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Keywords:

  • cardiovascular disease;
  • rheumatoid arthritis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

Aim

Cardiovascular disease is a substantial contributor to increased morbidity and mortality in rheumatoid arthritis (RA). The aim of this audit was to determine the rate of cardiovascular events in a cohort of newly diagnosed RA patients.

Method

The inpatient clinical database from Christchurch Hospital, Christchurch, New Zealand, was searched using the International Classification of Diseases 9th Revision (ICD9) and 10 codes representing RA and cardiovascular disease between 1 January 1999 and 31 December 2008. Notes were reviewed with additional demographic and medication data sought. Outpatient data for RA patients was collated from the Rheumatology Department's letter database.

Results

Four hundred and six patients were identified with combined ICD9 or 10 codes for RA and ischemic heart disease, of whom 194 had a confirmed myocardial event. Of these, 34 were diagnosed with RA between January 1999 and December 2008 prior to their myocardial event. Kaplan–Meier analysis showed risk of a cardiovascular event at 1 and 10 years was 0.64% and 9.4%, respectively. There were 26 confirmed deaths in the study period. The risk of death at 1 and 10 years was 0.48% and 8.16%, respectively.

Conclusion

We have shown a relatively low prevalence of cardiovascular events in this RA population diagnosed within a 10 year period. This is consistent with other reports and likely reflects the short follow-up period. Prospective longer-term studies will be required to further investigate the relative contribution of disease activity and other parameters to cardiovascular events in patients with early RA.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

Rheumatoid arthritis (RA) is a chronic inflammatory condition of unknown aetiology affecting approximately 1% of the population.[1] RA is associated with a two-fold increase in mortality due to myocardial infarction (MI) compared with the general population.[2] The increased cardiovascular risk cannot be explained by traditional risk factors alone. Studies in Europe and North America suggest that this increased risk is not demonstrable less than 7 years from the diagnosis of RA, and is most pronounced 20 years from diagnosis,[3] suggesting that prolonged inflammation may increase atherosclerosis. Many of these studies were undertaken in cohorts from long-term studies and in patients who were diagnosed with RA in the era before intensive disease-modifying anti-rheumatic drug (DMARD) therapy and biologics, which are thought to ameliorate cardiovascular risk, thus reducing cardiovascular events.[3-6] The aim of this study was to determine the rate of cardiovascular events in newly diagnosed RA patients in Christchurch, New Zealand.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

Christchurch is located in the Canterbury region of New Zealand. The population in December 2009 was approximately 372 600. Christchurch Hospital is the tertiary referral service for Canterbury, so the vast majority of patients with a cardiovascular event are admitted into Christchurch Hospital.

A retrospective audit of case notes identified from Christchurch Hospital's administrative records was performed. Ethical approval was obtained from the Upper South Regional Ethics Committee. Patients with a diagnosis of RA and a cardiovascular event between 1 January 1999 and 31 December 2008 were identified using International Classification of Diseases 9th Revision (ICD9) codes (714 [RA] and 410–413, respectively [cardiovascular event]) and ICD10 codes (M05–M06 [RA] and I20–I21, respectively [cardiovascular event]). ICD coding at Christchurch Hospital only captures inpatient admissions. Notes were reviewed to confirm diagnoses which required electrocardiogram changes, troponin elevation, and/or cardiologist diagnosis. Cardiovascular events were defined as unstable angina, non-ST or ST elevation MI, cardiac arrest or cardiac death confirmed at post mortem. Christchurch Hospital's administrative records are updated regularly with local and national data. Dates of death are entered into the records within 6 months of the issuing of a death certificate. These records were the source of this information during the study. Standard demographic data was obtained as well as date of RA diagnosis, date of cardiovascular event, time to cardiovascular event from RA diagnosis, type of cardiovascular event, cardiac and RA medications, and cardiovascular risk factors (hypertension, smoking history, family history of ischemic heart disease and diabetes).

