Stacey S. Cofield

A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis trial†‡

OBJECTIVE To assess whether it is better to intensively treat all patients with early rheumatoid arthritis (RA) using combinations of drugs or to reserve this approach for patients who do not have an appropriate response (as determined by a Disease Activity Score in 28 joints using the erythrocyte sedimentation rate [DAS28-ESR] of ≥ 3.2 at week 24) to methotrexate (MTX) monotherapy, and to assess whether combination therapy with MTX plus etanercept is superior to the combination of MTX plus sulfasalazine plus hydroxychloroquine. METHODS The Treatment of Early Aggressive Rheumatoid Arthritis (TEAR) study is a 2-year, randomized, double-blind trial. A 2 × 2 factorial design was used to randomly assign subjects to 1 of 4 treatment arms: immediate treatment with MTX plus etanercept, immediate oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or step-up from MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if the DAS28-ESR was ≥ 3.2. All treatment arms included matching placebos. The primary outcome was an observed-group analysis of DAS28-ESR values from week 48 to week 102. RESULTS At week 24 (beginning of the step-up period), subjects in the 2 immediate-treatment groups demonstrated a greater reduction in the DAS28-ESR compared with those in the 2 step-up groups (3.6 versus 4.2; P < 0.0001); no differences between the combination-therapy regimens were observed. Between week 48 and week 102, subjects randomized to the step-up arms had a DAS28-ESR clinical response that was not different from that of subjects who initially received combination therapy, regardless of the treatment arm. There was no significant difference in the DAS28-ESR between subjects randomized to oral triple therapy and those randomized to receive MTX plus etanercept. By week 102, there was a statistically significant difference in the change in radiographic measurements from baseline between the group receiving MTX plus etanercept and the group receiving oral triple therapy (0.64 versus 1.69; P = 0.047). CONCLUSION There were no differences in the mean DAS28-ESR during weeks 48-102 between subjects randomized to receive MTX plus etanercept and those randomized to triple therapy, regardless of whether they received immediate combination treatment or step-up from MTX monotherapy. At 102 weeks, immediate combination treatment with either strategy was more effective than MTX monotherapy prior to the initiation of step-up therapy. Initial use of MTX monotherapy with the addition of sulfasalazine plus hydroxychloroquine (or etanercept, if necessary, after 6 months) is a reasonable therapeutic strategy for patients with early RA. Treatment with the combination of MTX plus etanercept resulted in a statistically significant radiographic benefit compared with oral triple therapy.

Spironolactone reduces severity of obstructive sleep apnoea in patients with resistant hypertension: A preliminary report

Obstructive sleep apnoea (OSA) and hyperaldosteronism are very common in subjects with resistant hypertension. We hypothesized that aldosterone-mediated chronic fluid retention may influence OSA severity in patients with resistant hypertension. We tested this in an open-label evaluation by assessing the changes in the severity of OSA in patients with resistant hypertension after treatment with spironolactone. Subjects with resistant hypertension (clinical blood pressure (BP) ⩾140/90 mm Hg on ⩾3 antihypertensive medications, including a thiazide diuretic and OSA (defined as an apnoea–hypopnoea index (AHI) ⩾15) had full diagnostic, polysomnography before and 8 weeks after spironolactone (25–50 mg a day) was added to their ongoing antihypertensive therapy. In all, 12 patients (mean age 56 years and body mass index 36.8 kg m–2) were evaluated. After treatment with spironolactone, the AHI (39.8±19.5 vs 22.0±6.8 events/h; P<0.05) and hypoxic index (13.6±10.8 vs 6.7±6.6 events/h; P<0.05), weight and clinic and ambulatory BP were significantly reduced. Plasma renin activity (PRA) and serum creatinine were significantly higher. This study provides preliminary evidence that treatment with a mineralocorticoid receptor antagonist substantially reduces the severity of OSA. If confirmed in a randomized assessment, it will support aldosterone-mediated chronic fluid retention as an important mediator of OSA severity in patients with resistant hypertension.

