Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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NICE work...
- Christopher Anton (16 November 2001)
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An overlooked side-effect of statins:safety first!
- Sergio Stagnaro (16 November 2001)
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Premature conclusions from the Heart Protection Study
- Uffe Ravnskov (16 November 2001)
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Statins don't work by lowering lipids
- Paul J Rosch (16 November 2001)
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Serum Lipid Lowering and risk Reduction -- Where Is the Connection
- Jørgen Vesti Nielsen (19 November 2001)
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Finally, proof that statins don't work by lowering LDL
- Malcolm Kendrick (19 November 2001)
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Hidden side effects
- Nestor Galvez-Jimenez (21 November 2001)
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Any negative side effects?
- Margo Sommer (21 November 2001)
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Beware the denominator!
- Matthew Grove (29 November 2001)
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Re: Beware the denominator!
- Jorgen Vesti Nielsen (12 December 2001)
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Statins And Cancer: Cause For Concern
- Uffe Ravnskov, Paul J. Rosch, Peter H.Langsjoen, Joel M. Kauffman, and Kilmer S. McCully (22 October 2002)
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Effects of long term use of Statins in low risk people
- Jack Wert (23 November 2003)
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Christopher Anton, Administrative Co-ordinator West Midlands Centre for Adverse Drug Reaction Reporting
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Dear Sir Whilst the Heart Protection Study (1) is undoubtedly good news it's premature to say that statins are the "new aspirin". An aspirin tablet per day costs just over 1p whereas simvastatin costs £1.06 at the doses used, and it would cost the NHS almost £400m each year to treat 1 million people. Also, although the trial was large it would only detect adverse reactions which occur more often than about 1 in 3,000 patients and rare, serious reactions which may occur when the drug is exposed to a large population will have been undetectable. (2) Cerivastatin was voluntarily withdrawn by Bayer earlier this year after reports of 31 deaths in the US due to rhabdomyolysis. This disorder has also occurred with other statins. It sounds like another job for NICE to weigh up the risks, benefits and costs involved. 1.Kmietowicz Z. Statins are the new aspirin, Oxford researchers say. BMJ 2001;323:1145. 2. Eypasch E, Lefering R, Kum CK, Troidl H. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 1995;311:619-20. |
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Sergio Stagnaro, Specialist in Blood, Gastrointestinal and Metabolic Diseases Riva Trigoso 16037 (Genoa) Italy
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Sirs, I would like to tell to Oxford researchers (BMJ 2001, 323:1147 (17 November), who say that statins are the new aspirin: Safety first! In fact, they clearly overlook an interesting side effect of statins, I demonstrated in earlier papers. In 1990 I published already two papers (1, 2) (one of them in The Practitioner, Italian Edition), in which I described the risk of CoQ10 lowering, brought about, as side-effect, by all statins utilized in those years. One year thereafter, I fully illustrated these results of my clinical research by means of Biophysical Semeiotics in an Italian Congress (1). After 10 years all mass-media, all over the world, have told about rabdomyolysis and death caused by cerivastatin if prescribed in association with other anticholesterolemic drugs (fibrates). A part from the real role played by Cerivastatin, if prescribed without any hypocholesterolemic drugs in dose of 0,2 mg., which will be in any way ascertained in near future, a fact must be underlined: the above-referred data of my research have been unfortunately overlooked. As a matter of fact, in the above-mentioned articles I described, for the first time, the method to recognize “clinicaly”, i. e. at the bed-side, by means of a new, original physical semeiotics, the Biophysical Semeiotics, Co Q10 deficiency syndrome, even initial and asymptomatic. In a few words, every efficacious drugs is burdened notoriously with side- effects and not all individuals are equal: doctor must know both events in the best way as well as recognize them with the aid of a reliable physical semeiotics. Moreover, as far as this clinical method is concerned, it was been published and fully discussed elsewhere abundantly (3, 4, 5). Co Q10 is an essential coenzyme, unavoidable in reaching the normal free energy level in every cell of the body,including microvessels cells, necessary for the physiology of all biological systems, including scheletral muscle. I am sorry to find out that General Practitioners, at the beginning of 2000, do not learn this original physical semeiotics, cited in the best web-site around the world (Medscape, Forum Discussion), including bmj.com (See: http://digilander.iol.it/semeioticabiofisica), which allows doctor to evaluate “clinically” in quantitative manner, for instance, Co Q10 deficiency syndrome (which must be efficaciously treated in patients who need statines, as an inevitable result) as well as “Oncological Terrain” (See above-sited site and www.Staibene.it), conditio sine qua non of malignancies occurrence. Yours Stagnaro Sergio, Member NYAS and AAAS.
