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Rapid Responses: Rapid Responses published:
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An extra ingredient
- Haim Shapiro (27 June 2003)
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A clinical tool for recognizing cardiovascular disease, even silent?
- Sergio Stagnaro (27 June 2003)
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polypill paradigm
- Rakesh Biswas, PIN 33701 (27 June 2003)
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Chickens and Eggs
- Paul W Keeley (27 June 2003)
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Modern Medicine and Polypill Madness
- James W. Prescott, Ph.D. (28 June 2003)
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The fallacy of an assumption of simplicity
- Lawrence J. O,Brien, Arlington, VA 22209 USA (28 June 2003)
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Polypill is pie in the sky
- Robert J Woodward (28 June 2003)
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Re: An extra ingredient
- Peter A Sim (29 June 2003)
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Fantasy Medicine
- Kaiser Chaudhri (29 June 2003)
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As much fantasy as a multi-vitamin
- Eric Beeth (30 June 2003)
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Commercial consideration in medicine is a trend to be opposed
- Hean T Ong (30 June 2003)
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Social implications of different preventive approaches need to be carefully considered
- Rodolfo Saracci (30 June 2003)
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Coincidence?
- Gregor L Venters (2 July 2003)
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Optimistic interpretation of trial data by proponents of polypill
- Gerd Assmann, Paul Cullen, Helmut Schulte (2 July 2003)
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Hard to believe or accept
- Mark S. Kern (2 July 2003)
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Re: As much fantasy as a multi-vitamin
- Eddie Vos (2 July 2003)
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Additions to the drinking water
- Bertrand M Bell (7 July 2003)
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QUESTIONABLE COST-EFFECTIVENESS OF STATINS FOR PRIMARY PREVENTION OF CARDIOVASCULAR EVENTS
- Andrea Messori, Benedetta Santarlasci, Sabrina Trippoli, and Monica Vaiani (18 July 2003)
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Re: QUESTIONABLE COST-EFFECTIVENESS OF STATINS FOR PRIMARY PREVENTION OF CARDIOVASCULAR EVENTS
- Andrea Messori, Benedetta Santarlasci, Sabrina Trippoli, and Monica Vaiani (26 July 2003)
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Haim Shapiro, physician Wolfson Medical Center, 62 Lochamim Street, Holon 58220, Israel
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Much evidence suggests that adding long chain omega-3 polyunsaturated fatty acids to the polypill would boost its efficacy with virtually no side effects and at a minimal cost. Kris-Etherton PM, Harris WS, Appel LJ; Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease.Arterioscler Thromb Vasc Biol 2003;23(2):e20-30. Skerrett PJ, Hennekens CH. Consumption of fish and fish oils and decreased risk of stroke. Prev Cardiol 2003;6(1):38-41. Nordoy A, Bonaa KH, Sandset PM, Hansen JB, Nilsen H. Effect of omega- 3 fatty acids and simvastatin on hemostatic risk factors and postprandial hyperlipemia in patients with combined hyperlipemia. Arterioscler Thromb Vasc Biol 2000;20(1):259-65. Competing interests: None declared |
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Sergio Stagnaro, Specialist in Blood, Gastrointestinal, and Metabolic Diseases. Via Erasmo Piaggio 23/8 16037 Riva Trigoso (Genoa) Italy
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Sirs, A. Rodgers’ paper is really intriguing (1), stating that people with vascular disease can benefit of the pill (i.e, aspirin, statine, three hypotensive drugs and folic acid), suggested by Wald and Law, who propose that a single pill containing aspirin, statin, three blood pressure lowering agents in half dose, and folic acid is provided to people with vascular disease and those aged over 55 years (2). Convincingly, according to EBM but not to SPBM (3), they estimate, on the basis of a large number of information, that “the pill would reduce heart disease and risk of stroke by over 80%, while causing symptoms warranting withdrawal of the pill in one to two per 100 and fatal side effects in less than one in 10 000 users”. In fact, blood pressure lowering agents at half the standard dose are the best way to achieve large reductions in blood pressure, which are the main, if not only, mechanism of benefit of these agents. Certainly, from a pharmaceutical view-point, there are a lot of problems unresolved, apart from the scientific truth of above referred EBM-dependent statements (3). Rightly, A Rodger asks: “To whom should this new intervention be offered?”. This is the question! As a matter of fact, he continues: “The most important challenge is ensuring such interventions reach the many people at high risk in developing countries who currently receive little or no preventive care”. Until now, almost all doctors, around the world, overlook an existing bed-side tool, reliable in detecting Cardio-Vascular Disease and, therefore, they have to learn it to recognize people at “real” risk of CVD in easy, clinical, rapid, unexpensive manner, performing actually an efficacious CVD primary prevention on very large scale, even in symptomless patients, as I have been suggesting from a long time, unfortunately unheeded (4) (See HONCode site 233736, http://digilander.libero.it/semeioticabiofisica, URL: http://digilander.libero.it/semeioticabiofisica/Documenti/Eng/Cardiopatia%20ischemica_eng.doc). Finally, before administering pill(s) I prefer dietary changes, etymologically speaking, according to skilful colleagues (5), even though such a therapeutic measure is less interesting for drug producers, authors and NHS authorities. 1)Rodgers A. A cure for cardiovascular disease? BMJ 2003;326:1407- 1408 (28 June) 2) Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003;326: 1419-23. 3) Stagnaro S. Single Patient Based Medicine versus EBM. http://bmj.com/cgi/eletters/326/7398/1048#32299 4) Stagnaro-Neri M., Stagnaro S. Deterministic Chaos, Preconditioning and Myocardial Oxygenation evaluated clinically with the aid of Biophysical Semeiotics in the Diagnosis of ischaemic Heart Disease even silent. Acta Med. Medit. 13, 109 , 1997. 5) Trichopoulou A et al. Adherence to a Mediterranean Diet and Survival in a Greek Population.NEJM. 2003, 348:2599-2608 Competing interests: None declared |
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Rakesh Biswas, Asstt professor,Dept of Medicine Manipal teaching hospital,Pokhara,Nepal,pin-33701, PIN 33701
