New data support the use of total/HDL cholesterol ratio to assess stroke risk

HDL Forum Editor Professor M John Chapman discusses a recent meta-analysis on cholesterol and vascular risk, published by the Prospective Studies Collaboration, Oxford, in The Lancet, December 1, 2007.

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 207;370:1829-39.

The researchers included data from 61 prospective observational studies from Western Europe (70%), North America or Australia (20%) or Japan or China (10%), including 892,337 individuals without previous disease and with baseline measurements for total cholesterol and blood pressure. During nearly 12 million person-years at risk between the ages of 40 and 89, there were more than 55,000 vascular deaths (about 34,000 due to ischaemic heart disease [IHD], 12,000 due to stroke and 10,000 due to other causes). Information on high-density lipoprotein (HDL) cholesterol was available for 150,000 subjects among whom there were 5,000 vascular deaths (about 3,000 due to IHD, 1,000 due to stroke and 1,000 due to other causes) (slide 1).

 

Subjects included in meta-analysis
 With total cholesterol at baselineWith HDL cholesterol at baseline
Total subjects892337153798
Ischaemic heart disease61% (33,744)61% (3,020)
Stroke21% (11,663)18% (914)
Other vascular18% (9,855)21% (1,032)

 

Total cholesterol was positively associated with IHD mortality, across all age and blood pressure categories. A 1 mmol/L lower total cholesterol was associated with about one-half lower IHD mortality in subjects aged 40-49 years (Hazard ratio 0.44, 95%CI 0.42-0.48), about one-third lower IHD mortality in subjects aged 50-69 years (Hazard ratio 0.66, 95%CI 0.65-0.68) and about one-sixth lower IHD mortality in subjects aged 70-89 years (Hazard ratio 0.83, 95%CI 0.81-0.85) (slide 2).

1 mmol/L decrease in total cholesterol was associated with:
  • 56% lower IHD mortality, ages 40-49 years (HR 0.44, 95%CI 0.42-0.48)
  • 34% lower IHD mortality, ages 50-69 years (HR 0.66, 95%CI 0.65-0.68)
  • 17% lower IHD mortality, ages 70-89 years (HR 0.83, 95%CI 0.81-0.85)

Findings from a combined analysis of data from the Multiple Risk Factor Intervention Trial (MRFIT), involving a further 34,242 vascular deaths, and the Prospective Studies Collaboration, were also reported in this paper. The combined results were consistent with those of the Prospective Studies Collaboration (slide 3).

 

Change in IHD, stroke and other vascular mortality for 1 mmol/L decrease in total cholesterol – combined data

Age group (years)IHDStrokeOther vascular mortality
40-49-55%-13%-38%
50-59-43%-9%-25%
60-69-32%-7%-17%
70-79-21%+2%-11%
80-89-15%+5%+2%

 

The magnitude of the risk reduction decreased with increasing blood pressure, as the absolute effects of cholesterol and blood pressure on IHD risk were generally additive.

A positive association between cholesterol and stroke was only observed in middle-age, and in subjects with below average blood pressure. The researchers could not explain these findings on the basis of current evidence: ‘Further investigation of exactly how lipoprotein particles affect stroke risks might help to explain this discrepancy.’

Ratio of total: HDL cholesterol more informative
For HDL cholesterol, there was a strong inverse association with IHD in every age group. There was no evidence of any threshold (within the range studied), beyond which HDL cholesterol was no longer associated with lower IHD mortality. Interestingly, the ratio of total/HDL cholesterol was the strongest predictor of IHD mortality, 40% more informative than non-HDL cholesterol and more than twice as informative as total cholesterol.

In the AMORIS study (Apolipoprotein-related Mortality Risk Study),1 a prospective study in a very large cohort in Sweden, apoB/apoA was the strongest risk factor for fatal myocardial infarction (MI). A recent analysis of the AMORIS study has extended the predictive value of the ApoB/ApoA-I ratio to the risk of fatal stroke.2 In addition, the INTERHEART study,3 a global case-control study of acute MI involving 52 countries, demonstrated that the imbalance between atherogenic lipids (apoB) and atheroprotective lipids (apoA-I, indicative of levels of HDL cholesterol) was the most important risk factor for MI. This finding was applicable to both men and women and younger and older individuals, and accounted for up to 54% of the overall population attributable cardiovascular risk.

1. Waldius G, Junger I, Holme I et al. High apolipoprotein B, low apoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet 2001;358:2026-33.

2. Walldius G, A. H. Aastveit AH, Jungner I. Stroke mortality and the apoB/apoA-I ratio: results of the AMORIS prospective study. J Intern Med 2006; 259: 259–66.

3. Yusuf S, Hawken S, Ounpuu S et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004; 364: 937-52.

In an accompanying editorial, Drs Pierre Amarenco (INSERM U-698 and Université Paris 7-Denis Diderot, Paris, France) and P Gabriel Steg (INSERM U-698, Université Paris 7-Denis Diderot and Bichat-Claude Bernard University Hospital, Paris, France) discuss the implications of this analysis. They argued that while the evidence supports cholesterol as a strong risk factor for IHD, a link between cholesterol and stroke risk also probably exists (especially with respect to atherothrombotic stroke). In this editorial, the authors indicate that the weight of evidence supports a link between HDL cholesterol and risk of stroke and carotid atherosclerosis, based on a recent systemic review of studies evaluating the relationship between HDL cholesterol and stroke risk and carotid intima-media thickness, a validated measure of carotid atherosclerosis.

Taken together, the Prospective Studies Collaboration authors conclude that it is reasonable to suggest that clinicians might need to consider the ratio of total/HDL cholesterol, rather than low-density lipoprotein (LDL) cholesterol, when assessing vascular risk (slide 4).

Total/HDL cholesterol ratio
  • Significantly more informative about ischaemic heart disease risk than non-HDL cholesterol
  • Offers one of the best ways of predicting vascular risk

Amarenco P, Steg PG. The paradox of cholesterol and stroke. Lancet 2007;370:1803-4. Amarenco P, Labreuche J, Touboul PJ. High-density lipoprotein-cholesterol and risk of stroke and carotid atherosclerosis: a systematic review. Atherosclerosis 2007;Oct 6 (Epub ahead of print).

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