Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Cholesterol is good?
- Jacob F. de Wolff (4 June 2006)
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High Dose Statins – A Startling Absence of Policy
- Martin G Duerden (5 June 2006)
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These are questions that need asking
- Daniel R Hicks (5 June 2006)
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I am worried
- Alastair E Dobbin (6 June 2006)
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Its all about risk!
- Chris Gunstone (6 June 2006)
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Statin myopathy
- David W Evans (7 June 2006)
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The Cholesterol Frenzy Continues
- Dr. Herbert H. Nehrlich (10 June 2006)
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Surely some mistake?
- Alun D Hughes, Michael Schachter (12 June 2006)
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The safety concerns for high-dose statins in the primary or the secondary prevention of cardiovascular diseases.
- Hisashi Moriguchi, Takamoto Uemura and Chifumi Sato (12 June 2006)
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Re: Surely some mistake? - but does it matter
- Eddie Vos (13 June 2006)
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statin side effects
- Philipp Conradi, none (15 June 2006)
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subtle statin side effects nearly universal
- catey shanahan (18 June 2006)
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Re: subtle statin side effects nearly universal
- Zbignew A Woznica (19 June 2006)
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Rapid Response to Ravnskov's article "Should we lower cholesterol as much as possible?"
- Steven J Haas, Rosana Hage-Ali, Brian G Priestly, Andrew Tonkin, Lisa Demos, Mark Nelson and John J McNeil (27 June 2006)
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Are eligibility criteria for over the counter (OTC) statins appropriate?
- D Graham Mackenzie, Sarah H Wild, Philip Rutledge (15 August 2006)
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Re: Cholesterol is good?
- Raymond G Holder (7 September 2006)
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Further evidence that higher statin doses are ineffective
- Uffe Ravnskov (19 October 2006)
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Jacob F. de Wolff, SHO, general medicine Enfield EN2 8JL
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It is true, like Ravnskov et al state, that any revision of targets needs to be evidence-based and responsible, taking into account the risks and benefits of such a measure. However, some of the authors' assertions are unclear and potentially misleading. The authors do not explain in what way Q10 lowering is actually harmful. The Rundek study, one of the few that actually measured Q10 levels, did so in insufficient numbers of patients, and the authors of that study go at great length to still arrive at a conclusion of significance despite failing to show anything statistically solid. In one of the largest studies to date, the Heart Protection Study (1), no evidence was found for neuropsychiatric and pulmonary side-effects above placebo level. With regards to cancer, Ravnskov et al disregard recent evidence that statins seem to protect against several forms of cancer, not least the very common colorectal cancer (2); instead, they favour older evidence. The HPS had cancer incidence (including various subtypes) as an endpoint, and no increased cancer risk was found in that trial (1). With respect to the authors' competing interests, it is stated clearly that three of them dispute the very association between hypercholesterolaemia and heart disease. A most useful model here is familial hypercholesterolemia, in which young adults with no other risk factors may develop accelerated atherosclerosis. With the underlying biochemical abnormality very well known (LDL receptor defects), these authors' hypothesis becomes almost completely untenable. It does seem counterintuitive that a very large proportion of the population may require pharmacological prophylaxis for cardiovascular disease. At the same time it is widely aknowledged that dietary patterns have deteriorated, we are in the middle of an obesity epidemic, and that dietary measures are generally insufficient to mitigate cardiovascular risk in both hypercholesterolemia and obesity. With the benefits of statins documented in several very large studies (4S and Heart Protection Study for starters), why deny statin treatment on the basis of relatively inconclusive evidence? (1) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high- risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7 -22. PMID 12114036. (2) Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G. Statins and the risk of colorectal cancer. N Engl J Med 2005;352:2184-92. PMID 15917383. Competing interests: None declared |
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Martin G Duerden, General Practitioner Meddygfa Gyffin, Conwy, North Wales, LL32 8LT
