Rapid Responses to:
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Rapid Responses: Rapid Responses published:
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Did statins have an adverse effect upon outcome in those suffering acute illnesses or trauma?
- Richard G Fiddian-Green (1 July 2009)
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Statin therapy: a need to balance efficacy, safety and healthcare expenditure?
- Giuseppe Lippi, Emmanuel J. Favaloro (1 July 2009)
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The benefits are not for all
- Enzo Manzato (1 July 2009)
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What about clinical epidemiology?
- Martin Sprenger (2 July 2009)
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Statins not the only defence
- Rosemary A Stanton (2 July 2009)
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Will this Meta analysis Change Practice?
- Muhammad A. Hadi (2 July 2009)
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Statins, meta-analyses, and clinical practice
- Luca Mascitelli, Francesca Pezzetta MD, Tolmezzo, Italy, Mark R Goldstein, MD, FACP, Bonita Springs, FL, USA (2 July 2009)
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Re: Will this Meta analysis Change Practice?
- Raymond G Holder (3 July 2009)
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The pooled estimate of treatment effect could be of different magnitude depending on the level pf risk
- oscar mota (3 July 2009)
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What about the definition of the people without established cardiovascular disease but with cardiovascular risk factors?
- Zhili li (3 July 2009)
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The risks of statins are underestimated
- Uffe Ravnskov (4 July 2009)
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Statins: Sooner is Better?
- Carlos Escobar, Vivencio Barrios (5 July 2009)
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It’s big! Absolutely?
- Arnaud Chiolero (12 July 2009)
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Statins, hypercholesterolemia and blood viscosity.
- Les O. Simpson (14 July 2009)
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Re: It’s big! Absolutely?
- L Sam Lewis (3 August 2009)
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Primary cardiovascular prevention: what role for statins (and for public policy)?
- Roberto Buzzetti, Giulio Formoso, Oreste Capelli, Nicola Magrini, Massimo Valsecchi (7 August 2009)
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Re: Primary cardiovascular prevention: what role for statins (and for public policy)?
- Les O. Simpson (10 August 2009)
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Richard G Fiddian-Green, FRCS, FACS None
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A fall in tissue pH, which is associated with poor outcomes in the acutely ill, inhibits glycolysis by inhibiting phosphfructokinase and shifts substrate utilization in the citric acid cycle from glucose to fatty acids released from triglycerides in lipid stores by the activation of lipase. The lipid deposits include droplets within the cytoplasm. Autophagy of cytoplasmic and organelle products results in the formation of autophagosomes which fuse with the intracytplasmic lipid droplets to form autolipophagosomes that in turn fuse with lysosomes which convert the contents into fatty acids and amino acids, for consumption in the citric acid cycle and generation of ATP by oxidative phosphorylation (1). There are, thus, two means by which fatty acids are produced for ATP resynthesis by oxidative phosphorylation of which the autophagous route appears to be the more important for it regulates lipid metabolism. The formation of autolipophagasomes and lipolysis is increased by starvation thereby promoting the generation of ATP from lipid stores within adipose tissue. Conversely lipolysis and the generation of ATP by oxidative phosphorylation is inhibited and the accumulation of lipid droplets within cells and presumably lipid stores within adipose tissue is enhanced by a high fat diet. Thus autophagy appears to be necessary for the effective use of fatty acids for the generation of ATP by oxidative phosphorylation, the daily yield of ATP from fatty acids being far higher than that from glucose. Fatty acids are the primary substrate for ATP synthesis in healthy myocytes but, in making them "oxygen hungry", may cause myocyte damage in ischaemic myocardium. Glucose is the default substrate in anaerobiosis and far less productive than fatty acids in aerobiosis. Hence the benefit of beta blockers in ischaemic myocardium and adverse effect upon exercise tolerance. But what of statins? Might they have protect ischaemic myocardium but have an adverse effect upon healthy myocardium? What of other organs? Might the same occur in them? Mean follow-up in this study was 4.1 years (2). "Treatment with statins significantly reduced the risk of all cause mortality (odds ratio 0.88, 95% confidence interval 0.81 to 0.96), major coronary events (0.70, 0.61 to 0.81), and major cerebrovascular events (0.81, 0.71 to 0.93)" and did not increase the