Statins for the primary prevention of cardiovascular disease
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g280 (Published 27 January 2014) Cite this as: BMJ 2014;348:g280
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I thank Ebrahim and colleagues who cited a study(1) which outlined that the predicted life expectancy gains of a prudent diet might be small (2). However, in the study they referenced (2), on average, the calculated gain in survival was based on serum cholesterol-reducing diets with 8% to 10% saturated fat and 240 to 300 mg of daily cholesterol, respectively. By reducing cholesterol levels 0.45 mmol/L (17.4 mg/dL) to 0.75 mmol/L (29.1 mg/dL) from the baseline in men and 0.12 mmol/L (4.6 mg/dL) to 0.55 mmol/L (21.4 mg/dL) from the baseline values in women, the predicted increase in life expectancy would have been 0.03 to 0.4 year and 0.01 to 0.16 year, respectively. However, in the same study (2), smoking cessation would have increased life expectancy from 2.59 to 4.43 years among men and from 2.6 to 3.68 years among women!
Furthermore, in a longitudinal study of 1810 older participants followed up for 18 years (3) several lifestyle behaviours were associated with longevity, even after age 75 and independently of health status. Of note, healthy behaviours remained predictive of survival also among the oldest old and those with multiple morbidities.
Improving population health should not simply be made the work of drug companies! (4)
1)http://www.bmj.com/content/348/bmj.g280/rr/688747
2) Grover S, Gray Donald K, Joseph L, Abrahamowicz M. Life expectancy following dietary modification or smoking cessation. Estimating the benefits of a prudent life style. Archives Internal Medicine 1994;154:1697-1704.
3) Rizzuto D, Orsini N, Qiu C, Wang HX, Fratiglioni L. Lifestyle, social factors, and survival after age 75: population based study. BMJ 2012; 345:e5568.
4) McCartney M. Statins for all? BMJ 2012; 345:e6044.
Competing interests: No competing interests
We thank the many readers who took the time to write about our statins review.(1)
O’Sullivan and Tejani raised many points,(2) some of which would be clarified by a closer reading of our article. We agree that the use of a composite endpoint – major vascular events – is problematic as it combines outcomes of different type and severity. The Cholesterol Treatment Trialists’ (CTT) collaboration have published disaggregated outcomes which show similar effects to the composite endpoint but these are in the web appendix of their Lancet 2012 paper which is often overlooked.(3) Using symptomatic and disabling criteria to specify endpoints is not possible in meta-analyses (endpoints in trials are not categorised like this) and non-fatal events of whatever severity matter. Lowering LDL-cholesterol is one of the major effects of statins and, contrary to O’Sullivan and Tejani’s assertions that we misrepresent and over-simplify, trials that compare high with low dose statins achieve greater reduction in LDL-cholesterol and proportionately greater clinical benefit. Statins are of benefit to people at high risk of cardiovascular disease because they do lower mortality and morbidity. Furthermore Mendelian randomization studies, in which genetic variants that code for LDL-cholesterol level are used as proxies for plasma levels, show that these genetic variants are associated with incidence of coronary heart disease, strongly suggesting a causal relationship.(4,5,6) We cannot speak for the CTT’s use of risk of bias assessments for the trials included in their individual patient data (IPD) meta-analysis. IPD meta-analysis can deal with selective reporting of findings, aggregation of outcomes, and differences in analytic approach but cannot overcome short-comings in trial design or conduct. Cherry-picking the trials included in the evidence base, as suggested by O’Sullivan & Tejani, has the potential to generate bias; it is essential that all trials that are relevant to a clinical question are considered. Sensitivity analyses in the case of JUPITER and WOSCOPS do not alter the bottom line of our Cochrane review findings (all trials, total CVD events relative risk (95% CI): 0.73 [0.67, 0.80] vs. dropping JUPITER and WOSCOPS: 0.75 [0.65, 0.85]).(7) Issues concerning unintended effects of statins were dealt with in the three paragraphs following the sentence they quote and in our response (8) to Abramson et al’s BMJ article,(9) and, in more detail in our recent systematic review. (10)