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The polypill paradigm if viewed from an evolutionary time scale of paradigms will only take a few seconds to be replaced by another fresh upstart. The poly pill represents hope, a panacea for all evils, which our forefathers too fancied having developed in their time, which has been replaced as new evidence keeps being generated like fresh stories in fiction magazines every month. Most of the diseases which this polypill tries to prevent have had their birth in our Earth plundering attitude.(1) This pill only supports that attitude and is at best a poor addendum to life style modifications. It will definitely create a wave in the stream of financial energy as a lot of currency changes hands but then energy can neither be created nor destroyed. Ref: 1) Biswas R, The birth of poverty (personal view) BMJ 2002;325:51 ( 6 July )http://bmj.com/cgi/content/full/325/7354/51 Competing interests: None declared |
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Paul W Keeley, Specialist Registrar in Palliative Medicine Beatson Oncology Centre, Glasgow, G11 6NT
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This is going to sound horribly churlish, but the hype surrounding all this is rather akin to a headline reading "Chicken May Lay Eggs". Ringing still in my ears is the speech from 1971 when President Nixon declared "War on Cancer". Good advances have been made in the intervening 32 years in cancer treatment, but it's still there. Please don't sex up the evidence.The trials have not been done on the Wonder Pill. How will it be tolerated, how expensive will it be, what are the risks? What are the consequences of eradicating cardiovascular disease - a rise in cancer cases, an epidemic of Alzheimer's? Try to see the bigger picture and don't count your chickens... Competing interests: None declared |
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James W. Prescott, Ph.D., Retired Home--USA-14882
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The following claim by the BMJ is not only an overstatment of reality but provides a disservice to medicine, human health and the excellent reputation that has characterized the BMJ. "Today's BMJ contains one of the boldest claims for a new intervention—"a greater impact on the prevention of disease in the Western world than any other known intervention."1 Is it a new magic bullet for cancer or a new gene therapy? No, it is a new strategy to deliver some of our most well known medicines." I can think of at least four other human events that have "a greater impact on the prevention of disease in the Western world"-- 1. Breastfeeding for two years of age or beyond, as recommended by WHO and UNICEF; 2. Modern sanitary engineering that assures clean, safe water and safe disposal of human waste product; 3. Proper nutrition; and 4. Elimination of toxic environments. These four factors would contribut more to human health than all of modern medicine combined. Competing interests: None declared |
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Lawrence J. O,Brien, retired health plan CEO 1200 N. nash Street #535, Arlington, VA 22209 USA
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Under the stimulus of a ridiculous idea like the ¡§super pill¡¨ as a basis for adult humans to prevent disease and achieve health and long life, an Editorial like this in your highly respected Journal ought to first dissect what is really happening in contemporary medical experimentation. The conclusions of the meta-analysis that you cite are flawed because the clinical trials they are drawn from are fundamentally flawed. In an experiment conducted on the basis of classical scientific method the guiding presuppositions are that a specific cause is followed by a specific effect; that this effect can be predicted on the basis of an empirical understanding of its cause or causes; and that knowledge of the specific causation can be derived from knowledge of the effects. The fundamental error that calls into question conclusions being derived from an enormous number of randomized controlled clinical trials (RCCTs) being undertaken in the United States and elsewhere is that virtually every one of these medical experiments relies heavily on an ¡§assumption of simplicity.¡¨ Any analysis of human organisms that depends upon an assumption of simplicity can lead to none other than erroneous conclusions, because these organisms--quite apart from their fundamental idiosyncrasy--have evolved as one of the most complex living systems to be found in Nature. As soon as an assumption of simplicity enters into a clinical trial or other experiment that involves human bodies, any claim that the trial or experiment is scientific becomes fraudulent. Simply put, it is impossible to hold that a study of human organisms can have anything at all to do with a notion that these organisms are simple. Thinking that human organisms can be meaningfully studied on the basis of an assumption that they are simple would represent a high point in intellectual bankruptcy. Most unfortunately, conventional medicine in the United States has not understood this very plain matter of fact. As a result, clinical trials and other medical experiments that are demonstrably rooted in a flawed idea--the assumption of simplicity--are being launched at a furious pace. The victims of this folly on the part of the medical profession would be difficult to quantify with accuracy, however the entire population is placed at risk through this radical and foolhardy burst of experimentation, most of it paid for with taxpayer funds. The requirements of the scientific method have been traditionally defined as: ¡§[P]rinciples and procedures for the systematic pursuit of knowledge involving the recognition and formulation of a problem, the collection of data through observation and experiment, and the formulation and testing of hypotheses.¡¨ (Merriam-Webster¡¦s tenth edition). The ability to precisely replicate an experiment on demand is an essential element of the scientific method. In the face of the inescapable fact of overwhelming organismic complexity, biological science must proceed to make matters intelligible by describing what the structures and processes of an organism are, and how an organism does what it does. The scientist must begin by making certain that everything has been taken into consideration, and that nothing has been omitted from consideration. In classical scientific method, a theory or generalization is formed from empirically observed facts that are derived by the use of inductive and deductive reasoning; next, consistent connection must be demonstrated between and among the assembled facts, as well as with a body of systematic generalizations derived from other facts already accumulated and verified. Then, both the empirical and the logical implications and consequences that these ¡§new¡¨ facts may have for the pre-existing body of systematic generalizations must be drawn out in specific terms; the ¡§new¡¨ facts and any ¡§new¡¨ generalizations must then be systematically and empirically verified and justified; and, finally, it must be shown that all of the ¡§new¡¨ facts can be deduced, quantified, predicted, and replicated on the basis of the extant systematic body of generalizations. The American philosopher and educator John Dewey once observed that the greatest and most pervasive fallacy of human thinking is the neglect of context. Medicine¡¦s methodologies in the design and conduct of its ¡§gold standard¡¨ clinical trials constitute a striking example of this fallacy at work. Technological medicine¡¦s first mistake has been its misperception of the ¡§problem¡¨ about which knowledge is being systematically pursued. Its dominant and entirely erroneous conception of