The apo B/A-I Ratio -- A Stronger Predictor of Cardiovascular Events Than LDL, HDL, or Total Cholesterol, Triglycerides, or Lipid Ratios

Linda Brookes, MSc


July 28, 2006

Editorial Collaboration

Medscape &


For a number of years, evidence has been accumulating from clinical trials that assessing the levels of apolipoprotein (apo) B, a constituent of atherogenic lipoproteins; apo A-I, a component of antiatherogenic high-density lipoprotein (HDL) cholesterol; and the apo B/A-I ratio will provide better prediction of future cardiovascular events than measuring serum low-density lipoprotein (LDL)-cholesterol levels. In 2004, the global INTERHEART study of risk factors for acute myocardial infarction (MI) in 52 countries concluded that "the apo B/A-I ratio was the most important risk factor in all geographic regions.[1]" Now new data from the long-term follow-up of a prospective trial and analyses of major clinical trials of lipid-lowering therapy show that the predictive power of the apo B/A-I ratio is superior to, and cannot be improved by adding, any other lipid parameter or ratio.

Göran Walldius, MD, PhD (King Gustaf V Research Institute, Karolinska Institute, Stockholm, and AstraZeneca, Mölndal, Sweden), believes that the apo B/A-I ratio should be included in new guidelines for risk evaluation.[2] He outlined the methodological advantages in measuring the ratio compared with other parameters:

  • The availability of internationally standardized methods;

  • Measurements not affected by triglyceride levels up to at least 10 mmol/L (390 mg/dL);

  • Blood sampling does not require fasting; and

  • Analysis can be made on frozen samples.

Individuals with seemingly normal LDL cholesterol (< 3.3 mmol/L, 127.1 mg/dL) may in fact have high apo B values, revealing the presence of many small, dense LDL particles, thus indicating substantial risk, Prof. Walldius noted. On the other hand, these individuals can be identified by their high apo B/A-I ratio. Patients with metabolic syndrome and type 2 diabetes can also easily be identified.

The apo B/A-1 ratio is easy to use (and easy to explain to patients) because the risk is integrated into 1 number, and it indicates the cholesterol balance between potentially atherogenic and antiatherogenic particles, Prof. Walldius pointed out. "Cardiologists, diabetologists, and endocrinologists are jumping onboard this new way of thinking, because the hallmark of this is that it is easier and simpler," he said. It should be under discussion by guideline committees, he suggested. However, during ensuing discussions, US delegates blamed a lack of standardization as the reason why US organizations have not moved forward to adopt measurement of the apo B/A-I ratio with greater enthusiasm, despite many calls for guidelines to do so.

AMORIS: Apolipoprotein-Related Mortality Risk

Prof. Walldius and colleagues at the Karolinska Institute originally reported in 2001 that the apo B/A-I ratio is of potentially greater value than LDL cholesterol for predicting risk for fatal MI in men and women on the basis of a study in 175,553 individuals recruited from screening programs.[1] In the prospective Apolipoprotein-related MOrtality RISk (AMORIS) trial,[3] plasma levels of apo B, apo A-I, total cholesterol, and triglycerides were measured and the apo B/A-I ratio calculated. Mean follow-up was 66.8 months for 98,722 men and 64.4 months for 76,831 women, during which 864 men and 359 women had a fatal MI.

In an updated analysis after a mean follow-up of 10.3 years, during which 1111 subjects had died from stroke and 3409 from ischemic coronary heart disease (CHD), including 2213 from MI, the apo B/A-I ratio was again shown to be a strong predictor of stroke. After adjustment for age, sex, total cholesterol, and triglycerides, this ratio was superior to LDL-cholesterol levels alone and any other cholesterol ratio in predicting risk (all at least P < .025). Thus, the odds ratio (OR) of the apo B/A-I ratio for all strokes was 2.07 (P < .0001). The strongest association was for ischemic stroke. Low apo A-I was a common abnormality in all stroke subtypes, including subarachnoidal and hemorrhagic strokes. The OR (adjusted for stroke) was 4.25 for MI and 3.38 for all ischemic CHD (both P < .0001). In all conditions, risk was log-linearly related to the apo B/A-I ratio.

Prof. Walldius went on to advocate that the dependence of risk for MI or stroke on an elevated apo B/A-I ratio should be further evaluated in clinical trials. Low HDL and apo A-I are both major determinants of stroke, he noted, but this can be included in the apo B/A-I ratio.