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Ravnskov and colleagues raise some important concerns about the safety of treating much of the adult population with high-dose statins but do not review how effective this might be[1]. These issues are important in England and Wales as in January 2006, the National Institute for Health and Clinical Excellence (NICE) Technology Appraisal requested that the National Health Service (NHS) in England and Wales provide statin therapy to all those with cardiovascular disease and to all with a 20% or more risk of a cardiovascular event in the next ten years[2]. This guidance gives no clue as to the proposed intensity of treatment, what dose of statin should be used or what cholesterol targets people should be treated to (if any). The vacuum in this guidance leaves the updated Joint British Societies’ Guidelines (JBS2) published in December 2005 to fill the hole[3]. Is this wise? Their targets when using lipid-lowering therapy are to lower total cholesterol to less than 4mmol/l or a 25% reduction, or LDL-cholesterol less than 2mmol/l or a 30% reduction, whichever gets the person to the lowest absolute value. These guidelines are based on consensus, not evidence. What is apparent is that to achieve such targets for many will require high dose statin therapy. Is there evidence? There is emerging evidence to show some additional benefit compared with standard dose therapy in high risk people with established coronary disease but at the expense of harm related to myopathy and liver disorder, as pointed out by Ranskov et al[1]. If more aggressive therapy is applied to lower risk people, such as the primary prevention population with greater than 20% ten-year risk of cardiovascular event, as recommended by JBS2, there is a real worry that this potential for harm could exceed benefit. This worry is supported by evidence from the recently published Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) study[4] which compared simvastatin 20mg-40mg daily (the dose was increased if total cholesterol was greater than 5mmol/l, as in ‘4S’) with atorvastatin 80mg daily in 8,888 patients with a history of myocardial infarction. The primary endpoint of major coronary event was not significantly reduced by atorvastatin 80mg daily; HR 0.89 (95% CI 0.78–1.01), P=0.07. The incidences of adverse events resulting in discontinuation (9.6% vs. 4.2%, P<0.001) and raised liver enzyme levels (e.g. alanine aminotransferase >3 times upper limit of normal 0.97% vs. 0.11%, P<0.001) were significantly greater with atorvastatin than with simvastatin. Thus, even the IDEAL study does not provide compelling evidence that high-dose statin treatment should be used ahead of simvastatin (20mg and 40mg), as part of a general management strategy for secondary prevention of cardiovascular events, let alone in primary prevention. It is also instructive to look at the mean LDL-cholesterol throughout the study which was lower in the atorvastatin 80mg group – 2.1mmol/l vs. 2.7mmol/l with simvastatin; this suggests that even with high dose potent statin therapy at least 50% of people will not obtain the targets proposed by JBS2. Does this matter? Even putting aside concerns of safety the costs of lipid regulating drugs in England was £600 million over the last year, and this represented 8% of the total primary care drug spend; the single most expensive prescribing area. The NHS is under immense financial pressure and the absence of detail from NICE on intensity of therapy suggests it is failing to do its job in giving guidance on cost-effective interventions. [1] Ravnskov U, Rosche PJ, Sutter MC and Houston MC. Should we lower cholesterol as much as possible? BMJ 2006;332:1330-1332. [2] National Institute for Health and Clinical Excellence. Statins for the prevention of cardiovascular events. Technology appraisal 94 and related costing template and report. January 2006. Accessed from www.nice.org.uk on 4/06/06. [3] British Cardiac Society, British Hypertension Society, Diabetes UK, HEART UK, Primary Care Cardiovascular Society, The Stroke Association. JBS 2: Joint British Societies’ Guidelines on prevention of cardiovascular disease in clinical practice. Heart 2005;91(Suppl V):v1-v52. [4] Pedersen TR, Faergeman O, Kastelein JJP, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. JAMA 2005:294:2437–45. Competing interests: None declared |
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Daniel R Hicks, Programmer IBM Rochester MN USA 55901
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While there is good evidence that statins and other cholesterol- lowering drugs can be beneficial for a large number of people, my own personal experiences would suggest that there are many for whom statins can be injurious. During my correspondence with people who have "post-polio syndrome", I have found that many, like myself, have experienced severe myopathic symptoms when on statin therapy. Additionally, since these symptoms have been seen to occur when on supplemental CoQ10 and have also been seen to occur with non-statin cholesterol-lowering medications such as ezetimibe or cholestyramine, it appears that these symptoms may be due directly to lowered cholesterol levels, vs inhibited synthesis of CoQ10. A worrisome factor is that the onset of statin-induced myopathic symptoms can apparently occur months or even years after the initiation of statin therapy, and the primary symptoms are slowly increasing muscle pain that can easily be misdiagnosed (especially in aging patients) as "normal" overuse pain, fibromyalgia, or some other unrelated disorder. Initially, a reduction in muscle effort may alleviate the symptoms, resulting in a lowered level of physical activity and, ironically, increased morbidity due to loss of cardiovascular fitness. Yet, most of these adverse effects would be missed in short-term drug studies, and are likely to be missed by many prescribing physicians, greatly understating both the frequency and severity of the effects. Competing interests: None declared |
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Alastair E Dobbin, GP 9 Brunton Place, Edinburgh EH7 5EG