the human organism--the subject and the object of all medical inquiry--is that it is most like a clockwork, a machine. Although this remains in place as American medicine¡¦s most controlling and unquestioned paradigm, the concepts of clockworks or machines as useful analogies for the human organism can be seen to be entirely inappropriate as the basis for describing what the structures and processes of an organism are, and demonstrating how an organism does what it does. By its reliance on the assumption of simplicity, twentieth century technological medicine has most certainly neglected the context within which any legitimate inquiry involving the human organism must take place. Today, many physicians believe that the double-blind study rises to the level of a ¡§gold standard¡¨ because it results in ¡§objective, evidence-based proof¡¨ on the basis of which subsequent medical practices may rationally be defended. However, since the object of medical inquiry is the human organism in all of its complexity and idiosyncrasy; and since there is no alternative to the admission that far more is unknown than is known about the inner workings of human organisms; it is plainly an unproven belief to hold that all RCCTs result in knowledge about the treatment of human organisms that is so ¡§completely determined by the objective evidence¡¨ as to thereby be rendered certain and unassailable. The fact that the science of medicine must be accepted as being a science of complexity, because its subject matter is the human organism, does not mean that it will never be possible to experimentally isolate a specific chain of causality to explain or to treat some abnormality of the human body. As complex and idiosyncratic as medicine¡¦s basic subject matter is, there are some instances in which cause and cure turn out to be related one-to-one. But it does mean that, in human experimentation, we must expect specific etiologies of this variety to be very rare occurrences, very much the exception and not the rule. To qualify as science, the study of human organisms must always be rooted in the recognition of the fittingness of Nobel Laureate Sir James Black¡¦s conclusion that, in studying human organisms, ¡§we have entered the world of quantum theory, in which the whole is enfolded into each part and each part is enfolded into the whole, as in a hologram.¡¨ Whenever the specific subject matter of an RCCT is inherently more complex than a theory of specific causality could scientifically cope with, which will most often be the case in a clinical trial involving human organisms, it would thereby be demonstrable that no outcome of the trial could possibly be justified as representing ¡§the full collection of impersonal and objective¡¨ quantitative evidence, but would instead be a result of an unsubstantiated personal belief by the investigators in the completeness of their experiment. This means that, except for those rare exceptions when a ¡§specific etiology¡¨ basis for a trial can be conclusively demonstrated to be scientifically valid, the ¡§gold standard¡¨ clinical trials in use by conventional medicine today are based principally on the subjective and often biased beliefs of the designers of the particular RCCT--that is, on acts of faith by investigators that cannot possibly qualify as scientific evidence. For those who study medicine¡¦s subject matter from an organismic point of view, then, the ¡§gold standard¡¨ proofs claimed to be issuing from the plethora of RCCTs being conducted today can rarely be accepted as being based upon ¡§the full collection of impersonal and objective evidence,¡¨ as leaders of the American medical guild such as Arnold S. Relman, MD would have us believe. In a public forum held in Arizona during April 1999, Relman said the following: "Medical science teaches practitioners to look for objective evidence before adopting a clinical method. ...All clinical biases and preconceptions, whether in alternative or conventional medical practice, must fall before the objective evidence, and we should be assiduous in seeking such evidence to improve our practices. ...At the least, [physicians] owe their patients their best professional advice, based on the most reliable information." These are valid and high-minded statements as far as they go, but Relman was using them to defend the scientifically untenable position that medicine¡¦s use of RCCTs does in fact uniformly result in ¡§objective quantitative evidence¡¨ on which the medical treatment of individual patients can legitimately be based. What Relman and other physicians like him are doing in making unsound assertions like this is giving medical science a very bad name. They need to fully understand the following reminder by William James, which is called to mind in this connection: "Our actions, and with them their consequences, actually change according to the beliefs which we have chosen." (¡§Will To Believe¡¨). Arnold Relman is defending his belief in the universal evidentiary validity of medicine¡¦s ¡§gold standard¡¨ clinical trials. However, the RCCT usually will not qualify as science by any stretch of the human imagination. Instead, medicine¡¦s much-ballyhooed ¡§gold standard¡¨ can most often be seen as a quest for certitude in medical judgments that is rooted in a belief system which often merely pretends to be scientific, objective, and impersonal. To the extent that everything has not been taken into consideration in a given trial, the fact is that that trial has little to do with valid scientific method. In that there is a very great deal that is simply not understood about the human organism, including those intricate fail-safe capacities of the body that are based upon layers of redundant molecular, cellular and humoral processes, it is almost impossible to determine all of the conditions that could affect outcomes for even one human subject, much less for the ¡§average¡¨ subject in a supposedly randomized controlled trial. Recall what Dominique Lecourt has said of the living cell: ¡§[W]e cannot help but marvel at the monitoring and self-correcting devices for detecting and rectifying errors and at the strategies -- and we might even say ¡¥neat tricks¡¦--that it uses for this purpose.¡¨ These complex ¡§conditions¡¨ are part and parcel of every organism, and are inevitably ingredient in every clinical trial, yet they have been systematically--one might say chronically--omitted from consideration in most of the contemporary RCCT experiments. Because RCCTs are invariably designed within a mechanistic/dualistic rather than an organismic framework, there is no way around the consequence that the formulation of an issue to be tested will usually be flawed; or that, given the shortcomings of a reductionistic and mechanistic mind-set, the collection of data through observation and experiment will also be seriously flawed. Under the sway of this well- entrenched but erroneous paradigm of medical experimentation, the predominance of what Sir James Black has termed a ¡§mechanistic metaphor of biology¡¨ places severe limits on the possibility of designing a truly scientific experiment or trial. Conventional medicine is therefore using the RCCT to once again force technology to the forefront; and, with the active assistance of giant pharmaceutical conglomerates and of many federal agencies, is aggressively marketing the results of RCCTs as if they bore a clear relationship to true scientific inquiry. The buyer certainly needs to be wary of RCCTs, for at least the following reasons: „h The conceptual basis of most RCCTs can be seen to be mechanistic, and not organismic. The two dominant notions that: a) a trial can isolate a specific chain of cause and effect; and, b) all relevant variables within the complex biochemical and biophysical factory that is the human organism can be or have been determined and controlled for; usually lack any basis in fact--yet these flawed notions continue to drive most of the rapidly proliferating experimental trials. „h The conceptual basis of most RCCTs can also be seen to be dualistic. The impact of a ¡§placebo¡¨ group of subjects as representing an effective ¡§control¡¨ simply misconstrues the actuality of the placebo effect. Christiane Northrup, MD has provided us with this trenchant observation about the human organism: ¡§Thoughts and emotions can either create or destroy healthy tissue.