Further insight into risk and management of cardiovascular disease (CVD) from D:A:D cohort: no additional benefit of metabolic syndrome diagnosis; new HIV-specific CVD risk equations; increasing uptake of lipid lowering drugs but low smoking cessation

Simon Collins, HIV i-Base

Three posters from the D:A:D study presented at the conference provided additional insight into the management of cardiovascular risk in HIV-positive patients.

Signe Worm from the Copenhagen HIV Programme presented an analysis of whether the presence of metabolic syndrome (MS), a cluster of cardiovascular risk factors associated with an increased risk of CVD in the general population, is a more sensitive predictor than the sum of the component parts in HIV-positive individuals. [1] This issue has been the focus of recent presentations and debates at the Lipodystophy workshops (see ‘The role of Metabolic Syndrome in HIV, HTB October 2006 [2]).

D:A:D is a prospective multi-national cohort study of 23,236 HIV-infected subjects that has previously reported a cumulative risk of CVD associated with use of protease inhibitor-based combination therapy, supported by seven years follow-up data.

The effect of combinations of components of the metabolic syndrome (triglycerides =1.7mmol/L, HDL cholesterol </=1.0 mmol/L in men, </=1.3 mmol/L in women (HDL), systolic BP >130 or diastolic BP >85 mmHg, BMI >25 kg/m2, and a diagnosis of diabetes mellitus) were analysed for the risk of a CVD (myocardial infarction, stroke, and invasive procedures). The analysis adjusted for age, sex, family history of CVD, smoking status, calendar year, and exposure to combination ART).

The highest CVD rates were seen in patients with all traditional risk factors, compared to patients without those risk factors, and this increased with the number of individual risk factors. However, after adjusting for each of the individual risk factors as well as other confounders, there was no independent association with having metabolic syndrome (1.03, 95%CI 0.63 to 1.68).

This lead the authors to conclude that the presence of metabolic syndrome in HIV appears not to increase the CVD risk over and above that conferred by the components of the syndrome separately.

Data from the D:A:D cohort was also used to develop a model for CVD risk in HIV-positive patients, presented by Nina Friis-Møller from the Copenhagen HIV Programme. Currently, risk for clinical management is assessed by use of calculators developed in a non-HIV setting, for example using the Framingham equation, which was shown to under-predict risk of myocardial infarction in the D:A:D study.

The researchers first developing a model from just over 9000 patients (over 33,594 person-years, 157 cases of CHD occurred), which was later validated on a second separate dataset from the cohort.

The best fitting parametric model included the conventional risk factors (beta-coefficient; HR) of: age (per 5 years older –0.334; 1.42), sex (male –0.796; 2.35), family history of CVD (–0.478; 1.66), systolic BP (per 10 mmHg higher  –0.050; 1.05) and smoking status (current –1.042, ex –0.456; 2.97, 1.78), the ratio of TC/HDL (per unit higher –0.144; 1.16), diabetes (fitted separately by sex due to interaction (in men –0.683, women –1.349; 1.94 and 4.04), plus duration of protease inhibitor (PI) exposure (per additional year –0.114; 1.13). Overall, the D:A:D equation predicted 153 events (122 MI), compared with 157 (114MI) observed and 187 (103MI) predicted by the Framingham equation. Predictions were accurate in sub-groups of patients according to sex and smoking status (which Framingham had also underestimated).

Of the study population, 8.5% were estimated to be at high risk and 3.2% of developing cardiovascular heart disease in the next five years, with higher risks by gender, age, and smoking status, detailed in Table1.

Figure 1: 5-year risk of CHD in D:A:D cohort by risk factor

High risk Very high risk
Whole cohort 8.5% 3.2%
Women 0.8% 0.4%
Men 11.1% 4.1%
Age (<45m, <55W) 2.5% 0.3%
Age (<45m, <55W) 28.1% 12.5%
Non-smokers 4.2% 1.5%
Smokers 10.2% 3.7%

Finally, a poster presented by Caroline Sabin from the Royal Free Hospital looked at the use of interventions for cardiovascular risk in management of patients in the D:A:D cohort. [4]

348 patients were identified who had a first CVD event (204 myocardial infarction, 73 stroke, 71 invasive procedure) or were diagnosed with diabetes mellitus (626 patients) between December 1999 to February 2006, and use of lipid lowering drugs (LLD) was assessed in the previous and subsequent six month periods.

At the time of CVD event 80 (23%) were receiving LLD. 184 patients (53%) were using PI-based treatment. Overall, 149 (56%) of those not on LLD started these drugs in the next 6 months; LLD initiation, somewhat encouragingly, increased from 17% in 1999/2000 to 71% in 2005/2006 (p = 0.007), and was more common after a myocardial infarction (52%) or invasive procedure (46%) than after stroke (28%, p = 0.007).

Rates were similar after restricting the analysis to those with a total cholesterol of >3.5 mmol/L. However, smoking cessation was low with only 24 of 149 patients with a CVD event (16%) stopping smoking (myocardial infarction 21%, stroke 4%, invasive procedure 0%) and only 38 of 184 (21%) stopped their PI.

Among 626 patients diagnosed with diabetes, only 32 of 512 (6%) not on LLD started these drugs in the next 6 months, 10 of 193 (5%) smokers ceased smoking, and 86 of 316 (27%) on protease inhibitors stopped this drug class. There was no difference in the initiation of LLD over time in patients diagnosed with diabetes (p = 0.27).

The authors concluded that use of LLD following a CVD event has increased over time, although was only 70% in the most recent time period and was less common in those with stroke than myocardial infarctions or invasive procedures. Only a fifth of diabetics, a group at high risk for CVD mortality, not on LLD initiated such primary prevention. Smoking cessation was rare in both groups, and that greater emphasis should be placed on increasing use of LLD and reducing modifiable risk factors such as smoking.


  1. Worm SW, Sabin CA, Reiss P et al. Presence of the metabolic syndrome (MS) is not a better predictor of cardiovascular disease (CVD) that the sum of its components; Data from the D:A:D study. Poster abstract 815.
  2. The role of Metabolic Syndrome in HIV. Report from 8th International Lipodystrophy Workshop, September 2006, San Francisco.
  3. Friis-Møller N, Thiébaut R, Reiss P et al. Predicting the risk of coronary heart disease (CHD) in HIV-infected patients: The D:A:D CHD risk equation. Poster abstract 808.
  4. Sabin CA , Weber R, Dabis F et al. Underutilization of recommended interventions for prevention of cardiovascular (CV) disease in HIV-infected patients with established CV disease or diabetes. Poster abstract 816.
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