Whitaker accuses us of being pharmaceutical fetishists (11) but misses the point that the figure illustrates hypothetical scenarios which assume complete reversibility of risk and full adherence. Unfortunately, the drivers of high levels of risk factors are often stronger than most peoples’ motivation to alter their behaviour. We made the point that life style interventions have the potential to give effects equal to those of statins. However, depressingly, the randomized and non-randomized evidence on the effects of life style interventions as meted out by health promotion activists in clinics and workplaces to otherwise healthy people does not demonstrate clinical benefits.(12)
There is evidence to support use of statins in chronic renal failure and uncertainty about their role in end stage renal failure and in patients on dialysis. Use of statins in people with chronic renal failure may increase occurrence of myopathies.[13] A systematic review in chronic renal failure patients found no effect on myalgia or elevated creatine kinase level, but the lack of reporting of these adverse events in more than half the trials makes this finding uncertain.(14)
Examining the effects of many interventions in terms of survival results in rather dismal gains because, ultimately, we all die. The predicted life expectancy gains of a prudent diet are small.(15) Ravnskov is concerned that statins do not prolong life among people with low risk (<20% 5-year risk of a major vascular event), citing table 3 (actually figure 3) of the CTT Lancet 2012 paper.(16) But it is surely perverse to discount to zero the small, but beyond chance, benefits in terms of major vascular events avoided in these people. In our 2011 Cochrane review of statins for primary prevention we concluded: "Individual patient data meta-analyses have provided an initial appraisal of the evidence available to 2011. Further updates focusing on effects of statins among people without pre-existing disease, examining a wider range of potential adverse effects and for a range of predicted CVD risk would help clarify the role of statins in primary prevention." (17) The CTT Lancet 2012 analysis has provided the analyses required to examine the effect of statins for primary prevention in people at different baseline levels of CVD risk. Several systematic reviews of the unintended consequences of statins have also been published which have exposed the increased risk of diabetes but have not confirmed other potential adverse effects. Ravnskov also raises the 40 year-old hypothesis that low cholesterol predisposes to cancer, selectively reporting trials that have demonstrated increased cancer rates on statins. In a CTT collaboration analysis of cancers by site, there is no evidence of increased risk by type of cancer, age, duration of statin treatment, or baseline LDL-cholesterol level.(18) Mendelian randomization studies have demonstrated no excess risk of cancer by genotype, providing further evidence against the low cholesterol cancer hypothesis.(19,20)
Finally, in response to Scholl’s and other comments,(21) the American Heart Association/American College of Cardiology guidelines do recommend using statins in patients with raised LDL-cholesterol (5+mmol/l ;190mg/dl).(22) Both the American guidelines and the latest draft guidance from National Institute of Health & Care Excellence (NICE) stress the importance of discussing life style changes with patients and both have reduced the threshold for considering use of statins in line with evidence of clinical benefit, NICE to 10% 10-year cardiovascular risk.(23)
Shah Ebrahim, Fiona Taylor, Peter Brindle
1. Ebrahim S, Taylor F, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014;348:g280
2. O’Sullivan C, Tejani AM. Statins for the primary prevention of cardiovasular disease. Response to BMJ 2014;348:g280
3. Cholesterol Treatment Trialists’ Collaborators. The effects of lowering LDL cholesterolwith statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581-90.
4. Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012 Dec 25;60(25):2631-9. doi: 10.1016/j.jacc.2012.09.017.
5. Shah S, Casas JP, Gaunt TR, Cooper J, Drenos F, Zabaneh D, Influence of common genetic variation on blood lipid levels, cardiovascular risk, and coronary events in two British prospective cohort studies. Eur Heart J. 2013 Apr;34(13):972-81. doi: 10.1093/eurheartj/ehs243.
