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Rapid Responses: Rapid Responses published:
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Beta blockers?
- Joseph H. Bolotin, none (27 June 2003)
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Collectors Item
- John P Petrie (27 June 2003)
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It might be the most important for 50 years, but..
- Barrie Margetts (27 June 2003)
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The blue flower and the magic pill
- Dr. Herbert Nehrlich (27 June 2003)
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Old Wine in a New Opaque Bottle!
- BM Hegde (27 June 2003)
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Soma for so many?
- Mark Powlson (27 June 2003)
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Re: Collectors Item
- Jeremy G. Jones (29 June 2003)
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Name that Pill
- Chris Manning (29 June 2003)
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Cardiologists and cardiac surgeons may be better directed elsewhere
- James B Woolley, MRCP MRCPsych (29 June 2003)
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'POLY-PILL' FOR DIABETICS AS WELL?
- Henk A Dam van (29 June 2003)
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Let Them Not Eat Cake!
- Robert J Peers (29 June 2003)
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Polypill is only an hypothesis
- Wil A Hoefnagels (30 June 2003)
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A Birthday present
- Felipe H Ramos (30 June 2003)
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? mega-polypill.
- dr.manan vasenwalamd, mrcp (30 June 2003)
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Reality check: medical cardio prevention [MRFIT, Finnish Executives Study]
- Eddie Vos (30 June 2003)
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Oh Please!!!
- Justin Reid (2 July 2003)
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Healthy Rapid Response e-Forum
- Eric Beeth (7 July 2003)
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Why
- B.C. Rao (15 August 2003)
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Joseph H. Bolotin, active staff at Sharon (PA) Regional Health System SRHS, 740 E. State Street, Sharon, PA 16146, USA, none
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There is no evaluation of the effect of the Polypill on people with asthma or similar allergies. Competing interests: None declared |
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John P Petrie, Rheumatologist QE Hospital, Rotorua, New Zealand
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Undoubtedly a collectors item; the issue has been published on a date other than the intended 1st. April. Either that, or the BMJ has been deceived by the last gasps of the oxymoronic academic clinical epidemiologists. Competing interests: The author treats people with real diseases causing pain & disability, their treatment compromised by the inappropriate funding of cardiovascular prophylaxis |
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Barrie Margetts, Reader UNiversity of Southampton SO16 6YD
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As a Public Health Nutritionist my concern with your enthusiasm for the ultimate 'magic bullet' is that it gives the impression that people, in particular, and, society in general, may no longer need to consider or worry about the reasons why there is a need for this 'magic bullet'. Are you implying that we should not worry about the causes of the outcomes included in the reviews? 150 years ago massive improvements in health were achieved by public health, and it would be dangerous and misguided, in my opinion, to forget the need for a continued commitment to the maintennance of a collective sense of society. It is perhaps ironic timing that Dennis Thatcher died on the day this issue came out, as he and his wife, probably did more to undermine society than anybody else. Prevention is still better than cure, but a lot more work for people. Should we not be asking questions about the value of life and looking at quality not quantity? Is this 'magic bullet' going to reduce inequalities in the UK and beyond? Competing interests: None declared |
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Dr. Herbert Nehrlich, Private Practice Bribie Island , Australia 4507
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All my life I have been looking for the 'blue flower'(Novalis) and, as I got older the magic pill.Now that the pill has been found and even the editor of this informative journal has been bowled over I seem to be confronting a depressing emptiness - finding the blue flower has lost its importance. A (very) few years ago,(while searching for the blue flower in America) I came to a town called Wenatchee, Washington. Everyone I met there was extraordinarily friendly, in fact I was confronted with a kind of histrionic hospitality syndrome . Little did I know that almost the entire town was on Prozac (and loving it). A local, hysterically friendly psychologist was prescribing the 'happy drug' to everyone who ventured through his surgery doors.No tests, examinations and no questioning was required. Today, things are different in Wenatchee but perhaps the population would be interested? Competing interests: None declared |
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BM Hegde, Vice Chancellor Manipal-576 119. India
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Dear Sir, “Of the terrible doubt of appearances, Of the uncertainty after all-that we may be deluded.” Walt Whitman. Who is a well man? The present day answer would be “the one who has not come in contact with the modern medical establishment.” With the sales hype of the total body scanner in full swing, every human being, who comes in contact with the medical establishment, would be declared abnormal, anyway. To complete the process the present total medicalisation effort of the above 50s would be the last nail on the coffin of human health. Healthy society would be a curse on medi-business. Before we force the whole population above 50 to take the composite pill daily, we better look at the darker side of the coin. There is no controlled study available to date of multiple drugs used together for any ailment.(1) There are no controlled studies of any one of those drugs (inside the pill) having had studies done on them on long term basis, beyond a maximum of five years. Not a single ingredient of the pill has been cleared of the risk of higher incidence of total deaths in the study group compared to the controls in the long run.(2) The explanation given each time is that death was not the end point of the study and will not be significant in a five-year study period. Truthfully, therefore, we can not cross our hearts and say that these drugs, even singly, have acquitted themselves well in the long run. On the contrary, each of them has been shown to be dangerous in the long run term audits.