- Email: [email protected]
Cholesterol, statins, and mortality
Correspondence
In their meta-analysis of blood cholesterol and vascular mortality (Dec 1, p 1829),1 the Prospective Studies Collaborators comment that the negative association between cholesterol and mortality might be non-causal, owing to confounding. Additionally, they state that randomised trials of statins to lower cholesterol show no adverse effect on cancer or non-cardiovascular mortality. However, their comments are not supported by current data. The negative association between cholesterol and all-cause mortality has been found in middle-aged and older men and women, and reverse causation is unlikely to account for this finding.2 It might result from an increase in both cancer and noncardiovascular mortality with lower cholesterol concentrations. A meta-analysis of large prospective randomised statin trials showed an inverse relation between achieved LDL cholesterol concentrations and cancer risk in statin-treated patients (p=0·009).3 Statins might indirectly impair the host antitumour immune response by increasing regulatory T-cell concentrations4 and suppressing tumour-specific effector T-cell responses, leading to increased cancer risk, particularly in elderly people, since they are more apt to harbour cancer cells. Indeed, in the PROSPER trial,5 the statin-treated patients had a significant increase in cancer incidence, leaving all-cause mortality unchanged. Therefore, there are data suggesting that lower cholesterol concentrations are not always better. Furthermore, evidence suggests that statins increase cancer risk in elderly people. We declare that we have no conflict of interest.
*Mark R Goldstein, Luca Mascitelli, Francesca Pezzetta [email protected] Fountain Medical Court, 9410 Fountain Medical Court, Suite A-200, Bonita Springs, FL 34135, USA
www.thelancet.com Vol 371 April 5, 2008
(MRG); Comando Brigata Alpina “Julia”, Servizio Sanitario, Udine, Italy (LM); and Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy (FP) 1
2
3
4
5
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. Ulmer H, Kelleher C, Diem G, Concin H. Why Eve is not Adam: prospective follow-up in 149 650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Women’s Health 2004; 13: 41–53. Alsheikh AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol 2007; 50: 409–18. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 2007; published online Sept 10. DOI:10.1016/j.atherosclerosis.2007.07.031. The PROSPER Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–30.
The Prospective Studies Collaboration (PSC) authors1 express surprise at the absence of an association between cholesterol concentrations and stroke mortality despite good evidence that lowering cholesterol reduces total stroke incidence. In fact this finding can be easily explained by accepting the results of the SPARCL trial,2 which showed that lowering cholesterol with atorvastatin 80 mg reduces ischaemic but increases haemorrhagic stroke. More than 70% of total strokes are ischaemic in origin, so reducing the number of ischaemic strokes by lowering cholesterol will also successfully reduce total stroke incidence.3 Table 1 of the PSC report showed that, of the 11 663 stroke deaths reviewed, 18·3% were ischaemic, 23·2% haemorrhagic, 7·5% were from subarachnoid bleeds, and 51% were of unknown origin. Since the proportion of deaths from ischaemic and haemorrhagic stroke is almost equal, lowering cholesterol produces no net effect because the reduction in ischaemic stroke death is balanced by an increase in deaths from haemorrhagic stroke. Even in controlled trials, stroke subtypes are difficult to classify; the cause in more than 50% of stroke
deaths is unknown or unreported in the PSC analysis. This explains why the increase of haemorrhagic stroke with cholesterol lowering is not picked up in most statin studies, where stroke is one of many cardiovascular endpoints assessed. Only the SPARCL trial studied stroke incidence as its sole primary endpoint. Together, the PSC report and SPARCL trial reinforce previous epidemiological data that reducing cholesterol increases cerebral haemorrhage, an important message today when statin therapy is widely perceived to be safe.4,5
Photolibrary
Cholesterol, statins, and mortality
We declare that we have no conflict of interest.