6. Holmes MV, Asselbergs FW, Palmer TM, Drenos F, Lanktree MB, Nelson CP, Dale CE, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2014 Jan 27
7. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816. doi:10.1002 /14651858.CD14004816.pub14651855
8. Huffman M, Taylor FC, Ebrahim S. Statins for everyone? Huffman and colleagues’ response to Abramson and colleagues’ article on statins in low risk people Should people at low risk of cardiovascular disease take a statin? BMJ 2013;348:g1520
9. Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; 347:f6123. doi: 10.1136/bmj.f6123
10. Macedo AF, Taylor FC,. Casas JP, Adler A, Prieto D, Ebrahim S. Unintended effects of statins from observational studies in general population: systematic review and meta-analysis. BMC Medicine (in press)
11. Whitaker P. Statins for the primary prevention of cardiovasular disease. Response to BMJ 2014;348:g280
12. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD001561. DOI: 10.1002/14651858.CD001561.pub3
13. Sathasivam S, Lecky B. Statin induced myopathy. BMJ 2008;337:a2286
14. Palmer, S, Craig JC, Navaneethan SD, Tonelli M, Pellegrini F, Strippoli GFM. Benefits and Harms of Statin Therapy for Persons With Chronic Kidney Disease. A Systematic Review and Meta-analysis. Ann Int Med 2012; 157:263-75
15. Grover S, Gray Donald K, Joseph L, Abrahamowicz M. Life expectancy following dietary modification or smoking cessation. Estimating the benefits of a prudent life style. Archives Internal Medicine 1994;154:1697 1704
16. Ravnskov U. Statins for the primary prevention of cardiovasular disease. Response to BMJ 2014;348:g280
17. Taylor F, Ward K, Moore THM, Burke M, Davey Smith G, Casas J-P, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011 , Issue 1 . Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub4 .
18. CTT Collaboration (2012) Lack of Effect of Lowering LDL Cholesterol on Cancer: Meta-Analysis of Individual Data from 175,000 People in 27 Randomised Trials of Statin Therapy. PLoS ONE 7(1): e29849. doi:10.1371/journal.pone.0029849
19. Trompet S, Jukema JW, Katan MB, Blauw GJ, Sattar N, Buckley B, et al. Apolipoprotein e genotype, plasma cholesterol, and cancer: a Mendelian randomization study. Am J Epidemiol. 2009 Dec 1;170(11):1415-21. doi: 10.1093/aje/kwp294.
20. Benn M, Tybjærg-Hansen A, Stender S, Frikke-Schmidt R, Nordestgaard BG. Low-density lipoprotein cholesterol and the risk of cancer: a mendelian randomization study. J Natl Cancer Inst. 2011 Mar 16;103(6):508-19. doi: 10.1093/jnci/djr008.
21. Scholl JG. Statins for the primary prevention of cardiovasular disease. Response to BMJ 2014;348:g280
22 Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB, McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith Jr SC, Levy D, Watson K, Wilson PWF, 2013 ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults. J Am Coll Cardiol 2013; doi:10.1016/j.jacc.2013.11.002.
23. Lipid modification, cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE guideline. Draft for consultation, February 2014. http://www.nice.org.uk/guidance/index.jsp?action=download&o=66552
Competing interests: No competing interests
We see that many discerning readers felt compelled to comment on Ebrahim et al’s recent therapeutic review “Statins for the primary prevention of cardiovascular disease”(1). It is confusing to us that the evidence for statins is often presented with such certainty and with an almost unwillingness to share the evidence gaps with patients, where it exists. Some of the gaps include but are not limited to:
1. The review(1)reports that statins reduce the risk of “major” vascular events in the primary prevention context. In our view, it would be quite useful for persons considering statin therapy if the authors could clarify whether or not statins reduce the risk of symptomatic (specifically) myocardial infarctions and disabling (specifically) strokes when prescribed in this setting. We have been unable to find data that clarifies whether or not statins reduce the risk of events that patients, rather than trialists, likely consider to be “major”. If not, we suggest the term “major” be abandoned. This data might prove to be useful as the “Tips for patients” portion of Ebrahim et al’s review suggests that patients be advised that “Statins have to be taken every day and for the foreseeable future”.