risk of cancer. What of patients who develop acute illnesses or sustain severe trauma? Might those on statins be compromised because of an impaired ability to utilize fatty acids for ATP synthesis? What of the risk of developing degenerate diseases and cancers and/or the rates of progression in those who already have these diseases? If statins interfere with the utilization of fatty acids for the synthesis of ATP it will not be surprising if, when reassessed 10, 20, 30, or even 60 years hence [given that longevity might be expected to be 80 years or even a 100 or more years or more], their long-term consumption might well be associated with a marked increase in all-cause mortality relative to controls. Among the first to reveal an adverse effect upon outcome, if this hypothesis is valid, might well be those who develop acute illnesses or sustain severe trauma. Might there already be a difference in all-cause mortality in these subgroups even though the mean follow-up is a mere 4.1 years? 1. Rajat Singh, Susmita Kaushik, Yongjun Wang, Youqing Xiang, Inna Novak, Masaaki Komatsu, Keiji Tanaka, Ana Maria Cuervo & Mark J. Czaja1. Autophagy regulates lipid metabolism. Nature 458, 1131-1135 (30 April 2009). 2. J J Brugts, T Yetgin, S E Hoeks, A M Gotto, J Shepherd, R G J Westendorp, A J M de Craen, R H Knopp, H Nakamura, P Ridker, R van Domburg, and J W Deckers The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials BMJ 2009; 338: b2376 Competing interests: None declared |
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Giuseppe Lippi, Associate Professor of Clinical Biochemistry Sez. Chimica Clinica, Ospedale Policlinico, P.le Scuro 10, 37134 - Verona, Italy, Emmanuel J. Favaloro
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We read with interest the article of Brugts et al, who concluded that statin use was associated with significantly improved survival and reduction in the risk of major cardiovascular events in patients without established cardiovascular disease but with cardiovascular risk factors (1). Sometimes reports tell us the good news without mentioning the bad. Although statins are generally well-tolerated, some adverse effects may occur, including myopathy, severe rhabdomyolysis, hepatotoxicity, peripheral neuropathy, impaired myocardial contractility and autoimmune diseases (2). Therefore, the overall observed reduction of cardiovascular events in statin users should be always weighted against their potential individual risk as well as the economic expenditure related to adverse side effects. These considerations reflect a seemingly ignored aspect of studies that overtly report on the positive effects of medication use, and none of these issues were considered in the metaanalysis of Brugts and colleagues. Moreover, a definitive cost analysis (eg. costs for therapy plus treatment of adverse events versus overall savings from prevention of cardiovascular disease), to identify a conventional threshold for willingness to pay was not identified in all categories of patients. In conclusion, although the evidence that statins might improve overall survival and reduce the risk of major cardiovascular and cerebrovascular events in people without established cardiovascular disease is highlighted by the review by Brugts et al (1), further research on overall healthcare expenditure, adverse side effects, and identification of susceptible patients might be advisable. In the end, the concept of personalised medicine seeks to identify the best approach for management of the individual (3), and what is good for one individual is not always good for another. References. 1. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, J Shepherd J, Westendorp RGJ, de Craen AJM, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376 2. Be³towski J, Wójcicka G, Jamroz-Wiœniewska A. Adverse Effects of Statins - Mechanisms and Consequences. Curr Drug Saf. 2009 Sep 1. [Epub ahead of print] 3. Lippi G, Franchini M, Montagnana M, Guidi GC. Genomics and proteomics in venous thromboembolism: building a bridge toward a rational personalized medicine framework. Semin Thromb Hemost 2007;33:759-70. Competing interests: None declared |
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Enzo Manzato, Professor of Internal Medicine University of Padova - via Giustiniani, 2 - 35122 Padova, Italy
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From Table 3 I reach the conclusion that the benefits of statins are not significant for all 4 end points listed in women, people of age > 65, and patients with diabetes. If I am correct the benefits of statins are rather over-emphasized in the conclusion of this paper. Competing interests: None declared |
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Martin Sprenger, Coordinator postgraduate public health programme Medical University of Graz, 8010 Graz, Austria