(3) One in four prescription drugs, of which there were 3.4 billion last year in the US alone, has had serious side effects. All that glitters is not gold in the long run with reference to most drugs.(4) Reductionist science of controlled studies itself is flawed. Time evolution in a dynamic system like the human body depends on the total initial state of the organism and might not be altered just because someone has changed one or two body parameters of the initial state. There is the “butterfly effect” every time.(5) This explains all our problems in drugs therapy and interventions thus far. We need better methods for controlled studies. Doctors have been predicting the unpredictable in the past.(6) Even a simple drug like aspirin, which has been with us for hundreds of years, is not one hundred percent safe in the long run. While it certainly reduces the non-fatal myocardial infarctions, (or makes it painless) it increases total deaths marginally even in a very small dose.(7) It is ironic that we still do not know what dose of aspirin is good for what condition. In an interesting editorial, years ago, entitled What Dose Aspirin? Late Prof. Mitchell questioned our logic. Be that as it may, let us look at the dosage of drugs in hypertension treatment. In the early 70s, I was amazed that the raised pressures of poor patients, in the large government hospital that I used to work in Mangalore, South India, used to be well controlled even when they did not get the prescribed drugs in the hospital pharmacy for want of budgetary allocation. I used to ask them to take smaller doses, as small as 10 mg. Propranolol in place of 40-80 mg. The response was equally good. Then I mounted a cross over controlled study (patient being his own control-ideal holistic controlled study) of small doses thrice weekly vis-à-vis similar dose daily, with identical results. Who cares for such studies from the third world?(8) Lots of water has flown under the Hoogly Bridge since then. I had written in our book Hypertension-Assorted Topics, in 1993 (9) (the book has the foreword by Barry Hoffbrand, the then editor of Postgraduate Medical Journal) that the only safe and effective drug is thiazide diuretic. This was confirmed by the ALLHAT study.(10) Most of the other newer drugs were shown in bad light in the HOT study, despite the excellent response of box blood pressure.(11) To cap it the very concept that blood pressure as the product of cardiac output and peripheral resistance is fallacious. Step-down treatment of blood pressure should be the ideal way to try and stop treatment when the pressure stabilises over a period of time. In well over half the hypertensive population the pressures do not go up again. Let us try to promote wellness and try not to make everyone feel ill with drugs as a part of living. Even the water-soluble vitamins in the long run have shown their capacity to create trouble. Apparently healthy people being given so many drugs, even in small doses, for no good reason, only with the statistical prediction of 80% benefit, just can not be true if one understands the non-linear physiology of the human body.(12) Let us leave healthy people alone except helping them to change their mode of living-the most important advice given in the first English textbook of Medicine by Charles Scharsmidt in 1773.9 We have come a full circle. Doctors’ main role is to preserve, and, if possible, promote the health of the public.(13) Predicting future risks and trying to correct them does not fit in with the new science of Chaos and non-linear mathematics the way we have been doing it. Let us try to keep patient trust in doctors. If trust is lost everything is lost.(14) Yours ever, Bmhegde. BIBLIOGRAPHY 1. Steven Milloy. Science without Sense, 1997. Cato Institute, Washington. 2. McCormach J, Greenhalgh T. Seeing what you want to see in randomised controlled trails: versions and perversions of UKPDS data. United Kingdom prospective diabetes study. BMJ 2000 June 24; 320 (7251): 1720 –3. 3. Anderson OK, Almgren T, Persson B, et.al. Survival in treated hypertensives: BMJ 1998; 317 : 167 - 71 4. Velazquer EJ and Califf RM, All that glitters is not gold; Lancet 2000; 353: 1568 – 69 5. Gleick J. Chaos – The amazing science of the unpredictable. 1998. Vintage Books, London. 6. Firth WJ. Chaos – Predicting the Unpredictable. BMJ 1991; 303: 1565 – 8 7. Cleland JGF. Preventing atherosclerotic events with aspirin BMJ 2002; 324: 103 - 105 8. Hegde BM, Chandy PK and Bhat EK: A new method of treating mild to moderate hypertension. Karnataka Medical Jr. 1984 :51: 7-9 9. Hegde BM: Shetty MA, Shetty MR : Hypertension -1993, Bharatiya Vidya Bhavan Bombay, India. 10. ALLHAT Collaborative Research Group: JAMA 2002; 288: 2981 – 97 11. Principal results of the Hypertension optimal treatment (HOT) Hot Study group: Lancet. 1998;351(9118):1755-1762. 12. Hegde BM: Chaos a new concept in science. Jr. Assoc. Physi. India 1996: 44 : 167 – 168. 13. Hegde BM: Wellness a new concept – editorial JIMA 1996: 94 : 286 – 288 14. O'Neill O. Reith Lectures 2002. www.bbc.co.uk (bbc.com) Competing interests: None declared |
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Mark Powlson, Managing Editor, Prescribers' Journal Limited 49 Falcon Avenue, Bedford MK41 7DY
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Editor,- Your advocacy for universal polypharmacy is somewhat against recent beliefs in prescribing practice. Has there been sufficient emphasis on the fact that the proposal is a theoretical construct (admittedly enticing), based on extrapolation of data from many disparate studies, rather than on a trial itself? (Indeed, why bother with new trials if one can find such apparently definitive answers so conveniently from existing data?) Quite apart from immediate practical considerations - such as a reliable source and supply system - little thought seems to have been given, among other matters, to potential adverse events (particularly in certain population groups, such as those with asthma or allergies); duration of benefit and possible implications on further treatment should it be required; the effects on those unable to tolerate such a 'polypill' or on the 20% who 'would not benefit', and how to identify them; adverse lifestyle behavioural changes that might occur were it to be perceived that a universal cardiovascular panacea might be available to 'pick up the pieces' of adverse lifestyle choices; and alternative causes of death, which may substantially reduce any putative gains. A worthy idea, meriting future debate and research, but I fear that it will meet the fate of many such papers in the public and media viewpoint: namely that publication in a reputable scientific or medical journal is the endpoint of research and a finished piece of wisdom, rather than the start of a process of refutation and/or affirmation that might, at some future date, lead to an acceptable truth (if such there is). I wonder how many doctors will be asked tomorrow for the magic heart pill? Competing interests: The author has worked for medical journals that received money for advertisements for pharmaceutical advertisements. |