2. The authors state that “Lowering blood levels of LDL cholesterol, a major risk factor for cardiovascular disease, reduces the chances of having cardiovascular disease”(1). This is a common misrepresentation and cartoon-like oversimplification of LDL-C and of surrogate markers in general. It is understood that increasing LDL-C generally correlates with an increased risk of morbidity as the authors’ note, however, it is also understood that simply lowering LDL-C does not necessarily translate into a reduction in cardiovascular risk. LDL-C lowering interventions have proven LDL-C to be an inconsistent surrogate for morbidity risk reduction. Torcetrapib lowers LDL-C but increases the risk of mortality; ezetimibe lowers LDL-C but has never been shown on its own to reduce the risk of morbidity and mortality(2,3,4). This concept is critically important as statins are promoted based on their ability to lower LDL-C when the focus should obviously be on their impact on patient-centered outcomes. Thus, it occurs to us as irresponsible to continue to propagate this myth despite the available evidence. The review(1) also encourages consideration of the relationship between reductions in “major” vascular events and LDL-C lowering as described by the Cholesterol Treatment Trialists (CTT) Collaboration(5). It seems these post-randomization variable analyses have been sufficiently deconstructed(6,7). Further, the CTT meta-analysis seems to skip the critical and rigorous review processes such as those outlined by the Cochrane Review Group(8) but please do advise us if we are missing the risk of bias assessment of the RCTs the CTT performs their analyses on.
3. Ebrahim et al’s review reports that statins reduce the risk of combined fatal and non-fatal stroke(1). We note that in the recent Cochrane systematic review of statins for primary prevention(9), 65% of the weight of the analysis for this outcome is driven by two RCTs: JUPITER and WOSCOPS(10,11). By now numerous clinicians and researchers have outlined clearly for us why we should be suspect of analyses that are highly dependent on JUPITER (12,13,14,15). We wonder, is the WOSCOPS study still considered universally relevant? We ask because it is now decades old, enrolled only middle-aged men (mean age 55) from the West of Scotland district of whom 80% were current or ex-smokers. Likely not generalizable to women with an interest in reducing their risk of experiencing a disabling stroke.
4. The authors also contend that “Patients may expect not to be harmed in any way by prevention treatment with statins”(1). Does it seem appropriate to assure patients of this given four paragraphs earlier in the review they note that “unintended effects are not comprehensively reported in systematic reviews or trials”?. Also, is it currently possible to conclude that rhabdomyolysis is rare? We were not able to find a consistent event definition for rhabdomyolysis in statin RCTs and of course one statin RCT changed the event definition to one that was more exclusive but only after events were counted(16). Importantly, as has been recently discussed in this journal, considerable uncertainty remains of the effects of statins on total serious adverse events when prescribed in the primary prevention setting given the limited reporting of this net-benefit outcome(17,18).
5. Last, the reference made to ezetimibe and combination statin-fibrate therapy, as noted by others, was a surprise. We would suggest that the evidence is not “limited” as the authors describe but completely non-existent or entirely not supportive.
Given the less than complete picture of the net benefit of statins when prescribed for primary prevention we do hope clinicians will chose not to use the “Tips for patients” sheet to incompletely inform patients and that they will welcome tough questions raised when patients are advised that they must take a statin “every day and for the foreseeable future”(1).
Cait O’Sullivan (PharmD, BScPh, BA)
Clinical Pharmacist, Island Health, British Columbia, Canada
Cait.OSullivan@viha.ca
Aaron M Tejani (BSc(Pharm), PharmD)
Researcher, Therapeutics Initiative, University of British Columbia, Canada
References
1.Ebrahim S, Taylor F, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014;348:g280.
2.Barter P, Caulfield M, Eriksson M, et al. Effects of torcetrapid in patients at high risk of for coronary events. N Engl J Med 2007;357:2109-22.
3.Taylor A, Villines T, Stanek E. Parodoxical progression of atherosclerosis related to low-density lipoprotein reduction and exposure to ezetimibe. Eur Heart J 2012;33:2939-45.
4.Krumholz H. Emphasizing the burden of proof. The American College of Cardiology 2008 expert panel comments on the ENHANCE trial. Circ Cardiovasc Qual Outcomes 2010;3:565-67.
5.Cholesterol Treatment Trialists (CTT Collaboration). The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;378:67-5.