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Clinical epidemiology should be fully established now. Therefore no article should be published without mentioning a number needed to treat (NNT). This is especially important when you deal with issues around medical prevention. Statins are only used for that purpose. Their therapeutic aim is to prevent clinically relevant events. The likelihood of this therapeutic effect is sometimes higher and sometimes lower. For example published Skolbekken JA (1) that the NNT in the WOSCOPS study to prevent one extra coronary mortality event with 5 years of therapy is 200 (360,000 tablets have to be taken). To prevent one stroke the NNT is 641 (CI 135 to no benefit). (2) Gerd Gigerenzer and his colleagues recommended in their article "Helping Doctors and Patients Make Sense of Health Statistic (2008)" that it is time to use frequency statements instead of single-event probabilities,absolute risks instead of relative risks, mortality rates instead of survival rates, and natural frequencies instead of conditional probabilities. (3) Gigerenzer et al. also make clear that "reporting relative risk reductions without clearly specifying the base rates is bad practice because it leads readers to overestimate the magnitude of the benefit. Consider one medication that lowers risk of disease from 20% to 10% and another that lowers it from 0.0002% to 0.0001%. Both yield a 50% relative risk reduction, yet they differ dramatically in clinical importance." The communication of risks or therapeutic effects is therefore a very critical and responsible task. So I'm asking again: why is this meta- analysis published without presenting NNTs? (1) Skolbekken JA. BMJ 1998;316:1956–1958 (2) Shepherd J. et al. Prevention of coronary heart disease with privastatin in men with hypercholesterolaemia. New England Journal of Medicine 1995; 333:1301-7. (3) Gigerenzer G. et al. Helping Doctors and Patients Make Sense of Health Statistics. Association for Psychological Science. Volume 8, Number 2. 2008. Online available: www.psychologicalscience.org/journals/pspi/pspi_8_2_article.pdf (02.07.2009) =========================================== Martin SPRENGER, MD, MPH (Auckland/NZ)
=========================================== Competing interests: None declared |
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Rosemary A Stanton, Nutritionist Fitzroy Falls Australia 2577
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There is no doubt that prescribing statins is an easy way to reduce cardiovascular risk factors such as high LDL cholesterol. Patient compliance is reasonably good when they have only to take a pill. However, there are other ways to reduce cardiovascular risk factors, including changes to current exercise and dietary habits. Such changes may also reduce the risks of other problems, including several types of cancer and type 2 diabetes. The total cost-benefit potential of such interventions could be considerable. Overall, simple changes to diet can lead to a reduction in LDL cholesterol. As you might expect, those who adhere most closely to dietary changes achieve the greatest reduction (1). Encouraging changes in diet and exercise habits is often dismissed because of poor patient compliance. Perhaps we need to lobby government to provide an environment that is more conducive to a healthy lifestyle, and perhaps we also need to upgrade our skills (and set a good example) so that we help patients change unhealthy eating and exercise behaviours rather than encouraging long-term medication. (1) Clifton P, Colquhoun D, Hewat C, Jones P, Litt J, Noakes M, O'Brien R, Shrapnel B, Skeaff M. Dietary intervention to lower serum cholesterol. Aust Fam Physician. 2009 Jun;38(6):424-9. Competing interests: None declared |
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Muhammad A. Hadi, Lecturer in Clinical Pharmacy Faculty of Pharmacy, Universiti Teknologi MARA, 40450 Shah Alam, Selangor, Malaysia
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The findings reported by Brugts et al.1 are quite interesting especially when the benefit of aspirin in the primary prevention has been questioned in a recent Meta analysis2 published in Lancet. But this analysis failed to answer key questions on the safety of statins and cost- benefit analysis. Safety data is of high importance in decision making especially for elderly patients (>65 yrs), who are at higher risk of adverse events. With no data reported on the above mentioned key questions, it is unlikely that the results of this analysis will change current medical practice. 1. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomized controlled trials. BMJ 2009; 338:b2376. 2. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009; 373: 1849–60 Competing interests: None declared |
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Luca Mascitelli, Medical Officer Comando Brigata alpina Julia, Udine 33100, Italy, Francesca Pezzetta MD, Tolmezzo, Italy, Mark R Goldstein, MD, FACP, Bonita Springs, FL, USA
