of fertilizer used therein, exact amounts, specific mixing technique, right time of the day and temperature when the mixture is prepared, and an exact time of the day when this potion has to be consumed to be of use. A commonly available home-made mixture of five herbs, known as panchamrata (five components’ elixir of life) is still used by many Indian households as tonic. The proponents of the polypill need to remember the pharmaceutical properties of individual compound so that there is no interaction. The time of the day when such a pill would be most effective also needs to be considered, diuretics act best in the morning while statins are most effective at night. If we exclude the diuretics, a properly combined mixture of the remaining drugs could indeed be the panchamrata and can be consumed after God’s prayers in evenings. 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326:1419-1423 2. Gupta R, Gupta A. Ayurveda, cholesterol and coronary heart disease. South Asian J Prev Cardiol 2002; 6:86-122 Competing interests: None declared |
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James G Penston, consultant physician/gastroenterologist Scunthorpe General Hospital, Cliff Gardens, Scunthorpe, North Lincolnshire, DN15 7BH, England
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Sir, Of more than 80 rapid responses to the “polypill” publications, few have been in support of Wald and Law [1]. Yet, these authors used the generally recognised technique of meta-analysis of randomised controlled trials – the “gold standard” of clinical research - to provide the building blocks for their concept of the polypill. Why, then, has their work been greeted with such antagonism? Many of the criticisms relate to the assumption that the effects of the individual components of the polypill are additive, others concern underestimates of adverse drug reactions and questionable compliance, others emphasize the absence of direct experimental evidence while others depend on ad hominem arguments against epidemiologists. But do these criticisms really account for the discontent? If the trials on which the polypill is based were sound and if each showed a large treatment effect, then Wald and Law’s conclusions would be much more palatable. But this is not the case. Large-scale randomised trials are flawed, yielding at best a trivial, clinically meaningless difference in favour of one treatment.[2] For too long, this dubious methodology has held centre stage in medical research. Now, perhaps, the notion of treating a substantial proportion of the healthy population with drugs based on these studies has sharpened the focus on the underlying methodology. The comments in correspondence – “sloppy intellectual processes”, “fool’s gold”, “fundamentally flawed”, “as believable as the tooth fairy” and “defies common sense”, etc. – could just as easily apply to any large-scale randomised trial. Maybe it is not such a “sad day for British medicine” after all. If the fall-out from the polypill publications in the BMJ includes a healthy scepticism towards large-scale randomised trials, then Wald and Law may have contributed – albeit inadvertently - to the future medical research. 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326;1419-23. 2. Penston J. Fiction and Fantasy in Medical research: The Large-Scale Randomised Trial. The London Press. London, 2003. Competing interests: None declared |
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Teresa Tarnowski Goodell, RN, clinical nurse specialist research consultant - Portland, Oregon, USA
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Six drugs produce fifteen potential 2-drug combinations and twenty potential three-drug combinations. If the recipient of the polypill adds an over-the-counter pain reliever for his/her arthritis or headaches, the potential two-drug combinations rise to 21 and three-drug combinations to 35. Imagine the possibilties if the drug recipient takes a few herbal remedies plus a multi-vitamin supplement, and drinks alcohol regularly, not to mention potential food-drug interactions! Given that medication-related problems consitute a major cause of hospitalization among the elderly, why would we choose to compound the problem by administering drugs to those who clearly do not need them? Competing interests: None declared |
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William E. Feeman Jr., physician 640 South Wintergarden Bowling Green Ohio 43402 USA, William E. Feeman, Jr., M.D.
