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We studied variables known to change with thyroid hormone status in 18 patients with subclinical hypothyroidism before and during treatment with thyroxine in a dose sufficient to restore the plasma TSH response to TRH to normal. There was an associated increase in both plasma total T4 and free T4 within the normal range but plasma total T3 and free T3 were unchanged. As a result of thyroxine treatment there was a small but significant increase (P less than 0.05) in left ventricular ejection fraction (LVEF) with maximal exercise but no significant changes in LVEF at rest and moderate exercise, continuously monitored mean sleeping heart rate, day/night ratios of urinary sodium excretion, peripheral nerve conduction velocities, fasting serum triglycerides, total cholesterol (TC), high density lipoproteins (HDL) or TC/HDL ratios. On this evidence we do not consider that thyroxine replacement therapy is indicated in patients with subclinical hypothyroidism.

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RationaleA number of randomized trials are underway, which will address the effects of angiotensin receptor blockers (ARBs) on aortic root enlargement and a range of other end points in patients with Marfan syndrome. If individual participant data from these trials were to be combined, a meta-analysis of the resulting data, totaling approximately 2,300 patients, would allow estimation across a number of trials of the treatment effects both of ARB therapy and of β-blockade.Such an analysis would also allow estimation of treatment effects in particular subgroups of patients on a range of end points of interest and would allow a more powerful estimate of the effects of these treatments on a composite end point of several clinical outcomes than would be available from any individual trial.DesignA prospective, collaborative meta-analysis based on individual patient data from all randomized trials in Marfan syndrome of (i) ARBs versus placebo (or open-label control) and (ii) ARBs versus β-blockers will be performed.A prospective study design, in which the principal hypotheses, trial eligibility criteria, analyses, and methods are specified in advance of the unblinding of the component trials, will help to limit bias owing to data-dependent emphasis on the results of particular trials. The use of individual patient data will allow for analysis of the effects of ARBs in particular patient subgroups and for time-to-event analysis for clinical outcomes.The meta-analysis protocol summarized in this report was written on behalf of the Marfan Treatment Trialists' Collaboration and finalized in late 2012, without foreknowledge of the results of any component trial, and will be made available online (http://www.ctsu.ox.ac.uk/research/meta-trials).