6.Hayward R, Hofer Ti, Vijan S. Narrative review: lack of evidence for recommended low-density lipoprotein treatment targets: a solvable problem. Ann Intern Med 2006;145:520-30.
7.Hayward R, Krumholz H. Three reasons to abandon low-density lipoprotein targets. An open letter to the Adult Treatment Panel IV of the National Institutes of Health. Circ Cardiovasc Qual Outcomes 2012;5:2-5.
8.Higgens J, Green S (editors). Cochrane Handbook For Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.handbook.cochrane.org.
9.Taylor F, Huffman M, Macedo A, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Syst Rev 2013,1: CD004816.
10.Ridker P, Danielson E, Fonseca F, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207.
11.Shepherd J, Cobbe S, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-7.
12.De Lorgeril M, Salen P, Abramson J, et al. Cholesterol lowering, cardiovascular diseases, and the rosuvastatin-JUPITER controversy. A critical appraisal. Arch Intern Med 2010;170:1032-36.
13.Morrissey R, Diamond G, Kaul S. The JUPITER trial: myth or reality. Curr Atheroscler Rep 2011;13:413-21.
14.Serebruany V. Extreme all-cause mortality in JUPITER requires reexamination of vital records. Cardiology 2011;120:84-88.
15.Lopez A, Wright J. Rosuvastatin and the JUPITER trial: critical appraisal of a lifeless planet in the galaxy of primary prevention. Int J Occup Health 2012;18:70-8.
16.Simvastatin. Division of Metabolism and Endocrinology (DMEP) Clinical Review. NDA 19-766 E001. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/019766s077.pdf.
17.Abramson J, Rosenberg H, Jewell N, Wright J. Should people at low risk of cardiovascular disease take a statin? BMJ 2013;357:f6123.
18.Abramson J, Rosenberg H, Jewell N, Wright J. Authors’ reply to the Cochrane Review Authors. www.bmj.com.ezproxy.library.ubc.ca/content/347/bmj.f6123/rr/678736.
Competing interests: No competing interests
The issue of statins in primary prevention resurfaces every few years and has several difficult aspects. It is now of course higher on the health agenda since all but one of the statins is now generic. A huge mass of trail evidence tells us that the relativ risk reduction for coronary disease is always rather spookily similar, at about 30%. This is regardless of basal LDL cholesterol, age, gender, diabetic status etc. So ultimately we are dealing with the problem of a continuous variable where we want to choose a point for intervention. The same is true of course of blood pressure and to some extent of hyperglycaemia.The recommendation of intervention at the annual level of 1% rather than 2% is perfectly reasonable and the question comes down to whether we think that reducing risk from 1 to 0.7% is as important as reducing it from 2 to 1.4%. Clearly the patient and the prescriber need to come to a consensus on that, bearing in mind that the numerous side-effects of statins, described as "mild to moderate|"in clinical trials are of course of less concern if you are not actually taking the drugs. Doctors can still be rather high-handed about others' adverse drug effects.
Competing interests: No competing interests
Ebrahim and colleagues[1] succinctly reviewed the evidence based benefits and unintended effects of statin therapy in primary prevention of cardiovascular disease. The review is topical as subsequent draft guidance from NICE has suggested that statin therapy should be offered with a 10% or greater 10-year risk of developing cardiovascular disease.[2] Existing NICE guidance has a 20% or greater threshold for advocating stating therapy.[3] Further statin use may increase the absolute number of individuals at risk from interacting medication such as macrolide antibiotics and other drugs cited in Box 2 of the review article.[1] Not mentioned but previously highlighted is the risk of rhabdomyolysis from Fusidic acid prescriptions in patients on statin therapy.[4] GP electronic prescription alerts and the British National Formulary continue to highlight this real risk, which can have fatal consequences.
References
1. Ebrahim S, Taylor FC, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014;348:g280.
2. Lipid modification. Cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE guideline Draft for consultation, February 2014 http://www.nice.org.uk/nicemedia/live/13637/66552/66552.pdf
3. National Institute for Health and Care Excellence. Statins for the prevention of cardiovascular events in patients at increased risk of developing cardiovascular disease or those with established cardiovascular disease (Technology appraisal TA94). 2006. www.nice.org/TA094.
