The literature search and information from experts identified 1075 citations from which 20 studies which fulfilled the inclusion criteria were identified (). Selected investigators of 16 of these studies9-17, 19-25
agreed to participate in the ABI Collaboration and provided data prior to the analysis. The participating studies and investigators are shown in Appendix 1
. The studies were based in Australia, Belgium, Italy, Netherlands, Sweden, UK and USA and comprised predominantly white populations except for the Honolulu Heart Program (Japanese Americans)11
and the Strong Heart Study (American Indians). 12
The populations in the Cardiovascular Health Study10
and the Atherosclerosis Risk in Communities9
(ARIC) study comprised 15% and 26% blacks respectively. In the San Luis Valley Diabetes Study24
the included healthy non-diabetic population was 42% Hispanic. Eleven studies included both sexes, four only men and one only women.
Flow diagram of selection of studies for inclusion in meta-analysis.
The characteristics of the subjects in the studies at baseline when the ABI was measured are shown in . A total of 24,955 men and 23,339 women without a history of coronary heart disease were included. They were late middle aged to elderly with a mean age in the studies ranging from 47 to 78 years. The 10-year incidence of coronary heart disease (SD) predicted by the FRS at baseline varied across studies from 11.0 (6.1)% to 31.6 (14.1)% in men and from 7.1 (6.1)% to 14.5 (10.1)% in women. Mean ABI (SD) was greater than 1.00 in all studies and ranged from 1.02 (0.13) to 1.21 0.13) in men and 1.01 (0.16) to 1.15 (0.17) in women; most of the studies comprising both sexes had higher mean values in men than in women, as previously reported.24
Baseline characteristics of subjects in studies in the ABI collaboration
and show the total mortality, cardiovascular mortality and major coronary events occurring during follow up in each of the studies for men and women respectively. Median duration of follow up ranged from 3.0 to 16.7 years, with 9 of the 16 studies having greater than 10 years of follow-up. Overall, 9,924 deaths occurred during 480,325 person years of follow up with around one quarter of deaths due to coronary heart disease or stroke in both men and women. The annual rates of deaths and events varied considerably between the studies. For example, in men in the Belgian Physical Fitness Study with mean age (SD) 47 (4.4) years the annual mortality (95% CI) was 0.37 (0.29 to 0.45)% whereas in men in the Honolulu Heart Program with mean age (SD) 78 (4.6) years, the annual mortality (95% CI) was 4.91 (4.59 to 5.22)% (). Likewise, in women annual mortality (95% CI) varied between 0.55 (0.42 to 0.68)% in the Framingham Offspring Study to 7.34 (6.39 to 8.29)% in the Women's Health and Aging Study ().
Total mortality, cardiovascular mortality and major coronary events for men in studies in the ABI Collaboration
Total mortality, cardiovascular mortality and major coronary events for women in studies in the ABI Collaboration
The hazard ratios (HRs) of death for different levels of ABI compared with a reference ABI of 1.11 to 1.20 in all studies combined formed a reverse J shaped curve for both men and women (). For levels of ABI below 1.11 the HRs increased consistently with decreasing ABI. For an ABI >1.40 the HRs were also increased: 1.38 (95% CI 1.17 to 1.62) for men and 1.23 (95% CI 1.00 to 1.52) for women. For levels of ABI between 1.11 and 1.40 only small and mostly non significant differences in HRs were found. and show the HRs for total and cardiovascular mortality and major coronary events by ABI in men and women, respectively. The patterns of risk for cardiovascular mortality and major coronary events were similar to that for total mortality; for levels of ABI below 1.11, the HRs for cardiovascular mortality were consistently higher than for total mortality.
Hazard ratios of total mortality in men and women by ankle brachial index at baseline for all studies combined in the ABI collaboration.