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This is an extremely worrying piece, but I am very glad that the authors have written it. So one of the largest trials to test out the side effects of statins excluded 44% of those screened? I think any trial with such selectivity is practically invalid in terms of extrapolating the results to an everyday primary care population. In everyday practice we are not advised to exclude anyone from receiving statins, and the BNF says ‘They should be considered for all patients, including the elderly’, but the PROSPER trial would appear to have been completely overlooked in the rush to give everyone statins. No reduction in mortality? What on earth is going on? Have these drugs really been properly assessed? We are talking prophylaxis here with a drug that 50% of the population may end up taking, at a huge cost to society, denying legitimate healthcare costs in other clinical areas. The burden of proof of safety is far greater than the use of routine drugs for clinical conditions, but the findings would appear to be sketchy and certainly inadequate to back up one of the largest public health measures ever. I personally have always been dubious that there is anything other than a population link in the reduction of cholesterol levels having a beneficial effect on cardiovascular mortality. Sure, the statins may have an effect on LDL, but who is to say that this is not a co-incidental side effect of the drugs, and the main effect in reducing cardiovascular mortality is the well known anti-inflammatory effect? And if it is the anti-inflammatory effect then it would not be surprising that there is an increase in cancers. I personally have been studying depression in primary care for 5 years. When I started out I was flabbergasted to find the manipulation of trials and suppression of data that the drug companies had universally applied had totally skewed the outcomes, and that the evidence in favour of SSRI’s was virtually non existent. This was particularly brought home to me by the Cochrane meta–analysis which concluded that ‘differences between antidepressants and active placebo are small’(1), followed by the release of the 10 year data sets by the FDA for the four commonest anti- depressants when some researchers concluded that the difference (drug/placebo) was not clinically significant; indeed ‘medications must be interfering with responsiveness in at least some others who would fare better on placebo’(2). I am beginning to get a very bad feeling that similar things have been going on with statins as with SSRI's, and we are all dancing to big pharmas tune again here. Please someone, reassure me that this massive statin intervention has a firmer basis than it appears to. Someone please reassure me that there are more studies in the elderly with statins that do show a marked reduction in mortality. If no-one can reassure us of this, I think we all need to be very worried indeed. 1. Moncrieff J, Wessely S, Hardy R (2002) Active Placebo versus antidepressants for depression. (Cochrane Review) Cochrane Library, Issue 3,2002 2. Kirsch J, Antonuccio D (2002) Antidepressants versus Placebos: Meaningful advantages are lacking. Psychiatric Times September 2002 vol 19, issue 9 Competing interests: None declared |
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Chris Gunstone, GP Burton upon Trent, DE15 9AF
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Dear Sir, “The span of our life is seventy years –
Surprisingly little has changed since the time of the psalmist! The life expectancy of a male at 75 is less than 10 years according to government statistics. (2) Currently in our practice of 10,100 patients, only 3.43% get beyond 80 years, with 0.44% getting past their 90th birthday. The British Hypertension Society states that all whose risk is 20% or over should be started on statins, aspirin and an antihypertensive up to the age of 80 years. (3) Hence a 75 year old male, life-long non-smoker, non-diabetic with a BP of 140/90, cholesterol of 5 and an HDL of 1 would be put on triple therapy, rather than congratulated on his good health! The Whitehall study found, “After more than 25 years of follow up of civil servants aged 40-69at entry to the study, employment grade differences still exist in total mortality and in nearly all specific causes of death. The main risk factors (cholesterol, smoking, systolic blood pressure, glucose intolerance and diabetes) could only explain one third of this gradient.” (4) Recent articles by Brindle et al on the inaccuracy of the Framingham score sheds doubt on its usefulness. (5) A review article in the British Journal of General Practice commented that the best predictor of cardiac death was age. (6) So do we use a risk scoring system which gives results with a confidence interval of 50% either way, depending on local prevalence and social class – remembering that ethnicity and family history add further major inaccuracies? The push to provide primary prevention based on risk scores is surely flawed. There is also the issue of informed consent. If we accept that the risk of dying for each human being is 100%, there are only three main variables of death – where, when and how. The “where” is about geography and social systems, the “when” and “how” are the areas that medicine tries to influence. How we die tends to be related to when we die. As a child the main risks are from congenital inheritance, infection, some cancers and violence (accidental and non accidental). If a young male dies, it is most likely to be from violence (accidental, non accidental or self inflicted), a young woman (thinking globally) from child birth. An elderly person will die from cardiovascular disease, cancer or “bronchopneumonia” (a euphemism often used to describe the death of an octogenarian with senile dementia in residential care). If one reduces the risk of dying with cardiovascular disease, because the maths must add up, presumerably more people will die of cancer. Ravenskov et al (7) in their article suggest that this is true – either as a direct effect of statins themselves, or because mathematically one has to die from something!How often do we discuss this with patients in the final decades of their natural life? There is a seeming madness in the way Western Medicine is developing. Increasing polypharmacy in an aging population is a risk laden course of action, which promises few real benefits. 