1) Stagnaro-Neri M., Stagnaro S., Carenza di Co Q10 secondaria a terapia ipolipidemizzante diagnosticata con la Percussione Ascoltata. Epat.(S.E.U.) 37, 17, 1990, and Settimana Italiana di Dietologia, 9-13 Aprile 1991, Merano. Atti, pg. 65. 2) Stagnaro S., Ipercolesterolemia e Coenzima Q10. The Pract. Ed. It. 133, 5-6, 1990). 3) Stagnaro-Neri M., Stagnaro S., Acidi grassi W-3, scavengers dei radicali liberi e attivatori del ciclo Q della sintesi del Co Q10. Gazz. Med. It. – Arch. Sc. Med. 151, 341, 1992. 4) Stagnaro-Neri M., Stagnaro S., Sindrome clinica percusso-ascoltatoria da carenza di Co Q10. Medic. Geriatr. XXIV, 239,1993. 5) Stagnaro-Neri M., Stagnaro S., Auscultatory Percussion Coenzyme Q deficiency Syndrome. VI Int. Symp., Biomedical and clinical aspects of Coenzyme Q. Rome, January 22.24, Chairmen K. Folkers, G.L. Littaru, T. Yamagani, Abs., pg. 105, 1990. |
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Uffe Ravnskov Magle Stora Kyrkogata 9, S-22350, Lund, Sweden
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In their press release the directors of the Heart Protection Study did not mention that their results were substantially worse than in the previous simvastatin trial 4S (table). Table. Absolute risk reduction in the Simvastatin trials
HPS 2001 4S 1994
CHD mortality -1.2 % -3.5 %
Total mortality -1.7 % -3.3 %
All stroke -1.5 % -3.5 %
Any major CHD -3.1 % -6.7 %
Also, the way the results were presented exaggerates the benefit for the individual patient. The most interesting figure is survival because most myocardial infarctions heal with minimal cardiac dysfunction, if any. Tell the patient that his chance not to die in five years without statin treatment is 85.4 % and that simvastatin treatment can increase his chance to 87.1 %. With these figures in hand I doubt that anyone should accept a treatment the long-term effects of which are unknown. For instance, it was claimed that the study presented “uniquely reliable evidence” that simvastatin is not carcinogenic. But the study went on for about five years only, just as did the other statin trials. It is not possible to say anything about the risk of cancer because it takes decades to disclose chemical carcinogenesis in human beings. Heavy smoking, for instance, does not induce lung cancer in five years. All the statins and also the fibrates have proven carcinogenic in rodents (2) and it scares me that, if the new American guidelines for “cholesterol treatment” are followed strictly, half of mankind may take statins in a few years and for the rest of their lives. Add also that low cholesterol has been related to depression, cognitive impairment, and immune system suppression. Does a 1.7 % mortality reduction balance these risks? As in the previous trials, the effect of simvastatin was independent on the initial cholesterol concentration; patients with low cholesterol benefited just as much (or just as little) as patients with high cholesterol. The best results were seen in patients older than 75 years, an age group where a low cholesterol has shown predictive (3). That statin treatment works in patient and age groups where a high cholesterol is not a risk factor for cardiovascular disease clearly shows that the benefit is not due to cholesterol lowering. High or low cholesterol are with all certainty markers for other, more important disease factors, they are not causal factors themselves. 1. MRC/BHF Heart Protection Study. Press release. http://www.ctsu.ox.ac.uk/~hps/pr.shtml 2. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996;275:55-60. 3. Schatz IJ, Masaki K, Yano K, Chen R, Rodriguez BL, Curb JD. Cholesterol and all-cause mortality in elderly people from the Honolulu Heart Program: a cohort study Lancet 2001; 358: 351-5 |
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Paul J Rosch, Clinical Professor of Medicine and Psychiatry New York Medical College 10703
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There is abundant evidence that the beneficial effects of statins are not due to any lipid lowering activities but rather unassociated antiinflammatory effects. Cardioprotective effects following an infarct occur much too rapidly to invoke decreased atherosclerosis as an explanation, are seen in patients with normal lipid profiles, correlate better with reduction in CRP and other inflammation markers, etc. Lowering LDL to an arbitrary level may be an inappropriate target goal with respect to determining dosage and duration of treatment that could lead to an increase in disturbing side effects of memory loss and fatigue that are generally not appreciated. (See JAMA 11/21/2001). As with aspirin, the optimal cardioprotective dose may be much lower than originally suspected. |
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Jørgen Vesti Nielsen, Consultant physician Dept. Med. Blekingesjukhuset. 374 80 Karlshamn. Sweden
