Aims Initial treatment of vasovagal syncope (VVS) consists of advising adequate fluid and salt intake, regular exercise, and physical counterpressure manoeuvres. Despite this treatment, up to 30% of patients continue to experience regular episodes of VVS. We investigated whether additional Midodrine treatment is effective in these patients.

Methods and results In our study, patients with at least three syncopal and/or severe pre-syncopal recurrences during non-pharmacological treatment were eligible to receive double-blind cross-over treatment starting either with Midodrine or placebo. Treatment periods lasted for 3 months with a wash-out period of 1 week in-between. At baseline and after each treatment period, we collected data about the recurrence of syncope and pre-syncope, side effects, and quality of life (QoL). Twenty-three patients (17% male, mean age 32) included in the cross-over trial received both Midodrine and placebo treatment. The proportion of patients who experienced syncopal and pre-syncopal recurrences did not differ significantly between Midodrine and placebo treatment (syncope: 48 vs. 65%, P = 0.22; pre-syncope: 74 vs. 78%, P > 0.99). The median number of syncopes and pre-syncopes per 3 months were also not significantly different during Midodrine and placebo treatment (0 vs. 1; P = 0.57; and 6 vs. 8; P = 0.90). The occurrence of side effects was similar during Midodrine and placebo treatment (48 vs. 57%; P = 0.75). Also, QoL did not differ significantly.

Conclusion Our findings indicate that additional Midodrine treatment is less effective in patients with VVS not responding to non-pharmacological treatment than reported as first-line treatment.

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Effectiveness of midodrine treatment in patients with recurrent vasovagal syncope not responding to non-pharmacological treatment (STAND-trial).

The AB/BA design is reviewed from a historical perspective. Particular attention is paid to the problem of carry-over and various attempts to deal with it. The two-stage procedure, an approach which was popular for many years, is shown to be unsafe. The analysis of AB/BA designs with baseline data is also considered. It is shown that such baselines do not provide a cure for the problem of carry-over; and it is concluded that any rational analysis of such trials will always be dependent on assumptions regarding carry-over, and that it is necessary to pay particular attention to washout periods. Under such circumstances analysis of covariance may be useful. In conclusion, some speculative comments about future lines of research are offered.

The AB/BA crossover: past, present and future?

Crossover studies have been successfully conducted in the case of continuous responses. Existing procedures of analysis for ordinal responses, on the other hand, are rarely satisfactory unless strict, usually unrealistic, assumptions are made. In this paper we investigate a random effects model and show that the model is simple and general. Interpretation of parameters is easy, though with a complicated fitting procedure.

A random effects model for ordinal responses from a crossover trial. by F. Ezzet and J. Whitehead, Statistics in Medicine, 10, 901–907 )1991(

A non-exhaustive but nevertheless wide-ranging if biased and personal view of various matters affecting the allocation of treatments to patients in controlled clinical trials will be undertaken from the standpoint of a statistician working in drug development. The following topics are considered: the use of ?placebos' in the run-in phase; the use of crossover trials; selection of patients; various matters concerning centres; two extreme alternatives to randomization, and various matters linking blinding and allocation.

A personal view of some controversies in allocating treatment to patients in clinical trials

Background: In controlled clinical trials the new treatment may be a slight modification of the standard or be equivalent to it with the addition of a new component In this situation there is a positive correlation between the response to the new and the standard treatment Objective: The influence of the correlation between the treatment responses on the statistical sensitivity of testing was studied Randomized trials of equivalent treatments in psychiatry and hypertension research were studied for their design in relation to their level of correlation Results: With equivalent treatments and, thus, a positive correlation a paired analysis provides better power than an unpaired one Conclusions: Crossover studies are a better format than parallel‐group studies for comparing equivalent treatments The scientific community is technically largely unaware of the mechanisms by which correlation levels influence or lack to influence the statistical power of controlled clinical trials

Crossover studies are a better format for comparing equivalent treatments than parallel-group studies

https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2125.1991.tb05627.x

SJ Senn

Papers

Problems with the two stage analysis of crossover trials.