¡¨ This concept would completely undermine any conclusive comparison between the outcomes for the ¡§placebo¡¨ subjects and the experimental subjects in an RCCT. Therefore, in order to have a prayer of getting a marketable result from an RCCT, the human body has to be conceived of as being entirely separate from the mind and from the emotions. Consider the comments of Ian R. McWhinney, MD on this latter point: "Individual people have shown that they can alter their immune response both voluntarily and under hypnotic suggestion. The most plausible explanation of the beneficial effect of placebos--an anomaly within the mechanistic paradigm--is that it is a response of the organism to the symbolic meaning of a therapeutic relationship. There is abundant and growing scientific evidence, not only for the effect of relationships on health, but also for the physiological basis of these effects. The doctrine of specific etiology has been a dominant feature of the mechanistic paradigm, one cause being sought for each disease, based on the model of infectious diseases. ...In the organismic paradigm, etiology is viewed as a complex web of interacting causes, even when a proximal cause can provide the opportunity for therapeutic intervention. Rather than forces acting on a passive being, external agents may be triggers releasing processes that are already inherent in the person. The cause that precipitates an illness may be different from the causes that maintain it (i.e., the causes of chronicity, delayed healing, or death). This challenges the healer to identify the factors inhibiting healing and help the patient to strengthen and release his or her own healing powers." (Pew-Fetzer Task Force Report, pp.20-21) On the assumption that the human organism is a machine, it would follow that clinical trials might be designed in which a specific, linear chain of causation could always be isolated, and in which all of the relevant variables within the ¡§clockworks¡¨ could be known and controlled. However, once the concept of organism is given frank and full recognition, it becomes clear that the scientific basis of many RCCTs, and therefore the findings of such trials, would be exposed as unscientific. In her 1974 book ¡§Kind and Usual Punishment: The Prison Business,¡¨ Jessica Mitford reported the fact that drug companies and university-based medical ¡§centers of excellence¡¨ were paying prisoners one dollar per day to participate in a variety of medical and drug testing protocols, many of which were life-threatening. This practice may still be going on in prisons, but probably at a higher wage level. Mitford was one of the first to take notice, about a quarter of a century ago, that only males were used in these experiments for the stated reason that the hormonal processes of premenopausal females were deemed to be so complicated and idiosyncratic as to render women prisoners unreliable subjects for these experiments. What Mitford did not point out at the time, probably because she was focussed on the prison business and not on the medical business, was the fact that all of the medical/pharmaceutical miracles that emerged from the experimentation on this very captive audience were promptly prescribed for women patients, and usually with higher frequency than for male patients. Suddenly, and seemingly without a nanosecond of hesitation by physicians over the fact that the clinical trials of the specific pharmaceutical agents in question had excluded female subjects, medical concerns about the complex and idiosyncratic hormones of the female as a trial subject were dropped from practical consideration, and experimentally-sanctioned drug treatments were administered to female patients, willy-nilly. How can this possibly be considered science? It would appear to be not only unscientific, but simply a fraud to exclude females from clinical trials on the basis that their complex hormonal activity would be likely to distort the results, and to then utilize drugs resulting from such trials as if they had a legitimate, scientifically established unisex applicability. Male-only pharmaceutical experiments could prove nothing with regard to females of the species, nothing at all. Yet the drugs flowing from such experiments are actively prescribed by physicians in the treatment of females. There has been a great deal of talk from the medical guild about the integrity of ¡§gold standard,¡¨ double-blind clinical trials, yet in terms of actual medical practices resulting from these prisoner-based pharmacutical experiments, the snake-oil salesmen of yesteryear can be seen as a more honest bunch than the medical ¡§scientists¡¨ who designed these particular clinical trials, or than those physicians who have acted clinically on the basis of the reported outcome of such experiments. As another more recent example, diagnosed diabetics have been excluded from RCCT protocols governing experiments with new drugs to treat hypertension, for the stated reason that their disease would skew the results of the trial in ways that would simply be unfathomable. If the pancreas is functioning abnormally, as is the case with diabetics, hormonal activity would also be abnormal, which alone would render the results of an RCCT questionable if not meaningless. However, hypertension is a very common side effect of diabetes. It should not be a surprise to learn that it has been and is common practice for physicians to prescribe for their diabetic patients with hypertension the very hypertensive drugs that were ¡§proven¡¨ in trials in which diabetics were explicitly excluded as subjects. This is another concrete example of conventional medicine¡¦s ¡§gold standard¡¨ in action. It would also be well to recognize that, once a drug has been approved by the federal Food and Drug Administration (FDA) for a specific use, any licensed physician may then proceed to employ that drug for any other use that they personally deem to be appropriate. Again, it is a puzzle to figure out how any of this can possibly be considered to be science. Every RCCT being contemplated by medical professionals, and most certainly all such experiments being financed from the public treasury, ought to be required at the very least to demonstrate that the following criteria have been met: 1. The vision of the general nature of things which forms the intellectual framework of the clinical trial is explicitly organismic, taking into full consideration the processive characteristics of the human body; and the trial design does not in any manner reflect a mechanistic or dualistic conception of human organisms. This should be the standard for all trials, including those in which it appears to be scientifically possible to isolate a specific chain of causality for the treatment being tested. 