1) Psalm 90 vs 10 2) http://www.gad.gov.uk/Life_Tables/Notation.htm 3) Williams B. et al. Guidelines for the management of Hypertension: report of the fourth working party of the British Hypertension Society 2004 – BHS IV. Journal of Human Hypertension (2004) 18, 139-185 4) van Rossum et al (2000) Employment grade differences in cause specific mortality: a 25 year follow up from the first Whitehall Study quoted in “Risk Matters In Healthcare” K Mohanna and R Chambers Radcliffe Medical Press (2001) 5) Brindle P et al. The Accuracy of the Framingham risk-score in different socio-economic groups: a prospective study. BJGP 2005 Vol 55 Number 520 6) Fahy T, Schroeder K, Cardiology BJGP 2004 Vol 54 Number 506 7) Ravnskov U, Rosch P et al. Should we lower cholesterol as much as possible? BMJ 2006; 332: 1330-2 Competing interests: None declared |
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David W Evans, Retired physician 27 Gough Way, Cambridge, CB3 9LN
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Daniel Hicks's personal experience and concerns echo my own. Like him, I suspect that much weakness and increasing disability, particularly in the elderly, may not be recognised as the unwanted effects of these drugs - which are in such widespread use on the basis of their too-good-to -be-true image of efficacy without significant risk. Competing interests: None declared |
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Dr. Herbert H. Nehrlich, Private Practice Bribie Island, Australia 4507
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Dr. de Wolff states: "....It does seem counterintuitive that a very large proportion of the population may require pharmacological prophylaxis for cardiovascular disease. At the same time it is widely aknowledged that dietary patterns have deteriorated..." If dietary patterns have deteriorated does he think that the intake of cholesterol has increased significantly? Since there is no evidence that this is happening what would have justified White House physician Dr. Paul Dudley White's famous words about being unable to find patients with CVD to try out his new EKG machine on? Beef drippings, lard, eggs, butter, fatback....those were the order of the day a hundred years ago. As to CVD, where were the bodies? It is becoming increasingly clear to the man on the street that the "prophylaxis" of Modern Medicine is often nothing more than the transfer of wealth under false pretenses. As to Dr. de Wolff's mention of Familial Hypercholesterolaemia, the University of Leiden in the Netherlands published a study of three individuals with FH. They examined the medical histories of over 400 family members of these individuals. Mortality was unrelated to the cholesterol level, yet it seemed to be linked to the time during which the individuals lived.Those who lived during the nineteenth and early twentieth centuries had no increased mortality when compared to the population. If anything, they tended to live longer.1 Perhaps a thorough reading of Ravnskov's book would be worthwhile, it shows clearly why Professor George Mann (principal investigator of the Framingham Study) called the cholesterol hypothesis "the greatest scientific deception of our time" 2 References: 1 Sijbrands EJG and others. Mortality over two centuries in large pedigree with familial hypercholesterolaemia BMJ 322, 1019-1023 2001 2 www.fonteine.com/cholesterol_mythe.html Competing interests: None declared |
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Alun D Hughes, Professor of Clinical Pharmacology NHLI Division, Faculty of Medicine, Imperial College London, UK, Michael Schachter
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Ravnskov et al., state that 'all statins inhibit the synthesis of hydroxymethylglutaryl coenzyme A (HMG CoA) reductase, an enzyme involved in synthesis of the precursor of cholesterol'. This is incorrect. Statins act as inhibitors of hydroxymethylglutaryl coenzyme A reductase and reduce synthesis of mevalonate from HMG CoA. The consequent reduction in cholesterol synthesis leads to upregulation of receptors for low density lipoprotein (LDL) and a resultant increase in uptake of this lipoprotein (largely by the liver) and reduced circulating LDL. In fact use of statins is associated with increased amounts of HMG CoA reductase as a result of reduced negative feedback on synthesis (1). 1. Brown MS, Goldstein JL. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res. 1980;21:505-17. Competing interests: None declared |
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Hisashi Moriguchi, Professor, Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo. 4-6-1, Komaba, Meguro-ku, Tokyo, Japan., 153-8904, Takamoto Uemura and Chifumi Sato