Statistical analysis was performed with graphpad prism 5 (GraphPad Software Inc., La Jolla, CA, USA). Kaplan–Meier survival analysis was performed to identify time from RA diagnosis to first cardiovascular event and time from RA diagnosis to death. The denominator of all newly diagnosed RA patients within the 10-year study period, the vast majority seen as outpatients, was calculated from the Department of Rheumatology database. RA diagnosis was made using American College of Rheumatology (ACR) criteria and/or rheumatologist diagnosis. The rheumatology database case notes were also reviewed to confirm the presence or absence of a discharge diagnosis of ischemic heart disease to cross-check the accuracy and completeness of the ICD discharge coding search.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

Four hundred and six patients were discharged during the study period with combined ICD9 or 10 codes for RA and a cardiovascular event. One hundred and ninety-four of these had a confirmed cardiovascular event, of whom 34 were diagnosed with RA between January 1999 and December 2008 prior to their cardiovascular event. This was the first cardiovascular event following RA diagnosis in all 34 patients. A search of the Rheumatology Departmental database yielded 619 additional patients who were diagnosed with RA during the study period (who did not sustain a cardiovascular event) giving a total of 653 patients (Fig. 1, flowchart of patient selection). The median RA disease duration of the cohort as a whole was 5.8 years (i.e., in over half of cohort, RA diagnosis was made post-March 2002).

image

Figure 1. Flow diagram of patient selection for retrospective audit of new RA diagnosis and cardiovascular (CV) events in the study period January 1999 – December 2008.

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Of the 34 RA patients who had cardiovascular events, the median age was 64 years (range 47–79) and there was an equal sex distribution; 91% were rheumatoid factor positive; 59% of the cardiovascular events were non-ST elevation MI, 21% were ST elevation MI and 21% unstable angina. There were no cardiac arrests or deaths during the study period. The most common cardiovascular risk factors were smoking (41% current smokers, 35% ex-smokers) and hypertension (71%); 41% had a family history of ischemic heart disease and 12% had diabetes.

Table 1 shows the use of rheumatoid and cardiovascular medications. None of the patients were on biologics at the time of their event. Reliable data on non-steroidal anti-inflammatory drug (NSAID) use was unavailable.

Table 1. Medication use by 34 rheumatoid arthritis (RA) patients with cardiovascular events
RA therapyNumber (%)
Prednisone15 (44)
Methotrexate10 (29)
Sulphasalazine8 (24)
Hydroxychloroquine7 (21)
Leflunomide4 (12)
Azathioprine 2 (6)
Gold 1 (3)
Cardiovascular therapy
Aspirin20 (59)
β-blocker16 (47)
Angiotensin converting enzyme inhibitor (ACE I)/angiotensin receptor blocker (ARB)12 (35)
Statin/fibrate12 (35)
Calcium channel blocker10 (29)
Nil therapy7 (21)

The time to first cardiovascular event is shown in Figure 2. The probability of a cardiovascular event in the first year after diagnosis of RA was 0.64% and 9.4% after 10 years. The median time to first cardiovascular event from RA diagnosis was 2.53 years (range 0.02–8.31).

image

Figure 2. Kaplan–Meier survival analysis showing the time to first cardiovascular event after diagnosis of rheumatoid arthritis. (Figs 2 and 3 display median and 95% confidence intervals).

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In the whole cohort there were 26 documented deaths; cause of death could not be determined. Figure 3 shows the probability of death in the first year after RA diagnosis was 0.48% and at 10 years 8.16%. The median time to death for these 26 patients was 3.23 years (range 0.25–8.55).

image

Figure 3. Kaplan–Meier survival analysis showing time to death following rheumatoid arthritis diagnosis.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

Our study shows a relatively low risk of cardiovascular events in this RA population within a 10-year period from diagnosis (34/653). There are a number of mechanisms by which RA increases cardiovascular risk, involving both traditional and non-traditional risk factors. Traditional risk factors, such as dyslipidemia, hypertension and smoking, are clearly important, although their impact appears to be less in RA than non-RA patients.[7] Traditional cardiovascular risk factors appear more important in early RA, whereas chronic inflammation appears to play a more important role in established RA.[8]

Chronic inflammation and RA therapies also influence traditional risk factors. In active RA, although there is reduced total cholesterol and triglycerides, there is a raised atherogenic index due to a disproportionate reduction in high-density lipoprotein (HDL).[9] Suppression of disease activity with DMARDs improves the atherogenic index by increasing HDL cholesterol.[3-6, 10]