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Jeremy G. Jones, Consultant Rheumatologist Ysbyty Gwynnedd, Bangor, LL57 2PWw
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John Petrie, a much respected NZ rheumatologist, observes that governments spend so much of their health budget on heart drugs that there is no money left to treat the pain and disability of "real" diseases. He fears the provision of Polypill will absorb more of our limited health resources, and so leave even less for the treatment of the rheumatic diseases. As if this was not bad enough for the future of the specialty, further consideration of the subject will show that the use of Polypill will overwhelm already overcommitted rheumatology departments with iatrogenic disease. The diuretics will cause a glut of gout; the statins a mass of myalgia, myopathy and myositis; and the beta blockers a rush of Raynaud's phenomena. Ace inhibitor induced vasculitis and lupus will abound, while the folic acid will result in neuropathy in those with B12 deficency. Finally just when our lobbyists are persuading governments to fund the COX 2 inhibitors, the cause will be lost as the aspirin will negate the beneficial effects the COX 2 inhibitors might have on the risk of GI bleeding. So not only will the cost of Polypill mean less resources for drugs to treat the pain and disability of the rheumatic diseases, but the epidemic of iatrogenic rheumatic conditions it will produce will absorb so much of rheumatologists' time that they will have little left to spend on their "real patients Competing interests: I am a New Zealand rheumatologist on sabbatical in North Wales |
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Chris Manning, CE Primhe (Primary care mental health and education) Twickenham. London
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Dear Sir Whilst I was at medical school in the mid seventies, a number of us toyed with such a "BlocktheLot Retard LA" concept (John Launer; personal communication). Since then, we have all witnessed the steady medicalisation of everyone on the globe and it is now hard to resist the conclusion that, if HIV drugs are to be reduced in price, then the 'developed' West should also benefit from molecules that could be placed in the drinking water (the ultimate in 'social prescribing'?)and the pharmaceuticals therefore provide them at reduced societal rates. Alternatively, they could be sprayed onto crops, injected into animals along with all the antibiotics or included within the new genomes, so that plants produced them, which, in many cases, they do anyway. This combined with the new 'Expert Patients' initiative will result in unprecedented levels of self-empowerment and the final decline of the medical profession and all its attendant gobbledegook (new anti-obesity product from generic producer BuymeandStopOne Pharma). My personal preference would be for an ACE inhibitor (to prevent stroke and IHD); a statin (for its dementia-prevention effect also) and an SSRI (to prevent my platelets clumping; reduce my risk of diabetes and IHD from depression and increase the effect of any adjuvant chemotherapy) - called Nomorefreepensa. I gather that Pfizer are already working on a new product combination of Aricept and Viagra to give people a night to remember? ('Celebratalotooooooooooohlol') Perhaps we could have a competition for all this for the Christmas issue? Yours Faithfully Dr Chris Manning www.primhe.org www.depressionalliance.org Competing interests: Primhe and Depression Alliance both rely on unrestricted educational grants from the pharmaceutical industry, which provides 80% of what the Government should be enabling in the UK in terms of postgraduate education,training, research and voluntary sector enablement rather than spending our money on regime changing and searching for spurious weapons of mass destruction. |
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James B Woolley, MRCP MRCPsych, SpR - adult psychiatry Institute of Psychiatry, London SE5
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Editor - Whilst I appreciate your enthusiasm for the contents of your journal, the hyperbole in this editorial seems to overstate the case. One may even suggest that it's predominant aim appears to be an increase in lay publicity for the journal. What I do not appreciate is your use of psychiatry as the default for unwanted heart specialists, into which they could move safe in the knowledge they will never be out of a job. Perhaps it is tongue in cheek. Perhaps it is a tacit recognition of the woeful inadequecy of mental health service supply compared to need. However, the way I fear it comes across is merely to perpetuate stereotypes of psychiatry lacking effective treatments. Even more concerning is the nihilistic implication that it is unlikely to develop them. Misguided opinions such as this (even in jest), in widely read journals like the BMJ, influence medical students and junior doctors and hamper recruitment to areas that need it most. Huge strides have been made within psychiatry in recent years, and I find myself now making far more of an impact on my patients' lives than when I practiced general medicine. Please could we have some of your effusive enthusiam for the untested cardiovascular 'Polypill' directed at already proven effective psychiatric treatments to redress the balance? Competing interests: The author is a psychiatrist who would be delighted to retrain should an effective 'happy pill' be invented as the editor suggests. |
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Henk A Dam van, GP and diabetes care researcher Dep.of GP, Fac.of Medicine, Maastricht University, PO 616, 6200 MD MAASTRICHT, the Netherlands
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The message of a 'poly-pill' to protect people at risk for cardiovascular disease may well carry a promise for people with Type 2 Diabetes (DM2). As this group is the utmost risk group for CV disease, such a pill may be of special interest for them. Patient adherence to medication taking has been proven to be inversely correlated to the number of medications to be taken. This problem also goes for people with DM2, as they often get many drugs prescribed. More than once in the past years I called for the development of a 'poly-pill' or 'all-in-one pill' for this patient group. Farmacies should utilize machines to produce such pills, and make them suited for each individual patient, with various mixtures of medications: metformin, sulfonylurea, thiazolidin, statine, antihypertensives, and aspirin, on doctor's prescription. I know this idea will not solve the problem of the growing diabetes epidemic or the raised risk scores for CV disease and death in this patient group, but it might contribute to people with DM2 having less problems with medication taking and gaining more power to rule their own lives. Henk A. van Dam, GP/diabetes care researcher Maastricht University, the Netherlands Competing interests: None declared |
