Coronary artery calcium score prediction of all cause mortality and cardiovascular events in people with type 2 diabetes: systematic review and meta-analysis


 

Objective To investigate the association of coronary artery calcium score with all cause mortality and cardiovascular events in people with type 2 diabetes.

Design Systematic review and meta-analysis of observational studies.

Data sources Studies were identified from Embase, PubMed, and abstracts from the 2011 and 2012 annual meetings of the American Diabetes Association, European Association for the Study of Diabetes, American College of Cardiology, and American Heart Association (2011).

Eligibility criteria Prospective studies that evaluated baseline coronary artery calcium score in people with type 2 diabetes and subsequent all cause mortality or cardiovascular events (fatal and non-fatal).

Data extraction Two independent reviewers extracted the data. The predictive value of the coronary artery calcium score was assessed by random effects model.

Results Eight studies were included (n=6521; 802 events; mean follow-up 5.18 years). The relative risk for all cause mortality or cardiovascular events, or both comparing a total coronary artery calcium score of ≥10 with a score of <10 was 5.47 (95% confidence interval 2.59 to 11.53; I2=82.4%, P<0.001). The overall sensitivity of a total coronary artery calcium score of ≥10 for this composite outcome was 94% (95% confidence interval 89% to 96%), with a specificity of 34% (24% to 44%). The positive and negative likelihood ratios were 1.41 (95% confidence interval 1.20 to 1.66) and 0.18 (0.10 to 0.30), respectively. For people with a coronary artery calcium score of <10, the post-test probability of the composite outcome was about 1.8%, representing a 6.8-fold reduction from the pretest probability. Four studies evaluated cardiovascular events as the outcome (n=1805; 351 events). The relative risk for cardiovascular events comparing a total coronary artery calcium score of ≥10 with a score of <10 was 9.22 (2.73 to 31.07; I2=76.7%, P=0.005). The positive and negative likelihood ratios were 1.67 (1.30 to 2.17) and 0.11 (0.04 to 0.29), respectively.

Conclusion In people with type 2 diabetes, a coronary artery calcium score of ≥10 predicts all cause mortality or cardiovascular events, or both, and cardiovascular events alone, with high sensitivity but low specificity. Clinically, the finding of a coronary artery calcium score of <10 may facilitate risk stratification by enabling the identification of people at low risk within this high risk population.

Discussion

In people with type 2 diabetes, the presence of a coronary artery calcium score of ≥10 predicts both all cause mortality and cardiovascular events as well as cardiovascular events alone, with high sensitivity but low specificity. The negative likelihood ratio of the coronary artery calcium score for these outcomes was strikingly low (0.18 for all cause mortality and cardiovascular events, and 0.11 for cardiovascular events). Indeed, our evaluation of risk estimates through the Bayes normogram suggests that the coronary artery calcium score may be especially helpful in clinical practice when it is below 10.

Our meta-analyses showed that the coronary artery calcium score might have a role in predicting events in people with type 2 diabetes. The findings of an increased relative risk for all cause mortality and cardiovascular events and cardiovascular events alone were consistent. The exploratory analysis of heterogeneity identified the variables associated with higher variance between studies, especially for cardiovascular events alone (where the sensitivity analysis eliminated the heterogeneity). We used the likelihood ratio as an alternative statistic because of its clinical applicability. Interestingly, we found a low negative likelihood ratio, in the range (that is, 0.1) that Deeks and Altman have previously suggested as providing strong evidence for ruling out the occurrence of an outcome in most circumstances.37

When evaluating a predictor of adverse outcomes, it is recognised that a useful predictor should have a favourable risk-benefit ratio, reasonable cost, acceptability, and convenience. In addition, to make screening worthwhile an effective treatment should be available, and this treatment should not be equally effective in everyone.38 In this context, screening using the coronary artery calcium score is a convenient and non-invasive test, although it involves exposure to ionising radiation of about 1 millisieverts (which is comparable to screening mammography).39 No formal cost effectiveness analyses have been done on the coronary artery calcium score in people with type 2 diabetes integrating risk, benefits, and cost; however, the current findings raise the possibility that screening using the coronary artery calcium score may be cost effective in some subgroups of people with diabetes. Moreover, a previous report showed that patient awareness of an abnormal score was associated with increased adherence to aspirin use and lifestyle changes,40 suggesting that, besides risk stratification, the coronary artery calcium score might help to support behavioural modification.

