Cardiovascular disease is a major comorbidity for patients with RA. However, relatively little information is available to determine which RA patients are at risk of CV events and the relative contributions of traditional CV risk factors versus markers of RA severity. We examined these issues using the CORRONA registry, a very large prospective RA cohort from the US. Both traditional CV risk factors and markers of RA severity contributed independent information to predict risk of future CV events. When both types of variables were included, the model’s discrimination improved. Markers of RA severity added to the model’s c-statistic above and beyond the traditional CV risk factors plus age and gender. Moreover, with increasing numbers of either type of variable, there was a trend toward increasing incidence rates of CV events.
Our data support the important independent contributions of both traditional CV risk factors and markers of RA severity to CV risk models. In models with both types of variables plus age and gender, we observed a c-statistic comparable to those calculated for analyses of the Framingham Risk Score.25
Our findings largely confirm prior work that focused on surrogate CV endpoints.17,18
While epidemiologic data do not substitute for treatment trials, these results suggest that strategies to reduce CV risk should focus on a strategy of controlling both traditional CV risk factors as well as controlling RA severity. In addition, it would be interesting to tailor interventions based on the risk factor profile. For example, patients with a greater number of markers of RA severity might be targeted for more intensive control of traditional CV risk factors, such as LDL lowering with statins, as well as better control of their RA disease activity.
There currently are no CV treatment trial data specific to RA patients. There are data from non-RA patients supporting the benefits of HMG CoA reductase inhibitors (“statins”) for secondary prevention and primary prevention in high risk groups.26
In addition, the TARA trial found that statins effectively lower lipid levels in patients with RA and resulted in small decrements in CRP, while also modestly reducing disease activity.27
One large trial of statins for primary prevention of CVD events in patients with RA is ongoing, however no results are expected until at least 2011.28
Interestingly, a recently published trial of statin use in persons without hyperlipidemia but an elevated CRP found a significant reduction in CV events in the statin arm.29
The authors hypothesize that an independent anti-inflammatory effect of high-dose statin therapy could contribute to a diminished CV risk. If this is the case, it follows that other RA interventions which substantially reduce inflammation might also result in similar effects. Several observational studies found reduced CVD morbidity and mortality among methotrexate users.30,31
In addition, TNF antagonists may improve endothelial function.32
However, studies with actual CV endpoints demonstrate mixed findings.13, 15, 33
The strengths of the current study are the large number of subjects with RA, the inclusion of traditional CV risk factors and markers of RA severity derived from both rheumatologists and patients, and the use of confirmed and adjudicated CV events. However, several limitations are important to discuss. First, while the CORRONA cohort is large, there were relatively few CV events included in this analysis, resulting in few events in certain cells in . The majority of endpoints included were confirmed by the treating rheumatologist, and the majority were adjudicated by a panel of cardiologists based on primary data. Medical records could not be obtained for some of the confirmed endpoints. These hospital medical records are not routinely received by U.S. rheumatologists when patients are hospitalized, and CORRONA does not have patient personal identifiers or patient consent to directly request these records. Thus, the investigator needs to obtain the records for CORRONA. Because some hospital records were requested for events occurring as remotely as 2002, records were not obtained on all patients. It would have been ideal to include coronary re-vascularization, but this information was not included in the CORRONA assessment forms used at the time these data were collected Second, it is possible that there is some under-ascertainment of CV events. Fewer composite events may have been observed because the data collection forms for the study period (2002–2006) did not have information on unstable angina. In addition, because death certificates were not available for the majority of patients, we chose to exclude CV-related deaths for this study. However, based on reference populations such as the WHO MONICA Study, one might have anticipated 1.34 events per 1,000 person-years.34
We found 3.98 events per 1,000 person-years in this cohort with RA, a group with a relative risk of CV events of 1.5 – 3.0. Thus, we believe that under-ascertainment was not a major problem. It is also possible that the higher utilization rate for biologic DMARDs could have influenced the rate of CV events which we observed. Because of the large percentage of these patients who utilized biologic DMARDs or MTX, it is also possible that the incidence of CV events in this population would be lower than that described in European populations in which a much smaller percentage of patients with RA receive these agents.35
As has recently been described, diverse sources of epidemiologic information derived from different societies serve to enhance insights.36
Third, detailed data on actual blood pressure and lipid measurements were not collected and thus it is possible that hypertension and hyperlipidemia were under-reported. Literature estimates of hypertension and hyperlipidemia in similar cohorts argues against under-reporting.37, 38
This limitation has been addressed in current versions of CORRONA forms. Finally, data on acute phase reactants are not mandated in CORRONA and therefore these data were incomplete. However, the Clinical Disease Activity Index (which does not require an acute phase reactant) is highly correlated with the Disease Activity Score (which does include an acute phase reactant).39
In conclusion, we found that both traditional CV risk factors and markers of RA severity were important predictors of future CV events in this very large US cohort. The risk added by RA-related factors added independent information to the predictive models. However, our models only explain a portion of the variability, likely because of imprecision in variable measurement as well as there being other variables not included in our adjusted models. These might include serologic markers, medications, and genetics. The European League Against Rheumatism has recently published recommendations for cardiovascular risk management among patients with RA.40
These recommendations acknowledge the importance of both traditional cardiovascular risk factors and RA-specific variables, similar to our analyses. The proportion of variation explained by both types of factors is similar, suggesting that both traditional CV risk factors and markers of RA disease severity can be appropriately targeted to lessen the incidence of CV events, the major source of mortality in patients with RA.