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Robert J Peers, GP; Founder, National Institutes of Good Health 605 Rathdowne SAt , N Carlton, Victoria, Australia 3054
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Cheap cake, of course, frequently contains quite toxic trans-fatty acid isomers! Like natural saturated fats, these potent inhibitors of Essential Fatty Acid (EFA) metabolism cause peroxisomal activation and monounsaturate loading of plasma and mitochondrial membranes, thereby leading to aqueous oxidation, impaired physiological lipid peroxidation, and other profitable delights that keep all us Medicals in business, and enable the BMJ not to expire, so it can go on publishing historic earth-shaking research! The Polypill fellows guiltily admit that fatty diet seems "inescapable", which may be true in remotest New Zealand, but I have had almost all my patients on a ruthless but yummy Mediterranean diet since 1982, and I very rarely see a coronary, a stroke or a cancer in my practice. I suppose our new breed of epidemiologists don't get much opportunity to fling open fridge and pantry doors on home visits, to see what actually kills people, and do something about it on the spot. The most important journal papers ever published, which were ignored at the time, would include:- 1) Sir Harry Himsworth's 1935 paper in Clinical Science, linking fatty diet directly to diabetes. 2) Newburgh and Conn's JAMA paper of 1939 showing complete cure of 30 type 2 diabetics with diet alone. 3) Hugh Sinclair's long Lancet letter in 1956, on Essential Fatty Acid deficiency and atherosclerosis. 4) Sinclair's ref 18, on EFA deficiency and mitochondrial uncoupling, pointing to the unsuspected hidden hand of aqueous oxidation in common high-fat diseases, like diabetes, hypertension, Parkinson's disease and cancer. (P Klein and R Johnson, JBC 1954, 211/103-8) 5) B Silverman's 1991 paper from Chicago, describing shyness (+/- reduced IQ) in the children of diabetic gestational mothers, who eat too much fat. Other Polypill Pushers include diabetes clinicians in Australia, evidently suffering writer's cramp in out-patient clinics; I know one who wishes there was One Big Pill to kill the appetite in diabetes-a Monopill?; and Dr Pat Phillips in Adelaide dreams of a Type 2 Tablet, loaded with various empirics ! My suggestion for arterial disease and diabetes is: 1) Poly-Unsaturate Diet, with low saturate intake and abundant omega-6 and omega-3 EFA (Caution: Refined seed-oils are vitamin E-deficient and cause ADHD and Alzheimer's, so use olive or cold-pressed) 2) Inositol powder 5-8 gm a day for all persons with anxiety disorder, since a fatty diet eaten in pregnancy is the root cause of chronic biological stress in the offspring, and endogenous inositol production in anxious subjects is insufficient to calm the anxious brain and hyped-up sympathetic. Inositol, which is extractable from cereals and legumes, appears to be a complete cure for stress--it abolishes binge-eating, restores calmness and confidence, quells the raging Sympathetic, reverses insulin resistance , takes off fat, puts on muscle and scalp hair, corrects irritable bowel and fibromyalgia, markedly reduces dependence on nicotine, alcohol and marijuana, has significant anti-Parkinson's potential, slows the cell-cycle and cell division rate, differentiates breast cancer cells and even kills prostate cancer cells, through genetic and apoptotic actions also applicable to auto-immune clones. Its appeal is truly "inescapable". Such Cell Membrane Therapy And Signal Transduction Enhancer ("CMTASTE") could be marketed in a Big White Pillbox, containing an Inositol compartment and Ten Coasters listing the Ten Commandments of Healthy Diet (With Ale), with the name Peers's Big Pill on the hinged lid. The IQ- and cognition-enhancing effect would be useful in New Zealand. Competing interests: None declared |
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Wil A Hoefnagels, neurologist Ziekenhuis Zeeuws-Vlaanderen, 4500 AC, Oostburg, the Netherlands
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The most important issue for 50 years? Yes, in the sense that the editorial board of the BMJ should consider resigning after publication of this issue. Not so long ago, BMJ was a well-respected journal. It published many papers on the wise use of statistics (confidence-intervals, to name an example). It promoted the delivery of evidence-based health-care. But now things have gone wrong. There was a paper by Bosch et al. about the preventive effect of ramipril on stroke.(1)In this paper only relative risk reductions were mentioned.(2) And now there is this paper of Wald and Law about the polypill. The idea is that you can add up the relative risk reductions of each agent on the prevention of heart attack or stroke. An idea that was first described by Yusuf in an editorial in the Lancet.(3)But the editor of the Lancet did not ask us then to keep that issue as a collector’s item. So, what is the fuss, all about? What Wald and Law have done is this: suppose, a cholesterol-lowering drug gives a relative risk reduction of 30% and a blood-pressure lowering drug has a reduction of 20%. Then, if you take them both, 50% of the heart- attacks are prevented. From an epidemiological point of view, this may be correct. But, in real life, things are not that simple. The recent studies of ALLHAT-LLT and ASCOT-LLA showed that the combination of a cholesterol- lowering drug and a blood-pressure-lowering drug was not that successful. To quote from an editorial in the Lancet: active lipid-lowering treatment can be estimated to result in only a small increase in the probability of remaining free from a myocardial infarction over 5 years, from 95% to 97%, in patients with good control of blood pressure.(4) The only way to examine the hypothesis of Wald and Law would be a randomised trial. Their paper should have been published in a journal of medical hypotheses and not in the BMJ. The trial should take a long-time, at least 10 years. And side-effects should be carefully collected. Now the hypothesis is presented as a fact and the name of the pill is patented. Everybody of 55 years or over should take this pill. The good news has reached the major newspapers and Prof. Law had his interview on the television. But there is no real news to tell, there is only a weak hypothesis, despite all the studies about the different agents. The board of the BMJ should make a public apology and the editor-in-chief should resign from office. A well-respected journal does not publish a hypothesis as a fact. Dr. W.A.J. Hoefnagels, neurologist
