Transcript Slide 1

PSC
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
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
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)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Collaborators and investigators
Atherosclerosis 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.
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
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% steeper
than that with measured values
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol
256
80-89
1 mmol/L 
total cholesterol
15%  risk
128
70-79
18%  risk
60-69
28%  risk
50-59
42%  risk
40-49
56%  risk
Hazard ratio
(floating absolute risks & 95% CI)
Age at
risk
64
32
16
8
4
2
1
0·5
4·0
5·0
6·0
7·0
8·0
Usual total cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol
by age and sex
Age at
risk
Sex
80-89
Men
Women
Total
70-79
60-69
50-59
No. of
deaths
2919
2707
5626
0·85 (0·82-0·89)
Men
7372
Women
3457
Total
10 829
0·82 (0·80-0·85)
Men
8594
Women
1825
Total
10 419
0·72 (0·69-0·74)
Men
Women
Total
5001
560
5561
0·58 (0·56-0·61)
Men
Women
Total
1191
118
1309
0·44 (0·42-0·48)
Hazard ratio (& 95% CI)
40-49
0·4
0·6 0·8 1·0
Hazard ratio (& 95% CI) for
1 mmol/L lower usual total cholesterol Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol
by baseline SBP
Age at
risk
SBP
No. of
(mmHg) deaths
70-89
165+
7634
0·82 (0·79-0·84)
145-164
4645
0·79 (0·76-0·82)
<145
4176
0·76 (0·73-0·79)
165+
3174
0·81 (0·78-0·84)
145-164
3027
0·73 (0·70-0·76)
<145
4218
0·68 (0·65-0·70)
165+
1364
0·66 (0·62-0·70)
145-164
1908
0·62 (0·59-0·65)
<145
3598
0·53 (0·51-0·55)
60-69
40-59
0·4
0·6 0·8 1·0
Hazard ratio (& 95% CI) for
mmol/L lower usual total cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol
by smoking status
Age at Smoking No. of
risk
status
deaths
70-89
Current cig 2730
0·74 (0·71-0·78)
Other
11 168
0·80 (0·78-0·82)
2557
0·77 (0·74-0·81)
Current cig 3911
0·70 (0·68-0·73)
Other
5170
0·71 (0·68-0·74)
Never
smoker
1338
0·71 (0·67-0·76)
Current cig 3612
0·58 (0·56-0·60)
Other
2608
0·54 (0·52-0·57)
650
0·59 (0·54-0·64)
Never
smoker
60-69
40-59
Never
smoker
0·4
0·6 0·8 1·0
Hazard ratio (& 95% CI) for
1 mmol/L lower usual total cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol
by BMI
Age at
risk
BMI
(kg/m2)
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)
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)
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)
60-69
40-59
No. of
deaths
0·4
0·6 0·8 1·0
Hazard ratio (& 95% CI) for
1 mmol/L lower usual total cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (3020 deaths) versus usual
(a) HDL cholesterol; (b) non-HDL cholesterol; and (c) total/HDL cholesterol
by age at risk
1.33 units 
total/HDL
70-89 31% 
years
Hazard ratio
(floating absolute risks & 95% CI)
128
70-89
years
64
70-89
years
32
60-69 40% 
60-69
16
8
40-59 44% 
60-69
4
2
Hazard ratio (& 95% CI)
1
0·5
40-59
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
40-59
1·0
1·5
Usual HDL
(mmol/L)
3
4
5
6
Usual non-HDL
(mmol/L)
3 4 5 6 7
Usual total/HDL
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
IHD mortality (3020 deaths) versus usual HDL cholesterol
128
Hazard ratio
(floating absolute risks & 95% CI)
PSC
64
Age at
risk:
0.33 mmol/L 
HDL
32
70-89
35%  risk
60-69
83%  risk
16
8
4
2
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
1
40-59
Hazard ratio (& 95% CI)
63%  risk
0·5
1·0
1·5
Usual HDL cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
IHD mortality (3020 deaths) versus usual non-HDL cholesterol
128
Age at
risk:
1 mmol/L 
non-HDL
70-89
27%  risk
60-69
34%  risk
40-59
43%  risk
64
Hazard ratio
(floating absolute risks & 95% CI)
PSC
32
16
8
4
Hazard ratio (& 95%2CI)
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
1
0·5
3
4
5
6
Usual non-HDL cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
IHD mortality (3020 deaths) versus usual total/HDL cholesterol
128
Age at
risk
70-89
1.33 units 
total/HDL
31%  risk
60-69
40  risk
40-59
44%  risk
64
Hazard ratio
(floating absolute risks & 95% CI)
PSC
32
16
8
4
Hazard ratio (& 95%2 CI)
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
1
0·5
3
4
5
6
7
Usual total/HDL cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Stroke mortality (11 663 deaths) versus usual total cholesterol by age
Hazard ratio
(floating absolute risks & 95% CI)
64
Age at risk:
32
16
80-89
HR (95% CI)
per 1mmol/L :
1.06 (1.00-1.13)
70-79
1.04 (0.99-1.09)
60-69
1.02 (0.97-1.08)
40-59
0.90 (0.84-0.97)
8
4
Hazard ratio (& 95% CI)
2
1
4·0
5·0
6·0
7·0
8·0
Usual total cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Stroke mortality (11 663 deaths) versus usual total cholesterol
by type and age
Stroke
subtype
Age at No. of
risk
deaths
Total
stroke
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)
