PSCPSC

Lancet 2007; 370:1829-39

Blood cholesterol and vascular mortality by age, sex and blood pressure:a meta-analysis of individual data

from 61 prospective studieswith 55 000 vascular deaths

Lancet 2007; 370: 1829-39

PSCPSC

Lancet 2007; 370:1829-39

Prospective Studies Collaboration

• Established chiefly to investigate associations of blood pressure and cholesterol with cause-specific mortality

• Individual data on 900 000 participants without any previous history of vascular disease from 61 prospective cohort studies

• > 55 000 vascular deaths (34 000 ischaemic heart disease [IHD], 12 000 stroke, 10 000 other)

• 150 000 participants from 23 studies also had HDL cholesterol (5000 vascular deaths)

PSCPSC

Lancet 2007; 370:1829-39

Collaborators and investigatorsAtherosclerosis Risk in Communities (ARIC): L Chambless; Belgian Inter-university Research on Nutrition and Health (BIRNH): G De Backer, D De Bacquer, M Kornitzer; British Regional Heart Study (BRHS): P Whincup, SG Wannamethee, R Morris; British United Provident Association (BUPA): N Wald, J Morris, M Law; Busselton: M Knuiman, H Bartholomew; Caerphilly and Speedwell: G Davey Smith, P Sweetnam, P Elwood, J Yarnell; Cardiovascular Health Study (CHS): R Kronmal; CB Project: D Kromhout; Charleston: S Sutherland, J Keil; Copenhagen City Heart Study: G Jensen, P Schnohr; Evans County: C Hames (deceased), A Tyroler; Finnish Mobile Clinic Survey (FMCS): A Aromaa, P Knekt, A Reunanen; Finrisk: J Tuomilehto, P Jousilahti, E Vartiainen, P Puska; Flemish Study on Environment, Genes and Health (FLEMENGHO): T Kuznetsova, T Richart, J Staessen, L Thijs; Research Centre for Prevention and Health (Glostrup Population Studies): T Jorgensen,T Thomsen; Honolulu Heart Program: D Sharp, JD Curb; Ikawa, Noichi and Kyowa: H Iso, S Sato, A Kitamura, Y Naito; Imperial College, London and Oxon Clinical Epidemiology Limited: N Qizilbash; Centre d'Investigations Preventives et Cliniques (IPC), Paris: A Benetos, L Guize; Israeli Ischaemic Heart Disease Study: U Goldbourt; Japan Railways: M Tomita, Y Nishimoto, T Murayama; Lipid Research Clinics Follow-up Study (LRC): M Criqui, C Davis; Midspan Collaborative Study: C Hart, G Davey-Smith, D Hole, C Gillis; Minnesota Heart Health Project (MHHP) and Minnesota Heart Survey (MHS): D Jacobs, H Blackburn, R Luepker; Multiple Risk Factor Intervention Trial (MRFIT): J Neaton, L Eberly; First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study (NHEFS): C Cox; NHLBI Framingham Heart Study: D Levy, R D'Agostino, H Silbershatz; Norwegian Counties Study: A Tverdal, R Selmer; Northwick Park Heart Study (NPHS): T Meade, K Garrow, J Cooper; Nurses’ Health Study: F Speizer, M Stampfer; Occupational Groups (OG), Rome: A Menotti, A Spagnolo; Ohasama: I Tsuji, Y Imai, T Ohkubo, S Hisamichi; Oslo: L Haheim, I Holme, I Hjermann, P Leren; Paris Prospective Study: P Ducimetiere, J Empana; Perth: K Jamrozik, R Broadhurst; Prospective Cardiovascular Munster Study (PROCAM): G Assmann, H Schulte; Prospective Study of Women in Gothenburg: C Bengtsson, C Björkelund, L Lissner; Puerto Rico Health Heart Program (PRHHP): P Sorlie, M Garcia-Palmieri; Rancho Bernado: E Barrett-Connor, M Criqui, R Langer; Renfrew and Paisley study: C Hart, G Davey Smith, D Hole; Saitama Cohort Study: K Nakachi, K Imai; Seven Cities China: X Fang, S Li; Seven Countries (SC) Croatia: R Buzina; SC Finland: A Nissinen; SC Greece (Greek Islands Study): C Aravanis, A Dontas, A Kafatos; SC Italy: A Menotti; SC Japan: H Adachi, H Toshima, T Imaizumi; SC Netherlands: D Kromhout; SC Serbia: S Nedeljkovic, M Ostojic; Shanghai: Z Chen; Scottish Heart Health Study (SHHS): H Tunstall-Pedoe; Shibata: T Nakayama, N Yoshiike, T Yokoyama, C Date, H Tanaka; Tecumseh: J Keller; Tromso: K Bonaa, E Arnesen; United Kingdom Heart Disease Prevention Project (UKHDPP): H Tunstall-Pedoe; US Health Professionals Follow-up Study: E Rimm; US Physicians’ Health Study: M Gaziano, JE Buring, C Hennekens; Värmland: S Törnberg, J Carstensen; Whitehall: M Shipley, D Leon, M Marmot; Clinical Trial Service Unit (CTSU): J Armitage, C Baigent, Z Chen, R Clarke, R Collins, J Emberson, J Halsey, M Landray, S Lewington, A Palmer (deceased), S Parish, R Peto, P Sherliker, G Whitlock.

