Understanding the NSAID related risk of vascular events

Concern is growing about an increased risk of thrombotic events (including myocardial infarction and stroke) during the use of non-steroidal anti-inflammatory drugs (NSAIDs), in particular the so called selective cyclo-oxygenase-2 (COX 2) inhibitors. Although clinical trials give conflicting results with respect to the incidence of vascular events, increasing evidence shows that a class effect might exist for selective COX 2 inhibitors. Even before the massive introduction of selective COX 2 inhibitors, observational studies showed that the use of NSAIDs causes congestive heart failure in elderly patients.1,2 Conversely, the discontinuation of NSAIDs has also been associated with increased risk of myocardial infarction, especially in the first several weeks after stopping chronic NSAID treatment.3Many different mechanisms could explain the different effects of classic NSAIDs and selective COX 2 inhibitors in relation to thrombotic vascular events. In this review we link biochemical facts concerning NSAIDs and COX inhibitors with data from clinical trials

Hyperuricaemia: a marker of increased cardiovascular risk in rheumatic patients: analysis of the ACT-CVD cohort

Background Gout and hyperuricaemia may be associated with increased cardiovascular risk, but analyses in different populations show conflicting results. This study investigates the impact of serum uric acid, inflammation and traditional CV risk parameters on CV event risk in patients with gouty arthritis and patients with non-gouty rheumatic disease. Methods cross-sectional and prospective multivariate analysis of the relation between tertiles of serum uric acid and individual traditional CV risk factors in a cohort of gouty arthritis (GA, n=172), rheumatoid arthritis (RA, n=480) and osteoarthritis (OA, n=206) patients. Main outcome measures: systolic blood pressure, TC/HDL ratio, GlyHb, BMI and first CV events. Results Individual CV risk factors were significantly less favourable in GA (systolic blood pressure, TC/HDL ratio, BMI, p<0.05). In RA and OA, but not in GA, individual cardiometabolic parameters correlated with serum uric acid values (OA: RA: systolic blood pressure, TC/HDL ratio, BMI; systolic blood pressure, TC/HDL ratio, GlyHb, BMI; p<0.05). In non-GA individuals the highest tertile of serum uric acid (>0.34 mmol/L) and NT proBNP level were independent predictors of first CV events, against age and GlyHb level in GA (p<0.05). The hazard of first CV events was equally significantly increased in GA patients (HR 3.169, 95% CI 1.287-7.806) and non-GA individuals with a serum uric acid ≥ 0.34 mmol/L (HR 3.721, 95% CI 1.603-8.634) compared to non-GA individuals with a serum uric acid < 0.27. Conclusions GA is associated with a 3.1-fold hazard of first CV events. In non-GA rheumatic patients increasing serum uric acid is associated with increased CV risk, whereas CV risk in GA is independent of serum uric acid values. The presence of GA or a baseline serum uric acid in the upper range are possibly stronger predictors of first CV events than some traditional CV risk factors or parameters of inflammatio

Cardiovascular case fatality in rheumatoid arthritis is decreasing; first prospective analysis of a current low disease activity rheumatoid arthritis cohort and review of the literature

Background Previous studies found increased case fatality after myocardial infarction and more frequent sudden death in RA patients compared to non-RA subjects. The RA associated CV risk might be explained by the combined effects of chronic systemic inflammation and increased lifestyle associated cardiovascular risk factors, and modified by the use of medication such as non steroidal anti-inflammatory drugs, corticosteroids and disease modifying anti-rheumatic drugs. Trends in case fatality rate in RA after the introduction of potent anti-inflammatory biologic therapies and treat-to-target treatment strategies aiming at remission are not known. This study was performed to examine the cardiovascular fatality rate in current low disease activity RA, and to evaluate trends in RA associated CV case fatality over time. Methods Prospective study to determine the incidence of fatal and nonfatal CV events in 480 RA patients included in the ACT-CVD cohort between February 2009 and December 2011. Patients with prior CV disease were excluded. Cox regression analysis was performed to determine CV event risk and contributing risk factors over time. The results of the cohort analysis were put into the context of a review of the literature to evaluate trends in RA associated CV fatality rate over time. Results The study included 480 RA patients, 72.3% female with median disease duration of 4.2 years, 72.1% being in clinical remission (Disease Activity Score in 28 joints). During a mean follow up of 2.9 years 29 patients (6%) experienced a first CV event, 2 fatal and 27 non-fatal, corresponding to a 6.9% case fatality rate. Comparison with previous studies in cohorts with successive enrolment periods shows a trend towards a decrease in CV case fatality in RA from 52.9% in 1998 to 6.9% in our study. Conclusion CV case fatality in current low disease activity RA is importantly lower than in previous studies, and a trend towards decreasing CV fatality in RA is suggeste

Factors associated with treatment intensification in patients with axial spondyloarthritis and high disease activity in clinical practice