2. An overarching organismic vision of the nature of things explicitly underscores the importance of recognizing and of taking into full account the complexity and the idiosyncrasy of each of the individual human organisms participating in a medical experiment or trial. 3. The principal yardstick to be used in defining the parameters and content of any trial shall be the irreducible fact that human bodies are natural systems, designed and equipped to tend toward health. Therefore, the highest possible level of reverence must be paid to the processes of homeostasis within each individual subject, and to the full range of organismic messages that a physician, a true healer, should be capable of discerning from natural systems in which disease is present. 4. RCCTs must be designed in frank and full recognition of their ¡§ever-not-quite¡¨ character, as well as of the fact that a linear chain of cause and effect is seldom achievable because the quantity and complexity of the variables at work in such experiments can only rarely be either determined or controlled. 5. No federal dollars will be invested in any RCCT unless or until there is a clear demonstration and assurance that the trial will not result in harm to any subject, either during the relatively short term of an experiment, or over the long term beyond the termination of a trial; and unless or until it can be affirmatively demonstrated that interventions or procedures used in the RCCT will not harm the natural and inherent processes of the human organism that tend toward health. In other words, a stipulation must be required that no intervention or procedure will interfere with, inhibit, or damage the organism¡¦s immune system, the heart of its natural and inherent processes of maintaining homeostasis; and that, to the contrary, steps that have been scientifically validated will be undertaken as an element of all such trials to support and strengthen immune function for all prospective experimental subjects. Medicine cannot afford to support the deeply flawed idea that the immune system of an individual patient must be destroyed in order to save that patient. It seems certain that a renaissance of disciplined classical taxonomy will be required in order to ¡§prove¡¨ much of anything that would be of real clinical value in medicine. Today, conventional medicine in the United States stands a very long way from an insight of this kind, a vision that would directly contradict the radical course of human experimentation that it is currently pursuing. The medical guild would first have to recognize and accept a most disturbing fact: that many of the ¡§evidence based¡¨ procedures or treatments derived from the accumulation of RCCTs constitute aberrations of a particularly malignant variety, especially in light of the often untold but nonetheless lethal ramifications of such experiments for human subjects who have been recruited into these trials as ¡§volunteers.¡¨ Many of these souls are potential victims of medicine¡¦s wrongheaded ¡§assumption of simplicity.¡¨ The notion that an aggregation of conclusions from a selection of non -scientific medical experiments could somehow yield a super pill that will optimize health and prevent disease in adults over the age of fifty-five represents the pinnacle of absurdity for technological medicine. Competing interests: None declared |
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Robert J Woodward, Retired Heathcare Co Director GU337EU
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Polypharmacy as exemplified in the proposed Polypill for Cardiovascular disease prevention will not meet with the approval of any regulatory authority. New multicomponent medicines are rare beasts these days. The complexity of the chemistry and pharmacokinetics of such products means that demands for tight specifications are not achievable economically . Storage stability and consistency of results throughout claimed life is a nightmare. These demands are being made for products before clinical trial certificates can be issued. No company looking for a sound investment would touch the idea with a sterilised bargepole! Doctors who believe in the concept of the mixture should prescribe the single items that are on prescription only and tell their patients to buy the OTC items for themselves. Competing interests: None declared |
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Peter A Sim, writer New Zealand
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Agreed that Omega 3 fatty acids are beneficial. Not agreed that "magic bullet polypill" plus such fats would be helpful. There is no established causal link between cholesterol levels and heart disease. Omega 3 fats are not very stable and it is unlikely that they could be processed into a "poypill". The statin providers would object to a possible cholesterol lowering ingredient being added to anything they were supporting. Competing interests: None declared |
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Kaiser Chaudhri, GP principal Broadway Surgery, Fulwood, Preston, PR2 9TH
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The article by Wald and Law on reducing cardiovascular deaths reminded me of the current popularity of "Fantasy" football games where one can pick famous footballers and console oneself that you have achieved success if they do well on the pitch. When I first heard the hype on the national news I thought that a new treatment had been developed which had shown great results. Instead it turns out that statistics have been manipulated and assumptions made. As a practising GP there is no reason that my at-risk patients couldn't already be prescribed these drugs if it were so simple. However, if you exclude patients with contraindications and cautions that would get rid of asthmatics, diabetics, dyspeptics and patients with gout. Of the few left many would stop because of side- effects such as lethargy, impotence and cough. If side-effects did occur it would be difficult to decide which component of the poly-pill was responsible. Even combinations of diuretics and beta-blockers are rarely used nowadays because of the problems of combination pills. Whilst academics can dream about the possible reduction in death rates clinicians find that the reality is different from the fantasy. Competing interests: None declared |
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Eric Beeth, Family Practice (I run my own..) Brussels, B-1040 Belgium
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Dear Dr Chaudhri, A General Practioner like you, I see the un-acceptable side effects in the thiazide and the beta-blocker (+ the asperin also, of-course depending on the dose that was planned). I wrote the following response to Dr Wald and Dr Law before reading these other reactions. Maybe you could swallow a pill like this one day… 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!