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Previous meta-analyses consistently showed that statin therapy reduced the risk of coronary heart disease events in men without prior cardiovascular disease, but not in women; statins did not reduce the risk of total mortality both in men and women (1). We were therefore surprised that in the meta-analysis by Brugts and colleagues (2), 'statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events'. What led to this difference? How could our clinical practice be influenced by a smart meta-analysis of selected trials of short duration, when it is well known that selection criteria used in those trials (which studied patients so different from individuals seen in the real world) may result in elimination of patients with characteristics that may foster vulnerability? (3) As physicians, we have to practice the science and art of medicine when treating individual patients. Founding the primary prevention of cardiovascular disease on statin drugs is questionable science and poor art. 1. Petretta M, Costanzo P, Perrone-Filardi P, Chiariello M. Impact of gender in primary prevention of coronary heart disease with statin therapy: A meta-analysis. Int J Cardiol 2008 Sep 13. [Epub ahead of print] 2. Brugts JJ, Yetgin T, Hoeks SE, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009 Jun 30;338:b2376. doi: 10.1136/bmj.b2376. 3. Evans MA, Golomb BA. Statin-associated adverse cognitive effects: survey results from 171 patients. Pharmacotherapy 2009;297:800- 11. Competing interests: None declared |
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Raymond G Holder, Long retired engineer BH9 3NF
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An enormous amount of effort has been put into this meta analysis, but can the original trial results be relied upon as true data as a foundation for their conclusions. It is now well known that at least the PROSPER amd the HPS trials were started with the infamous run-in period, and all those who left the trial in this period were excluded from the results. These must have included large numbers who had the now well known side effects, not acknowledged by official medicine, but a very angry and vociferous collection of thousands whose doctors told them "Statins don't do that", but they most definitely DO. The Jupiter trial results, kept under wraps for about 2 years, should have convinced people that cholesterol is not the real problem, but is not the funding of the research groups dependant upon keeping up sales of these dangerous drugs? The great demon cholesterol is still being used to frighten people, I know older men whose TC has been brought down to 3, a ridiculous and unhealthy low level, and women 70-80 on statins, where no benefit has ever been demonstrated, and mortality among the most elderly is greater among those with low cholesterol. The whole subject, NICE guidelines and all, needs a completely fresh approach, freed from commercial and career interests, to free us from the cholesterol myths and introduce a more patient oriented way of dealing with cardiac problems Competing interests: Badly statim damaged patient |
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oscar mota, internal medicine retired Coimbra University Hospital
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The results of the above meta-analysis of randomized controlled trials (1) showed that treatment with statins significantly reduced the risk of all cause mortality, the primary end point, and of other secondary end points. It was stated that, “In view of the large treatment effects, it is likely that a considerable number of such people would benefit from long term statin use at reasonable costs.” But that “The correct identification of such people remains a challenge” The mean age of the 70 388 participants was 63 years (range 55.3 to 75.0) and the overall annual mortality in the placebo groups was in the range of 1.4%. This basal risk of 1,4% is similar to that in general population of the same age: 1,116%, 0,874% and 0,94%, respectively in USA, UK and Portugal (2). The mean values of risk factors of cardiovascular events of the participants were similar to those of the general population at the same age range (Low density lipoprotein cholesterol; High density lipoprotein cholesterol; Hypertension (%); with diabetes (%)). Thus it is possible to conclude that the study population is representative of the general population of the same age range. It is not allowed, in my opinion, to translate the results of those studies for younger people, with much lower levels of risk. As the authors had made salient, “Although study population comprised participants without established cardiovascular disease, the pooled risk was high”… “not too different from the event rates reported in trials of patients at relatively low risk in secondary prevention” The risk of death in one year increases with age, in an exponential manner from the middle to old age. For example, the overall annual mortality in general population with 40 to 44 years of age are much lower, 0,227%, 0,0215% and 0,015%, respectively in USA, UK and Portugal. (2) In my opinion, the results of those studies of the meta-analysis are applicable to the general population but only in the age range of the study participants (55 to 75 years). This segment represents only 13 to 15% of total population of all European countries (3). The Ages Groups of 50 to 64 and 25 to 49 years of age represent a considerable higher percentage of the total population in Europe (19% and 36%) (3). Hypothetical pretensions, in the future, to translate those conclusions to a much broader segment of of younger people will be not fair. As was emphasized in the text, “still, the absolute overall treatment benefit observed in the current study population would certainly be less than 1%, and significant numbers of participants would need to be treated to prevent one event.