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- PATIENTS AND METHODS
In this retrospective cohort study, patients with RA had a significantly higher risk of both hospitalized and unrecognized MI prior to the incidence of RA, suggesting that the risk of CHD associated with RA precedes the ACR criteria–based diagnosis of RA. Patients with RA were also less likely to have symptoms of angina, were less likely to receive CABG, and had a significantly higher risk of sudden deaths. Together, these findings indicate that the presentation of CHD differs markedly in RA subjects compared with that in persons without the disease.
A higher risk of CHD in RA was reported previously in controlled studies (9–14), including one from our group. These studies are summarized in Table 4. Despite the differences in methods and CHD end points, all of these controlled studies reported a ≥40% higher risk of CHD associated with RA. However, these previous studies included mainly RA prevalence cohorts, with limited duration of followup, and relied heavily on self-reports to ascertain CHD events. Furthermore, the CHD events were limited to hospitalized MIs and sudden deaths and did not consider the complete spectrum of CHD events (20). The present study extends the findings of previous studies by demonstrating the complete spectrum of CHD events and reveals the striking shift in clinical presentation of CHD in RA.
Table 4. List of controlled studies examining the risk of coronary heart disease (CHD) in rheumatoid arthritis (RA)*
|Authors, year (ref.)||Study design||Data source||RA definition||Population-based||Incidence cohort||MI definition||Risk estimate|
|Gabriel et al, 1999 (9)||Cohort||Rochester Epidemiology Project||ACR 1987 criteria (n = 450)||Yes||No||Physician diagnosis, validation with medical records (n = 111)||1.35†|
|Del Rincon et al, 2001 (10)||Cohort (external control group) with 1 year followup||ORALE cohort‡||ACR 1987 criteria (n = 236)||No||No||Hospitalized MI (n = 7) + revascularization + stroke||3.96|
|Solomon et al, 2003 (11)||Cohort with >10 years followup||NHS§||Self-reports verified for ACR 1987 criteria (n = 527)||No||No||Self-reports of MI verified by medical record review, MI + sudden death (n = 2,296)||2.00|
|Wolfe et al, 2003 (12)||Cross-sectional survey||Participants of NDB¶||Rheumatologist diagnosis (n = 9,093)||No||No||Self-reports + 50% medical record validation||2.14|
|Watson et al, 2003 (13)||Cohort with 4.5 years followup||GPRD#||Physician diagnosis, no validation (n = 11,633)||No||No||Physician diagnosis, no validation||1.60|
|Fischer et al, 2004 (14)||Case–control (MI)||GPRD#||Physician diagnosis, no validation (n = 770)||No||No||Physician diagnosis, partial validation (n = 8,688)||1.47|
The first major finding of this study is the demonstration of a higher risk of both hospitalized and unrecognized MI prior to the clinical onset of RA. This finding is consistent with the absence of any association between cardiovascular mortality and RA disease duration in this cohort (36). Furthermore, recent studies demonstrated the presence of systemic inflammatory activity and serologic abnormalities several years prior to the onset of RA symptoms (37). Therefore, our findings are in accordance with the presence of a preclinical phase of RA, during which the risk of CHD appears to be elevated. Investigation of the risk of CHD prior to RA incidence was feasible, due to our unique ability to accurately ascertain and confirm incident CHD events using established reproducible criteria over an average period of 27 years prior to and 15 years following the RA incidence/index date in population-based cohorts. Previous studies included prevalent RA cohorts with limited or no followup data prior to study entry (Table 4), and therefore, it was not possible to accurately distinguish the timing of CHD events. This was further complicated by reliance on self-reports or physician diagnoses to ascertain CHD events, as well as lack of validation in most studies. In addition, analysis of combined end points, as was the case in previous studies, does not distinguish between the various CHD events. Thus, it is possible that excess CHD-related deaths in previous studies were driven, in large part, by an excess risk of sudden cardiac deaths.
The CHD event rates (i.e., hospitalized MI and sudden death) in our study are within the range of values reported in various CHD surveillance studies, including one in our community (34, 38, 39), but are substantially higher than those reported among the participants of the Nurses' Health Study (11). This may be due, in part, to censoring of subjects at the time of revascularization and angina in that study, and due, in part, to inclusion of a healthier cohort of health-conscious nurses with a more favorable CHD risk profile and lower CHD rates (40).
The second major finding of our study is the demonstration of a higher risk of unrecognized MIs and sudden deaths and a lower likelihood of angina symptoms in RA patients. These consistent findings demonstrate that CHD manifests differently in RA. Access to the original ECGs performed for screening or other clinical purposes in the routine clinical setting allowed us to reexamine ECG findings, using current diagnostic criteria, consistently throughout the long followup. The rates of coronary angiograms and ECGs were similar in both cohorts, both prior to and following the index date, excluding the possibility of differential ascertainment of unrecognized MIs in the 2 cohorts. Thus, if the likelihood of recognizing an MI is lower among RA subjects than among non-RA subjects, then in comparison with a prospective design with regular ECG assessments, our study would result in an underestimation of the true risk of unrecognized MI in RA.
Unrecognized MIs constitute up to 30% of the MIs in the community and were previously described in other diseases, such as diabetes mellitus and end-stage renal disease (41). Several pathophysiologic mechanisms have been implicated (41, 42), including individual differences in pain perception and generalized hyposensitivity to myocardial ischemia (41), and more recently, the balance between proinflammatory and antiinflammatory cytokines (43, 44). According to the inflammation-based hypothesis, there is higher production of antiinflammatory cytokines with lower expression of CD11b/CD18 adhesion molecules on phagocytes among patients with asymptomatic ischemia (43). It is possible that the actual experience of angina itself is equally frequent in the RA and the non-RA subjects, but the RA patients may be less likely to consult a physician for this symptom, or they may be more inclined to rationalize their chest pain and think that it may be related to their arthritis. It is equally possible that their physicians do not label the problem as being of cardiac origin. Further investigation of these possible mechanisms is warranted in RA patients because the long-term prognosis after an unrecognized MI may be worse than that after a recognized MI (41, 42). Because these infarctions are accompanied by minimal or no symptoms, they escape detection until ultimately resulting in sudden deaths, as was observed in our study.
