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Reduction in the Incidence of Myocardial Infarction in Patients with Rheumatoid Arthritis Who Respond to Anti–Tumor Necrosis Factor ␣ Therapy

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Reduction in the Incidence of Myocardial Infarction in Patients with Rheumatoid Arthritis Who Respond to Anti–Tumor Necrosis Factor ␣ Therapy View metadata, citation and similar papers at core.ac.uk brought to you by CORE ARTHRITIS & RHEUMATISM provided by PubMed Central Vol. 56, No. 9, September 2007, pp 2905–2912 DOI 10.1002/art.22809 © 2007, American College of Rheumatology Reduction in the Incidence of Myocardial Infarction in Patients With Rheumatoid Arthritis Who Respond to Anti–Tumor Necrosis Factor ␣ Therapy Results From the British Society for Rheumatology Biologics Register W. G. Dixon, K. D. Watson, M. Lunt, K. L. Hyrich, British Society for Rheumatology Biologics Register Control Centre Consortium, A. J. Silman, and D. P. M. Symmons, on behalf of the British Society for Rheumatology Biologics Register Objective. Rheumatoid arthritis (RA) is associ- rate of 4.8 events per 1,000 person-years and 5.9 events ated with an increased risk of coronary artery disease, per 1,000 person-years, respectively. After adjustment possibly acting via shared mechanisms of inflammation. for baseline risk factors, there was no reduction in the This study was undertaken to test the hypothesis that rate of MI in the anti-TNF␣ cohort compared with the the powerful antiinflammatory effect of anti–tumor DMARD cohort (incidence rate ratio 1.44 [95% confi- necrosis ␣ (anti-TNF␣) therapy might lead to a reduc- dence interval 0.56–3.67]). In an analysis of anti-TNF␣– tion in the incidence of myocardial infarction (MI) in treated patients who responded to the treatment within patients with RA. 6 months versus those who did not, MI rates were found Methods. Using data from the British Society for to be 3.5 events per 1,000 person-years in responders Rheumatology Biologics Register, a national prospective and 9.4 events per 1,000 person-years in nonresponders. observational study, we compared MI rates in 8,670 The adjusted incidence rate ratio (95% confidence in- patients with RA treated with anti-TNF␣ and 2,170 terval) for responders compared with nonresponders patients with active RA treated with traditional disease- was 0.36 (0.19–0.69). modifying antirheumatic drugs (DMARDs). Conclusion. These results indicate that RA pa- Results. Through July 2006, 63 MIs occurred in tients treated with anti-TNF␣ do not have a lower the anti-TNF␣ cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort incidence of MI compared with RA patients treated with during 2,893 person-years of followup, equivalent to a traditional DMARDs. However, the risk of MI is mark- edly reduced in those who respond to anti-TNF␣ ther- apy by 6 months compared with nonresponders. This Dr. Hyrich is a former Fellow of the Canadian Arthritis finding supports the notion that inflammation plays a Society. Drs. Symmons and Silman’s work was supported by the Arthritis Research Campaign, UK. The British Society for Rheuma- pivotal role in MI. tology Biologics Register is supported by a research grant from the British Society for Rheumatology to the University of Manchester, which is indirectly funded by Schering-Plough, Wyeth Laboratories, It is now well established that rheumatoid arthri- Abbott Laboratories, and Amgen. tis (RA) is associated with increased mortality and W. G. Dixon, MRCP, K. D. Watson, PhD, M. Lunt, PhD, K. L. Hyrich, MD, PhD, FRCPC, A. J. Silman MD, FRCP, D. P. M. morbidity due to accelerated atherosclerosis, including Symmons, MD, FRCP: University of Manchester, Manchester, UK. from myocardial infarction (MI) (1–5). This increased Address correspondence and reprint requests to D. P. M. risk cannot be attributed to traditional cardiovascular Symmons, MD, FRCP, ARC Epidemiology Unit, Division of Epide- miology and Health Sciences, Stopford Building, University of risk factors, such as smoking and hypertension, alone Manchester, Oxford Road, Manchester M13 9PT, UK. E-mail: (2,5,6). There is mounting evidence that the increased [email protected]. Submitted for publication January 9, 2007; accepted in re- risk is related to the overall burden of inflammatory vised form May 4, 2007. disease in RA (7,8). In addition, atherosclerosis itself 2905 2906 DIXON ET AL is increasingly being viewed as an inflammatory condi- Comparison cohort. A cohort of patients with active tion (9). RA who have never taken biologic agents is being recruited in ␣ The cytokine tumor necrosis factor ␣ (TNF␣) parallel with the anti-TNF cohort by the BSRBR Control Centre Consortium (see Appendix A for a list of BSRBR plays a key role in the pathogenesis of RA (10). Intro- Control Centre Consortium members). The comparison co- duction of the anti-TNF␣ therapies infliximab, etaner- hort is followed up using the same methodology used to follow cept, and adalimumab has dramatically improved the up the anti-TNF␣ cohort (19). The patients in the comparison outcome of severe RA beyond that achieved with tradi- cohort were diagnosed as having active RA (guideline Ն tional disease-modifying antirheumatic