“ Than the NNT would be over 100 and would be substantially higher in populations with much lower level of risk. It was concluded also that “there was no significant heterogeneity of the treatment effect in clinical subgroups”, namely in men and women. It must be remembered that the mean age of the participants was high (63 years; range 55.3 to 75.0) and that women were sub represented (34%). The relative advantage of women in mortality rate decreases with age after adolescence and is only modest in those with 63 years. The differences in risk by sexes are considerable higher in lower age ranges. I think that it is not possible to conclude that there are no significant differences of the treatment with statins in younger men and women, in primary prevention. One more reason not to extrapolating the results of those studies to much different age ranges. I am not sure if “the numbers and duration of follow-up of our study allow for relatively strong inferences on risk of cancer with long term statin use”. JUPITER trial (2008w1) was the study with higher number of participants but had a follow-up of only 1,9 years. Such a short time does not permit any inferences about the risk of cancer. Oscar Mota, Internal Medicine, retired Coimbra University Hospital, Portugal 1) J J Brugts, T Yetgin, S E Hoeks, A M Gotto, J Shepherd, R G J Westendorp, A J M de Craen, R H Knopp, H Nakamura, P Ridker, R van Domburg, and J W Deckers The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials BMJ 2009; 338: b2376 2) WHO Statistical Information System (WHOSIS) WHO Statistics Life Tables for WHO Member States 2006 3) http://epp.eurostat.ec.europa.eu/tgm People by age classes - Share of total population (%) Competing interests: None declared |
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Zhili li, MD,assistant professor Department of Cardiology, Tangdu Hospital, Fourth Military Medical University, Shaanxi 710038, China
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I am surprised at the final conclusions that stains use was significantly improved survival and 12% risk reduction in all cause mortality compared with the control, especially that 4.1% of participants in the stain group had a major coronary event compared with 5.4% in the control group(1). If so, it would open a new era for the secondary provention of the coronary heart disease(CHD). However, I wondered the definition about the people without established cardiovascular disease but with cardiovascular risk factors. First, doctor Brugts and coworkers did not mention how to confirm the diagnosis of CHD in the paper; to our knowledge, the gold criteria for diagnosis is more than 50% lesions in any of the coronary arteries identified by coronary angiogram or volume CT scans of the coronary arteries. Secondly, we have completed more than 1000 cases of percutanous transluminal coronaryangiography every year in our Cardiological Department. In our experience, coronary artery lesions are usually severe and diffuse in the patients with diabetes mellitus, even though some of them are asymptomatic. It is published that 16 078 (23%) people with diabetes mellitus were involved in the study. It is unbelievable that many people without established cardiovascular disease but with diabetes mellitus suffured from the major coronary events such as death from CHD and myocardial infaction in 4.1 years. Finally, apart from high cholesterol and diabetes mellitus, there are many other risk factors of CHD, for example, smoking, obsety,hypertention, sex,age,drugs and sn on(2). To reduce the statistical heterogeneity of the study, the double-blind randomised and pair test should be performed so as to get accurate conclusions. References 1. Brugts JJ, Yrtgin T, Hoeks SE, Gotto AM, Shephrerd J, Westendorp RGJ, de Craen AJM, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckes JW. The benefits of stains in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009; 338:b2376 2. Zhili L, Xinguo Y, Yi W, Luxing Z, Kuihua J, Xueqin W. comparision of risk factors and coronary artery lesions between young and elderly patients with coronary heart heart disease. Heart 2009;21;511-513 Competing interests: None declared |
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Uffe Ravnskov, researcher Magle Stora Kyrkogata 9, 22350 Lund, Sweden
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Based on a meta-analysis of ten randomised, controlled statin trials
Brugts et al. concluded that healthy people can reduce their risk of dying
during the next 4-5 years by 12 %. Another way to show the benefit is to
calculate the users’ chance to survive. According to the figures it was 94.3 %
without treatment and 94.9 % if they took a statin drug every day, providing
that the figures of the meta-analysis are valid. Of interest is also whether
the benefits persist after a life-long exposure to the drug. There are reasons
to question both assumptions.
