Background Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known. Design ...The Cardiovascular Inflammation Reduction Trial (CIRT) ( ClinicalTrials.gov NCT01594333 ) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants. Summary CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.
Abstract Objective There is little information comparing the potential risk of cancer across conventional and biologic disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid ...arthritis (RA). Methotrexate has not been the focus of most contemporary pharmacoepidemiologic studies of cancer. Methods We conducted a comparative effectiveness study with cancer as the outcome. A large observational cohort of RA was followed up from 2001 to 2010. Reports of any cancer prompted a confirmation process that included adjudication of the primary cancer records. We used a propensity score (PS) with relevant covariates and cohort trimming to improve the balance between DMARD cohorts. Cox proportional hazard regression models were constructed to estimate the risk of cancer with various DMARDs, all compared with methotrexate. Results We identified 6806 DMARD courses for analysis (1566 methotrexate; 904 nbDMARDs; 3761 TNF antagonists; 408 abatacept; and 167 rituximab). Non-biologic DMARDs (HR 0.17, 95% CI 0.05–0.65) and TNF antagonists (HR 0.29, 95% CI 0.05–0.65) were associated with a reduced adjusted risk of cancer compared with methotrexate. Abatacept (HR 1.55, 95% CI 0.40–5.97) and rituximab (HR 0.42, 95% CI 0.07–2.60) were similar in risk of cancer with methotrexate. These results were robust to sensitivity analyses. After controlling for DMARD exposures, risk factors for cancer included male gender, age, and alcohol consumption. Conclusions Cancer risk was elevated for methotrexate users compared with nbDMARDs and TNF antagonists.
Abstract Background Elevated tumor necrosis factor (TNF)-α likely contributes to the excess cardiovascular risk observed in rheumatoid arthritis. We compared the cardiovascular risk in rheumatoid ...arthritis patients starting a TNF-α blocking agent versus a nonbiologic disease-modifying antirheumatic drug (nbDMARD). Methods Subjects with rheumatoid arthritis participating in several different US insurance programs between 1998 and 2007 who received methotrexate were eligible. Those who added a TNF-α blocking agent were compared with subjects who added a nbDMARD in Cox regression models stratified by propensity score decile and adjusted for oral glucocorticoid dosage. We examined the composite cardiovascular end point of myocardial infarction, stroke, or coronary re-vascularization after 6 months. Results We compared 8656 new users of a nbDMARD with 11,587 new users of a TNF-α blocking agent with similar baseline covariates. Incidence rates per 100 person-years for the composite cardiovascular end point were 3.05 (95% confidence interval CI, 2.54-3.65) for nbDMARDs and 2.52 (95% CI, 2.12-2.98) for TNF-α blocking agents. The hazard ratio (HR) for the TNF-α blocking agent compared with nbDMARD carrying the first exposure forward was 0.80 (95%, CI 0.62-1.04), while the HR for the as-treated analysis was 0.71 (95% CI, 0.52-0.97). The potential cardiovascular benefit of TNF-α blocking agents was strongest among individuals ≥65 years of age (HR 0.52; 95% CI, 0.34 -0.77; P for interaction = 0.075). Conclusion Among subjects with rheumatoid arthritis, TNF-α blocking agents may be associated with a reduced risk of cardiovascular events compared with an nbDMARD. Randomized controlled clinical trials should be considered to test this hypothesis.
Rheumatoid arthritis and cardiovascular disease Crowson, Cynthia S., MS; Liao, Katherine P., MD, MPH; Davis, John M., MD ...
The American heart journal,
10/2013, Letnik:
166, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Background Rheumatic disease and heart disease share common underpinnings involving inflammation. The high levels of inflammation that characterize rheumatic diseases provide a “natural experiment” ...to help elucidate the mechanisms by which inflammation accelerates heart disease. Rheumatoid arthritis (RA) is the most common of the rheumatic diseases and has the best studied relationships with heart disease. Methods A review of current literature on heart disease and RA was conducted. Results Patients with RA have an increased risk of developing heart disease that is not fully explained by traditional cardiovascular risk factors. Therapies used to treat RA may also affect the development of heart disease; by suppressing inflammation, they may also reduce the risk of heart disease. However, their other effects, as in the case of steroids, may increase heart disease risk. Conclusions Investigations of the innate and adaptive immune responses occurring in RA may delineate novel mechanisms in the pathogenesis of heart disease and help identify novel therapeutic targets for the prevention and treatment of heart disease.