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Ravnskov et al. raise concerns about the safety of high-dose statins [1]. A recent retrospective analysis of pooled data from 49 clinical trials of atorvastatin (n=14,236 patients) has shown that the incidence of treatment-associated adverse events for high-dose atorvastatin (80 mg) is similar to that of atorvastatin at a dose of 10 mg and placebo. Based on this analysis, the safety profile of atorvastatin at the highest dose is supported [2]. However, a recent meta-analysis (n=71,108) of randomized controlled trials have shown that atorvastatin is associated with the greatest risk of adeverse events among atorvastatin, fluvastatin, lovastatin, simvastatin, and pravastatin [3]. On the other hand, though we analyzed the incidence of rhabdomyolysis, based on Japanese post-marketing survey for pitavastatin as a new statin [4], the incidence was 0 (95% CI: 0-12.9) per 10,000 person-years in monotherapy of pitavastatin (n=7,880). Furthermore, pitavastatin (2 mg/day) decreased the risk of any adverse events significantly compared with simvastatin (20 mg/day) in (p=0.015 by using Fisher exact test), though the mean rate of low density lipoprotein (LDL) cholesterol reduction was not significantly different (pitavastatin: 38.2%, simvastain: 39.4%) [5]. Therefore, these studies indicate the rate of adverse events differs among statins. On the other hand, though we think that there are the benefits of high-dose statins in the secondary prevention of cardiovascular diseases, the benefits are not sufficiently shown in the primary prevention of cardiovascular diseases. Furthermore, the worries about the increase of high-dose statins-related adverse events remain even in the secondary prevention of cardiovascular diseases [1]. Therefore, statins should be used, considering the difference of the rate of adverse events among statins in the primary or the secondary prevention of cardiovascular diseases. Furthermore, it should be still avoided to use high-dose statins in the primary prevention of cardiovascular diseases. References: [1] Ravnskov U, Rosche PJ, Sutter MC and Houston MC. Should we lower cholesterol as much as possible ? BMJ 2006;332:1330-1332. [2] Newman C, Tsai J, Szarek M, Luo D, Gibson E, Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients, Am J Cardiol 2006;97: 61-67. [3] Silva MA, Swanson AC, Gandhi PJ, Tataronis GR, Statin-related adverse events: a meta-analysis. Clin Ther 2006;28:26-35. [4] Kurihara Y., Douzono S.,Fujita S., Kakuda T., Nachi S., Uematsu H. Interim Report, 8083 Patients on the Drug Use Investigation of Pitavastatin (LIVALO Tablet), Jpn Pharmacol Ther 2006;34:317-326. (in Japanese) [5] Park S, Kang HJ, Rim SJ, et al, A randomized, open-label study to evaluate the efficacy and safety of pitavastatin compared with simvastatin in Korean patients with hypercholesterolemia, Clin Ther 2005;27:1074-1082. Competing interests: None declared |
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Eddie Vos, maintains health-heart.org Sutton (Qc) Canada J0E 2K0
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Pharmacology professor Hughes is evidently correct in
that statins occupy, with various permanency, the active site in the enzyme
resulting in reduced production of mevalonate, the 6 carbon precursor to
the 5 carbon group based isoprenoid family. While interesting, the
point is not how statins don't work but if or why they don't.
Clearly, when there is mathematical certainty from 2 meta analysis [JAMA and JACC 2004, ref's in (1)] that women don't have a mortality benefit from a statin or, in secondary prevention, no benefit in myocardial infarction one has to come with answers why this might be. Why PROSPER found no mortality benefit in over 70 year olds also needs to be answered first and, I suggest, before we argue method of action or side-effects from any dose. I suggest there may be an 'event' benefit in statins in younger males since statins mimic nitroglycerin [promote the NO-synthase pathway] and thus lower the rate of 'classic' male stable angina symptoms, arguably not ever a fatal condition but certainly one that can send one to the cath-lab while in a trial. Pharmacologists should split out this statin effect as a confounder in combined endpoint studies and then we can see if anyone really benefits from impeding the mevalonate pathway and that affects every system in the body. Regarding the 'lower is better' concept, the 1/4 million patient-year observational J-LIT study (2) showed that simvastatin 'hyper-responders' achieving the LDL levels the various guidelines propose had significantly greater mortality than those remaining near total cholesterol 6 ± 0.5 mmol/L and LDL 4 ± 0.8 mmol/L [J-LIT graphs from table 5 Medline 12499611] Eddie Vos- vos{at}health-heart.org 1.) Vos E, Rose CP. Questioning the benefits of statins. CMAJ Nov 8, 2005; 173 (10). doi:10.1503/cmaj.1050120. 2.) Matsuzaki M, Kita T, Mabuchi H, Matsuzawa Y, Nakaya N, Oikawa S et al Large scale cohort study of the relationship between serum cholesterol concentration and coronary events with low-dose simvastatin therapy in Japanese patients with hypercholesterolemia. Circ J. 2002 Dec;66(12):1087-95. Competing interests: None declared |
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Philipp Conradi, GP Otto-Dix-Ring 98 01219 Dresden, Germany, none