*H T Ong, A G Haniffah [email protected] H T Ong Heart Clinic, Penang 10350, Malaysia (HTO); and Island Hospital, Penang, Malaysia (AGH) 1
2
3
4
5
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. The Stroke Prevention by aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–59. Thrift AG, Dewey HM, Macdonell RAL, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: Initial findings from the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke 2001; 32: 1732–38. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320: 904–10. Armitage J. The safety of statins in clinical practice. Lancet 2007; 370: 1781–90.
In the most recent Prospective Studies Collaboration (PSC) meta-analysis,1 49% of stroke deaths were classified as either ischaemic or haemorrhagic. This seems high since most prospective studies are unable to distinguish the two types of stroke reliably. Misclassification of strokes through use of clinical features alone could help explain two surprising results. First, that the positive association between total cholesterol and ischaemic stroke in PSC was much weaker than in MRFIT (see webfigure 8)1 and other cohort studies2 in which CT scans or autopsy were used to classify stroke, and weaker than the reduction in
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1161
Correspondence
ischaemic stroke in randomised trials of cholesterol reduction.2 Second, that the inverse relation between total cholesterol and haemorrhagic stroke was weaker in PSC1 than in MRFIT and other cohort studies.2 Another surprising observation was that lower cholesterol was associated with a lower risk of all stroke at lower blood-pressure levels, but a higher risk at higher blood-pressure levels.1 This could be explained if blood pressure were more strongly associated with haemorrhagic than ischaemic stroke. Then more of the strokes at higher blood-pressure levels would be haemorrhagic (thereby reversing the cholesterol effect). A separate issue relates to ischaemic heart disease (IHD). The quantitative estimates of the association between total serum cholesterol and IHD underestimate the reduction in IHD achievable from lowering cholesterol by dietary change or taking statins. This is because a given difference in total cholesterol concentration will include all types of cholesterol (HDL, LDL,VLDL) in cohort studies, but will be due largely to a reduction in LDL cholesterol through diet or statins.3 Thus a 1 mmol/L cholesterol difference in cohort studies does not correspond biologically to a 1 mmol/L decrease in cholesterol through diet or statins.3 The problem can be resolved by raising the relative risk estimate to the power of 1·14 (the regression slope Age (years)
PSC relative-risk estimate
of IHD mortality on LDL cholesterol is 1·14 times greater than IHD on total cholesterol),3,4 as shown in the table. These estimates are similar to previous ones, based on an analysis of the ten largest cohort studies.2,4 We declare that we have no conflict of interest.
*Malcolm Law, Nicholas Wald [email protected] Wolfson Institute of Preventive Medicine, Barts and The London Queen Mary’s School of Medicine, Charterhouse Square, London EC1M 6BQ, UK 1
2
3
4
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423–27. Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study. BMJ 1994; 308: 363–66. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994; 308: 367–72.
Authors’ reply The suggestion that lowering cholesterol might be associated with an increased risk of cancer is not supported by the available randomised evidence. Notwithstanding the small excess risk seen in one trial (PROSPER1) among 6000 people, the Cholesterol Treatment Trialists’ (CTT) meta-analysis of data from 90 000 individuals in 14 large-
Proportional risk Previous estimate from reduction in risk of IHD ten largest cohort studies2,4
Published
Adjusted
40–49
0·44
0·39
(45–55)
··
··
50–59
0·58
0·54
46%
..
(55–65)
··
··
(39%)*
41%
60–69
0·72
0·69
(65–75)
··
··
70–79
0·82
80–89
0·85
61%
..
(54%)*
56%
31%
..
(26%)*
31%
0·80
20%
..
0·83
17%
..
*Risk reductions for mid-decade age ranges, calculated as an average of the risk reductions either side.
