Summary
Background
While there are convergent data suggesting that overall cardiovascular mortality is increased in patients with rheumatoid arthritis, the relative contributions of myocardial infarction and stroke remain unclear.
Aims
We sought to clarify this issue by conducting a meta-analysis of cohort studies on myocardial infarction and stroke in patients with rheumatoid arthritis.
Methods
A MEDLINE search from January 1960 to September 2009 and abstracts from international conferences from 2007 to 2009 were searched for relevant literature. All cohort studies reporting on standardized mortality ratio or incidence rate ratio of myocardial or stroke associated with rheumatoid arthritis, with available crude numbers, were included. STATA meta-analysis software was used to calculate pooled risk estimates.
Results
Seventeen papers fulfilled the inclusion criteria, corresponding to a total of 124,894 patients. Ten studies reported on standardized mortality ratio for fatal myocardial infarction, which ranged from 0.99 to 3.82. The overall pooled estimate was 1.77 (95% confidence interval [CI] 1.65–1.89). Incidence rate ratio for myocardial infarction was reported in five studies; the pooled estimate was 2.10 (95% CI 1.52–2.89). Nine studies reported on fatal stroke, with standardized mortality ratio ranging from 1.08 to 2.00; the pooled estimate was 1.46 (95% CI 1.31–1.63). The pooled incidence rate ratio for stroke (three studies) was 1.91 (95% CI 1.73–2.12).
Conclusion
Our results show that risks of myocardial infarction and stroke are increased in patients with rheumatoid arthritis. In addition, both account for the observed increased mortality in individuals with rheumatoid arthritis.
Résumé
Introduction
La mortalité cardiaque globale est augmentée au cours de la polyarthrite rhumatoïde, mais le niveau de risque de survenue d’un infarctus du myocarde et d’un accident vasculaire cérébral demeurent incertains.
Objectif
Préciser ce niveau de risque à l’aide d’une méta-analyse.
Méthodes
La recherche a été effectuée sur Medline, de janvier 1960 à septembre 2009 et à partir des abstracts des conférences internationales de 2007 à 2009. Les études de cohorte rapportant les risques de mortalité (SMR) et les taux d’incidence (IRR) d’infarctus du myocarde ou d’accident vasculaire cérébral au cours de la polyarthrite rhumatoïde ont été inclues.
Résultats
Dix-sept articles et/ou abstracts ont été retenus, ce qui correspond à une population totale de 124 894 patients. Dix études rapportent le SMR pour l’infarctus du myocarde fatal; il varie entre 0,99 et 3,82 selon les études. Le SMR global calculé est de 1,77 (IC 95 % : 1,65–1,89). Le risque de survenue d’infarctus du myocarde total a été rapporté dans cinq études ; le risque global calculé est de 2,10 (IC 95 % : 1,52–2,89). Neuf études ont rapporté le risque d’accident vasculaire cérébral fatal avec des SMR compris entre 1,08 et 2,00 ; le SMR global est de 1,46 (IC 95 % : 1,31–1,63). Le risque d’accident vasculaire cérébral total est de 1,91 (IC 95 % : 1,73–2,12).
Conclusion
Nos résultats montrent qu’il existe un sur-risque d’infarctus du myocarde et d’accident vasculaire cérébral au cours de la polyarthrite rhumatoïde ; tous deux contribuent à la surmortalité observée au cours de la polyarthrite rhumatoïde.
Background
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease, of unknown origin, that affects 0.5–1% of the adult population . Over the past decade, several studies have shown that RA is associated with an increased cardiovascular (CV) mortality . This has been confirmed by some meta-analyses that documented a 50–60% increase in CV mortality in RA patients . However, although some studies specifically reported the risk of myocardial infarction (MI), there are fewer data on stroke. Additionally, it has been suggested that the impact of RA on the risk of stroke may be weaker . Two meta-analyses investigated concomitantly CV mortality, MI and stroke, but these studies had some limitations . One pooled standardized mortality ratio (SMR) and incidence rate ratio (IRR), and was not exhaustive . The other meta-analysis did not include studies performed after 2005, a period of major advances in disease-modifying antirheumatic drugs . Therefore, the relative impact of RA on MI and stroke remain unclear. To clarify this issue, we performed a systematic review of published studies to assess the risk of MI and stroke in RA patients.
Methods
Search methods for identification of studies
We sought studies published between January 1960 and September 2009, without restriction in settings or language. Electronic searches were performed using MEDLINE, with both keywords and free text words “rheumatoid arthritis” and (“mortality” or “myocardial infarction” or “cardiovascular disease” or “stroke” or “cerebrovascular accident” or “coronary artery disease”). We reviewed the reference lists of all included studies, any relevant guidelines, general reviews, and commentaries pertaining to the management of patients with rheumatoid arthritis. To identify recent studies not yet published as full papers, we also searched books of abstracts from 2007 to 2009 conferences (European League against Rheumatism [EULAR] and American College of Rheumatology [ACR]).