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Ravnskov and his colleagues (1) have to be congratulated on their article stating that statins have more side effects than usually claimed. They highlight selection bias and scientific mishandling of data as possible sources for this misconception. Selection Bias: The main statin studies exclude patients with concomitant diseases ( mainly cancer and COPD). Additionally, some studies like TNT (2) and HPS (3) exclude all patients who had side effects with statin medication in the pre run. The reported low number of patients with side effects therefore refers to those patients only who did not have side effects in the first place and were not excluded from the main trial. Scientific Mishandling: PROSPER (4) showed a small but significant increase in cancer incidence with Pravastatin treatment. The result was buried in a makeshift meta analysis of unmatched trials. Where does it leave us? What are the medical, ethical and legal implications when we know that benefits from statin therapy for the individual patient are small and fraught with problems. Should UK General Practitioners receive ,quality payments’ by spending approximately 4 – 6% of the total UK drug budget on drugs with growing concerns about safety and tolerability. Could this money be better spend on health promotion relating to life style changes ? ( Explanation for the Non-British readers : GPs in the UK receive so called quality payments for reaching certain targets like putting patients on statins etc.) I seriously hope, that the article by Ravnskov et al. will start a discussion of evidence. 1) Ravnskov U, Rosch PJ, Sutter MC, Houston MC. Should we lower cholesterol as much as possible? BMJ 2006; 332:130-1332 2) LaRosa JC, Grundy SM, Waters DD, Shear S, Barter P, Fruchart J et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005; 352: 1425 - 1435 3) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with Simvastatin in 20,536 high risk individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7- 22. 4) Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomized controlled trial. Lancet 2002 ; 360: 1623 - 30 Competing interests: None declared |
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catey shanahan, Family Practice MD Kalaheo HI, 96741
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I have not done anything like a formal study, but I have an opportunity to see many many patients on statins and ask them nosy questions. I am in private practice with two internists, one of whom is a statin fanatic, even prescribing statins to elderly women with HDLs of 80 and LDLs of 130 or 140. She goes on vacation 3 months of the year and I see her patients in that time, some for routine refills, some for medical problems. When I'm in the mood, I scrounge around asking them for potential statin side effects. Almost without exception they have minor complains that could certainly be attributed to statins. By minor I mean subtle forgetfullness, vague muscle fatigue at the end of the day, mild disequilibrium; the type of stuff they probably wouldn't have told me about had I not specifically asked. A small minority of these have severe muscle aches and are miserable and dying to stop the drug if only it were "safe." Many of these patients become my patients because they don't want to have to go back onto the statin again. Of the hundred or so of my statin-loving coworker's statin-using patients whom I have seen over the past two and one half years since she joined our clinic, I would guess about three or four definitively denied having any symptoms, but I didn't question all one hundred well enough to be sure it was only those few--it could have been lots more. But my general, vague and possibly biased, impression is that it's the exception not the rule for people to deny potential statin caused symptoms began after starting their statins. Most doctors would be crazy to ask elderly women about dizziness, fatigue, and forgetfulness because of course they're going to be dizzy, tired, and forgetful sometimes, and just by asking, now you've got them worried. Unless you also happen to have a potential solution for their mild complaints (ie "you should stop your Lipitor, Mrs. Pumpernickle) you just don't want to open that can of worms. But it seems to me we have a nation of dizzy, achey, tired older middle aged and elderly men and women who feel better after stopping the drug. Competing interests: None declared |
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Zbignew A Woznica, internist Hartford , CT 06114
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Catey Shanahan wrote: "Most doctors would be crazy to ask elderly women about dizziness, fatigue, and forgetfulness because of course they're going to be dizzy, tired, and forgetful sometimes, and just by asking, now you've got them worried. Unless you also happen to have a potential solution for their mild complaints (ie "you should stop your Lipitor, Mrs. Pumpernickle) you just don't want to open that can of worms. But it seems to me we have a nation of dizzy, achey, tired older middle aged and elderly men and women who feel better after stopping the drug." If you really think you are doing something for these patients, then you have to ask them all these questions including those not on statins. You could trying giving those not on statins, placebos or Lipitor and see if you get an improvement. Don't underestimate the power of placebo or jus talking to the patient. Competing interests: None declared |
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Steven J Haas, PhD student / lecturer / pharmacist Monash University, Department of Epidemiology & Preventive Medicine, Melbourne, Australia 3004, Rosana Hage-Ali, Brian G Priestly, Andrew Tonkin, Lisa Demos, Mark Nelson and John J McNeil