Dr Eric Beeth
Competing interests: None declared |
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Hean T Ong, Consultant Cardiologist, H T Ong Heart Clinic, 251C Burma Road, Penang 10350, MALAYSIA
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Dear Sir, Rodgers correctly writes in praise of the extensive analysis done by Wald and Law in support of their concept that a combination of aspirin, statin, angiotensin-converting enzyme inhibitor, beta-blocker, diuretic and folic acid can significantly reduce cardiovascular disease (1,2,3,4). Given that all these drugs are available in their generic forms, the potential availability of an effective and inexpensive treatment to combat the scourge of cardiovascular disease would be most welcomed. It is thus disappointing to note that patents have been filed by the authors for the proposed polypill. This can only have the effect of increasing medical costs with the result that some who would benefit will not be able to afford the treatment. Commercial consideration seems to have penetrated the highest halls of British medical academia. How many less would have been saved had Fleming filed a patent for penicillin? Dr H T Ong FRCP (Edin, Glasg)
References : 1. Anthony Rodgers. A Cure for Cardiovascular Disease? Combination Treatment has Enormous Potential, Especially in Developing Countries. BMJ 2003; 326:1407-8. 2. Wald NJ, Law MR. A Strategy to Reduce Cardiovascular Disease by more than 80%. BMJ 2003; 326:1419-23. 3. Law MR, Wald, NJ, Rudnicka, AR. Quantifying Effect of Statins on Low Density Lipoprotein Cholesterol, Ishaemic Heart Disease, and Stroke: Systematic Review and Meta-analysis. BMJ 2003; 326:1423-27. 4. 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; 326:1427-31. Competing interests: None declared |
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Rodolfo Saracci, MD . Director of research in epidemiology, IFC-National Research Council via Trieste 41, 56100 PISA (Italy)
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In a couple of recent meetings on diets rich in fruits and vegetables I half-seriously argued that whatever the uncertainties surrounding their beneficial effects on ischaemic heart disease and stroke they may soon be made irrelevant by eating a "banasta" a day, namely a genetically engineered banana containing a dose of statin. Wald and Law present an otherwise realistic preventive scenario[1].Taking the estimated beneficial effect of the composite pill at face value Richard Smith raises [2] , among other issues, the question of medicalization of health interventions. Strictly speaking an intervention, in the present case a pill, can be legitimately regarded as inducing less rather than more medicalization if actually shown capable of eliminating the need for screening for cardiovascular risk factors and of reducing the need for therapeutic and rehabilitation services, intensive in technology and personnel. But equally important is the question of whether the intervention enhances or reduces people's autonomy in the etymological meaning of self- given rule of behaviour. Can a lifetime (after age 55) use of a pill result in weakening of personal, and then collective, efforts to abandon tobacco smoking, avoid overweight, exercise regularly ( which all affect the risk of diseases like cancers at different sites) ? How far this may in turn help in perpetuating, in a vicious circle, the influence of agents like the tobacco industry ? How much will it reinforce the tendency to depend on pills rather than on feasible but will-based behavioural changes ? Empirical evidence in different populations (eg by gender, country, social class) is needed on these issues. One of the less often quoted sections in the classic book [3] on preventive strategies by Geoffrey Rose stresses (chapter 8, p.113 and ff.) prevention as largely relying on responsible free choices rather than on the passive adoption of ready made solutions or, in the health education area, on conviction forced through propaganda. Primary and primordial prevention on "healthy" people contribute not only to disease avoidance but also, through the specific means it becomes implemented on a vast scale, to the habit formation of citizens, hence to their general attitude towards solving societal problems of direct personal relevance.This aspect should not be underrated whenever a new preventive approach is proposed. [1] Wald NJ and Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ 2003; 326 : 1419-23. [2] Smith R. The most important BMJ for 50 years ? BMJ 2003; 326 : 1405. [3] Rose G. The strategy of preventive medicine.Oxford University Press, Oxford, 1992. Competing interests: None declared |
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Gregor L Venters, GP Bellevue Medical Centre, 26 Huntingdon Place, Edinburgh, EH7 4AT
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Was it any coincidence that the papers about the Polypill were published the same week as the paper "Effect of interpretive bias on research evidence" by Professor Kaptchuk?(1) 1 BMJ 2003;326:1453-1455 (28 June) Effect of interpretive bias on research evidence Ted J Kaptchuk Competing interests: None declared |
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Gerd Assmann, Professor of Laboratory Medicine Institute of Clinical Chemistry, University of Muenster, 48149 Germany, Paul Cullen, Helmut Schulte
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Over the past years, a consensus has emerged that treatment decisions should be based, wherever possible, on empirical evidence. And in few areas of medicine have the demands placed on that evidence been as stringent as in the field of prevention of cardiovascular disease in general and coronary heart disease in particular. The paper by Wald and Law, however, seems to cast doubt on this rigorous approach, suggesting that a cocktail of six medications in a single pill (“polypill”) would lower the incidence of ischaemic heart disease events by 88% and of stroke by 80%, and that it might therefore be given with impunity to “everyone aged 55 and older and [to] everyone with existing cardiovascular disease”. In spite of the claim by the authors that widespread use of this cocktail might have a “greater impact on the prevention of disease in the Western world than any other single intervention”, we feel obliged to introduce a note of caution into the argument before this approach is made the basis of treatment recommendations. It is generally accepted that treatment effects can only be determined within the context of a randomised controlled clinical trial. The results of the trial must take non-compliance and a range of dose- responses into account. It is not