Inclusion criteria
Eligible studies were cohort studies of patients with RA diagnosed according to the recommendations available during the study period . Articles had to report either enough data to compute a SMR or an IRR for at least one of the following outcomes: fatal or non-fatal MI, fatal or non-fatal stroke. Studies that reported death related to “ischemic heart disease”, “arteriosclerotic heart disease” or “coronary artery disease” were considered as relevant; their results were computed as fatal MI. In cases of multiple publications from the same cohort, we chose the study that provided the greatest amount of information (i.e., the largest number of patient-years).
Study selection
Two reviewers independently reviewed the studies to assess their eligibility for inclusion in the review. Disagreements were resolved by consensus. The two reviewers extracted data from the selected studies separately. Disagreements were resolved by consensus among all authors. To describe population characteristics, we abstracted the following: geographic area, mean age, female proportion, and mean duration of disease. To assess quality criteria, we abstracted the following: prospective study, consecutive enrolment, population-based study and completeness of follow-up.
Statistical analysis
SMR and IRR and their 95% confidence intervals (CIs) were calculated with crude numbers extracted from individual studies. Publication bias was assessed graphically, using a funnel plot .
If SMRs were reported without 95% CI, the interval was calculated using observed and expected number of deaths and assuming a Poisson distribution of observed cases. Pooled estimates of SMR for fatal MI and fatal stroke–IRR for MI and stroke–were calculated using the inverse variance method with the STATA meta-analysis program (STATA 10 software, StataCorp L, College Station, TX, USA). According to the heterogeneity test (significance at 5% level) either a fixed or a random-effects model was applied. To estimate the influence of individual studies on the summary effect estimate, meta-analysis estimates were re-computed omitting one study at a time.
Results
Among a total of 1939 references identified, 16 studies fulfilled our inclusion criteria. From abstract books of conferences we retrieved one abstract that fulfilled our inclusion criteria. Thus, we ultimately selected and included 17 studies, including one abstract, corresponding to a total population of 124,894 patients ( Fig. 1 ). The characteristics of the studies included in the review are given in Table 1 (SMR)Table 2 (IRR) . SMRs stratified by specific cohort characteristics are presented in Table 3 as highest, lowest and pooled estimates.
| Study | Location, study period | Patients ( n ) | Age | Women (%) | Disease duration at inclusion | Follow-up (RA patients) | Completeness of follow-up | Validation | Consecutive |
|---|---|---|---|---|---|---|---|---|---|
| Monson | USA, 1930–1960 | 1035 | NA | 74 | NA | Up to 1972 | 27% lost to follow-up | DC | Yes |
| Lewis | UK, 1966–1976 | 311 | NA | NA | NA | 11 years | Complete | DC (41% autopsy) | Yes |
| Allebeck | Sweden, 1971 | 1165 | NA | 46 | NA | Up to 1978 | Complete | Autopsy (67%) Medical records | Yes |
| Prior | England, 1964–1978 | 489 | NA | 65 | NA | 11.2 years | 8.4% lost to follow-up | DC | Yes |
| Erhardt | UK, 1979 | 308 | 59 | 71 | 7.4 years | Up to 1985 | Complete | DC | Yes |
| Reilly | England, 1957–1963 | 100 | 51 | 64 | 3.7 months | 25 years | Adequate | Autopsy ( n = 19), medical records | < 1 year duration |
| Wolfe a | USA, 1965–1990 Canada, 1966–1974 | 3501 | 53 | 74 | NA | Canada: 15.8 US: 8.5 years | 2.5, 4.5 33.6 and 10.5% lost to follow-up | DC | Yes |
| Wallberg-Jonsson | Sweden, 1979 | 606 | 55 | 68 | 12.5 years | 15 years | Complete | Medical records and DC | No, seropositive |
| Bjornadal | Sweden, 1964–1994 | 46,917 | NA | 71 | NA | 489,048 persons–years | Complete | DC | Yes |
| Thomas | Scotland, 1981–2000 | 33,318 | 61.8 | 73 | NA | 6.9 years | Complete | DC | Yes |
| Goodson | England, 1981–1996 | 1010 | 60.4 | 72 | Newly diagnosed | 11.4 years | 97% | DC | Newly diagnosed |
| Young | England, 1986–1997 | 1429 | 55 | 66 | 6 months | 9.1 years | Complete | DC | < 2 years’ duration |
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