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Serum lipid lowering and risk reduction – where is the connection? In the report from the Heart Protection Study (HPS) in the present issue of BMJ(1) it is constantly stated that the risk reducing effect is due to the lowering of the serum lipids. A look at the figures from the website (2) tells another story. The risk reduction happens without any apparent relationship to the risk levels, supposed to be caused by the serum lipid levels. The effect is the same for all without exceptions, high risk, low risk, no risk, (read high, low lipids) they all have the same response to the treatment. The ordered statistical cause-effect correlation in an x-y graph, where the risk, y, depends on the risk factor, x, has all disappeared. Consider for instance the following figures for LDL: Table. Vascular events by prior lipid levels LDL levels(Mmol/l: <3 3-3,5 >3 Risk placebo(%): 7,4 6,3 11,9 Risk Statin)%): 5,9 4,7 9,3 The cardiovascular risk increases for the placebo group when LDL dives below 3 mmol/l. How a further lowering of the selfsame LDL, when the lowest levels obviously are connected with higher risk, suddenly should, somehow, change quality and reduce risk instead is incomprehensible. It is simply too deep. The authors must roam in realms, from where the rest of mortals are excluded. It certainly would take a bit of interesting imagination to put this together in an orderly cause-effect graph. (try it yourself) What this study shows is that the effect of the statins is completely independent of serum lipid levels. The lipid levels therefore cannot be the cause of the risk level, but rather an innocent bystander, a marker of risk. The strength of this study is its size and its demonstration of equal statin effect even in people with low serum lipids. Considering that several meta-analyses consistently have noted higher mortality in people without manifest cardiovascular disease in lipid lowering studies (except for the statins) (3,4) lipid lowering per se does not seem to be especially healthy. In the light of this fact and in combination with the complete absence of relation between serum lipids and effect in the present HPS study, one can be safe in assuming that serum lipids in the normal range do not cause heart disease. Median serum lipids in populations may be risk markers but not determinants in heart disease. The same goes for dietary saturated fat. And since we know next to nothing about the control of the serum lipid levels in the human organism, perhaps we could see some research in that area instead of applying demonising properties to them: how do the feed-back systems work? what triggers fluctuations in individuals? Why are the serum lipid levels normally so strictly controlled? 1 Kmietowicz Z. Statins are the new aspirin, Oxford researchers say. BMJ 2001;323:1145 2 MRCIBHF heart protection Study. Press http://www.ctsu.ox.ac.uk/~hps/slides/results/index.htm 3 Muldoon MF, Manuck SB, Mendelsohn AB, et al. Cholesterol reduction and non-illness mortality: meta- analysis of randomised clinical trials. BMJ 2001;322:11-15 4 Law MR, Thompson SG, Wald NJ. Assessing possible hazards of reducing serum cholesterol. BMJ 1994;308;373-379 Jørgen Vesti Nielsen
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Malcolm Kendrick, Medical Director Lifelong Learning Partnership Lifelong Learning Partnership
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The biological hypothesis for the effect of statins on CHD is that they work by lowering rasied LDL levels. In the CARE trial, those who had their LDL lowered by the greatest amount, had the least protection against CHD events. In this latest Heart Protection Study, statins protect against CHD even in people with normal LDL levels. What is now clear is that the statin trials, taken together, have failed to demonstrate any dose- response effect on LDL lowering. Ergo, however else they do work - and there are a plethora of other possible actions including plaque stabilisation, increased NO production in the endothelium, reduction of various clotting factors - they do not work by lowering LDL. Yes, Statins are the new aspirin. They protect against CHD by reducing blood coagulability. Malcolm Kendrick. |
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Nestor Galvez-Jimenez, Chief. Movement Disorders Program, Department of Neurology The Cleveland Clinic Florida. 2950 Cleveland Clinic Blvd, Weston, Fl 33331
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Sir. I read with interest the news on the use of statins and prevention of heart disease and stroke. Unfortunately, no mention was made of potential side effects. Specifically, the incidence of drug-induced myopathy. Myalgias and a severe form of necrotizing drug-induced myopathy may occur in up to 1% of patients treated with HMG-CoA reductase inhibitors. The exact cause of these disorders is unknown but it may due to direct mitochondria toxicity/dysfunction. One percent of the adult population represents millions of patients eligible to use these drugs worldwide. Other side effects such as severe liver failure have only now become recognized. The ensuing disability may at times be so severe and dramatic that it makes you wonder how long it will take before we realize that perhaps we should be cautious with their general use. This point was clearly exemplified by the recent withdrawal of cerivastatin by the Food and Drug Administration (USA) due to rhabdomyolysis and myopathy. Longer periods of observations may be required before we can recomend the use of these medications as freely as we do with aspirin today. |
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Margo Sommer, Assistant Professor of Mathematics Richard Bland College, Petersburg, VA, USA 23805