Table. Cancer
incidence and/or mortality in five randomised, controlled statin trials 1.
Brugs
JJ, Yetgin T, Gotto AM, Shepherd J, Westendorp RGJ, de Craen AJM et al. The
benefits of statins in people without established cardiovascular diseasebut
with cardiovascular risk factors: meta-analysis of randomised controlled
trials. BMJ 2009;338:b2376doi:10.1136/bmj.b2376 2.
Bradford
RH, Shear CL, Chremos AN, Dujovne C, Downton M, Franklin FA, et al. Expanded
Clinical Evaluation of Lovastatin (EXCEL) study results. I. Efficacy in
modifying plasma lipoproteins and adverse event profile in 8245 patients with
moderate hypercholesterolemia. Arch Intern Med 1991;151:43-9. 3.
Shepherd
J, Blauw GJ, Murphy MB, Bollen ELEM, Buckley BM, Cobbe SM, et al . Pravastatin
in elderly individuals at risk of vascular disease (PROSPER): a randomised
controlled trial. Lancet
2002;360:1623–30 . 4.
Scandinavian
Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in
444 patients with coronary heart disease the Scandinavian Simvastatin Survival
Study (4S) Lancet 1994;344:1383–9. 5.
Heart
Protection Study Collaborative Group. MRC/BHF heart protection study of
cholesterol lowering in 20536 high-risk individuals: a randomised
placebo-controlled trial. Lancet 2002;360:7–22. 6.
Sacks
FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG et al. The effect
of pravastatin on coronary events after myocardial infarction in patients with average
cholesterol levels . N Engl J Med 1996;35:1001–9 . 7.
Rossebø AB, Pedersen
TR, Boman K, Brudi P, Chambers JB, Egstrup K, et al. Intensive lipid lowering with simvastatin and
ezetimibe in aortic stenosis. N
Engl J Med 2008;359:1343-56. 8.
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;66:1087-95 . 9.
Iwata
H, Matsuo K, Hara S, Takeuchi K, Aoyama T, Murashige N, et al . Use of
hydroxy-methyl-glutaryl coenzyme A reductase inhibitors is associated with risk
of lymphoid malignancies . Cancer
Sci 2006;97:133–8. 10. Hoffmann P, Roumeguère T, Schulman
C, van Velthoven. Use of statins and outcome of BCG treatment for bladder
cancer. N Engl J Med 2006;355:2705-7. Competing interests: None declared |
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Carlos Escobar, Cardiologist Hospital Infanta Sofia, Vivencio Barrios
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The ATHEROMA study (1) showed that an aggressive lipid-lowering therapy over a 3-month period was associated with significant reduction in carotid plaque inflammation. On the other hand, it has been reported that continuity of statin treatment provides an ongoing reduction in mortality, even greater than expected from randomized clinical trials (2). Furthermore, as Brugts et al have reported in their meta-analysis, in patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events (3). However, recent evidences have shown that the same therapy may have different consequences on outcomes along the cardiovascular continuum (4-7). In AURORA trial (4), despite LDL-cholesterol and high-sensitivity C- reactive protein (hsRCP) were reduced with rosuvastatin, this did not translate into a decrease on the primary end point in patients undergoing hemodialysis. It was previously documented that treatment with rosuvastatin did neither demonstrate any advantage in patients with advance heart failure (5). However, other studies have shown undoubtedly benefits. Thus, in JUPITER (6), in “healthy” subjects without hyperlipidemia but with elevated hsRCP, rosuvastatin reduced both the hsRCP and the mortality. In ASTEROID (7), rosuvastatin regressed atheroma volume in patients with coronary heart disease. How can these differences be explained? It is most likely that the progression of cardiovascular disease could be the key. In advanced stages, in addition to a more extended coronary disease, there is a relative state of cachexia in which cholesterol levels are lower. As a result, the effects of statins could be reduced. These data emphasize the importance of the early treatment with statins for the cardiovascular prevention. Otherwise, in the most advanced stages, the therapy benefit could be minimal or even absent. References: 1. Tang TY, Howarth SP, Miller SR, Graves MJ, Patterson AJ, U-King-Im JM, et al. The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease. J Am Coll Cardiol. 2009;53:2039-2050. 2. Shalev V, Chodick G, Silber H, Kokia E, Jan J, Heymann AD. Continuation of statin treatment and all-cause mortality: a population-based cohort study. Arch Intern Med 2009;169:260-268. 3. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, et al. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ. 2009;338:b2376. 4. Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al; AURORA Study Group. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395-1407. 5. Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-2261. 6. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175-1182. 7. Ballantyne CM, Raichlen JS, Nicholls SJ, Erbel R, Tardif JC, Brener SJ, et al. Effect of rosuvastatin therapy on coronary artery stenoses assessed by quantitative coronary angiography: a study to evaluate the effect of rosuvastatin on intravascular ultrasound-derived coronary atheroma burden. Circulation. 2008;117:2458-2466. Competing interests: None declared |