References 1. Bosch J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, Davies R, Ostergren J, Probstfield J on behalf of the HOPE Investigators. Use of ramipril in preventing stroke: double-blind randomised trial. BMJ. 2002; 324: 1–5 2. Hoefnagels WAJ. Ramipiril works, but does it help my patient with a T. I. A. or a stroke? bmj.com/cgi/eletters/324/7339/699#20768, 23 Mar 2002 3.Yusuf S. Two decades of progress in preventing vascular disease. Lancet 2002;360:2-3. 4.Lindholm LH, Samuelsson O. What are the odds at ASCOT today?. Lancet 2003;361:1144-5. Competing interests: None declared |
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Felipe H Ramos, Internist Hypertension Section, Favaloro Foundation, Belgrano 1746, C1093AAS, Buenos Aires, Argentina
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Sir As a citizen of one of those “developing countries” quoted by Wald, Law et al., since I first began to access BMJ on line a few years ago, I enjoyed the wide scientific range of information, the excellent summaries, the collected resources, books, etc., adding to these advantages the unusual free access to all these contents and very generous samples of English humour. Today, however, I got really amazed at the “Collector´s issue”, also published on my birthday! I’m still wondering if the “Editor´s choice” commentary is a product of astonished admiration, faithful friendship or a critical view. As in some meetings, where non-English-speaking attendants are not able to understand some jokes, this misunderstanding could be based on my ignorance of subtle linguistic intricacies, or even more probably on my medical limitations, since I belong to one of the countries in which a wonderful pill may overcome almost all health catastrophes by means of just a little and grateful retribution to the unique British magic bullet and -please don´t forget- their inventor´s pockets. This renewed recipe of the old eminent physicians by which the pharmacist delivered sound medical art and science to the patients, after a thorough and somehow mysterious diagnostic, therapeutic and overall empiric process is now the new paradigm of epidemiologic and trialistic science: we don´t need anymore costly evaluations, risk stratifications, control visits; we don’t even need physicians, they will not be necessary, human disease is going to be eliminated, we are not going to treat patients, we’ll treat populations, let’s begin with “developing countries”, and after that treat them all! The next step will be delivering polypills to babies right through the sucking-bottles. The basis of this outstanding paper is an incredible intellectual achievement, because the authors quote themselves fourteen times in the references, and no doubt remains that they deserve the polypill patent ownership. In my view as, perhaps, in many other physician’s, medicine is patient- based and not a population-based practice. Strategies that forget the essence of the physician’s job are forgettable, and several good ideas like combination treatments deserve better efforts of the medical community to grow and to be implemented in clinical practice; Wald, Law and other´s propposal smells only to profitable business. Anyway, I am grateful to the BMJ as I enjoyed my birthday reading the answers to this article. I am eagerly waiting the next magic bullet of “007BMJ”, that could be –why not?- the final solution to all human health problems. Sincerely yours
Competing interests: None declared |
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dr.manan vasenwalamd, mrcp, consultant-cardiologist(non-invasive) k.k.heartcenter, aligarh-202002.india
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?mega-polypill. although armed with many mega studies, the suggestion of a polypill for cardiovascular ills appear at first response to be outrageous. firstly, the major cause of ihd is adoption of western-like lifestyle. thus till now, major thrust by epidemiologist has been in advocating a change in lifestyle. this included a restriction in salt intake, a change in diet from red meat to white, vegetarianism,cessation of smoking, moderation in alcohol consumption,increased physical activity, stress busting etc. none of these guides have made any impact.patients continue to over-eat, lead sedentary life, and fail to cope with stress.there is a steep rise in graphics for cardio-vascular diseasesin developing countries. a plethora of books have been written on the subject. gymns have sprung up everywhere. also a variety of contraptions for exercise have flooded the markets. you can buy a stepper, a pedestal bike, treadmill etc. now companies offer electronic gadgets like ab-energiser which you strap on whichever parts of body you fancy and at press of a button it will do your bidding. another outlandish claims is a contraption which you strap on your feet, and while you have alcohol, food and watch tv it will do your exercise. in addition a large number of herbal products claim to cure obesity without any effort although there is always a small print stating that results vary.all this is very well. but what if a pill could do the job for you? i am sure it will be a mega block-buster. no more dieting or exercise, which anyway most patients are averse. just pop a pill and reduce your risk of heart attacks or stroke by 80%! i think it is very ingenious. no more sweat it out,or going hungry. of course it can be stretched further. why not add an appetite suppressant like metformin,or sibutramine, or insulin sensitiser like pioglitazone and a pinch of anti-oxidants especially Q 10 enzyme systems. it will increase the cost a little, but when mass production occurs and practically everyone takes it as a ritual, the costs will plummet.call it a mega- polypill if you like.the drug companies will benefit tremendously.this will be reflected as an improvement in economy of developed countries.it is akin to finding elusive WMD, read "weapons against modern diseases" the number of people taking anti-hypertensives will multiply like a virus. there will be competition. some will argue that arb will be better than ace, or calcium channel blocker or beta blocker inclusion mandatory. a plethora of retrospective and prospective studies will be thrown in. controversy will surface as to which statin meets all requirements.simvastatin vs atorvastatin. in developing countries, triglycerides levels tend to be high. would not a fibrate do better than a statin? what about adding fish oils like 5-omega-free fatty acids? as for homocystein levels,although proper studies are not available in general