Table: Relative risk of ischaemic heart disease (IHD) for a 1 mmol/L lower total serum cholesterol, adjusted estimates for a 1 mmol/L lower LDL cholesterol, and corresponding risk reduction in IHD
1162
scale statin trials (including PROSPER) showed no evidence that reducing LDL cholesterol with a statin increases overall cancer risk (relative risk 1·00, 95% CI 0·95–1·06) in any type of patient (eg, women, older people, or those with below-average cholesterol concentrations).2 In the non-randomised ecological comparison referred to by Mark Goldstein and colleagues,3 the crude inverse relation between each trial’s average achieved LDL cholesterol and average cancer risk seems most likely to be due to a lack of appropriate control for confounding (eg, by age). The randomised trial evidence is also clear about the ability of statins to reduce the overall risk of stroke. The CTT meta-analysis, involving more than 800 first strokes after randomisation, indicated that a standard statin regimen (reducing LDL cholesterol by about 1·5 mmol/L) could reduce the overall risk of stroke by about a third in a wide range of people at risk of major vascular events.2 The possibility that statin therapy might produce a small excess risk of haemorrhagic stroke (as suggested by the SPARCL trial:4 55 atorvastatin vs 33 placebo), while reducing ischaemic stroke substantially, needs further exploration in randomised trials with many more subtyped strokes (such as by the forthcoming update of the CTT meta-analysis). In response to Malcolm Law and Nicholas Wald, the Prospective Studies Collaboration (PSC)5 did not request information on the method of stroke subtype classification, but the associations are similar in both shape and magnitude when analyses are restricted to the 26 cohorts (4000 stroke deaths) in which at least half of stroke deaths were given a subtype. Although the stroke results in the PSC report5 remain unexplained, and invite further research, treatment should still be guided chiefly by the clear evidence from randomised trials that statins substantially reduce not only coronary event rates but also stroke rates in patients with a wide range of ages and blood pressures. www.thelancet.com Vol 371 April 5, 2008
In their meta-analysis of blood cholesterol and vascular mortality (Dec 1, p 1829),1 the Prospective Studies Collaborators comment that the negative association between cholesterol and mortality might be non-causal, owing to confounding. Additionally, they state that randomised trials of statins to lower cholesterol show no adverse effect on cancer or non-cardiovascular mortality. However, their comments are not supported by current data. The negative association between cholesterol and all-cause mortality has been found in middle-aged and older men and women, and reverse causation is unlikely to account for this finding.2 It might result from an increase in both cancer and noncardiovascular mortality with lower cholesterol concentrations. A meta-analysis of large prospective randomised statin trials showed an inverse relation between achieved LDL cholesterol concentrations and cancer risk in statin-treated patients (p=0·009).3 Statins might indirectly impair the host antitumour immune response by increasing regulatory T-cell concentrations4 and suppressing tumour-specific effector T-cell responses, leading to increased cancer risk, particularly in elderly people, since they are more apt to harbour cancer cells. Indeed, in the PROSPER trial,5 the statin-treated patients had a significant increase in cancer incidence, leaving all-cause mortality unchanged. Therefore, there are data suggesting that lower cholesterol concentrations are not always better. Furthermore, evidence suggests that statins increase cancer risk in elderly people. We declare that we have no conflict of interest.
*Mark R Goldstein, Luca Mascitelli, Francesca Pezzetta [email protected] Fountain Medical Court, 9410 Fountain Medical Court, Suite A-200, Bonita Springs, FL 34135, USA
www.thelancet.com Vol 371 April 5, 2008
(MRG); Comando Brigata Alpina “Julia”, Servizio Sanitario, Udine, Italy (LM); and Cardiology Service, Ospedale di Tolmezzo, Tolmezzo, Italy (FP) 1
2
3
4
5
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. Ulmer H, Kelleher C, Diem G, Concin H. Why Eve is not Adam: prospective follow-up in 149 650 women and men of cholesterol and other risk factors related to cardiovascular and all-cause mortality. J Women’s Health 2004; 13: 41–53. Alsheikh AA, Maddukuri PV, Han H, Karas RH. Effect of the magnitude of lipid lowering on risk of elevated liver enzymes, rhabdomyolysis, and cancer: insights from large randomized statin trials. J Am Coll Cardiol 2007; 50: 409–18. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 2007; published online Sept 10. DOI:10.1016/j.atherosclerosis.2007.07.031. The PROSPER Study Group. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet 2002; 360: 1623–30.