4. Kearney S, Carr AS, McConville J, McCarron. Rhabdomyolysis after co-prescription of statin and fusidic acid. BMJ 2012;345:e6562
Competing interests: No competing interests
The elephant in this room is the fact this patient is overweight. While mentioned in the introduction, it is ignored thereafter in the narrowly focused attempts to find out which drug treatments may best compensate for the poor fellow's unhealthy lifestyle.
As a GP without a special interest in anything in particular, I have found, in cases like this, that advice to stop adding sugar to hot drinks, to stop eating sugary drinks and sugared products, to stop, or reduce, the consumption of biscuits buns cakes and confectionery, and if this is not enough, to reduce the consumption of starches, results in an average weight loss of about 7% (and counting). I have noticed some pretty remarkable improvements in patients biochemistry, but that is not all.
By removing sugar from the diet, patients avoid eating trans fats in particular and excessive saturated fats as a side effect. A low sugar diet is a low junk food diet! With weight loss, they feel better, can exercise more, and reduce the multitude of problems associated with obesity and gain control over their own lives.
Advising patients to take statins to reduce their theoretical risk of disease at best makes them feel no better but often makes them feel physically worse. Benefits are theoretical and taken on faith, while side effects are real and current. Also, prescribing statins can side-line the possibility of helping them control their own risk factors for themselves.
Too much lip service is given to dietary advice, which is central to the pathologies concerned. To prescribe statins in primary prevention without having put energy and resources into improving a patient's diet, particularly by reducing sugar intake from its present high levels, is bad medicine.
Competing interests: No competing interests
Ebrahim et al's evident enthusiasm for statins in primary prevention causes them to make a misleading claim, whilst simultaneously ignoring a major drawback to their reductive pharmaceutical fetishism:
'Adding a statin to these lifestyle measures would, on average, almost halve his risk to 8% (assuming he does not revert to his adverse lifestyle as the statin is now "doing the job")'
In fact, as their table shows, adding a statin to the lifestyle measures their patient could follow (stopping smoking, losing weight, lowering blood pressure ... to say nothing of taking regular exercise) would, at most, reduce his risk by a further 2%. The bulk of the halving of risk to which Ebrahim et al refer comes from those lifestyle measures.
And there's the rub. Medicalise people like this and you run the risk, exactly as Ebrahim et al state, of leading them to believe our pharmaceuticals are 'doing the job', weakening motivation for lifestyle change. And, of course, if this hypothetical patient goes back to smoking, puts weight back on, and allows his exercise to fizzle out, it's not just his cardiovascular risk that starts to rise again ... it's his cancer risk too; to say nothing of the risk of falls and fractures when more elderly.
We need truly holistic approaches to these questions, and reductive analyses such as Ebrahim et al present at best confuse, and at worst distract and detract from efforts to look at people's health in the round.
Competing interests: No competing interests
In Ebrahim et al's commentary on 'Statins for primary prevention of cardiovascular disease' they state 'General contraindications to prescribing statins include….renal failure…’.
The term ‘renal failure’ is imprecise. It could be interpreted as acute kidney injury, any stage of chronic kidney disease or end-stage renal failure requiring maintenance haemodialysis, peritoneal dialysis or transplantation. Indeed, regardless of the intended definition of ‘renal failure’, the SHARP study (1) showed that statins can be used safely in all stages of chronic kidney disease. Whilst statins in endstage renal failure may not be effective in reducing cardiovascular events (2), lack of effectiveness is different to a general contraindication. The most specific national guidance (3) in dialysis suggests that statins should be continued when endstage renal failure develops but not initiated if the patient was not on them prior to commencement of dialysis.
We feel this statement requires further clarification from the authors.
Kind regards.
Dr Rupert Major
Professor Nigel Brunskill
References:
1. Baigent C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. The Lancet (2011). 377:2181-2192
2. Palmer S et al. Benefits and Harms of Statin Therapy for Persons With Chronic Kidney Disease - A Systematic Review and Meta-analysis. Ann Intern Med (2012). 157(4):263-75
3. KDIGO Clinical Practice Guideline for Lipid Management in Chronic Kidney Disease. Kidney International Supplements (2013) 3, 259
Competing interests: No competing interests
Just as procedures which prolong survival do not transform patients into immortal individuals, so drugs which reduce the risk of a clinical event in fact only delay its clinical manifestation.