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Arnaud Chiolero, Epidemiologist Montreal, Qc, Canada, H2H 1X1
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Dr Faust: I've studied clinical medicine; biochemistry, pharmacology; and even, alas!, epidemiology and bio-statistics; from end to end, with labor keen; and here, poor fool, with all my lore I stand, no wiser than before. [1] I still doubt: should I take statin to reduce my risk of death in the coming years? I have reached the mid-fifties, my blood cholesterol is slightly elevated. But, as far as I know, I am healthy. Mephistopheles: Healthy? Don’t deny that you have a substantial risk of cardio-vascular diseases, “the leading cause of death in the Western world”! [2] Dr Faust: But could statin use reduce all cause mortality in people like me? Mephistopheles: Absolutely. Look at the evidence: this study pooled data on more than 70,000 men and women aged 55 to 75. [2] It’s big! And all cause mortality over four years, the primary end point, was reduced by 12% in participants taking statin! Dr Faust: Absolutely? Mephistopheles: Well, not exactly. The absolute mortality risk reduction was 5.7% - 5.1% = 0.6% over four years. I let you calculate uncertainty around this estimate or the number needed to treat, if you bother. Dr Faust: Any differences in risk reduction by sex or by age categories? Mephistopheles: No heterogeneity was found by sex or by age categories. Dr Faust: Do you mean that the reduction was observed in both sexes and in older and younger participants? Mephistopheles: Well, not exactly. I just mean that the risk reduction was not heterogeneous. Subgroup analysis did not show statistically significant all cause mortality reduction in men or in women, or in participants aged more than 65 or less than 65. Merely a statistical power issue, if you bother. Dr Faust: And you conclude that, potentially, “from current risk scoring systems, as well from current data”, the benefit could be greater notably among "older men (>65 year) with risk factors", don't you? [2] Mephistopheles: Absolutely. Convinced? Dr Faust: Well, I think that, for the moment, I rather need an aspirin… Reference 1. Freely adapted from Faust, by Johann Wolfgang von Goethe, full text available online The Project Gutenberg EBook of Faust, http://www.gutenberg.org/, accessed 3 July 2009 2. Brugts JJ, Yetgin T, Hoeks SE, Gotto AM, Shepherd J, Westendorp RG, de Craen AJ, Knopp RH, Nakamura H, Ridker P, van Domburg R, Deckers JW. The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials. BMJ 2009;338:b2376. Competing interests: None declared |
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Les O. Simpson, retired experimental pathologist Dunedin, New Zealand, 9077
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Not one of the many contributors to this discussion has noted that in hypercholesterolemic states, blood viscosity is increased. In addition, the cholesterol content of the red cell membrane is increased, causing a reduction in red cell deformability which adds to blood flow problems. The aging process is associated with an increase in blood viscosity and this will be added to the effects of a high level of LDl cholesterol. Smoking also increases blood viscosity as does inactivity. Statin treatment has been shown to lower blood viscosity and to increase red cell deformability. Cessation of smoking reduces blood viscosity as does regular, low intensity physical activity. It is unclear just why middle aged people without raised cholesterol values should be expected to benefit from statins. However, it is clear that in those with elevated cholesterol levels, statin treatment should be the starting point for individuals to accept responsibility for their health problems. This would require a suitable dietary regimen, cessation of smoking and a programme of regular physical activity. Competing interests: None declared |
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L Sam Lewis, GP Surgery, Newport, Pembrokeshire, SA42 0TJ