The Prospective Studies Collaboration (PSC) authors1 express surprise at the absence of an association between cholesterol concentrations and stroke mortality despite good evidence that lowering cholesterol reduces total stroke incidence. In fact this finding can be easily explained by accepting the results of the SPARCL trial,2 which showed that lowering cholesterol with atorvastatin 80 mg reduces ischaemic but increases haemorrhagic stroke. More than 70% of total strokes are ischaemic in origin, so reducing the number of ischaemic strokes by lowering cholesterol will also successfully reduce total stroke incidence.3 Table 1 of the PSC report showed that, of the 11 663 stroke deaths reviewed, 18·3% were ischaemic, 23·2% haemorrhagic, 7·5% were from subarachnoid bleeds, and 51% were of unknown origin. Since the proportion of deaths from ischaemic and haemorrhagic stroke is almost equal, lowering cholesterol produces no net effect because the reduction in ischaemic stroke death is balanced by an increase in deaths from haemorrhagic stroke. Even in controlled trials, stroke subtypes are difficult to classify; the cause in more than 50% of stroke
deaths is unknown or unreported in the PSC analysis. This explains why the increase of haemorrhagic stroke with cholesterol lowering is not picked up in most statin studies, where stroke is one of many cardiovascular endpoints assessed. Only the SPARCL trial studied stroke incidence as its sole primary endpoint. Together, the PSC report and SPARCL trial reinforce previous epidemiological data that reducing cholesterol increases cerebral haemorrhage, an important message today when statin therapy is widely perceived to be safe.4,5
Photolibrary
Cholesterol, statins, and mortality
We declare that we have no conflict of interest.
*H T Ong, A G Haniffah [email protected] H T Ong Heart Clinic, Penang 10350, Malaysia (HTO); and Island Hospital, Penang, Malaysia (AGH) 1
2
3
4
5
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. The Stroke Prevention by aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med 2006; 355: 549–59. Thrift AG, Dewey HM, Macdonell RAL, McNeil JJ, Donnan GA. Incidence of the major stroke subtypes: Initial findings from the North East Melbourne Stroke Incidence Study (NEMESIS). Stroke 2001; 32: 1732–38. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum cholesterol levels and six-year mortality from stroke in 350,977 men screened for the multiple risk factor intervention trial. N Engl J Med 1989; 320: 904–10. Armitage J. The safety of statins in clinical practice. Lancet 2007; 370: 1781–90.
In the most recent Prospective Studies Collaboration (PSC) meta-analysis,1 49% of stroke deaths were classified as either ischaemic or haemorrhagic. This seems high since most prospective studies are unable to distinguish the two types of stroke reliably. Misclassification of strokes through use of clinical features alone could help explain two surprising results. First, that the positive association between total cholesterol and ischaemic stroke in PSC was much weaker than in MRFIT (see webfigure 8)1 and other cohort studies2 in which CT scans or autopsy were used to classify stroke, and weaker than the reduction in
Submissions should be made via our electronic submission system at http://ees.elsevier.com/ thelancet/
1161
Correspondence
ischaemic stroke in randomised trials of cholesterol reduction.2 Second, that the inverse relation between total cholesterol and haemorrhagic stroke was weaker in PSC1 than in MRFIT and other cohort studies.2 Another surprising observation was that lower cholesterol was associated with a lower risk of all stroke at lower blood-pressure levels, but a higher risk at higher blood-pressure levels.1 This could be explained if blood pressure were more strongly associated with haemorrhagic than ischaemic stroke. Then more of the strokes at higher blood-pressure levels would be haemorrhagic (thereby reversing the cholesterol effect). A separate issue relates to ischaemic heart disease (IHD). The quantitative estimates of the association between total serum cholesterol and IHD underestimate the reduction in IHD achievable from lowering cholesterol by dietary change or taking statins. This is because a given difference in total cholesterol concentration will include all types of cholesterol (HDL, LDL,VLDL) in cohort studies, but will be due largely to a reduction in LDL cholesterol through diet or statins.3 Thus a 1 mmol/L cholesterol difference in cohort studies does not correspond biologically to a 1 mmol/L decrease in cholesterol through diet or statins.3 The problem can be resolved by raising the relative risk estimate to the power of 1·14 (the regression slope Age (years)
PSC relative-risk estimate
of IHD mortality on LDL cholesterol is 1·14 times greater than IHD on total cholesterol),3,4 as shown in the table. These estimates are similar to previous ones, based on an analysis of the ten largest cohort studies.2,4 We declare that we have no conflict of interest.