Randomized study combining interferon and glatiramer acetate in multiple sclerosis

A double‐blind, randomized, controlled study was undertaken to determine whether combined use of interferon β‐1a (IFN) 30μg intramuscularly weekly and glatiramer acetate (GA) 20mg daily is more efficacious than either agent alone in relapsing–remitting multiple sclerosis.

REFRACTORY HYPERTENSION: DEFINITION, PREVALENCE AND PATIENT CHARACTERISTICS

J Clin Hypertens (Greenwich).

Assessing changes in relapse rates in multiple sclerosis

Multiple Sclerosis (MS) annualized relapse rates (ARRs) in trials may be declining due to changes in diagnostic criteria, MS etiology, study criteria, and selection biases. This review examines if there is a trend in the ARR for relapsing—remitting MS patients (RRMS) over time and if so, why. A comprehensive literature search was performed using PubMed, Web of Science®, and the Cochrane Library using electronic searches, screen scraping for abstracts, and hand searching of references for randomized trials conducted between 1960 and 2008. Out of 72 randomized trials, 56 (77.8%) defined relapse. This study uses 32 placebo relapsing—remitting studies out of the 37 (66.1%) with RRMS. The mean ARR for the treatment arms was 0.68 and the one for the placebo groups was 1.002. The year of publication was negatively associated with the ARR (p = 0.0001). The annual reduction amounts to 0.36 relapses over a 10-year period. Age and duration of symptoms were negatively associated with the ARR. Year of publication was significantly negatively associated with ARR after controlling for covariates. ARRs have fallen with relapse definition, entrance criteria remain important, but time exceeds all these variables and reflects two likely sources, selection of patients for trials by clinicians and rescue of patients truncating the number of multiple relapses. The impact of truncating the number of relapses on the falling rates is important, not only on the ARRs, but also on the impact of informative censoring in drop-outs.

Changes in lipoproteins associated with methotrexate or combination therapy in early rheumatoid arthritis: results from the treatment of early rheumatoid arthritis trial.

OBJECTIVE To study changes in lipid profiles at 24 weeks among patients with early rheumatoid arthritis (RA) participating in the Treatment of Early RA (TEAR) trial and randomized to receive methotrexate (MTX) plus etanercept, triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or aggressively titrated MTX monotherapy. METHODS This TEAR substudy included 459 participants with biologic specimens. Serum levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol were measured at 0 and 24 weeks. RESULTS At 24 weeks, there were statistically significant increases in mean cholesterol levels in the MTX plus etanercept, triple therapy, and MTX monotherapy arms. The observed increases were 31.4 mg/dl, 28.7 mg/dl, and 30 mg/dl in LDL cholesterol, 19.3 mg/dl, 22.3 mg/dl, and 20.6 mg/dl in HDL cholesterol, and 56.8 mg/dl, 53 mg/dl, and 57.3 mg/dl in total cholesterol (P < 0.0001 versus baseline for each comparison). There was a statistically significant decrease in the ratio of total cholesterol to HDL cholesterol at 24 weeks in all 3 treatment groups versus baseline. There was no difference in any lipid changes between the 3 treatment arms. After multivariable adjustment, change in C-reactive protein, but not the Disease Activity Score in 28 joints, was associated with change in LDL cholesterol (P = 0.03) and total cholesterol (P = 0.01). Baseline glucocorticoid use was associated with changes in HDL cholesterol (P = 0.03) and total cholesterol (P = 0.02). CONCLUSION Levels of total cholesterol, LDL cholesterol, and HDL cholesterol increased comparably shortly after initiation of MTX plus etanercept, triple therapy, and MTX monotherapy among patients with early RA with active disease participating in a clinical trial. The clinical relevance of short-term changes in traditional lipids on cardiovascular outcomes remains to be determined.