permissible to extrapolate from a post- hoc analysis of a trial what result might be expected with 100% compliance and taking account only of those individuals who showed maximum benefit in terms of risk-factor reduction. Thus the theoretical figure of an expected 61% reduction in ischaemic heart disease events from cholesterol-lowering using statins is about twice the actual risk reduction seen in any statin trial to date. The same reasoning can be applied to blood-pressure lowering – here trials have shown a lowering of ischaemic heart disease risk of about 20%, not the 46% suggested by Wald and Law. Trial evidence for the benefits of anti-thrombotic therapy in primary pervention is not as strong as that for cholesterol or blood pressure lowering, while trial evidence of a benefit from folate use does not exist. Moreover, combination therapies must be subjected to the same scrutiny as therapies containing single ingredients before claims can be made for their effectiveness, and, of course, no such trial evidence for the polypill exists. It would be nice if we lived in a polypill world. One for heart disease, one for mood (perhaps the “happy pill” suggested by the Dr. Richard Smith in the editorial accompanying the paper), and maybe even one for finding the right partner. However this is not the case, and we are forced to deal with each problem in turn, often compromising and accepting a less than perfect result. There are no quick fixes, in life or in medicine, and the polypill is not one for heart disease. Competing interests: None declared |
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Mark S. Kern, none 80302
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A cure for 80% of cardiovascular diseases for people over 55. So, people will die from a more painful cancer. Is that it? The greater the hype, the more I suspect it. No way can there be long term, 20-30 year studies on this magic drug. I've been subject to congenital heart disease my entire adult life. My mom died from it when I was 15, and her mom had a lethal stroke when she was 15. My blood pressure was 198/88 when I was 22. I maintain my health with long distance bicycling, 30 miles, or 50 kilometers most days, and decent vegetarian eating. Competing interests: None declared |
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Eddie Vos, http://www.health-heart.org Sutton Qc J0E 2K0 Canada
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Dear Dr. Beeth, Your suggestion that vitamin B12 should be included in Polypill [tm] is a good one. Polypill's 0.8 mg folic acid (vitamin B9) is below the several milligrams needed to mask possibly irreversible B12 deficiency problems but B12 works with folic acid in homocysteine [Hcy] remethylation to methionine. I would suggest to also include vitamin B6 that acts to cover a second Hcy lowering pathway, to cysteine. Moreover, these additions could be without increased cost and it's illogical to chose one Hcy lowering pathway over another. One problem with Polypill is that it has never been tested in a population with ample omega-3 intake and with Hcy levels below 10 micromol/L, a level attainable in most with a high "potency" multiple B vitamin supplement. Let's assume for a moment that mortality and cardiovascular events can be reduced by 70% with the omega-3 oil alpha-linolenic acid [found, for example, in flax, canola and walnut oils]. This percentage is in line with the Wald/Law estimate for Polypill and is not unrealistic according to Medline PMID 12668490, 12433513 and 9989956. My guess is that none of the studies in the Wald/Law meta analysis were adjusted for these apparently enormously efficacious omega-3 oils or for the family of Hcy lowering nutrients. It would seem to me that unleashing the Wald/Law methodology on the omega-3 and Hcy lowering pathways would yield results -not only in the cardio department- that may well obviate the need for pharma-based polypills with side-effects that these nutrient approaches clearly don't have. I note that high Hcy status has now been positively associated with over 100 diseases or conditions while the statins in Polypill are linked to the same number of harmfull side-effects. Competing interests: None declared |
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Bertrand M Bell, Professor of medicine Albert Einstein College of Medicine 1400 Morris Park Avenue The Bronx N.Y. 10461
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For a long time I have made my students keenly aware that SAAB is not the name of an imported Swedish automobile but rather the abbreviation of the name of drugs which should be addded to the drinking water..S...Statins... A...Ace inhibitors...A...Aspirin...B...Beta blockers..It is now confirmed that SAAB in the drinking water should be the new preventive medicine strategy! Competing interests: None declared |
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Andrea Messori, Coordinator Laboratorio di Farmacoeconomia, c/o Pharmaceutical Service, Careggi Hospital, 50132 Firenze, Italy, Benedetta Santarlasci, Sabrina Trippoli, and Monica Vaiani
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The Polypill has been proposed by Wald and Law [1] as a medication for
universal use by people aged over 55 years. In the editorial comments about the
Polypill, Rodgers [2] addresses the issue of the price that could be recognised
to this medication and discusses the cost-effectiveness implications of this
pharmacological intervention. Both the original paper [1] and the
above-mentioned editorial [2] implicitly or explicitly rely on the assumption
that the benefits of all the components of the Polypill, including the statin, are conclusively
demonstrated in terms of both effectiveness and cost-effectiveness. A large number of
studies indicate that statins are effective and cost-effective for secondary
prevention of cardiovascular events [3]. However, their role in primary
prevention is more controversial. In the present analysis, we focused our
attention on the pharmacoeconomic studies published from 1995 to June 2003 that
evaluated statins for primary prevention. Extraction of these studies from the
PubMed MEDLINE data bank [syntax of the query: "(cost[titl] OR
economic[titl]) AND (simvastatin OR pravastatin OR atorvastatin OR fluvastatin
OR cerivastatin OR lovastatin OR statin*)"; time limits: from January 1995
to June 2003; query launched on 11 July 2003] yielded a preliminary database of
articles that were candidate for our analysis. Direct inspection by AM, BS, ST,
and MV of the abstracts and, when necessary, of the full text of the papers of
this preliminary database allowed us to identify a total of 18 original