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We agree with Ravnskov et al that little is known about the adverse effects of high dose statins[1] but would also propose that little is known about the long term safety of more modest doses used at present. Lifetime use of statins may equate to therapy for thirty years or more.[2] As stated by the authors, multi centre large-scale trials have established efficacy of these agents but are much less reliable for detection of infrequent serious adverse outcomes such as cancer. Recent studies provide reassurance regarding the safety of statins with respect to all-cause carcinogenicity in the short term[3,4] and up to ten years.[5] However, whilst the length of post-marketing surveillance remains quite short compared to the medically accepted latency period for cancer of twenty years,[2] it seems prudent to establish systems examining and linking large databases to allow extended follow-up for malignancy. Such monitoring can also help ascertain whether any class effect or dose- response exists and whether certain categories of carcinogenicity are influenced by statins either favourably (as suggested by some case-control studies) or deleteriously. These data linkage systems should include a variety of stakeholders, among them regulatory authorities from different countries and the pharmaceutical industry, all cooperating in the provision of more robust information in this and other important areas of pharmacovigilance. Recent issues surrounding the long term uncertainty of COX-2 inhibitors and hormone replacement therapy have highlighted that medication safety must be proven rather than assumed, especially for very widely used medications utilised for long-term therapy. Corresponding author: Steven Joseph Haas - Steven.Haas@med.monash.edu.au References 1. Ravnskov U, Rosch PJ, Sutter MC, Houston MC. Should we lower cholesterol as much as possible? BMJ 2006;332(7553):1330-2. 2. Newman TB, Hulley SB. Carcinogenicity of lipid-lowering drugs. JAMA 1996;275(1):55-60. 3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366(9493):1267-78. 4. Kaye JA, Jick H. Statin use and cancer risk in the General Practice Research Database. Br J Cancer 2004;90(3):635-7. 5. Strandberg TE, Pyorala K, Cook TJ, Wilhelmsen L, Faergeman O, Thorgeirsson G, et al. Mortality and incidence of cancer during 10-year follow-up of the Scandinavian Simvastatin Survival Study (4S). Lancet 2004;364(9436):771-7. Competing interests: Steven Joseph Haas has received assistance via an Australian National Health and Medical Research Council Public Health Postgraduate Research Scholarship, Scholarship application I.D. #237059. As corresponding author, Steven Joseph Haas had full access to all data in the study and had final responsibility for the decision to submit for publication. Andrew Tonkin has received funding for studies and speakers fees from pharmaceutical industry companies including AstraZeneca, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, and Sankyo. Mark Nelson has received funding for studies and consultancies from pharmaceutical industry companies including AstraZeneca, Bayer AG, Sanofi-Aventis, Sanofi-Synthelabo, Bristol-Myers Squibb, Merck Sharp and Dohme, and Pfizer. John McNeil has served on advisory boards for Pfizer, GlaxoSmithKline, Johnson & Johnson, Bristol-Myers Squibb, Schering-Plough, Sanofi-Aventis, and Merck Sharp and Dohme. |
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D Graham Mackenzie, Specialist Registrar in Public Health Public Health Department, NHS Fife, Cameron House, KY8 5RG, Sarah H Wild, Philip Rutledge
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Dear Editor, Ravskov et al discuss optimal cholesterol levels and more widespread use of statins.1 Over the counter (OTC) statins should also be considered in this debate. In primary prevention of coronary heart disease (CHD), current guidelines recommend that high-risk patients (equivalent to CHD risk ≥ 15% using Framingham equations) should be prescribed a statin by their general practitioner (typically simvastatin 20-40mg).2 Royal Pharmaceutical Society of Great Britain (RPSGB) criteria for OTC simvastatin 10mg aim to target patients at moderate risk of CHD (10-year CHD risk 10-15%) using an assessment of age, sex and a count of CHD risk factors.3 Higher risk patients are also identified using RPSGB criteria, ideally including blood pressure (BP) and cholesterol checks (when available), and are advised to see a doctor. We have investigated how accurately RPSGB criteria for OTC statins identify patients at moderate risk of CHD using data from the nationally representative Scottish Health Survey 1998 (SHS). The analysis included data from 2,760 people aged 40 to 74 years without cardiovascular disease (CVD) or diabetes, identifying those with 10-year CHD risk 10-15% using two methods – Framingham equations, and RPSGB criteria. Agreement between the two approaches was assessed using the kappa statistic (SPSS 11.5, Chicago). The analysis for RPSGB criteria was then repeated without taking BP and cholesterol readings into account. Using Framingham equations, 1587 (58%) SHS participants aged 40 to 74 years were at low risk of CHD (10-year CHD risk <10%), 528 (19%) were at moderate risk of CHD (10-year CHD risk 10-15%), and 645 (23%) were at high risk (10-year CHD risk ≥15%). The numbers of people in each risk category, and those eligible for OTC statins, are shown in the figure. Using RPSGB criteria (including BP and cholesterol) for OTC statins, 312 (11%) SHS participants were eligible for OTC statins, agreement about which participants were eligible for OTC statins was less than that expected by chance when compared with Framingham equations (kappa -0.1, p<0.001), and 35 (5%) SHS participants at high-risk of CHD would have been identified as being eligible for OTC statins. Using RPSGB, but