drugs DAS28 4.2) despite current treatment with a traditional DMARD. These patients also had to have been followed up (DMARDs) (11–13). Proinflammatory cytokines, in- for Ն6 months by July 31, 2006. cluding TNF␣, are involved in modification of lipid Baseline assessment. Baseline data assessed in both profile and insulin resistance (14) and the initiation and cohorts included demographic characteristics, disease dura- progression of atherosclerosis (15,16), hemostasis (17), tion, 28-joint counts for swelling and tenderness, erythrocyte and atherosclerotic plaque rupture, the most common sedimentation rate and/or C-reactive protein level, and patient ␣ global assessment, and enabled calculation of a DAS28 score event leading to an acute MI (15). Inhibition of TNF in (20). Details of all previous and current DMARD therapy and patients with RA may therefore lead to a reduction in all other current medications were obtained. Patients com- MI rates by inhibiting one or more of these mechanisms. pleted a Health Assessment Questionnaire (HAQ) adapted for However, some patients do not respond well to anti- British use (23). Townsend scores of multiple deprivation were TNF␣ drugs. Therefore, we hypothesized that any re- calculated based on the patient’s area of residence and com- pared with UK quintiles (24). Data were also collected on duction in the incidence of MI would be limited to those other variables that might influence cardiovascular risk, includ- patients who displayed a good clinical response to TNF␣. ing all baseline drugs, body mass index (BMI), prior cardio- The aims of this study were, first, to determine vascular comorbidity (including previous MI, angina, and whether the incidence of MI in RA patients treated with hypertension), diabetes, and smoking history. anti-TNF␣ was lower than that in patients treated with Followup. Data on changes in therapy, disease activity, and the occurrence of adverse events were collected in 3 ways. traditional DMARDs and, second, to explore the impact Rheumatologists were sent a questionnaire every 6 months, of response to treatment on the rates of MI in the patients were sent a 6-month diary in which to document all anti-TNF␣ cohort. To date, 1 study has shown a reduced hospital admissions, new medications, and new hospital refer- rate of all cardiovascular events following anti-TNF␣ rals, and all patients were flagged with the UK General therapy (18), but no published studies have so far Register Office, which provides the BSRBR with information on deaths and cause of death (coded according to the Inter- explored MI incidence or the influence of treatment national Statistical Classification of Diseases and Related response. Health Problems, Tenth Revision) (25). If an MI was reported from any of the 3 sources, further supporting information, such PATIENTS AND METHODS as a hospital discharge summary, was requested from the Patients. Subjects were participants in a large national rheumatologist. prospective observational study, the British Society for Rheu- All available clinical information on the MIs was matology Biologics Register (BSRBR). Methods of patient reviewed by 2 physicians (WGD and KLH) independently to recruitment and followup have been described in detail else- verify the diagnosis according to an adapted European Society where (19). Briefly, the study aims to recruit all UK patients of Cardiology (ESC)/American College of Cardiology (ACC) with rheumatic diseases treated with biologic agents, and an definition (26). ESC/ACC criteria define an acute, evolving, or appropriate comparison group, in order to examine the long- recent MI as a typical rise and fall of biochemical markers of term safety of these drugs. UK national guidelines recommend myocardial necrosis with Ն1 of the following: ischemic symp- that anti-TNF␣ drugs be reserved for patients with active RA, toms, Q waves, ischemic electrocardiography changes, coro- defined as a Disease Activity Score in 28 joints (DAS28) (20) nary artery intervention, or pathologic findings of an acute MI. Ͼ5.1 despite previous therapy with at least 2 DMARDs, one of Additional BSRBR verification criteria were thrombolysis which should be methotrexate (21), and that “any clinician and/or MI recorded on death certificate, regardless of autopsy prescribing these medications must (with the patient’s permis- confirmation. Any disagreement was resolved by consensus sion) undertake to register the patient with the [BSRBR] and following discussion. Only verified MIs were included in the forward information on dosage, outcome and toxicity on a analysis. six-monthly basis” (22). Statistical analysis. Response to treatment in the Anti-TNF␣ cohort. This cohort was restricted to pa- anti-TNF␣ cohort was defined according to European League tients registered with the BSRBR who were diagnosed as Against Rheumatism criteria (27). Responders were those having RA and were treated with an anti-TNF␣ drug. Patients patients who achieved either a good or a moderate response, who were registered with the BSRBR Ͼ6 months after the i.e., a reduction in the DAS28 score from baseline to 6 months start of biologic therapy were excluded.
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