Steering Committee — S Lewington (coordinator and statistician), S MacMahon (chair), R Peto (statistician), A Aromaa, C Baigent, J Carstensen, Z Chen, R Clarke, R Collins, S Duffy, D Kromhout, J Neaton, N Qizilbash, A Rodgers, S Tominaga, S Törnberg, H Tunstall-Pedoe, G Whitlock.

PSCPSC

Lancet 2007; 370:1829-39

Analysis

• Cox regression adjusted for age, sex & study

• Hazard ratios are presented as floating absolute risks (does not alter values but adds appropriate confidence interval to every group, including even reference group)

• Adjustment for regression dilution bias makes relationship with usual values about 50% steeperthan that with measured values

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterol

80-89

70-79

60-69

50-59

40-49

Age atrisk

1 mmol/L total cholesterol

15% risk

18% risk

28% risk

42% risk

56% risk

Usual total cholesterol (mmol/L)

4·0 5·0 6·0 7·0 8·00·5

1

2

4

8

16

32

64

128

256H

azar

d r

atio

(flo

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CI)

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterolby age and sex

Age atrisk

Sex

No. ofdeaths

80-89 Men 2919Women 2707Total 5626 0·85 (0·82-0·89)

70-79 Men 7372Women 3457Total 10 829 0·82 (0·80-0·85)

60-69 Men 8594Women 1825Total 10 419 0·72 (0·69-0·74)

50-59 Men 5001Women 560Total 5561 0·58 (0·56-0·61)

40-49 Men 1191Women 118Total 1309 0·44 (0·42-0·48)

0·4 0·6 0·8 1·0Hazard ratio (& 95% CI) for

1 mmol/L lower usual total cholesterol

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterolby baseline SBP

No. ofdeaths

7634 0·82 (0·79-0·84)

4645 0·79 (0·76-0·82)

4176 0·76 (0·73-0·79)

3174 0·81 (0·78-0·84)

3027 0·73 (0·70-0·76)

4218 0·68 (0·65-0·70)

Age atrisk

70-89

60-69

40-59 1364 0·66 (0·62-0·70)

1908 0·62 (0·59-0·65)

SBP(mmHg)

165+

145-164

<145

165+

145-164

<145

165+

145-164

<145 3598 0·53 (0·51-0·55)

0·4 0·6 0·8 1·0Hazard ratio (& 95% CI) for

mmol/L lower usual total cholesterol

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterolby smoking status

Age atrisk

Smokingstatus

No. ofdeaths

70-89 Current cig 2730

Other 11 168

Neversmoker

2557

60-69 Current cig 3911

Other 5170

Neversmoker

1338

40-59 Current cig 3612

Other 2608

Neversmoker

650

0·74 (0·71-0·78)

0·80 (0·78-0·82)

0·77 (0·74-0·81)

0·70 (0·68-0·73)

0·71 (0·68-0·74)

0·71 (0·67-0·76)

0·58 (0·56-0·60)

0·54 (0·52-0·57)

0·59 (0·54-0·64)

0·4 0·6 0·8 1·0

Hazard ratio (& 95% CI) for1 mmol/L lower usual total cholesterol

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterolby BMI

Hazard ratio (& 95% CI) for1 mmol/L lower usual total cholesterol

Age atrisk

BMI(kg/m2)

No. ofdeaths

70-89 30+ 2369 0·77 (0·73-0·81)

25-29 7198 0·78 (0·75-0·80)

<25 6736 0·79 (0·76-0·81)

60-69 30+ 1518 0·74 (0·70-0·79)

25-29 4679 0·72 (0·69-0·74)

<25 4123 0·70 (0·68-0·73)

40-59 30+ 827 0·62 (0·57-0·67)

25-29 3105 0·56 (0·54-0·59)

<25 2881 0·55 (0·53-0·58)