*Malcolm Law, Nicholas Wald [email protected] Wolfson Institute of Preventive Medicine, Barts and The London Queen Mary’s School of Medicine, Charterhouse Square, London EC1M 6BQ, UK 1
2
3
4
Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55 000 vascular deaths. Lancet 2007; 370: 1829–39. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326: 1423–27. Law MR, Wald NJ, Wu T, Hackshaw A, Bailey A. Systematic underestimation of association between serum cholesterol concentration and ischaemic heart disease in observational studies: data from the BUPA study. BMJ 1994; 308: 363–66. Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ 1994; 308: 367–72.
Authors’ reply The suggestion that lowering cholesterol might be associated with an increased risk of cancer is not supported by the available randomised evidence. Notwithstanding the small excess risk seen in one trial (PROSPER1) among 6000 people, the Cholesterol Treatment Trialists’ (CTT) meta-analysis of data from 90 000 individuals in 14 large-
Proportional risk Previous estimate from reduction in risk of IHD ten largest cohort studies2,4
Published
Adjusted
40–49
0·44
0·39
(45–55)
··
··
50–59
0·58
0·54
46%
..
(55–65)
··
··
(39%)*
41%
60–69
0·72
0·69
(65–75)
··
··
70–79
0·82
80–89
0·85
61%
..
(54%)*
56%
31%
..
(26%)*
31%
0·80
20%
..
0·83
17%
..
*Risk reductions for mid-decade age ranges, calculated as an average of the risk reductions either side.
Table: Relative risk of ischaemic heart disease (IHD) for a 1 mmol/L lower total serum cholesterol, adjusted estimates for a 1 mmol/L lower LDL cholesterol, and corresponding risk reduction in IHD
1162
scale statin trials (including PROSPER) showed no evidence that reducing LDL cholesterol with a statin increases overall cancer risk (relative risk 1·00, 95% CI 0·95–1·06) in any type of patient (eg, women, older people, or those with below-average cholesterol concentrations).2 In the non-randomised ecological comparison referred to by Mark Goldstein and colleagues,3 the crude inverse relation between each trial’s average achieved LDL cholesterol and average cancer risk seems most likely to be due to a lack of appropriate control for confounding (eg, by age). The randomised trial evidence is also clear about the ability of statins to reduce the overall risk of stroke. The CTT meta-analysis, involving more than 800 first strokes after randomisation, indicated that a standard statin regimen (reducing LDL cholesterol by about 1·5 mmol/L) could reduce the overall risk of stroke by about a third in a wide range of people at risk of major vascular events.2 The possibility that statin therapy might produce a small excess risk of haemorrhagic stroke (as suggested by the SPARCL trial:4 55 atorvastatin vs 33 placebo), while reducing ischaemic stroke substantially, needs further exploration in randomised trials with many more subtyped strokes (such as by the forthcoming update of the CTT meta-analysis). In response to Malcolm Law and Nicholas Wald, the Prospective Studies Collaboration (PSC)5 did not request information on the method of stroke subtype classification, but the associations are similar in both shape and magnitude when analyses are restricted to the 26 cohorts (4000 stroke deaths) in which at least half of stroke deaths were given a subtype. Although the stroke results in the PSC report5 remain unexplained, and invite further research, treatment should still be guided chiefly by the clear evidence from randomised trials that statins substantially reduce not only coronary event rates but also stroke rates in patients with a wide range of ages and blood pressures. www.thelancet.com Vol 371 April 5, 2008