population of developing countries, a little folate not going to harm anyone. if homocystein levels are high, folic acid is going to lower it. if it already low, it will be a nutritional supplement.it is a new strategy, not to deliver, but sell some of most well known medicines en block to all in both worlds.in the end, when hype is overtaken by rationality, science by gimmics and personal gain by social compulsions, something, but more dwarfed version will evolve with clear cut guidelines, where many will be out and few will be in. things will plateau out so to speak.certain questions remain to be answered. what is validity of statistical analysis used?. how many research articles were sponsored? can findings of western or developed world be projected on developing world? what about certain peculiarities of developing world.. in india ischaemic heart disease occur in 40's, thus would be deprived of the pill benefits which is recommended for 55yrs and above. what about tobacco chewing rampant in these parts and cause of mi in young? what about lipoprotein 'a'levels and other pecularities of developing world to which the pill is targetted? Competing interests: None declared |
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Eddie Vos, http://www.health-heart.org Sutton Qc Canada J0E 2K0
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Before we all run out to get PolyPill [tm], let's not forget past medical intervention trials like: JAMA 1982 248(12):1465-77 MRFIT [multiple risk factor intervention] n=12,866, 7 years; half Special Intervention, i.e. stepped hypertension treatment, cholesterol counseling, other. Non significant cardio mortality benefit yet a slight OVERALL MORTALITY DETRIMENT. Five more deaths after ~45,000 years of special medical intervention. PMID 7050440 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7050440&dopt=Abstract JAMA 1991 266(9):1225-9. Long-term mortality in 1222 high-risk Finnish male business executives. Half randomized to 15 doctor visits each over 5 years + "frequently" blood pressure and pre-statin cholesterol lowering drugs. Cardio "risk factors" reduced at 5 years. However, mortality over study + 10 year follow-up (1974-1989): 67 deaths in intervention vs. 46 in control group [RR mortality 1.45 p=0.048]. Here's another kicker: cardio mortality was more than double: 34 vs. only 14 deaths in the control group [RR=2.42 p=0.001] PMID 1870247 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Retrieve&list_uids=1870247&dopt=Abstract Now, 12 years later, realize that the latest 3 statin trials PROSPER, ALLHAT and ASCOT saved exactly nobody at great expense [combined patient- years on statin ~55,000], patient inconvenience and long-term unknown risk. The wonders of meta analysis à la Wald and Law never cease. The devil is always in the confounders: the law of the unexpected side-effects. Competing interests: None declared |
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Justin Reid, GP Principle Partner Bromley by Bow HLC, St Leonards St,London E3 3BT
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What on earth are the editorial team thinking about? Why am I filled with frustration everytime I read Richard Smith's articles? Im appalled at the choice of topic and prose. I feel he has gained his medical qualifications by reading the American Journal of Hello Magazine!! Why on earth should he choose to write about an unknown,and unpatented, "magic pill" when there are so many deserving medical advancements and issues more pressing? I find his suggestion of using India as cheap labour offensive. Why does he feel that psychiatrists have more job longevity than cardiologists. His inference that they are less likely to cure disgusts. And what is his obcession with supermarkets?? (I refer alo to his previous editorial on patient centered care!!!) Competing interests: None declared |
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Eric Beeth, Family Practice Brussels, B-1040 Belgium
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Dear Dr Richard Smith, Dear colleague, Perhaps you would also enjoy an overview of how your BMJ Rapid Response e-forum works for an individual contributor. Maybe you could even pass it on to some-one who could put it to more practical use. Best regards, Eric. Dear Dr Wald and Dr Law, The concept of the “Polypill” is a good one, but I believe an un- necessary amount of the 8 to 15 % of the possible side effects will be coming from the beta-blocker and the thiazide component. On close examination, a very large amount of people detect a if all so slight feeling of lack of spark, which influences their lives negatively. They often don’t even realize how “spark-less” they had become until they stop taking the beta-blocker, perhaps in favor of a slow- release formulation of verapamil. Verapamil, like the beta-blocker, has a negative chronotropic and inotropic effect on the heart. Surprisingly though, it increases the effort capacity test more than an ACE inhibitor can achieve on patients who where not in a prior state of heart decompensation, something which diltiazem, a calciumblocker with comparative negative chronotropic but less inotropic, effect never managed to prove. Another verapamil specific particularity is that it has increased blood pressure lowering activity depending on the salt intake of the patient: no more salt restrictions(, means also continued good hydration and nutrition of the elderly). It has a stabilizing effect on the smooth muscle of the airways, causing less bronchial hyper-reactivity, while the beta-blocker could actually destabilize an asthmatic patient, and there are VERY many of these in the population group that the pill would be directed to. Verapamil, like the beta-blockers are proven to be effective in the prevention of arythmia, also in post-myocardial infarct studies. Slow- release verapamil has a surprisingly beneficial profile, but it is often looked over by the medical community because it became a generic during the days when a lot of pharmaceutical attention was given to newer molecules. It is rare to find a comparison between slow-release verapamil and these other products, because there was little chance the newer molecules could turn up better. The problems one would encounter with verapamil would be a potentially dangerous bradycardia if combined with a (especially i.v. administered) beta-blocker. It quite often gives some constipation due to the effect on the smooth muscle. This is practically always correctible by increased fluid intake, and more fiber in the food. It causes much less headaches and ankle edema than the dihydropyridines, in fact it is used to prevent migraine. Many cardiologists fear the possibility of exacerbation a state of heart decompensation with verapamil. This is because they are used to verapamil under it’s injectable or immediate release oral form. In my