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(Your article states: Five years of statin treatment typically prevents heart attacks, strokes, or other major vascular events in 11 in 10 people... I think this should be 11 in 100.) I have been concerned for many years about the possible relationship between lowering cholesterol levels and increased incidence of accidents, suicide, or violence, as shown in several previous studies. Did your study find this or any other negative side effects? |
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Matthew Grove, Consultant Physician North Tyneside Hospital
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Whilst agreeing with Jorgen Nielsen's general argument, I must pick him up on a detail. The percentage risks he gives in his table for vascular events by prior lipid level are calculated assuming N=10269 for the statin group and N=10267 for the placebo group. This is fair enough, as that is how the HPS investigators have displayed the data in their table on their website. However, the denominator for the event rate should be the number of patients in each subgroup with each baseline LDL level, not the total number in each treatment group. This data is not given on the website; we don't know how many patients had a baseline LDL <3, how many >3 and <3.5 and how many >3.5, and how many in these subgroups were allocated statin or placebo. Until the data is published in full, this kind of risk calculation is not possible. Can we have the numbers in each subgroup please? |
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Jorgen Vesti Nielsen, Consultant physician Dept. Med. Blekingesjukhuset, 37480 Karlshamn, Sweden
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Thanks to Matthew Grove for pointing out the obvious problem with the denominator. He is right, of course. It was a case of hasty writing and wishful thinking, an expectation of the same absence of statistical cause- effect correlation as in the other statin studies that led me astray. The relations in these such as the CARE, LIPID and AFCAPS/TexCAPS studies or the completely inverse relation in the MIRACL study all suffer from the same problem, they disprove a cause-effect correlation, a problem, which I expect we shall see repeated in the present HPS study. 1 Sacks FM, Pfeffer MA, Move LM et al. The effect of pravastatin in coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9 2 The Lipid Study Group. Prevention of cardiovascular events and death with pravastat in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349-57. 3 Gotto AM, Whitney E, Stein EA, et al. Relation Between Baseline and On-Treatment Lipid Parameters and First Acute Major Coronary Events in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS). Circulation 2000;101:477-484. 4 Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of Atorvastatin on Early Recurrent Ischemic Events in Acute Coronary Syndromes. JAMA 2001;285;1711-1718 Jorgen Vesti Nielsen
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Uffe Ravnskov Magle Stora Kyrkogata 9, S-22350 Lund, Sweden, Paul J. Rosch, Peter H.Langsjoen, Joel M. Kauffman, and Kilmer S. McCully
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We
are questioning the wisdom of recommending statin treatment for a large segment
of the world’s population simply because they have elevated lipid levels or
are assumed to be at increased risk for coronary events because of the presence
of other risk markers. Even using the outcome in the Heart Protection Study
(HPS)1 with the most optimistic figures (“Any major vascular event”),
the number of individuals who benefited from treatment did not exceed 5.4%, a
figure that included many events with minor or no future health consequences.
Such small treatment rewards demand a careful analysis of the potential risks. 1.
Heart
Protection Study Collaborative Group. MRC/BHF heart protection study of
cholesterol lowering in 20 536 high-risk individuals: a randomised
placebo-controlled trial. Lancet 2002;
360: 7-22. 2.
Newman TB,
Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996; 275: 55-60 3.
Randomised
trial of cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344:1383-1389. 4. Sacks FM, Pfeffer MA, Moye LA, et al. for the Cholesterol and Recurrent Events Trial investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001-1009. |
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Jack Wert, Retired 19056
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My wife has "been on" statins for about fifteen years - the first ten on Mevacor, and the past five on Lipitor. She is not a high risk CHD (Coronary Heart Disease)person as she has none of the characteristice of such (never smoked / not overweight / no hereditery history / eats a very sensible diet/. But her total cholesterol was close to 300, so she was "put on" statins as indicated. The statins did result in lowering her "numbers" to very acceptable levels, but she is no longer a healthy person, and cannot enjoy life as she had early in the year. Many visits to our family doctor and two specialists provided no guidlines for improvement. Tests such as Bone scan, and blood tests also indicated no definite treatable condition. Steroids had no positive effect, nor did a series of Doxycycline (for possible Lyme disease). We tend to suspect the long use of statins to be the culprit, and look for help anyplace. Jack Wert Competing interests: None declared |
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