Subclinical hypothyroidism and mortality in a large Austrian cohort: a possible impact on treatment?

BACKGROUND: Clinical implications of subclinical hypothyroidism (SCH) are still matter of intense debate, resulting in the controversial discussion whether subclinical hypothyroidism should be treated. We performed a cohort study to evaluate the impact of subclinical hypothyroidism on vascular and overall mortality. METHODS: Between 02/1993 and 03/2004, a total of 103,135 persons attending the General Hospital Vienna with baseline serum thyrotropin (TSH, thyroid-stimulating hormone) and free thyroxin (fT4) measurements could be enrolled in a retrospective cohort study. Subclinical hypothyroidism was defined by elevated TSH ranging from 4.5 to 20.0 mIU/L and normal fT4 concentration (0.7-1.7 ng/dL). Overall and vascular mortality as primary endpoints were assessed via record linkage with the Austrian Death Registry. RESULTS: A total of 80,490 subjects fulfilled inclusion criteria of whom 3934 participants (3.7%) were classified as SCH (868 males and 3066 females, median age 48 years). The mean follow-up among the 80,490 subjects was 4.1 years yielding an observation period of 373,301 person-years at risk. In a multivariate Cox regression model adjusted for age and gender TSH levels showed a dose-dependent association with all-cause mortality. The association between SCH and overall or vascular mortality was stronger in men below 60 years compared to older males or females. CONCLUSION: Our data support the hypothesis that SCH might represent an independent risk factor for overall and vascular mortality, especially in men below 60 years. Whether this group would benefit from replacement therapy should be evaluated in interventional studies.

Association between mycophenolic acid 12-h trough levels and clinical endpoints in patients with autoimmune disease on mycophenolate mofetil.

BACKGROUND: Triggered by heightened interest in mycophenolate mofetil (MMF) for the treatment of autoimmune diseases (AID) and encouraged by the results from a previous study, we hypothesized that therapeutic drug monitoring of mycophenolic acid (MPA) based on troughs may be useful for effective MMF dosing in patients with AID. METHODS: A two-step approach was pursued. First, we confirmed in 38 AID patients (26 with antineutrophil cytoplasmic antibody-associated vasculitis; 12 with systemic lupus erythematosus) a significant correlation (r = 0.545, P < 0.001) between MPA C(12 h) and MPA exposure (AUC). Second, we performed an analysis of 294 MPA 12-h trough levels serially collected from 39 patients (same indications) receiving MMF for remission maintenance therapy to elucidate possible associations with disease activity and MMF toxicity. RESULTS: Higher MPA trough levels were associated with better protection from recurrence of active disease. While at levels <3 mg/L 29% of collected samples (43/147) were from patients with active disease, this was only the case in 2% of samples (3/147) with an MPA concentration of >or=3 mg/L. Remission persisted in all patients with MPA troughs >or=3.5 mg/L. Upon combined analysis of efficacy and safety data, most favourable results were obtained with MPA troughs between 3.5 and 4.5 mg/L. There was no discernable relationship between MMF dose and clinical endpoints. CONCLUSION: The target range proposed by this explorative study may serve as an initial guidance for MPA monitoring in the context of further prospective controlled trials in patients with AID.

Pharmacokinetics of enteric-coated mycophenolate sodium: comparative study in patients with autoimmune disease and renal allograft.

BACKGROUND: Recently, mycophenolic acid drugs have gained interest in the treatment of autoimmune diseases. However, only limited pharmacokinetic data are available on enteric-coated mycophenolate sodium in non-transplant indications. OBJECTIVE: This study compared the pharmacokinetics of mycophenolic acid from enteric-coated mycophenolate sodium in patients with autoimmune disease and renal transplant recipients. METHODS: Twelve autoimmune disease patients (mainly with antineutrophil cytoplasmic antibody-associated vasculitis) and 11 stable renal transplant patients, all of whom had been on enteric-coated mycophenolate sodium for > or = 10 weeks, received an oral dose of enteric-coated mycophenolate sodium of 720 mg under fasting conditions. Blood samples for the determination of mycophenolic acid in the plasma were collected over 24 h. RESULTS: Overall, no significant difference was found between both groups for their 0 - 12 h and 0 - 24 h areas under the concentration-time curve, C(max), T(max), C(0 h), C(12 h) and C(24 h), although the mean C(max) was numerically higher by 39% in the autoimmune disease patients (autoimmune disease 27.3 +/- 17.4 mg/l and renal transplant 19.6 +/- 15.7 mg/l). Patients on concomitant ciclosporin tended to have a lower mycophenolic acid exposure than patients on a non-ciclosporin regimen. The intersubject variabilities in the mycophenolic acid pharmacokinetics were high in both patient populations (around 40% for the area under the curve values). Both groups exhibited a weak and non-significant correlation between their mycophenolic acid trough (C(12 h)) levels and mycophenolic acid 0 - 12 h area under the curve (autoimmune disease r = 0.482 and renal transplant r = 0.138), whereas in the autoimmune disease group the mean C(1.5 h) and C(2 h) concentrations provided a satisfactory association with the 0 - 12 h area under the curve (for both r > 0.7 and p < 0.001). CONCLUSION: These data suggest that mycophenolic acid exposure (in terms of the area under the curve) from enteric-coated mycophenolate sodium is comparable in autoimmune disease and renal transplant patients. The mycophenolic acid trough levels did not reflect the systemic exposure to mycophenolic acid adequately; a limited sampling strategy for estimating mycophenolic acid exposure in autoimmune disease patients should include times around C(1.5 h) and/or C(2 h) reflecting T(max) if further studies confirm its usefulness.

Assessing aspirin-induced attenuation of platelet reactivity by flow cytometry.

INTRODUCTION: Certain patient subpopulations do not respond to antithrombotic effects of aspirin and different approaches have been proposed to detect and define this so-called aspirin resistance. In this study, a methodological and clinical evaluation of a flow cytometric method for the detection of aspirin-induced inhibition of platelet cyclooxygenase (COX) is presented. MATERIALS AND METHODS: Platelet CD62p-antigen (P-selectin) expression was determined by flow cytometry after incubating diluted platelet rich plasma (PRP) with arachidonic acid (ARA). After establishing the method's technical characteristics, it was used to investigate 114 individuals (70 patients with atherosclerotic vascular disease under long-term medication of 100 mg aspirin daily, 29 age-matched patients with vascular disease without anti-platelet medication and 15 healthy volunteers). Data were compared to those obtained by the PFA-100 platelet function analyzer. RESULTS: Imprecision was between 3.3% and 13%. Sample storage at room temperature increased baseline activity of platelets already after 2 h. After ARA stimulation, the proportion of CD62p-positive platelets was considerably lower in aspirin-treated patients than in controls (median [lower-upper quartile]: 4% [3-6] vs. 50% [29-68], p<0.001). Only one aspirin-treated patient (1.5%) showed normal reactivity to ARA. In contrast to flow cytometry, PFA-100 analysis yielded normal results in 17% of aspirin-treated patients. CONCLUSIONS: The presented flow cytometric method can be used to monitor aspirin-induced inhibition of platelet COX. Aspirin resistance defined as failure to inhibit platelet COX is a rare phenomenon suggesting that most cases of aspirin resistance detected using the PFA-100 are caused by COX-independent mechanisms.