IDEAL: Incremental Decrease in Events Through Aggressive Lipid Lowering

An analysis of the Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) study, presented by Anders G. Olsson, MD, PhD (Linköping University Linköping, Sweden), showed that apo B/A-I was superior to LDL/HDL cholesterol in predicting the reduction in risk for major cardiac events achieved by statin therapy in the IDEAL trial.[4]

The main IDEAL trial, funded by Pfizer (New York, NY) compared the effects of 2 strategies of lipid lowering on the risk for cardiovascular disease among patients aged ≤ 80 years with a history of acute MI.[5] Patients were randomized to treatment with high-dose atorvastatin (80 mg/day) or usual-dose simvastatin (20 mg/day). During treatment, mean LDL-cholesterol levels were 104 mg/dL (2.7 mmol/L) in the simvastatin group and 81 mg/dL (2.1 mmol/L) in the atorvastatin group. Over a median follow-up of 4.8 years, major coronary events (coronary death, nonfatal acute MI, or cardiac arrest with resuscitation) were reduced by 11% in the atorvastatin group compared with the simvastatin group, although this reduction was not statistically significant (P = .07). Significant reductions were seen in other secondary endpoints, including major cardiovascular events (13%, P = .02), any CHD (16%, P < .001), and any cardiovascular event (16%, P < .001).

Prof. Olsson and colleagues used the IDEAL data to compare the ability of apo B/A-I with that of the LDL-/HDL-cholesterol ratio to predict relative risk reduction (RRR) on major cardiovascular events. They used Cox fixed covariate regression analysis, adjusting for age and sex and using data from 2 time points, baseline, and on-treatment (average of the 3- and 6-month values). On-treatment analysis excluded major cardiovascular events that occurred during the first 6 months.

Analysis of the apo B/A-1 and LDL-/HDL-cholesterol ratios as categoric quintile variables showed a significant relationship for both baseline and on-treatment values between both ratios and RRR for major cardiovascular events. With both sets of values, there was a tendency for a better relationship with apo B/A-I.

Analysis of the ratios as continuous covariates showed that when the LDL/HDL ratios were adjusted for apo B/A-I, no predictive value remained, but when the apo B/A-I ratio was adjusted for LDL/HDL cholesterol, there was a residual explanatory effect by apo B/A-I, showing that there is more predictive value in apo B/A-I (Table 1).

Table 1. IDEAL: Residual Relative Risk Change After Adjustment for Competing Ratio (Age and Sex Adjusted)
HR 95% CI
LDL/HDL cholesterol adjusted for apo B/A-I:
Baseline 1.004 0.89-1.15
On-treatment 0.96 0.84-1.10
Apo B/A-I adjusted for LDL/HDL cholesterol:
Baseline 1.16 1.07-1.25
On-treatment 1.25 1.10-1.43
Apo = apolipoprotein; CI = confidence interval; HDL = high-density lipoprotein; HR = hazard ratio; LDL = low-density lipoprotein

Over the course of the IDEAL study, the LDL-/HDL-cholesterol ratio could only predict two thirds of the RRR observed either at baseline or on-treatment, whereas apo B/A-I predicted all the RRRs observed (Table 2).

Table 2. IDEAL: Observed vs Predicted Risk Reduction
Ratio Observed
Baseline RRR (%) On-treatment RRR (%)
Observed Predicted Observed Predicted
LDL/HDL 0.53 11 7 15 10
Apo B/A-I 0.16 11 11 15 15
Apo = apolipoprotein; HDL = high-density lipoprotein; LDL = low-density lipoprotein; RRR = relative risk reduction
CARDS: Collaborative Atorvastatin Diabetes Study

The hypothesis that apo B and apo A-I are better predictors of cardiovascular disease has also been tested in patients who participated in the Collaborative Atorvastatin Diabetes Study (CARDS). Paul Durrington, MD (University of Manchester, United Kingdom), reported that in the CARDS patients, all with type 2 diabetes, the apo B/A-I ratio predicted cardiovascular disease and CHD events and total mortality better than other lipoprotein variables.[6]