There is suggestive evidence in the literature supporting the importance of attending to both traditional risk factors[11-15] and the suppression of chronic inflammation[5] in order to decrease cardiovascular events in RA patients. A low threshold for instituting 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors has also been advocated.[11, 12]

The relatively low number of cardiovascular events in our study was likely due to the short period of study (median follow-up 5.8 years), and is consistent with other reports.[3] The overall mortality of the RA cohort was also low in keeping with this observation. As indicated above, previous authors have suggested that over this timeframe it is more likely that traditional risk factors would predominate rather than inflammation.[8] Other factors, such as use of DMARDs and cardiovascular therapy, were not apparent in our cohort, perhaps due to the small numbers affected.

In conclusion, we have shown a low prevalence of cardiovascular events in this RA population within 10 years of diagnosis. Although this descriptive audit suggests that cardiovascular risk factors may be important predictors, a prospective longer-term study with information on disease activity and traditional risk factors for both the cases and the unaffected cohort will be required to elucidate the relative contributions of these factors on cardiovascular events in patients with early RA.

Author Contribution

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References

All authors contributed to the intellectual planning of the study, Dr Khan did the bulk of the clinical database searching, all authors contributed to the intellectual analysis of the data and writing of the paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Funding Information
  8. Author Contribution
  9. References
  • 1
    Silman AJ, Hochberg MC (2001) Epidemiology of the rheumatic diseases, 2nd edn. Oxford University Press, Oxford.
  • 2
    Van Halm V, Peters M, Voskuyl A et al. (2009) Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. Ann Rheum Dis 68, 1395400.
  • 3
    Choy E, Sattar N (2009) Interpreting lipid levels in the context of high-grade inflammatory states with a focus on rheumatoid arthritis: a challenge to conventional cardiovascular risk actions. Ann Rheum Dis 68, 4609.
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    Boers M, Nurmohamed M, Doelman C et al. (2003) Influence of glucocorticoids and disease activity on total and high density lipoprotein cholesterol in patients with rheumatoid arthritis. Ann Rheum Dis 62, 8425.
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    Greenberg J, Kremer J, Curtis J et al. (2011) Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 70, 57682.
  • 6
    Munro R, Morrison E, McDonald A, Hunter J, Madhok R, Capell H (1997) Effect of disease modifying agents on the lipid profiles of patients with rheumatoid arthritis. Ann Rheum Dis 56, 3747.
  • 7
    Kitas G, Gabriel S (2011) Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives. Ann Rheum Dis 70, 814.
  • 8
    Sattar N, McCarey D, Capell H, McInnes I (2003) Explaining how “High-Grade” systemic inflammation accelerates vascular risk in rheumatoid arthritis. Circulation 108, 295763.
  • 9
    Snow M, Mikuls T (2005) Rheumatoid arthritis and cardiovascular disease: the role of systemic inflammation and evolving strategies of prevention. Curr Opin Rheum 17, 23441.
  • 10
    Kaplan M (2006) Cardiovascular disease in rheumatoid arthritis. Curr Opin Rheum 18, 28997.
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    Van Doornum S, McColl G, Wicks I (2004) Atorvastatin reduces arterial stiffness in patients with rheumatoid arthritis. Ann Rheum Dis 63, 15715.
  • 12
    McCarey D, McInnes I, Madhok R et al. (2004) Trial of Atorvastatin in Rheumatoid Arthritis (TARA): double-blind, randomised placebo-controlled trial. Lancet 363, 201521.
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    Stavropoulos-Kalinoglou A, Metsios G, Panoulas V et al. (2009) Associations of obesity with modifiable risk factors for the development of cardiovascular disease in patients with rheumatoid arthritis. Ann Rheum Dis 68, 2425.
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    Dessein P, Joffe B, Veller M et al. (2005) Traditional and non-traditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J Rheumatol 32, 43542.
  • 15
    Bjornadal L, Brandt L, Klareskog L, Askling J (2006) Impact of parental history on patients' cardiovascular mortality in rheumatoid arthritis. Ann Rheum Dis 65, 7415.