pharmacoeconomic studies evaluating statins for primary prevention; 8 were not
sponsored by any pharmaceutical company (table 1), whereas the other 10 were sponsored
(table 2). The design of the analysis was similar across these 18 original
studies (i.e. either comparison or statins vs. no therapy or head-to-head
evaluations between statins). On the other hand, the pharmacoeconomic results
showed that different studies favoured different statins. In the independent
reports, the inter-study variations in the cost per life year gained were
extremely wide (table 1); this indicates a profound uncertainty in the
pharmacoeconomic convenience of using statins for primary prevention. The sponsored studies (table 2) raised another and more important
question, i.e. whether the sponsor had any influence on the pharmacoeconomic
results. For this purpose, we reviewed all of the studies listed in Table 2 and
we assessed the relationship, if any, between the study sponsor and the type of
pharmacoeconomic result. In more detail, we analysed each study to determine
whether or not the pharmacoeconomic results were in favour of the statin
produced by the study sponsor. The last
column of table 2 shows the results of our analysis. In all of these studies
(10 cases out of 10; 100%), the pharmacoeconomic results were in favour of the
statin produced by the study sponsor (p=0.00098 by signs’ test). Thus, our overview of
these data provides a very negative picture on the scientific value of the
pharmacoeconomic research in the area of primary prevention with statins. One
negative finding is that most of these studies (N=10) were directly sponsored
by the pharmaceutical industry while the independent ones were fewer (N=8). In
addition, the research question of most of these studies did not address the
point of contrasting statins vs no statins for primary prevention (the most
relevant one from scientific and practical viewpoints), but considered various
head-to-head comparisons aimed at determining which statin is more
cost-effective than the others. In these head-to-head comparisons between
different statins, while the underlying question was the same across the
studies (“which statin has the best cost-effectiveness profile for primary
prevention?”), the results were surprisingly different. This casts doubts on
the robustness of the pharmacoeconomic methodology of these studies (inasmuch
as their results were conflicting from one another in the absence of specific
explanations). Last but not least, all of the sponsored pharmacoeconomic
studies found a better profile for the statin produced by the study sponsor
thus showing a clear bias towards favouring a pre-specified statin; this finding,
supported by a high statistical significance, is clearly the main result of our
literature analysis. To explain our
findings, one hypothesis is that the high level of uncertainty in the
pharmacoeconomics of statins for primary prevention (table 1) has contributed
to creating a context where the sponsored studies could be guided towards the
"desired" result. Anyhow, one problem with pharmacoeconomic studies
in general is that the methods for constructing the statistical variability
around the primary result are still far from being standardised; so, interpreting these data can be extremely
difficult under certain circumstamces. In conclusion, after
reading the paper by Wald and Law [1] and the editorial by Rodgers[2], we
wonder whether these authors have over-estimated the clinical and economic
evidence about primary prevention with statins. Our view is that more rigorous
data are still needed in this field (particularly as regards the
cost-effectiveness indexes) before one can propose an indiscriminate use of
these agents in people aged more than 55 years. REFERENCES 1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more
than 80%. BMJ. 2003;326(7404):1419. 2. Rodgers A. A
cure for cardiovascular disease? BMJ 2003; 326: 1407-1408. 3. Johannesson M, Jonsson B, Kjekshus J, Olsson AG, Pedersen TR, Wedel H.
Cost effectiveness of simvastatin treatment to lower cholesterol levels in patients with
coronary heart disease. Scandinavian Simvastatin
Survival Study Group.N Engl J Med. 1997;336(5):332-6. Table 1. Cost-effectiveness of statins for primary prevention: list of
the studies not sponsored by pharmaceutical companies.
§ Unless otherwise indicated, all of these analyses have considered
exclusively direct costs. The complete reference list is presented in the
footonote. §§ = This study included both patients receiving primary prevention and
patients receiving secondary prevention. † The figures enclosed by
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of a managed-care organization. Clin Ther. 1997;19(3):582-602. Table 2. Cost-effectiveness of statins for primary prevention: list of
the studies sponsored by pharmaceutical companies.§
§ Unless otherwise indicated, all of these analyses have considered exclusively
direct costs. The complete reference list is presented in the footonote. §§ = This study included both patients receiving primary prevention and
patients receiving secondary prevention. † The figures enclosed by
brackets show the annual discount rate employed in the analysis. * The pharmacoeconomic result of this study has been considered
favourable to the statin according to current international standards for
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1. FOOTNOTE: -
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Caro J, Klittich W, McGuire A, Ford I, Norrie
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Caro JJ, Huybrechts KF, De Backer G, De Bacquer
D, Closon MC.Are the WOSCOPS clinical and economic findings generalizable to
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Huse DM, Russell MW, Miller JD, Kraemer DF,
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Koren MJ, Smith DG, Hunninghake DB, Davidson
MH, McKenney JM, Weiss SR, Schrott HG, Henley RW Jr, Tresh P, McLain RW,
Bakker-Arkema RG, Black DM. The cost of reaching National Cholesterol Education
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Lacour A, Derderian F, LeLorier J. Comparison
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2003;21 Suppl 1:13-23. Competing interests: None declared |
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Andrea Messori, Coordinator Laboratorio di Farmacoeconomia, c/o Pharmaceutical Service, Careggi Hospital, 50132 Firenze, Italy,, Benedetta Santarlasci, Sabrina Trippoli, and Monica Vaiani
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Our rapid response contained the following typographical errors which
we would like to correct: Competing interests: None declared |
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