Safety of Rapid Intravenous Loading of Valproate

Summary:  Background: The introduction of IV valproic acid (VPA) has facilitated its use in situations where oral administration is not feasible. The present study was designed to evaluate the safety of administration of undiluted VPA (20 or 30 mg/kg/min) administered intravenously at rates of 6 or 10 mg/kg/min.

Aldosterone excess and resistance to 24-h blood pressure control

Background Aldosterone excess has been reported to be a common cause of resistant hypertension. To what degree this represents true treatment resistance is unknown. Objective The present study aimed to compare the 24-h ambulatory blood pressure monitoring (ABPM) levels in resistant hypertensive patients with or without hyperaldosteronism. Methods Two hundred and fifty-one patients with resistant hypertension were prospectively evaluated with an early-morning plasma renin activity (PRA), 24-h urinary aldosterone and sodium, and 24-h ABPM. Daytime, night-time, and 24-h blood pressure (BP) and nocturnal BP decline were determined. Hyperaldosteronism (H-Aldo) was defined as suppressed PRA (<1.0 ng/ml per h or <1.0 μg/l per h) and elevated 24-h urinary aldosterone excretion (≥ 12 μg/24-h or ≥ 33.2 nmol/day) during ingestion of the patients routine diet. Results In all patients, the mean office BP was 160.0 ± 25.2/89.4 ± 15.3 mmHg on an average of 4.2 medications. There was no difference in mean office BP between H-Aldo and normal aldosterone status (N-Aldo) patients. Daytime, night-time, and 24-h systolic and diastolic BP were significantly higher in H-Aldo compared to N-Aldo males. Daytime, night-time, and 24-h systolic BP were significantly higher in H-Aldo compared to N-Aldo females. Multivariate analysis indicated a significant interaction between age and aldosterone status such that the effects of aldosterone on ambulatory BP levels were more pronounced with increasing age. Conclusions In spite of similar office BP, ABPM levels were higher in resistant hypertensive patients with H-Aldo. These results suggest that high aldosterone levels impart increased cardiovascular risk not reflected by office BP measurements.

Long-term effects of aldosterone blockade in resistant hypertension associated with chronic kidney disease.

Hypertension is a major risk factor for the development and progression of chronic kidney disease (CKD). Mineralocorticoid receptor antagonists (MRAs) are effective in the management of resistant hypertension but are not widely used in CKD because of the risk of hyperkalemia. We retrospectively evaluated the long-term effects and safety of MRAs added to a pre-existing antihypertensive regimen in subjects with resistant hypertension associated with stage 3 CKD. In all, 32 patients were treated with spironolactone and 4 with eplerenone for a median follow-up of 312 days. MRAs induced a significant decrease in systolic blood pressure from 162±22 to 138±14 mm Hg (P<0.0001) and in diastolic blood pressure from 87±17 to 74±12 mm Hg (P<0.0001). Serum potassium increased from 4.0±0.5 to 4.4±0.5 mEq l−1 (P=0.0001), with the highest value being 5.8 mEq l−1. The serum creatinine increased from 1.5±0.3 to 1.8±0.5 mg dl−1 (P=0.0004) and the estimated glomerular filtration rate decreased from 48.6±8.7 to 41.2±11.5 ml min−1 per 1.73 m2 (P=0.0002). One case of acute renal failure and three cases of significant hyperkalemia occurred. MRAs significantly reduced blood pressure in subjects with resistant hypertension associated with stage 3 CKD, although close biochemical monitoring is recommended because of an increased risk of hyperkalemia and worsening of renal function.

Recruitment and Retention of Patients into Emergency Medicine Clinical Trials

The emergency medicine (EM) and prehospital environments are unlike any other clinical environments and require special consideration to allow the successful implementation of clinical trials. This article reviews the specific issues involved in EM clinical trials and provides strategies from EM and non-EM trials to maximize recruitment and retention. While the evidence supporting some of these strategies is deficient, addressing recruitment and retention issues with specific strategies will help researchers deal with these issues in their funding applications and in turn develop the necessary infrastructure to participate in EM clinical trials.