Ebrahim and colleagues, analyzing results from randomized trials, stated that statins may reduce cardiovascular risk also in the primary prevention setting (1). Indeed, in people at high risk, such as those treated in secondary prevention, the average delay of a major cardiovascular event has been calculated at 0.09 years (33 days) over 5 years of statin therapy (2). It is likely that this delay may even be lower in primary prevention!
Is it always worth treating a healthy individual with lifelong statin therapy with the hope of a few months’ delay in the clinical manifestation of a vascular event, considering that statin induced side-effects, easily dismissed in randomised trials, are not trivial in real life? (3)
1. Ebrahim S, Taylor FC, Brindle P. Statins for the primary prevention of cardiovascular disease. BMJ 2014; 348: g280.
2. Bassan M, Panush N. Treating hypercholesterolemia—without the hype. Am J Cardiol 1997; 79: 1001–03.
3. Mascitelli L, Goldstein MR. Statins for people at low risk of cardiovascular disease. Lancet 2012; 380: 1816.
Competing interests: No competing interests
Re: Statins for the primary prevention of cardiovascular disease
According to Ebrahim et al it was “perverse to discount to zero the small, but beyond chance, benefits in terms of major vascular events avoided”. May I therefore suggest them, in case they have a healthy patient with high cholesterol whom they intend to treat with a statin, to tell the patient the following: Your chance not to get a non-fatal heart event during the next five years according to Cochrane is 97.1 per cent. You can increase your chance to 98.1 per cent if you take a statin every day. But then your risk of suffering muscle problems is about 25 per cent unless you never exercise (1); your risk of becoming sexually impotent is about 20 per cent (2); your risk of suffering from diabetes is about 4 per cent (3), and you also run a risk of memory loss, liver damage, peripheral neuropathy, cataract, and cancer, but we do not yet know how large these risks are. And don´t forget that many non-fatal heart events may heal with minor health consequences or none at all.
A new argument for the idea that high LDL is a risk factor for CVD, used by Ebrahim et al. as well, is Mendelian randomization. Proponents of that argument claim that it has been documented because nine single-nucleotide polymorphisms are associated with high LDL, and because these polymorphisms are found more often in patients with cardiovascular disease. But association is not the same as causation. These polymorphisms may instead mark a causal risk factor without being causal themselves, and this explanation is most likely because many observations have documented that high LDL lacks causality. The strongest argument is the fact that no cholesterol-lowering trial has found exposure-response between degree of cholesterol-lowering and outcome (4,5). Furthermore, eight studies of patients with familial hypercholesterolemia without cholesterol-lowering treatment found no significant difference between LDL of those with CVD and those without (6-13).
Ebrahim et al. think that statin treatment is safe and refer to meta-analyses of the statin trials. But in their previous analysis they stated that there was a failure to report adverse events in these trials, and there is indeed. They also claim that there is no evidence that statin treatment may cause cancer although I referred to several scary cohort and case control studies and to randomized controlled statin trial showing the risk of cancer, and there are more in our cancer paper (14). Are they totally insensitive? If their advice is followed these side effects may hit millions of people without producing any benefits.
1. Sinzinger H, Wolfram R, Peskar BA. Muscular side effects of statins. J Cardiovasc Pharm 2002;40:163-71.
2. Solomon H1, Samarasinghe YP, Feher MD, Man J, Rivas-Toro H, Lumb PJ, et al.. Erectile dysfunction and statin treatment in high cardiovascular risk patients. Int J Clin Pract. 2006;60:141-5.
3. Culver A, Ockene IS, Balasubramanian R, Olendzki BC, Sepavich DM, Wactawski-Wende J et al. Statin use and risk of diabetes mellitus in postmenopausal women in the Women's Health Initiative. Arch Intern Med. 2012;172:144-52
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Competing interests: No competing interests