The main CARDS trial, also funded by Pfizer, investigated the effectiveness of atorvastatin 10 mg/day vs placebo for primary prevention of major cardiovascular events in 2838 diabetic patients without a high concentration of LDL cholesterol (≤ 4.14 mmol/L [160 mg/dL]), with fasting triglycerides ≤ 6.78 mmol/L (601 mg/dL), and with at least 1 risk factor, such as retinopathy, albuminuria, current smoking, or hypertension.[7] The trial was terminated early after a median follow-up of 3.9 years because of significant benefit seen on the atorvastatin arm. Compared with placebo, patients on atorvastatin showed a 37% reduction in acute CHD events, coronary revascularization, or stroke, the primary endpoint of the study (P = .001). Assessed separately, acute CHD events were reduced by 36%, coronary revascularizations by 31%, and rate of stroke by 48%. Atorvastatin reduced mortality by 27%. Levels of LDL, HDL, and total cholesterol and triglycerides were all significantly reduced with atorvastatin during the trial.

Complete laboratory data for apo analysis were available in 2627 patients. Total events in these patients were 108 fatal and nonfatal MI, 132 all-cause mortality, and 59 strokes. Apo B/A-I was found to be most significant parameter for risk for a primary endpoint (Table 3). Prof. Durrington stressed that that even among patients whose LDL cholesterol reached the target of ≤ 2 mmol/L (80 mg/dL), there was considerable variation in levels of apo B. Apo B levels tended to be greater in patients on atorvastatin compared with those on placebo (91 mg/dL vs 62 mg/dL for placebo).

Table 3. CARDS: Baseline Parameters and Cardiovascular Disease Events (Primary Endpoint)
Rank Parameter HR* 95% CI P Value
1 Apo B/A-I 1.248 1.107-1.408 .0007
2 LDL cholesterol/HDL cholesterol 1.256 1.094-1.442 .0014
3 LDL cholesterol 1.252 1.081-1.450 .0023
4 Apo B 1.199 1.044-1.377 .0104
5 Apo A-I 0.832 0.716-0.967 .0145
6 Non-HDL cholesterol 1.167 1.015-1.341 .0303
7 Cholesterol 1.139 0.989-1.311 .0701
8 Total cholesterol/HDL cholesterol 1.126 0.989-1.281 .0823
Apo = apolipoprotein; CI = confidence interval; HDL = high-density lipoprotein; HR = hazard ratio; LDL = low-density lipoprotein

*for standardized covariate

Categorizing apo B/A-I as tertiles for each endpoint showed an increasing predictive power at higher tertiles. A steep relationship was seen for CHD death plus nonfatal MI, showing that this was driving the cardiovascular endpoint. However (unlike the findings of Prof. Walldius and colleagues), neither apo B/A-I nor any other lipid parameter predicted stroke or transient ischemic attack in this study. Analysis of the CARDS data showed that treatment, age, female gender, albumin/creatinine ratio, and degree of glycemic control were the major determinants of stroke risk in this diabetic population. Some additional factor(s) not included in the investigation and altered by atorvastatin therapy must explain the decline in stroke risk and perhaps some of that in CHD, Prof. Durrington suggested.

  1. Yusuf S, Hawken S, Ounpuu S, et al; INTERHEART Study Investigators. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937-952. Abstract

  2. Walldius G, Jungner I. The apo B/apo A-I ratio -- a new predictor of fatal stroke, myocardial infarction and other ischaemic diseases -- stronger than LDL and lipid ratios. Atherosclerosis. 2006;7(suppl):468. Abstract Th-W50.6.

  3. Walldius G, Jungner I, Holme I, et al. High apolipoprotein B, low apolipoprotein A-I, and improvement in the prediction of fatal myocardial infarction (AMORIS study): a prospective study. Lancet. 2001;358:2026-2033. Abstract

  4. Durrington PN, Livingstone S, Charlton-Menys V, et al. Apolipoproteins as predictors of cardiovascular risk in the Collaborative Atorvastatin Diabetes Study (CARDS). Atherosclerosis. 2006;7(suppl):37. Abstract Mo-W14:4.

  5. Colhoun HM, Betteridge DJ, Durrington PN, et al; CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696. Abstract

  6. Olsson A, Holme I, Pedersen T. Apolipoprotein B/A1 ratio is a better discriminator of risk of coronary heart disease than is LDL/HDL-cholesterol ratio in the IDEAL study. Atherosclerosis. 2006;7(suppl):161. Abstract Tu-W20:4.

  7. Pedersen TR, Faergeman O, Kastelein JJ, et al; Incremental Decrease in Events through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445. Abstract


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