Objective: To investigate which factors are associated with treatment intensification (TI) in axial SpA (axSpA) patients with high disease activity (HDA).Methods: Patients with axSpA and HDA [Ankylosing Spondylitis Disease Activity Score (ASDAS) ≥2.1] from the Dutch SpA-Net registry were included. TI was defined as: (i) higher dose or shorter interval of the same drug, (ii) switch from current drug to another due to inefficacy or (iii) addition of a new drug. Only anti-inflammatory drugs were considered. Primary determinants considered were ASDAS, Assessment of SpondyloArthritis international Society Health Index (ASAS HI) and physician global assessment (PhGA). Acceptable symptom state according to patient (PASS-patient) or physician (PASS-physician) were included in sensitivity analyses. Patient-centred and physician-centred logistic regression models were used to investigate the association between potential determinants and TI.Results: In total, 121 patients with HDA were included. TI was conducted in a minority (41/121, 33.9%), and mainly involved a switch or addition of a drug. In multivariable regression analyses, a higher ASDAS was associated with TI in the patient-centred model [odds ratio (OR)ASDAS = 1.94 (95% CI 1.00–3.74)]. However, in the physician-centred model, this association attenuated, and PhGA or PASS-physician were the primary factors associated with TI [ORPhGA = 1.71 (1.24–2.34); ORPASS-physician = 94.95]. Interestingly, patient-centred factors (ASAS HI/PASS-patient/education level) did not contribute to TI.Conclusion: In practice, treatment is intensified in a minority of axSpA patients with HDA. Physician-centred factors are associated with the decision to change treatment, independently of disease activity or patient perspective. Further research is needed to better understand these decisions

Further optimization of the reliability of the 28-joint disease activity score in patients with early rheumatoid arthritis

BACKGROUND: The 28-joint Disease Activity Score (DAS28) combines scores on a 28-tender and swollen joint count (TJC28 and SJC28), a patient-reported measure for general health (GH), and an inflammatory marker (either the erythrocyte sedimentation rate [ESR] or the C-reactive protein [CRP]) into a composite measure of disease activity in rheumatoid arthritis (RA). This study examined the reliability of the DAS28 in patients with early RA using principles from generalizability theory and evaluated whether it could be increased by adjusting individual DAS28 component weights. METHODS: Patients were drawn from the DREAM registry and classified into a "fast response" group (N = 466) and "slow response" group (N = 80), depending on their pace of reaching remission. Composite reliabilities of the DAS28-ESR and DAS28-CRP were determined with the individual components' reliability, weights, variances, error variances, correlations and covariances. Weight optimization was performed by minimizing the error variance of the index. RESULTS: Composite reliabilities of 0.85 and 0.86 were found for the DAS28-ESR and DAS28-CRP, respectively, and were approximately equal across patients groups. Component reliabilities, however, varied widely both within and between sub-groups, ranging from 0.614 for GH ("slow response" group) to 0.912 for ESR ("fast response" group). Weight optimization increased composite reliability even further. In the total and "fast response" groups, this was achieved mostly by decreasing the weight of the TJC28 and GH. In the "slow response" group, though, the weights of the TJC28 and SJC28 were increased, while those of the inflammatory markers and GH were substantially decreased. CONCLUSIONS: The DAS28-ESR and the DAS28-CRP are reliable instruments for assessing disease activity in early RA and reliability can be increased even further by adjusting component weights. Given the low reliability and weightings of the general health component across subgroups it is recommended to explore alternative patient-reported outcome measures for inclusion in the DAS28

Construct Validation of a Multidimensional Computerized Adaptive Test for Fatigue in Rheumatoid Arthritis

Objective Multidimensional computerized adaptive testing enables precise measurements of patient-reported outcomes at an individual level across different dimensions. This study examined the construct validity of a multidimensional computerized adaptive test (CAT) for fatigue in rheumatoid arthritis (RA). Methods The ‘CAT Fatigue RA’ was constructed based on a previously calibrated item bank. It contains 196 items and three dimensions: ‘severity’, ‘impact’ and ‘variability’ of fatigue. The CAT was administered to 166 patients with RA. They also completed a traditional, multidimensional fatigue questionnaire (BRAF-MDQ) and the SF-36 in order to examine the CAT’s construct validity. A priori criterion for construct validity was that 75% of the correlations between the CAT dimensions and the subscales of the other questionnaires were as expected. Furthermore, comprehensive use of the item bank, measurement precision and score distribution were investigated. Results The a priori criterion for construct validity was supported for two of the three CAT dimensions (severity and impact but not for variability). For severity and impact, 87% of the correlations with the subscales of the well-established questionnaires were as expected but for variability, 53% of the hypothesised relations were found. Eighty-nine percent of the items were selected between one and 137 times for CAT administrations. Measurement precision was excellent for the severity and impact dimensions, with more than 90% of the CAT administrations reaching a standard error below 0.32. The variability dimension showed good measurement precision with 90% of the CAT administrations reaching a standard error below 0.44. No floor- or ceiling-effects were found for the three dimensions. Conclusion The CAT Fatigue RA showed good construct validity and excellent measurement precision on the dimensions severity and impact. The dimension variability had less ideal measurement characteristics, pointing to the need to recalibrate the CAT item bank with a two-dimensional model, solely consisting of severity and impact