STATISTICAL ANALYSIS OF POSSIBLE BIAS OF CLINICAL JUDGEMENTS DUE TO OBSERVING AN ON-THERAPY MARKER VARIABLE

In certain double-blind clinical trials there is the possibility that certain ‘marker variables’ observable during the trial may in part unblind the trial, even at a subliminal level. At issue is whether or not this potential unblinding biases the investigators clinical efficacy assessments. This issue arose after the completion of three clinical trials that compared tretinoin emollient cream (TEC) 0⋅05 per cent to its vehicle in patients with photodamaged skin. The question raised was whether or not possible ‘subliminal unblinding’ of the investigators and patients, due to the cutaneous irritation associated with topical tretinoin, might have caused a treatment bias in the study. To address this issue, we undertook a reanalysis of these three clinical trials. In doing so, we develop in this paper a statistical modelling approach to address issues of possible bias introduced by the ability to observe such marker variables. The approach utilizes a linear discriminant analysis to introduce an auxiliary categorical variable for the efficacy analysis. A suitable categorical data model permits the estimation of relevant bias effects. We illustrate this approach with data from the three TEC 0⋅05 per cent trials.     

Impact of Age and Basic Heart Rate on Heart Rate Turbulence in Healthy Persons

Postextrasystolic acceleration of heart rate (HR), known as HR turbulence (HRT) is attenuated in patients with coronary artery disease at increased risk of adverse events. The influence of age and basic HR on HRT have not been evaluated in a large cohort of persons. In 95 healthy individuals, HRT onset (TO) and slope (TS) were calculated from 24-hour ambulatory electrocardiograms, as well as the turbulence timing (TT). Gender specific differences in TO and TS were compared in simple, linear, weighted regression model. The influence of age and the basic HR preceding ventricular premature contractions on HRT were examined. We found that, in men and women, TO decreases as basic HR increases (P < 0.01). In contrast, in men, TS decreased as basic HR increases, whereas in women, basic HR influenced TS only slightly (P < 0.01). A multiple, linear regression model revealed a decrease in HRT with increasing age in men. In conclusion, physiological acceleration of the HR within the first 11 beats after premature ventricular complex (VPC) was observed in >75% of healthy individuals. An accelerating HR preceding the VPC influenced HRT in men. An increasing age was associated with a decrease in HRT in men and a decrease in TO in women. These results illustrate the importance of physiological modulations of HRT when used for risk stratification, especially in older populations.     

Advanced Pacemaker Diagnostic Features in the Characterization of Atrial Fibrillation: Impact on Preventive Pacing Algorithms

YANG, A., et al .: Advanced Pacemaker Diagnostic Features in the Characterization of Atrial Fibrillation: Impact on Preventive Pacing Algorithms. Pacing algorithms to prevent PAF are mainly based on the suppression of premature atrial complexes (PACs), which play an important role in its initiation. In contrast to 24-hour ambulatory electrocardiograms, advanced pacemaker (PM) diagnostic features are capable of recording AF episodes during long follow-up periods and of characterizing AF in a detailed fashion. For the specific use of these algorithms, a detailed characterization of AF was performed in 91 dual chamber PM recipients with histories of AF. Fifteen patients with episodes of oversensing due to far-field signals or frequent episodes of "2:1-undersensing" of atrial flutter were excluded. The remaining 76 patients had high recurrence rates of AF (median 0.8 episodes/day), however, the majority of episodes lasted <7 minutes. Despite frequent PACs (median 10.8/hour) during sinus rhythm, a median of 66.4% of the AF episodes were preceded by <2 PACs/min before onset. In conclusion, frequent, short-lived AF episodes seem best suited for AF preventive pacing therapies. However, the small number of PACs preceding many AF episodes may limit the efficacy of PAC suppressing algorithms. (PACE 2003; 26[Pt. II]:310–313)