Abstract Background/purpose Treat-to-target (TTT) is a recommended strategy in the management of rheumatoid arthritis (RA), but various data sources suggest that its uptake in routine care in the US ...is suboptimal. Herein, we describe the design of a randomized controlled trial of a Learning Collaborative to facilitate implementation of TTT. Methods We recruited 11 rheumatology sites from across the US and randomized them into the following two groups: one received the Learning Collaborative intervention in Phase 1 (month 1–9) and the second formed a wait-list control group to receive the intervention in Phase 2 (months 10–18). The Learning Collaborative intervention was designed using the Model for Improvement, consisting of a Change Package with corresponding principles and action phases. Phase 1 intervention practices had nine learning sessions, collaborated using a web-based tool, and shared results of plan–do–study–act cycles and monthly improvement metrics collected at each practice. The wait-list control group sites had no intervention during Phase 1. The primary trial outcome is the implementation of TTT as measured by chart review, comparing the differences from baseline to end of Phase 1, between intervention and control sites. Results All intervention sites remained engaged in the Learning Collaborative throughout Phase 1, with a total of 38 providers participating. The primary trial outcome measures are currently being collected by the study team through medical record review. Conclusions If the Learning Collaborative is an effective means for improving implementation of TTT, this strategy could serve as a way of implementing disseminating TTT more widely.
Abstract Background The role of lose dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared ...LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. Design CIRT will randomize up to 7,000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose 15–20 mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1 mg daily for six days each week. The primary endpoints of CIRT include recurrent vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. Summary CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.
Abstract Objective Documentation of quality measures (QMs) in rheumatoid arthritis (RA) is used as a surrogate for measure of quality of care, but the association of this documentation with ...radiographic outcomes is uncertain. We examined documentation of RA QMs, for disease activity and functional status and the association with radiographic outcomes. Methods Data were analyzed for 438 RA patients in a longitudinal cohort with complete data on van der Heijde-modified Total Sharp Score (TSS). All rheumatologist ( N = 18) notes in the electronic medical record during a 24-month period were reviewed for RA QMs. Any mention of disease activity categorized as low, moderate, or high was considered documentation of the QM for disease activity. Functional status QM documentation included any mention of the impact of RA on function. Change in TSS was quantified with progression defined as ≥1 unit per year. We compared percent of visits with an RA QM documented and mean change in TSS. Results The mean age in the cohort was 56.9 years, disease duration was 10.8 years, baseline DAS28 score was 3.8 (±1.6), 67.7% were seropositive, and 33.9% used a biologic DMARD. Radiographic progression was observed in 28.5%. Disease activity was documented for 29.0% of patient visits and functional status in 74.7%; neither had any significant relationship to mean TSS change (both P > 0.10). Conclusion The documentation of RA QMs was infrequent and not associated with radiographic outcomes over 24 months.