The American Heart Association has supported the use of the coronary artery calcium score quantification in people at intermediate risk to improve risk assessment (class IIb recommendation).41 Conversely, the American Diabetes Association does not recommend its routine use in people with type 2 diabetes because the overall balance of risk, benefits, and cost of such an approach in people without symptoms remains controversial.1 In light of the lack of previous evidence to support the routine use of the coronary artery calcium score as a screening test in people with type 2 diabetes, we feel that the current meta-analysis is much needed and holds implications for the design of future studies. In particular, the finding of such a low likelihood ratio suggests that a coronary artery calcium score of <10 might help with risk stratification of people with type 2 diabetes and potentially would change prevention strategies in those people. In fact, it has been suggested that the coronary artery calcium score may help to identify people with diabetes who may benefit from aspirin therapy among those without a clear indication based on current guidelines.13 Most importantly, if we consider that the prevalence of a coronary artery calcium score of <10 was 28.5% in our study population, the current findings might have an important impact on clinical care. Indeed, considering the worldwide prevalence of 346 million cases of type 2 diabetes,42 these data suggest that about 86.5 million people with type 2 diabetes would have a coronary artery calcium score of <10 and hence a low risk of cardiovascular events. In addition, a score of <10 has been observed in a significant proportion of people with diabetes at intermediate risk on pretest assessment, a subgroup of people who would most benefit from the coronary artery calcium score test.13 33 In this way, screening using the coronary artery calcium score may facilitate clinical risk stratification by identifying a sizeable subgroup of people at low risk within the high risk population of people with diabetes.

The concept of a low risk subgroup within the population of people with diabetes has been demonstrated in a previous report that showed a similar risk of all cause mortality between people with and without diabetes who had no coronary artery calcium score at baseline (survival 98.8% v 99.4% over five years, P=0.49).30 These data reinforce the results of our meta-analysis, in which a coronary artery calcium score of <10 was indicative of low risk for future events in people with diabetes. In addition, in the same way that the coronary artery calcium score adds to current predictive scores in the general population,6 these data raise the possibility that incorporation of coronary artery calcium score into existing risk scores for people with diabetes might improve risk prediction and hence warrants further investigation.

Limitations of this review

A limitation of our meta-analysis is that an analysis of additional risk stratification beyond current available risk scores for people with type 2 diabetes could not be performed owing to the absence of such studies. Secondly, most studies did not take into consideration the use of drugs (that is, aspirin and lipid lowering drugs) that could interfere with the estimates of event rate prediction based on the coronary artery calcium score. Nevertheless, as all studies were performed after 2004, we believe that the people were possibly treated similarly based on current clinical practice recommendations. Thirdly, only three studies reported baseline glycated haemoglobin A1c and duration of diabetes. However, although these covariates could not be included in metaregression analyses, our models were able to identify the studies that better explained the variance between studies. Of note, although most studies measured the coronary artery calcium score using the same technique, differences in the protocol for obtaining the scores could also have contributed to the variance between studies. Finally, we recognise that publication bias and the quality limitations of individual studies may still be relevant despite our best efforts to conduct a comprehensive search and the lack of statistical evidence of bias. The subjective nature of the Newcastle-Ottawa scale by which the quality of studies was assessed should also be noted.

Our meta-analysis strongly suggests that the coronary artery calcium score warrants further investigation as a prediction tool in people with type 2 diabetes. In particular, randomised controlled trials evaluating the impact of screening using the coronary artery calcium score on mortality are needed. Another point to consider in future studies is that atherosclerosis is a dynamic process, as shown by studies documenting both progression and regression of plaque.43 44 45 Glucose levels are an independent risk factor for progression of coronary artery calcium score,46 and people with type 2 diabetes have been shown to have a higher rate of progression than those without diabetes.47 Thus, the optimal frequency of screening using the coronary artery calcium score also needs to be established.

Conclusion

The coronary artery calcium score predicts all cause mortality and cardiovascular events and cardiovascular events alone in people with type 2 diabetes. People with a coronary artery calcium score of <10 were 6.8 times less likely to have cardiovascular event. Taken together, our meta-analysis strongly suggests the need for further investigation of the utility of using the coronary artery calcium score, particularly because of the implications that a negative screening test may hold for clinical risk stratification and preventive management in this population.

What is already known on this topic

  • The coronary artery calcium (CAC) score has been shown to predict the risk for cardiovascular events and facilitate reclassification of people from intermediate to low or high risk in large prospective studies of the general population
  • However, most of these studies excluded people with diabetes
  • The role of the CAC score in people with type 2 diabetes is unclear and given the broad range of cardiovascular risk observed in people with diabetes, this population warrants focused investigation on the predictive capacity of the CAC score
  • A CAC score of ≥10 predicted all cause mortality or cardiovascular events, or both compared with a score of <10, with high sensitivity but low specificity
  • For people with a CAC score of <10, the post-test probability of all cause mortality or cardiovascular events was reduced by 6.8-fold from their pretest probability
  • In people with diabetes, the finding of a CAC score of <10 may facilitate risk stratification by enabling the identification of low risk people within this otherwise high risk population

What this study adds

Source: BMJ

 

 

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