Re: Statins for the primary prevention of cardiovascular disease
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
Rapid Response:
Re: Statins for the primary prevention of cardiovascular disease
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