Our findings also indicate that RA subjects were almost 70% less likely to undergo CABG than the non-RA subjects. This is not surprising, because a main impetus for undergoing revascularization procedures is pain, and in the absence of angina pectoris, subjects would be less likely to receive these procedures.
An interesting observation in our study was the higher incidence of hospitalized MIs during the 2 years preceding RA diagnosis. This may be due to Berkson's bias (45, 46), i.e., people who are seen in medical settings are more likely to have other diseases identified. Alternatively, an inflammatory activation or trigger that contributes to the acute MI event may, at the same time, cause a flare of RA symptoms that leads to diagnosis of RA. Further elucidation of this hypothesis may provide new insights into the inflammatory mechanisms of both CHD and RA. Moreover, the higher risk of acute hospitalized MI immediately prior to RA diagnosis in conjunction with the higher risk of sudden deaths raises the possibility that some individuals who would have become RA subjects (i.e., fulfilled the diagnostic criteria for RA) may have died before RA was diagnosed. This suggests that the risk of CHD prior to RA could have been underestimated and emphasizes the importance of studying incidence cohorts, rather than referral cohorts, when examining outcomes such as MI, which may be fatal at first presentation.
The strengths of our study are several-fold. This is the first population-based study examining the risk of CHD in RA. This study extends the findings of previous studies, and addresses various limitations through the longitudinal followup of an RA incidence cohort and a non-RA cohort sampled from the same community. In contrast to previous studies, we accessed and reviewed the entire inpatient and outpatient medical records of all subjects, including review of the original ECGs, for ∼27 years prior to and 15 years following the index date. We examined the complete spectrum of CHD events, including angina pectoris, revascularization procedures, and unrecognized MIs. We applied rigorous and validated diagnostic criteria to ascertain CHD events and CHD risk factors. Our CHD criteria are identical to the case definitions used in CHD surveillance studies in the United States (20, 38). Furthermore, we ascertained the traditional CHD risk factors throughout followup, and used them as time-dependent variables to fully account for the risk factors that developed during followup. To our knowledge, this is the first study to demonstrate that the increased risk of CHD in RA actually precedes the ACR criteria–based diagnosis of RA, and that unrecognized MIs and sudden deaths are the major contributors to the CHD risk in these subjects.
Our results should be interpreted in light of some potential limitations. Our findings may not be generalizable to nonwhite individuals, because the Rochester population during the calendar years under investigation was >95% white. With the exception of a higher proportion of the working population employed in the health care industry, and correspondingly higher education levels, the local population is socioeconomically similar to American whites (16). Second, we were not able to examine whether the increased risk of CHD was directly due to RA itself or to a complication of RA-associated therapy, because only 57% of the RA patients in our study ever received a disease-modifying antirheumatic drug. However, the absence of any calendar-year effect on the incidence of CHD in the RA cohort (P = 0.21) suggests that the increased risk cannot be completely explained by RA-associated therapy. Third, selection bias is a potential problem due to losses to followup. At the end of the study, the vital status of 10% of the study population was not known. In fact, these subjects remained under observation (and at risk for the CHD outcomes) for a mean of 13.1 years (median 10.7 years, interquartile range 5.6–19.1 years). Their followup data were censored in the analysis. There were no differences with respect to vital status followup information between the RA and the non-RA cohorts, and comparison of the baseline characteristics of subjects who remained under observation during the entire followup period (n = 1,086) and those who had either migrated or were lost to followup (n = 120) revealed that there were no baseline differences and there were no differences in availability of vital status data in the RA and the non-RA cohorts (P = 0.56). Therefore, the absence of vital status data is unlikely to affect the comparison of the CHD risk in the RA and non-RA cohorts. Fourth, this was a retrospective cohort study that relied on the clinical information recorded in the patients' medical records, and therefore, it was not possible to ascertain risk factors and CHD outcomes prospectively at regular intervals. Similarly, conditions not recorded in the medical records would have been missed. This could have been a potential problem for the ascertainment of unrecognized MIs. However, ECG rates were similar in both cohorts, suggesting that differential misclassification is unlikely. Fifth, multivariable analysis of CHD events and risk factors prior to the incidence/index date was essentially cross-sectional and did not distinguish among the risk factors that preceded the CHD event. Our ongoing analyses are focused on investigating whether RA acts as an effect modifier by interacting with the traditional CHD risk factors to increase the risk of CHD. Furthermore, the role of RA disease characteristics and medications on the clinical presentation and outcome of CHD in RA warrants further investigation.
Our findings provide compelling evidence that the increased risk of CHD precedes the ACR criteria–based diagnosis of RA and is not due to an increased incidence of traditional CHD risk factors. CHD in RA may remain unrecognized and may manifest as sudden cardiac deaths. In addition to the etiologic implications of these findings with regard to the inflammation-based etiology of atherosclerosis in RA, we believe that these findings have important implications for the detection and prevention of CHD comorbidity in RA patients. Physicians who care for RA patients should be aware of the higher risk of CHD that is already present at the time of initial diagnosis of RA and should actively monitor for subclinical CHD. A more vigilant and aggressive approach to screen for unrecognized CHD, using noninvasive methods, and to initiate treatment of CHD comorbidity may be warranted, since it could lead to reductions in the rate of CHD-related mortality in RA patients.