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I would like to comment on the article by Wald and Law concerning a strategy to reduce cardiovascular disease by more then 80%. In a similar fashion I incorporated LDL-cholesterol and HDL-cholesterol into a fraction, the cholesterol retention fraction (CRF, or [LDL-HDL]/LDL), and systolic blood pressure (SBP) to make a global risk assessment graph, using the CRF on the ordinant and SBP on the abcissa. A threshold line, based on the results of eight published angiographic regression trials (STARS, Heidelberg Study, POSCH, LCAS, FATS, PLAC-1, LOCAT, and NHLBI Type II Secondary Prevention Trial), can be drawn based on a CRF-SBP loci of (0.74-100) and (0.49-140). In my own database of 971 patients with some form of atherothrombotic disease (ATD), 85% of all ATD patients at any age have CRF-SBP plots above the threshold line. Of the 15% of ATD patients with CRF-SBP plots below the threshold line, most are cigarette-smokers, leaving 6% of all ATD patients at any age who could not be predicted by CRF-SBP plots above the threshold line and/or cigarette smoking. If the CRF-SBP plot is brought below the threshold line, angiographic stabilization/regression of coronary plaque occurs in a minimum of 75% of cases. (Had POSCH been structured to control blood pressure, then the angiographic stabilization/regression rate would have been 95% or more.) I submit that this is possible to predict the population at risk of ATD using a global risk graph. Thsi same graph guides therapy to maximally stabilize/reverse angiographic plaque. ATD events fall dramatically when this occurs. Competing interests: None declared |
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das sabapathy, retired nil
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I admire Bala Subramaniam's response. He speaks from personal experiance. Even now most seniors are on several drugs for the same conditions which are targetted by polypill. If this will lessen morbidity, why not? Mortality - we are all mortal - let the polypill enhance our quality of life. I am a former specialist in public health, & infectious diseases. I was a GP after retirement in a 'developing country'& am now in a 'developed country' enjoying the benefits of 'polypharmacy'- like polypill in my old age. Competing interests: None declared |
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Tom Fahey, Professor of Primary Care Medicine, University of Dundee, Kirsty Semple Way, Dundee DD2 4AD, Alan A Montgomery, Yoav Ben-Shlomo
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Dear Sir, Wald and colleagues have not provided any answers to the questions we raised in our letter of 4 July. The methods they have used in constructing their Markov model are entirely opaque. Their Markov model was not published on the website, no sensitivity analyses are presented and estimates and assumptions about the probabilities are not clear or referenced. They present no data on utilities and costs of treatment (it seems that these have not been measured). This is equivalent to publishing the results of a controversial randomised controlled trial without any CONSORT details, flow diagram, details regarding randomisation, allocation concealment, losses to follow up and blinding of outcome assessment and simply stating the results. This is in the context of clear guidance about the methodological issues and checklists for constructing decision analysis trees.1-3 We have published a Markov model examining the lifetime benefit and cost effectiveness of blood pressure lowering medication.4 We made several assumptions and performed sensitivity analyses to test the robustness of our findings. Wald et al must have made many more assumptions when constructing their model- it involves four different drug classes (six different drug ingredients). This makes adequate reporting of their Markov model and sensitivity analysis to test the robustness of their findings all the more important. Wald and colleagues themselves say that the summary of rapid responses by Caroline White "concentrates of the hyperbole". We agree but add that no discussion around their modelling has been addressed. Whilst we think the tenant of their idea is promising and worth pursuing, the validity of their findings rests on clear and adequate reporting of their methods and results incorporating adequate sensitivity analyses. We would appreciate a response to our questions. References 1. Richardson WS,.Detsky AS. Users` guides to the medical literature:VII.How to use a clinical decision analysis:A.Are the results of the study valid? Journal of the American Medical Association 1995;273:1292-5. 2. Richardson WS, Detsky AS. Users` guides to the medical literature:VII.How to use a clinical decision analysis:B.What are the results and will they help me in caring for my patients? Journal of the American Medical Association 1995;273:1610-3. 3. Naimark D, Krahn MD, Naglier G, Redelmeier DA, Detsky AS. Primer on Medical Decision Analysis: Part 5 - Working with Markov Processes. Medical Decision Making 1997;17:152-9. 4. Montgomery AA, Fahey T, Harding J, Ben-Shlomo Y. The influence of absolute cardiovascular risk, patient utilities and costs on the decision to treat hypertension: A Markov Decision Analysis. Journal of Hypertension 2003;21:1753-9. Competing interests: None declared |
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A. Mark Clarfield, Sidonie Hecht Professor of Gerontology, Ben Gurion University of the Negev Dept. of Geriatrics, Soroka Hospital,Beersheva 84101, Israel