0·4 0·6 0·8 1·0

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (3020 deaths) versus usual(a) HDL cholesterol; (b) non-HDL cholesterol; and (c) total/HDL cholesterol

by age at risk

Usual non-HDL(mmol/L)

3 4 5 6

40-59

60-69

70-89years

Usual HDL(mmol/L)

1·0 1·50·5

1

2

4

8

16

32

64

128

40-59

60-69

70-89years

Haz

ard

rat

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ab

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isks

& 9

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Usual total/HDL

3 4 5 6 7

40-59

60-69

70-89years

31%

40%

44%

1.33 units total/HDL

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (3020 deaths) versus usual HDL cholesterol

Usual HDL cholesterol (mmol/L)

1·0 1·50·5

1

2

4

8

16

32

64

128

40-59

60-69

70-89

Age atrisk:

63% risk

83% risk

35% risk

0.33 mmol/L HDL

Haz

ard

rat

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ab

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isks

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PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (3020 deaths) versus usual non-HDL cholesterol

Usual non-HDL cholesterol (mmol/L)

3 4 5 60·5

1

2

4

8

16

32

64

128Age atrisk:

40-59 43% risk

60-69 34% risk

70-89 27% risk

1 mmol/L non-HDL

Haz

ard

rat

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PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (3020 deaths) versus usual total/HDL cholesterol

Usual total/HDL cholesterol3 4 5 6 7

0·5

1

2

4

8

16

32

64

128

40-59 44% risk

60-69 40 risk

70-89 31% risk

Age atrisk

1.33 total/HDL

Haz

ard

rat

io(f

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ab

solu

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isks

& 9

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PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (11 663 deaths) versus usual total cholesterol by age

Usual total cholesterol (mmol/L)4·0 5·0 6·0 7·0 8·0

1

2

4

8

16

32

64

80-89 1.10 (1.05-1.16)

70-79 1.15 (1.09-1.20)

60-69 0.94 (0.90-0.99)

40-59 0.84 (0.78-0.91)

Age at risk: HR (95% CI) per 1mmol/L

Haz

ard

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PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (11 663 deaths) versus usual total cholesterolby type and age

Strokesubtype

Age atrisk

No. ofdeaths

Totalstroke

80-89 2632 1·06 (1·00-1·13)

70-79 4311 1·04 (0·99-1·09)

60-69 2938 1·02 (0·97-1·08)

40-59 1782 0·90 (0·84-0·97) Test for trend: 12 = 9.3 (P=0.002)

Haemorrhagicstroke

80-89 422 1·06 (0·90-1·25)

70-79 915 1·18 (1·06-1·31)

60-69 743 1·09 (0·97-1·23)

40-59 620 0·92 (0·81-1·04)

Ischaemicstroke

80-89 519 1·09 (0·95-1·26)

70-79 850 1·06 (0·95-1·17)

60-69 540 0·89 (0·79-1·01)

40-59 225 0·73 (0·61-0·87)

0·6 0·8 1·0 1·2 1·4Hazard ratio (& 95% CI) for

1 mmol/L lower usual total cholesterol

Test for trend: 12 = 4.3 (P=0.04)

Test for trend: 12 = 15.1 (P=0.0001)

PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (11 663 deaths) versus usual total cholesterolby baseline SBP

Usual total cholesterol (mmol/L)4·0 5·0 6·0 7·0 8·0

1

2

4

8

<145

145-164

165-184

185+

Baseline SBP(mmHg):

1 mmol/L total cholesterol

10% risk

7% risk

15% risk

42% risk

Haz

ard

rat

io(f

loat

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ab

solu

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isks

& 9

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PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (16 497 deaths) versus usual total cholesterolby baseline SBP

Strokesubtype

SBP(mmHg)

No. ofdeaths

Totalstroke

185+ 2473 1·10 (1·05-1·16)

165-184 2498 1·15 (1·09-1·20)

145-164 3092 1·07 (1·02-1·12)

125-144 2562 0·94 (0·90-0·99)

<125 1038 0·84 (0·78-0·91) Test for trend:12 = 53·2 (p<0·0001)

Haemorrhagicstroke

185+ 662 1·16 (1·05-1·27)

165-184 631 1·30 (1·18-1·43)

145-164 674 1·12 (1·03-1·23)

125-144 528 1·01 (0·90-1·13)

<125 205 0·83 (0·71-0·98) Test for trend: 12 = 15·7 (p=0·0001)

Ischaemicstroke

185+ 476 0·99 (0·89-1·11)

165-184 439 1·13 (1·01-1·26)

145-164 574 1·00 (0·91-1·11)

125-144 433 0·92 (0·82-1·03)

<125 212 0·78 (0·67-0·90)