Haemorrhagic 80-89
stroke
70-79
422
1·06 (0·90-1·25)
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) Test for trend: 12 = 4.3 (P=0.04)
Ischaemic
80-89 CI)519
Hazard
ratio (& 95%
stroke
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) Test for trend: 12 = 15.1 (P=0.0001)
0·6
0·8 1·0 1·2 1·4
Hazard ratio (& 95% CI) for
1 mmol/L lower usual total cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
Stroke mortality (11 663 deaths) versus usual total cholesterol
by baseline SBP
8
Hazard ratio
(floating absolute risks & 95% CI)
PSC
Baseline SBP
1 mmol/L 
(mmHg):
total cholesterol
4
185+
10%  risk
165-184
15%  risk
145-164
7%  risk
<145
42%  risk
2
Hazard ratio (& 95% CI)
1
4·0
5·0
6·0
7·0
8·0
Usual total cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Stroke mortality (16 497 deaths) versus usual total cholesterol
by baseline SBP
Stroke
subtype
Total
stroke
SBP
(mmHg)
No. of
deaths
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)
Haemorrhagic 185+
stroke
165-184
662
1·16 (1·05-1·27)
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)
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)
Ischaemic
stroke
0·6
Test for trend:12 = 53·2 (p<0·0001)
Test for trend: 12 = 15·7 (p=0·0001)
Test for trend: 12 = 8.9 (p=0·003)
0·8 1·0 1·21·4
Hazard ratio (& 95% CI) for
1 mmol/L lower usual total cholesterol
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Stroke mortality (914 deaths) versus usual:
(a) HDL cholesterol; (b) non-HDL cholesterol; and (c) total/HDL cholesterol
128
HR (95%CI)
per 1.33 units 
total/HDL
Hazard ratio
(floating absolute risks & 95% CI)
64
32
70-89
years
16
70-89
years
70-89 years
0.95 (0.83-1.10)
8
4
2 Hazard ratio (& 95% CI)
1
Hazard ratio (& 95% CI)
40-69
0·5
1·0
1·5
Usual HDL
(mmol/L)
UDV3:[VEP.PSC.FIGURES.TCHOL.240907]stroke-thing4.ctrl: 24-SEP-2007 14:47:23.91
40-69
3
4
5
6
Usual non-HDL
(mmol/L)
Hazard ratio (& 95% CI)
40-69
0.86 (0.74-0.99)
3 4 5 6 7
Usual total/HDL
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
Stroke mortality (914 deaths) versus usual HDL cholesterol
128
Hazard ratio
(floating absolute risks & 95% CI)
PSC
64
HR (95%CI) per
0.33 mmol/L  HDL
32
70-89 years
1.02 (0.88-1.17)
16
8
4
Hazard ratio (& 95%2CI)
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
40-69 years
1.04 (0.89-1.23)
1
0·5
1·0
UDV3:[VEP.PSC.FIGURES.TCHOL.240907]stroke-thing4.ctrl: 24-SEP-2007 14:47:23.91
1·5
Usual HDL
(mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
Stroke mortality (914 deaths) versus usual non-HDL cholesterol
128
HR (95%CI) per
1 mmol/L  non-HDL
64
Hazard ratio
(floating absolute risks & 95% CI)
PSC
32
70-89 years
1.05 (0.91-1.20)
16
8
4
Hazard ratio (& 95% 2CI)
Hazard ratio (& 95% CI)
40-69 years
0.96 (0.83-1.12)
1
0·5
Hazard ratio (& 95% CI)
3
4
5
6
Usual non-HDL
(mmol/L)
UDV3:[VEP.PSC.FIGURES.TCHOL.240907]stroke-thing4.ctrl: 24-SEP-2007 14:47:23.91
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Stroke mortality (914 deaths) versus usual total/HDL cholesterol
128
HR (95%CI)
per 1.33 units 
total/HDL
Hazard ratio
(floating absolute risks & 95% CI)
64
32
70-89 years
0.95 (0.83-1.10)
16
8
4
Hazard ratio (& 95% 2CI)
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
40-69 years
0.86 (0.74-0.99)
1
0·5
3 4 5 6 7
Usual total/HDL
UDV3:[VEP.PSC.FIGURES.TCHOL.240907]stroke-thing4.ctrl: 24-SEP-2007 14:47:23.91
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
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)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
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
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
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
• The contrast between these statistically reliable
observational epidemiological results and the statistically
reliable randomised trial results is substantial and invited
further research
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
Selected WEB material
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (33 744 deaths) versus usual total cholesterol by SBP
8
Baseline SBP
(mmHg):
Hazard ratio
(floating absolute risks & 95% CI)
185+
165-184
145-164
4
<145
2
Hazard ratio (& 95% CI)
1
4·0 5·0 6·0 7·0 8·0
Usual total cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39
PSC
IHD mortality (3020 deaths) versus:
(a) usual HDL cholesterol by baseline non-HDL cholesterol
(b) usual non-HDL cholesterol by baseline HDL cholesterol
(a)
(b)
Baseline HDL
(mmol/L)
<1·25
4
1·25+
2
Baseline non-HDL
(mmol/L)
5+
1
Hazard ratio (& 95% CI)
Hazard ratio (& 95% CI)
<5
0·5
1·0
1·5
Usual HDL cholesterol (mmol/L)
UDV3:[VEP.PSC.FIGURES.TCHOL.240907]ihd-hdl-ndl.ctrl: 24-SEP-2007 17:19:17.65
3·0 4·0 5·0 6·0
Usual non-HDL cholesterol (mmol/L)
Prospective Studies Collaboration
Lancet 2007; 370:1829-39