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[I realise that the responses to this piece died out a while ago, but I ask your permission to re-open the correspondance, given a dramatic and relevant development in the medical literature.] Jan 30, 2004 Letter to the Editor BMJ Recently, your journal published a provocative article (ref 1) and supportive leader (ref 2) decribing a “Polypill”, meant to be taken by all people over age 50 in order to prevent cardiovascular disease. Its elements would include aspirin, a statin, ACE inhibiter, B-blocker , thiazide diuretic, folic acid and ASA. While a spirited correspondence ensued (ref 3) and not all agreed with such a sweeping recommendation, there certainly does seem to be a certain logic in the idea - at least for those, both men and women, entering the sixth decade. But now, after reading the impressive study by McConnell et al (ref 4) in the New England Journal of Medicine on the efficacy of combination therapy (doxazosin and finasteride) in preventing progression of benign prostatic hypertrophy, I wonder whether the Polypill purveyors have not been premature in recommending only six medications. As almost all middle-aged men are at risk, not only for cardiovascular disease, but for benign prostatic disease as well (ref 5), is it not perhaps time to consider adding these two medications to the original Polypill? For women, only the six -medication version would be recommended and the original name would be maintained. For men, an eight element "Polypill-Pr" would be made available. And what about another infamous "p", polypharmacy? Yours sincerely, A.Mark Clarfield, MD FRCPC. Ben Gurion University of the Negev, Israel (email:markclar@bgumail.bgu.ac.il) References 1. Wald NJ, Low MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326: 1419-24. 2. Smith R. Polypill may be available in two years. BMJ 2003; 327: 0-9. 3. White C. Polypill to fight cardiovascular disease: summary of lack of responses. BMJ 2003; 327:809. 4. McConnell, JD Roehrborn CD, Bautista OM et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. NEJM 2003; 349:2387-98. 5. Vaughan Jr., ED. Medical management of benign prostatic hyperplasia- are two drugs better than one? NEJM 2003; 349:2449-51. Competing interests: None declared |
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Jeremy G Jones, Specialist in Rheumatology and Rehab Medicine QE Health, Rotorua, New Zealand
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The women could have a bisphosphonate and calcium for their osteoporosis. This will counteract the men's 2 prostate drugs, making it eight drugs each. This should avoid mobilisation of the feminist grievance industry. Competing interests: None declared |
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Nicholas J Wald, Professor Wolfson Institute of Preventive Medicine, Barts and the London, Charterhouse Sq, London EC1M 6BQ, Malcolm R Law, Joan K Morris
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We are pleased to respond to the questions raised by Fahey et al[1][2] in connection with our use of the Markov model to estimate the years of life gained without a heart attack or stroke among people aged 55 years or older who take the polypill each day.[3] They ask for input parameters. These are specified in the paper, though not in a simple list. For clarity, we set these out in table 1 on our website - www.smd.qmul.ac.uk/wolfson/polypillpapers/markovmodelling (tables cannot be submitted in rapid responses). The Markov model had two states: (i) alive not having had an IHD event or stroke, and (ii) dead from any cause, or alive having had an IHD event or stroke. Their second query is whether a sensitivity analysis was carried out. Such an analysis shows that our estimates were reasonably precise, as shown in table 2 on our website, where we estimate the benefits of the Polypill based on the upper and lower 95% confidence intervals of the relative risk reductions, and show these together with the original point estimates. In 100 men we estimated that 37 would benefit with an everage of 12 event free years of life, the estimates using the confidence intervals are 34 to 39 and 11-12 respectively. In 100 women we estimated that 35 would benefit with an everage of 11 event free years of life, the estimates using the confidence intervals are 32 to 37 and 11-11 respectively. Nicholas J Wald, Malcolm R Law, Joan K Morris Wolfson Institute of Preventive Medicine Barts and the London School of Medicine and Dentistry Charterhouse Square London EC1M 6BQ (n.j.wald@qmul.ac.uk) References 1. Fahey T, Montgomery A, Ben Shlomo Y. Modelling and assumptions need clarification. Bmj.bmjjournals.com/cgi/eletters/326/7404/1419 (20/02/2004) 2. Fahey T, Montgomery AA, Ben Shlomo Y. Methodological issues remain unanswered. Bmj.bmjjournals.com/cgi/eletters/326/7404/1419 (20/02/2004) 3. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326:1419 Competing interests: See original paper submitted |
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Guy-André Pelouze, cardiovascular & thoracic surgeon Larrieu clinic 64000 Pau France
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Instead of delicious butter margarin
For bad cholesterol statin
For thick blood aspirin
For diabetes metformin
For high blood pressure nicardipin
As I stopped smoking a full patch of nicotin
And tomorrow a nightmare, imagine !
Don’t be foolish !
Take fresh spinach and fatty fish
Roquette, nuts, kiwis and have a large meal
Pour your glass with wine and make a deal
After a snap I will go running
Work a bit and get light dining
Smoke a big havana once a year
And forget doctors for ever
Competing interests: None declared |
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