Abstract Objective Current recommendations advocate treatment with disease-modifying anti-rheumatic drugs (DMARDs) in all patients with active rheumatoid arthritis (RA). We analyzed short-term ...disease outcome in patients according to the consistency of DMARD use in a clinical rheumatology cohort. Methods Patients in an RA registry ( n = 617) were studied for DMARD use at semi-annual study time points during the first 18 months of follow-up and were divided into 4 groups according to the number of study time points with any DMARD use 0–1 study time points ( n = 31), 2 study time points ( n = 24), 3 study time points ( n = 77), and 4 study time points ( n = 485). The primary outcome analyses were performed at 24 months and included Disease Activity Score 28 (DAS28-CRP), modified Health Assessment Questionnaire (MHAQ) change, Short Form Health Survey-12 physical and mental summary scores (SF-12 PCS, SF-12 MCS), EuroQol 5-Dimensional health index (EQ-5D), and radiographic progression. Unadjusted, adjusted, and analyses stratified for seropositivity and disease activity were performed. A secondary analysis investigated 36-month outcomes. Results No significant 24-month outcome differences could be found between the DMARD use categories. For seropositive patients, there was evidence of a linear trend for SF-12 PCS ( p = 0.02) and EQ-5D ( p = 0.01) with worse outcomes for inconsistent DMARD users. At 36 months, there was a linear trend for higher DAS28-CRP scores for inconsistent users ( p < 0.01). Conclusions Overall, we found poor correlation between inconsistent DMARD use and short-term disease outcome. However, outcome in the longer term could be negatively influenced by inconsistent DMARD use, as well as short-term outcome in seropositive patients.
Purpose Randomized controlled trials (RCTs) have demonstrated the efficacy of biologic agents in the treatment of rheumatic diseases. However, results from RCTs may not be generalizable to clinical ...practice because of their strict inclusion and exclusion criteria. Assessment of safety using RCT data also is limited by short duration of follow-up and relatively small sample sizes, which generally preclude analysis of longer term outcomes and rare adverse events. In rheumatology, various observational cohorts and registries have been created to complement information obtained from RCTs, some with the primary purpose of monitoring effectiveness and safety of biologic agents. Most registries are either drug based or disease based. These registries include patients with a variety of rheumatic diseases including RA. Methods To provide a qualitative comparison of selected U.S. and European rheumatoid arthritis (RA) biologics registries and cohorts including ARTIS, BIOBADASER, BSRBR, BRASS, CLEAR, CORRONA, NDB, RABBIT, SCQM, and VARA. Results A careful comparison of these registries, as provided in this article, can provide a basis for understanding the many similarities and differences inherent in their design, as well as societal context and content, all of which can significantly impact their results and comparisons across registers. Summary The increasing use of biologic agents for treatment of rheumatic diseases has raised important questions about cost, safety, and effectiveness of these agents. The unique and variable features of patient populations and registry designs in Europe and the U.S. provide valuable and complementary data on comparative effectiveness and safety of biologic agents to what can be derived from RCTs.
Abstract Background Hyperuricemia and gout are associated with an increased risk of cardiovascular disease (CVD). It is unknown whether treating hyperuricemia with xanthine oxidase inhibitors (XOIs), ...including allopurinol and febuxostat, modifies cardiovascular risks. Methods We used US insurance claims data to conduct a cohort study among gout patients, comparing XOI initiators with non-users with hyperuricemia defined as serum uric acid level ≥6.8 mg/dL. We calculated incidence rates of a composite nonfatal cardiovascular outcome that included myocardial infarction, coronary revascularization, stroke, and heart failure. Propensity score (PS)-matched Cox proportional hazards regression compared the risk of composite cardiovascular endpoint in XOI initiators vs those with untreated hyperuricemia, controlling for baseline confounders. In a subgroup of patients with uric acid levels available, PS-matched Cox regression further adjusted for baseline uric acid levels. Results There were 24,108 PS-matched pairs with a mean age of 51 years and 88% male. The incidence rate per 1000 person-years for composite CVD was 24.1 (95% confidence interval CI 22.6-26.0) in XOI initiators and 21.4 (95% CI, 19.8-23.2) in the untreated hyperuricemia group. The PS-matched hazard ratio for composite CVD was 1.16 (95% CI, 0.99-1.34) in XOI initiators vs those with untreated hyperuricemia. In subgroup analyses, the PS-matched hazard ratio for composite CVD adjusted for serum uric acid levels was 1.10 (95% CI, 0.74-1.64) among XOI initiators. Conclusions Among patients with gout, initiation of XOI was not associated with an increased or decreased cardiovascular risk compared with those with untreated hyperuricemia. Subgroup analyses adjusting for baseline uric acid levels also showed no association between XOI and cardiovascular risk.
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