Hazard ratios of total mortality, cardiovascular mortality and major coronary events by ankle brachial index at baseline for men in all studies combined in the ABI Collaboration
Hazard ratios of total mortality, cardiovascular mortality and major coronary events by ankle brachial index at baseline for women in all studies combined in the ABI Collaboration
Values of the ABI less than 0.90 have been taken traditionally as a measure of increased risk. In nearly all the studies in men (), the HRs for total mortality were statistically significantly higher in individuals with an ABI ≤0.90 than in individuals with normal ABI values of 1.11 to 1.40, with a total HR (95% CI) of 3.33 (2.74 to 4.06). In women, the results were more heterogeneous () but the total HR of 2.71 (2.03 to 3.62) was comparable to that in men. Likewise, significantly increased total HRs (95%CI) were found in men and in women both for cardiovascular mortality, men 4.21 (3.29 to 5.39), women 3.46 (2.36 to 5.08), and for major coronary events, men 2.97 (2.33 to 3.78), women 3.05 (2.25 to 4.15). Adjustment of the HRs of ABI ≤0.90 relative to 1.11 to 1.40 for FRS reduced the HRs but they were still elevated substantially and significantly. In men adjusted HRs (95% CI) for total mortality, cardiovascular mortality and major coronary events were 2.34 (1.97 to 2.78), 2.92 (2.31 to 3.70) and 2.16 (1.76 to 2.66), respectively, and in women were 2.35 (1.76 to 3.13), 2.97 (2.02 to 4.35) and 2.49 (1.84 to 3.36), respectively.
Hazard ratios of total mortality for low (≤0.90) compared with normal (1.11-1.40) ankle brachial index in men in studies in the ABI collaboration.
Hazard ratios of total mortality for low (≤0.90) compared with normal (1.11-1.40) ankle brachial index in women in studies in the ABI collaboration.
and show the impact of inclusion of an ABI measurement on the apparent risk of 10-year total mortality, cardiovascular mortality and major coronary events over the range of FRSs in men and women. Compared with the overall rates without ABI included, an ABI ≤0.90 was associated with a greatly increased risk of mortality (total and cardiovascular) and major coronary events across all FRS categories in both men and women, more so in the lower than higher categories. Women had especially high mortality and event rates in the lowest FRS category. Men and women with an ABI 0.91 to 1.10 also had higher mortality and event rates than those with a normal ABI (1.11 to 1.40) but the magnitudes of the increase were much less than for those with ABI ≤0.90. Those with an ABI >1.40 also had higher rates across most FRS categories.
10-year total mortality, cardiovascular mortality and major coronary event rates in men by Framingham Risk Category and Ankle Brachial Index at baseline for all studies combined in the ABI Collaboration
10-year total mortality, cardiovascular mortality and major coronary event rates in women by Framingham Risk Category and Ankle Brachial Index at baseline for all studies combined in the ABI Collaboration
Inclusion of the ABI had an overall effect on the prediction of events, especially in women. In men the area under the ROC curve, (95% CI) when predicting major coronary events using only the FRS was 0.646 (0.643 to 0.657) and with the addition of the ABI was 0.655 (0.643 to 0.666). In women the area (95% CI) increased from 0.605 (0.590 to 0.619) to 0.658 (0.644 to 0.672).
The FRS is mostly used to predict risk of total coronary heart disease (CHD) (including coronary death, myocardial infarction and angina) and shows the impact of including the ABI on this prediction. The calibration of the FRS categories was reasonable because the overall CHD rate in each FRS category was within the range predicted, except for low risk women in which the overall CHD rate of 11% was higher than predicted. Likewise, the ability of the FRS to discriminate between risk categories was good, except that the overall CHD rate in women in the low risk group was only slightly lower than those in the intermediate risk group (11% v 13%). In each category of FRS in both men and women a low ABI (≤0.90) was associated with an increased risk of future CHD. Normal levels of the ABI (1.11 to 1.40) were associated with a slightly reduced risk from the overall rates but levels >1.40 did not differ consistently from the overall rates, although this may have been influenced by the relatively low numbers of subjects.
10-year total coronary heart disease rates in men and women by Framingham Risk Category and Ankle Brachial Index at baseline for all studies1 combined in the ABI Collaboration
The results in also indicate in which categories of FRS the ABI is likely to change individuals' clinical risk levels i.e. between <10%, 10-19%, and ≥20%. In men, the greatest impact would be in high risk individuals (≥20%) with a normal ABI (1.11 to 1.40) in whom the risk level would be reduced to intermediate (10-19%). All men with a low ABI (≤0.90) had a relatively high risk but their clinical risk level would not change from that predicted overall by the FRS. In women the main impact of the ABI would be to change all women in the low FRS category (<10%) with an abnormal ABI (≤0.90 or 0.91 to 1.10 or >1.40) to a higher risk level. Also women in the intermediate FRS category (10-19%) with a low ABI (≤0.90) would become high risk (≥20%). also shows that the number of men changing risk category (shaded numbers) would be 4,106 out of a total of 21, 433 (19%) and in women would be 8,154 out of a total of 22,486 (36%).