experience with the slow release form, it is much safer than a beta- blocker, and it has none of the unpleasant side effects of beta-blockers. It should of-course not be given if the patient is in a state of heart- decompensation. The combination of an ACE-inhibitor with slow-release verapamil is one of my favorites, because of optimal effect on blood pressure (Without hardly ever causing hypo-tension, or ortho-statism which we often see with the combination thiazide + ACE inhibitor), on the kidneys, on the intima of the blood-vessels (I prefer having a slight risk of dry cough, due to decreased brady-kinine degradation that also increases nitric oxide and prostacycline which is not increased to the same amount with the (more expensive) sartans), and on sexual function, including stamina. These last two decrease hopelessly with thiazides and beta-blockers. What-ever negative inotropic effect that the slow release verapamil may have given seems to clinically disappear thanks to the addition of the ACE-inhibitor. The thiazides cause not only loss of precious water, but also of minerals including Potassium, Magnesium and Calcium. This is not only a frequent cause of cramps among the elderly, but also sudden death through arythmia. This, combined with the hip fractures due to ortho-statism and calcium depletion contributes to make also the thiazide component a questionable asset to the “Polypill” (see also effect on uric-acid, lipid profile, reflex activation of the angiotensine levels.. the diuretics should only be given under strict indications, and preferably then loop- diuretics). So, if we throw out two components and substitute it with one, should we add something else instead? How about selenium (and/or vitamin E). The selenium has proven anti-cancer activity, and also helps maintain a healthy thyroid function which is of great importance when considering cardio-vascular risk. And vitamin E is the least questioned useful vitamin supplement for a long and happy life. That’s what we are here for, isn’t it! With kind regards from Belgium, keep up the good work! cc to Dr A. Rodgers (N.Z.) Dr Eric Beeth Family Practice Av. de l’Armée 127 B-1050 Brussels, Belgium (Assistant teacher of GP medicine at the Vrije Universiteit Brussel) drbeethbrux@msn.com Tel + 32 2 647 55 69 Dear Dr. Beeth: I smiled when I read your comments. The reason is that I was very much involved in the commercial introduction of verapamil IV, verapamil immediate release, and verapamil sustained release in the United States while working for the company (Searle) that Knoll licensed verapamil to in the US. I was also the "champion" of the development of a delayed controlled release verapamil product, eventually sold as Covera HS in the US. The concept was/is to take the product at night and the release is delayed for several hours resulting in the highest serum levels when the patient is arising, when blood pressure and heart rate are increasing most rapidly. In addition to the salt aspect that you noted, if I recall correctly, verapamil also reduces blood pressure to the degree that the blood pressure is elevated. The higher the pressure, the more antihypertensive effect. Again if I recall correctly, the same is true for heart rate. Also perhaps you have seen Dr. Fleckenstein's papers on verapamil in the prevention of arterial calcinosis. I recall seeing photographs that were dramatic. I cannot recall the publication. This is one of the publications but not one that I saw: Fortschr Med. 1984 Jul 26;102(27- 28):713-7. As you probably know, Fleckenstein was the discoverer of verapamil. Your comments regarding the level of interest in verapamil are well- taken. Tom Keller From: Tom Keller [mailto:tomkeller@comcast.net] Sent: Thursday, July 03, 2003 5:45 AM To: drbeethbrux@msn.com Subject: Your comments on the BMJ Polypill article Dr. Beeth: I'm a doctor and a writer. I'm writing a story based on the Polypill idea proposed in last week's BMJ, and wanted to get your comments on it, after seeing your Rapid Response. Do you think this is a good idea for all people over 55? And if you had to design your own Polypill, what would it include -- and this can include non-pharmacologic interventions, since it's a hypothetical? I look forward to hearing from you. Ivan Oransky, MD ivan-oransky@erols.com 001-212-465-9110 Dear Ivan, I liked your question/project very much, and will answer it in greater detail- perhaps while I'm in Sweden on vacation in about two weeks. In the mean time I'm sending you a copy of a response I sent yesterday to M. Tom Keller ( tomkeller@comcast.net ) Dear M. Tom Keller, It was very nice to read your reaction about Verapamil. No, I had also lost sight of these interesting original articles, and I'm learning only now who originally developed the molecule, including you! Good choice! I became interested in the molecule after learning about the particularity on salt, and had I been involved in more fundamental physiology research, I would like to have researched the exact mechanism, most likely via Natri-uretic Peptide secreted via a greater distensibility of the atria through the effect of the drug. This greater distensibility comes back into focus on what you mentioned that it will never give hypotension or ortho-statism, since it relaxes the carotid wall on the Carotid Sinus, to help this organ better adjust to all changes in position and for example rises of blood pressure on exertion, part of the reason why the exertion tests turn up better on verapamil. As I was browsing the web looking for additional information about verapamil, I crossed an article about 75 to 83 % success rates in the treatment of pain and deformity in Peyronies disease, through topical application of verapamil. This is an otherwise almost untreatable condition, so it is definitely again a very special effect of this molecules capacity to increase distensability, and make our old dry bamboo green again! Would you want a beta-blocker and a thiazide in your future "Polypill"?? I really appreciated to have the reaction from you, and I could be mistaken, but it seems to me that too few doctors and health professional are aware about the unusually beneficial profile of verapamil, and if they are aware of it, it is almost our duty to remind others, for example in this collective "think tank" to choose the most quality of life enhancing ingredients to a possible future "BMJ Polypill". With kind regards, and please keep in touch if something related attracts your attention (with a smile or a frown, or possibly a EUREKA!). Yours sincerely, Eric Beeth Thanks for getting back to me -- unfortunately my deadline is next week (9 July). May I quote from your letter? Sunday, July 5th 2003, + a PS at midnight.. Dear Dr Ivan Oransky, Yes, I am enthusiastic about discussing the safest and most quality of life enhancing ingredients to a possible future “Polypill” intended