omitting BP and cholesterol, 766 (28%) SHS participants were eligible for OTC statins, there was poor agreement with Framingham equations (kappa 0.2, p<0.001), and 250 (39%) SHS participants at high-risk of CHD would have been identified as being eligible for OTC statins. In conclusion, large numbers of middle aged and elderly people would potentially be eligible for OTC statins. However, RPSGB criteria for OTC statins show little agreement with more commonly used Framingham equations. These findings introduce further complexity to the statin debate as up to 40% of high-risk patients could be under-treated with low dose statins, while people at low-risk could be exposed to the potential side-effects of statins unnecessarily. It would be preferable if the assessment for OTC statins included a full assessment of CVD risk using Framingham equations (or an alternative such as the SCORE system4) and BP and cholesterol measurement – but this would require additional training for some pharmacists.5 D Graham Mackenzie, Specialist Registrar in Public Health, Public Health Department, NHS Fife, Cameron House, Leven, KY8 5RG Sarah H Wild, Senior Lecturer in Public Health and Epidemiology, Public Health Sciences, University of Edinburgh, Teviot Place, EH8 9AG Philip Rutledge, Consultant in Medicines Management, Lothian NHS Board, 148 Pleasance, Edinburgh, EH8 9RS Figure. CHD risk of SHS participants (n=2760). Those eligible for OTC statins using full RPSGB criteria are shown in black, and the additional participants identified after removing BP and cholesterol from the criteria are shown in white. Participants at moderate risk not identified using RPSGB criteria are shown in blue. (a higher resolution version of this image can be viewed at http://www.doctors.net.uk/DocStore/DSView/Document.aspx?docid=427271) References
Competing interests: None declared |
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Raymond G Holder, Retired engineer BH9 3NF
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Please forgive me for raking up a June posting, but it still bothers me that a doctor should have to ask why Q10 lowering is actually harmful. Now I am in no way criticising Dr de Woolf, because this information has not received the enormous publicity that has been accorded to statins by the drug companies, but has been kept very much under wraps. Had Dr de Woolf asked why the inability to take in sufficient breath and sufficient oxygen supply, he would have been laughed out of court, and with good reason. But sufficient oxygen is totally necessary for the life of the body because it is needed for the creation of energy to supply the totality of individual systems which go to make up the whole. This energy is only available to every individual cell, of whatever function, through the electron transfer mechanism of that cell's Q10 molecule(s). While asphyxiation would destroy the body totally in a few moments, a shortage of Q10 leaves cells without access to their energy supply and death occurs cell by cell, but at the point where Q10 needed renewal at the particular moment. These cells do not seem able to regenerate, and permanent damage has taken place. Heart, liver, kidneys and muscle have the greatest need for energy and thus of Q10, but what else might be affected, insulin supply? thyroid? all subject to pure chance effect of the moment, so creating the large range of problems associated with statin use complained of by victims, and the 6000 odd reports recorded by the yellow card system for simvastin plus atorvastatin, not to mention about 60 deaths thought to have resulted. I find it hard to believe that NICE, MHRA, and MRC, as guardians of the patients' wellbeing, have not been aware of these matters which are well documented, but the dissemination of the information to medical staff has been totally neglected. The lowering of Q10 also seems to affect its ability to replenish itself, as a vulnerable 17 stage process is involved, so a long self- destruct process is put into effect. The remark "it can't be due to the statin, because it would have stopped when you stopped taking it" is not valid, and the same applies to the reduction consequently of Carnitine, necessary for energy production from fat in skeletal and heart muscle, and permanent Secondary Carnitine Deficiency results, the cause of the muscle pain side effect. To add a note to "Surely some mistake" submitted by Prof.Alun Hughes, if his hypothesis were true, the supply of cholesterol would not be inhibited, as the recirculated CoA reductase would maintain its volume, but we know that it is reduced, and Q10 along with it. Competing interests: Only as a badly damaged statin victim. |
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Uffe Ravnskov, independent researcher Magle Stora Kyrkogata 9, 22350 Lund, Sweden
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In
their recent subgroup analysis of the TNT trial Deedwania and coworkers found
that coronary patients with the metabolic syndrome gained more benefit from
high-dose atorvastatin therapy than coronary patients without, but they didn´t
mention that the latter group gained no benefit at all (table 1). The small
differences between the low-dose and the high-dose groups were far from
significant in this subgroup implying that there is no reason to increase
atorvastatin by eight times in the absence of the metabolic syndrome.
Table 1. Primary outcomes in the TNT trial in patients with coronary heart disease after exclusion of patients with the metabolic syndrome. References
Competing interests: None declared |
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