Abstract
BackgroundThe standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration.DiscussionBuilding upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75–80 mmHg) versus lower (60–65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence.ConclusionsIn trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.
Highlights
The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered
In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence
In the OVATION pilot trial, we considered reporting non-adherence as the proportion of hourly mean arterial pressure (MAP) values that were out-of-range during vasopressor therapy (Table 1a)
Summary
Case study – The OVATION pilot trial The OVATION pilot trial was an open-label randomized controlled trial of higher versus lower mean arterial pressure (MAP) targets for vasopressor therapy in shock [9]. From May 2013 to April 2014, 118 patients participated in the OVATION pilot trial and 117 received vasopressor infusions for 695 patient-days In this trial, we defined potential protocol deviations a priori as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. One patient developed acute aortic regurgitation after randomization This unexpected event required a vasopressor dose reduction and a protocol amendment was prepared for the planned larger trial mandating that clinicians stop the assigned intervention in a similar clinical situation. Such careful assessment of protocol adherence in a pilot study can be used to characterize usual care and provide other useful insights into the acceptability of the intervention. Central and blinded adjudication of clinical events and associated protocol decisions can help make these distinctions
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