0·6 0·8 1·0 1·21·4

Test for trend: 12 = 8.9 (p=0·003)

Hazard ratio (& 95% CI) for1 mmol/L lower usual total cholesterol

PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (914 deaths) versus usual:(a) HDL cholesterol; (b) non-HDL cholesterol; and (c) total/HDL cholesterol

Usual non-HDL(mmol/L)

3 4 5 6

40-6940-69

70-8970-89years

Usual HDL(mmol/L)

1·0 1·50·5

1

2

4

8

16

32

64

128

40-6940-69

70-8970-89years

Haz

ard

rat

io(f

loat

ing

ab

solu

te r

isks

& 9

5% C

I)

Usual total/HDL

3 4 5 6 7

40-6940-690.86 (0.74-0.99)

70-8970-89 years0.95 (0.83-1.10)

HR (95%CI)per 1.33 total/HDL

PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (914 deaths) versus usual HDL cholesterol

Usual HDL (mmol/L)

1·0 1·50·5

1

2

4

8

16

32

64

128

40-69 years1.04 (0.89-1.23)

70-89 years1.02 (0.88-1.17)

Haz

ard

rat

io(f

loat

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ab

solu

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isks

& 9

5% C

I)

HR (95%CI) per0.33 mmol/L HDL

PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (914 deaths) versus usual non-HDL cholesterol

Usual non-HDL (mmol/L)

3 4 5 6

40-69 years0.96 (0.83-1.12)

70-89 years1.05 (0.91-1.20)

0·5

1

2

4

8

16

32

64

128

Haz

ard

rat

io(f

loat

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ab

solu

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isks

& 9

5% C

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HR (95%CI) per1 mmol/L non-HDL

PSCPSC

Lancet 2007; 370:1829-39

Stroke mortality (914 deaths) versus usual total/HDL cholesterol

Usual total/HDL

3 4 5 6 7

40-69 years0.86 (0.74-0.99)

70-89 years0.95 (0.83-1.10)

HR (95%CI)per 1.33 total/HDL

0·5

1

2

4

8

16

32

64

128

Haz

ard

rat

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ab

solu

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& 9

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PSCPSC

Lancet 2007; 370:1829-39

Conclusions:Total cholesterol & IHD mortality

• Total cholesterol is a major risk factor for IHD both in middle and in old age

• There is no threshold level of total cholesterol in the range commonly occurring in Western populations below which lower cholesterol is not associated with lower IHD mortality

• There are no important sex differences in the relative effects of total cholesterol on vascular mortality

• The joint relative effects of total cholesterol and blood pressure are approximately additive (rather than multiplicative)

PSCPSC

Lancet 2007; 370:1829-39

Conclusions:HDL, non-HDL cholesterol & IHD mortality

• The joint relative effects of HDL and non-HDL cholesterol are approximately independent and additive

• HDL cholesterol adds worthwhile predictive information beyond either total or non-HDL cholesterol

• The ratio of total/HDL cholesterol is statistically twice as informative as total cholesterol alone

PSCPSC

Lancet 2007; 370:1829-39

Conclusions:Total cholesterol & stroke mortality

• A positive relationship with ischaemic and total stroke mortality was seen only in middle age and only in those with below-average blood pressure

• At older ages and, particularly, for those with systolic blood pressure over about 145 mm Hg, total cholesterol was negatively related to haemorrhagic and total stroke mortality

• There is conclusive evidence from randomised trials that statins substantially reduce stroke rates in a wide range of patients

• The contrast between these statistically reliable observational epidemiological results and the statistically reliable randomised trial results is substantial and invites further research

PSCPSC

Lancet 2007; 370:1829-39

Web material

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (33 744 deaths) versus usual total cholesterol by SBP

Usual total cholesterol (mmol/L)

4·0 5·0 6·0 7·0 8·0

1

2

4

8

<145

145-164

165-184

185+

Baseline SBP(mmHg):

Haz

ard

rat

io(f

loat

ing

ab

solu

te r

isks

& 9

5% C

I)

PSCPSC

Lancet 2007; 370:1829-39

IHD mortality (3020 deaths) versus:usual HDL cholesterol by baseline non-HDL cholesterolusual non-HDL cholesterol by baseline HDL cholesterol

Usual HDL cholesterol (mmol/L)1·0 1·50·5

1

2

4

<5<5

5+5+

Baseline non-HDL(mmol/L)

Usual non-HDL cholesterol (mmol/L)3·0 4·0 5·0 6·0

<1·25<1·25

1·25+1·25+

Baseline HDL(mmol/L)

Haz

ard

rat

io(f

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ab

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isks

& 9

5% C

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