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Mephistopheles : Aspirin ? Aspririn !!! ? have you not read the Antithrombotic Triallists' BMJ Paper showing the utter uselessness of that particular pill in primary prevention ?? Faust: No.. But I was taking it for the evidential headache. Competing interests: None declared |
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Roberto Buzzetti, MD 47900 RIMINI, Giulio Formoso, Oreste Capelli, Nicola Magrini, Massimo Valsecchi
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The metanalysis from Brugts JJ et al(1) provides practitioners with potentially useful data that could influence their prescribing practices. However, we think this study should be interpreted in light of possible limits of generalizability and validity. About generalizability, if the objective is to clarify the "ambiguous answers research has provided to date" about statin use in primary cardiovascular prevention, we have doubts that all the 10 included RCTs are truly focused on primary prevention. All but one of the trials include diabetic patients (100% of the studied population in 3 of them; 12 to 34% in 4 of them), and a line of thought some of the Authors embrace consider diabetes as ischemic equivalent.(2) Moreover, some of the trials also include people with previous stroke or TIA. Finally, we definitively do not agree that patients in the included studies are "at relatively low risk" of cardiovascular events: if we use event data and try a (very conservative) linear estimate of the 10-year risk, we can see that at least in 8 trials out of 10 the event risk exceed 20% (guidelines recommend to treat such people with statins (3)). About validity, subgroup results may be a bit difficult to interpret: for example, the overall OR for mortality is 0,88; when making a gender subgroup analyses (data were not available from all the studies) OR rise to 0,95 in men and 0,91 in women. On average, in these populations at relatively high risk, statins may save one life every 150 people in about 5 years of treatment (deriving an average control rate from the primary data and applying the formula proposed for NNT by McQuay and Moore(4)). Considering these results, we think non-pharmacologic preventive interventions should deserve more attention, in spite of the lack of RCT results and of the many socio- economic and cultural determinants which make it difficult for people to change their lifestyles (and which can even make health inequalities worse). Public policy should pay more attention to all these determinants: that would be the best way to promote people's health (and fight health inequalities).(5) (1) Brugts JJ, Yetgin T, Hoeks SE, et al.,The benefits of statins in people without established cardiovascular disease but with cardiovascular risk factors: meta-analysis of randomised controlled trials BMJ 2009;338:b2376 doi:10.1136/bmj.b2376 (2) Grundy SM, Bazzarre T, Cleeman J, et al. Beyond secondary prevention: identifying the high-risk parient for primary prevention. Circulation 2000;101:e3-e11 (3) Lipid modification. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. National Institute for Health and Clinical Excellence clinical guideline 67. May 2008 (4) McQuay HJ, Moore RA. Using numerical results from systematic reviews in clinical practice. Ann Intern Med 1997;126:712-20 (5) Marmot M, Friel S, Bell R, et al. Closing the gap in a generation: health equity through action on the social determinants of health. Lancet 2008; 372: 1661-9 Competing interests: None declared |
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Les O. Simpson, retired experimental pathologist Dunedin, New Zealand, 9077
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The importance of Dr.Buzzetti's contribution is that it draws attention to the need to compare apples with apples, by pointing out that several studies have included patients with diabetes. Indirectly, Dr.Buzzetti's response highlights the need for the recognition of the main elements in the pathophysiology of cardiovascular disorders. Perhaps, as an outcome of Greenberg's demonstration of citation bias leading to erroneous conclusions, editors will require authors to address the published information which shows that cardiovascular disorders are associated with increased blood viscosity and altered blood rheology. This would show why the diabetic state, with its increased blood viscosity, is a risk factor for cardiovascular dysfunction. Therefore if cardiovascular prevention is the objective, it is essential that management includes the lowering of blood viscosity. Competing interests: None declared |
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