to help prevent cardio-vascular disease. The “Rapid Response” forum in the www.bmj.com is a fun way to interact among Medical Faculty Professors, Senior Scientists, science and health writers and other General Practioners prepared to share their lifelong experience. Truly, the Wald & Law “Polypill” article and its ensuing discussion brought out the elements declared in the BMJ’s mission statement. The intention of my initial contribution was on the one hand, to seriously reflect on the insidious side effects of thiazide diuretics and beta-blockers, and on the other hand to remind my colleagues that we have an often forgotten (i.e. public domain) alternative to the beta-blockers under the shape of slow release verapamil. I would personally not swallow any beta-blocker or thiazide, even if the absolute risk reduction was 10x greater than Peter and Catherine Trewby from Durham (UK) calculated for the “Polypill”” (less than 1 % chance of benefit and 6% chance of side effects over the coming 10 years…). However, when I look at my own patients >55y with slight risk factors, I believe that a cheap “Polypill” type medicine would be able to give a much more favorable individual risk reduction, and quality of life enhancing characteristics that far outweigh the few possible side effects. We must remember that our body is genetically programmed for health only during our procreative years(+ the time parents care for their offspring-> caring for your grandchildren is good for longevity factors in our genome!) After that, we may as well accept to intervene a little bit to slow down (vascular) ageing, as long as the treatment doesn’t weigh us down in other ways (,including financial, time consuming, indigestion..). Lately, we have seen quite encouraging results on preserved or even improved cognitive ability on older patients on statines (atorvastatine 10 mg), but knowing that the HMG-CoA reductase is also needed for the body’s own production of CoEnzyme Q10, we should think about adequately supplementing CoQ10 (in the Polypill??) if we are to give a statine. I am curious about which ingredients (in particular which of the statines) would enhance the overall anti-oxidant activity of the “Polypill” in our body. Laboratory methods, used f.ex. by the NASA to determine optimal anti-oxidant potential of different Space food preparations, could easily be used to check each ingredient, and also the combination product, on its measure to enhance or deplete overall anti- oxidant activity in the aged human. I would choose the most enhancing “Polypill”, with an ACE inhibitor, (quinapril, perindipril or lisinopril, perhaps the first one since it seems to bind more preferentially to vascular tissues), a slow release form of about 200 mg of verapamil, 60 to 70 mg of buffered acetyl- salicylic acid, folic acid with some added Vit B6 and Vit B12. I would choose my statine based on price, least interaction on liver and muscles, and least ill effect on general anti-oxidant activity, + I would supplement it with a well resorbed (+/- 50 mg) CoEnzyme Q10. At last, as mentioned before, I wouldn’t mind adding Vit E and Selenium. This would already put 10 constituents in “my” Polypill, assuming they were mixable in the same pill. I would prefer to keep it as simple as that. Other supplements and medicines are often beneficial, but one doesn’t exclude the other. On the contrary, the “Polypill” could simplify the curative and preventive treatment for a large amount of my cardiovascularly “at-risk” patients over and under 55 years. You are very welcome to quote my former letters and this one in the purpose of furthering a healthy debate. Although I’m sure your use of language will be better than mine, I would enjoy to, preferably before- hand, seeing how you quote me, so that I could perhaps prevent my contributions from being misunderstood. With warm and Collegial regards, Dr Eric Beeth Family Practice Av de l’Armée 127 1040 Brussels, Belgium drbeethbrux@msn.com PS: Checking if I had answered your original questions, for example: would I recommend it for all patients above 55? No, at least not in an initial phase, since the individual risk reduction would not outweigh the price or possible side effects in patients whom seem to be at low risk. But patients with a personal or family history of cardio-vascular disease, rebellious smokers (along with 600 mg of acetylcysteine, + perhaps extra dose (slow release) anti-oxidants, high LDL, low HDL, high serum homocysteine (along with change of diet), high or even slightly high blood pressure, migraines, sinus tachycardia, diabetics and many more could definitely benefit from this type of polypill without having to wait out the results of prospective studies to see f.ex if this type of pill has a potential to prevent stroke and cerebral vascular degeneration in vascular “low-risk” patient groups who were included early (i.e. around 55y old) in the study. The most common troublesome interaction would be the desire to use f.ex sotalol in the case of arythmia, but verapamil in itself has a protective effect against the most common forms of arythmia. Digoxine levels will accumulate more quickly if given to a patient under verapamil treatment. (half dose is advised.) Other interactions are described, but to my knowledge seldom dangerous. As to your question about other interventions, I am often tempted to give biologically active silicium (2% Si(OH)4 in a stabilized solution)to this patient category. The acidic drops that I give with an orange juice in the morning do not lend themselves to an inclusion in the polypill. (They are popular with the patients for a wide range of musculo-skeletal degenerative complaints, but it has also been shown that they have a protective effect on the arteries, thus less cardio vascular risk, and less degeneration of cerebral vascular tissue.) Another “supplement” is the for some people controversial neuro-peptide melatonin. As this should be given (3mg) on a fixed hour, ca 8 hours before the most commonly preferred moment of awakening, and not to patients who have a tendency towards Hashimoto’s disease (very common) or a sex hormone dependant cancer growth (luckily less common) then, although it is given as a preventive measure to the same age group, it does not either lend itself to an inclusion in the “Polypill”. Enough “Polypill” for tonight, it’s passed my melatonin hour. Good luck with your project! Eric Competing interests: None declared |
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B.C. Rao, G.P. 847,2nd cross,7th main,H.A.L,2nd Stage,Bangalore,India
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Are they attempting immortality? Or would theu want all old frail men to die of terminal cancer whcih is worse. Taking this miracle pill will not solve any problem. Competing interests: None declared |
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