Kate Hayward, PhD, PT
@kate_hayward_
Stroke recovery and rehabilitation trials have received much criticism for underdosing the tested intervention,1 which remains an important consideration when interpreting past trials in the field.2
In this trial of aerobic exercise during inpatient rehabilitation by Klassen et al.,3 the intensity (heart rate reserve during training and walking steps) and amount (minutes of training) of aerobic exercise were increased from usual care. The control group (usual care) typically received 1 hour, 5 days/week, while the Determining Optimal Post-Stroke Exercise 1 (DOSE1) group received 1 hour, 5 days/week (with a target of double the intensity of the control group), and the DOSE2 group received 2 hours, 5 days/week (with a target of quadruple the intensity of the control group), each for a 4-week duration (20 sessions).
For the primary outcome, when controlling for the baseline 6-minute walk test (6MWT), both DOSE1 (mean difference from usual care 61 m, 95% CI 9–113, P=0.02) and DOSE2 (mean difference from usual care 58 m, 95% 6–110, P=0.03) walked a statistically and clinically significantly greater distance than the control group. However, the difference between DOSE1 and DOSE2 was marginal for a considerably greater investment of time. This trend was similar for 5-meter walking speed (m/s) and quality of life (EQ-5D). At 6- and 12-months follow-up, gains in 6MWT were maintained, but this was not the case for the 5-meter walk test (gait speed) and EQ-5D (quality of life).
The authors should be commended for their detailed reporting of dose (heart rate reserve during training, amount of training minutes and walking steps) within all study groups, i.e., usual care, DOSE1, and DOSE2. Often, usual care descriptions are vague,4 which is not the case in this trial. Furthermore, they effectively implemented a consistent training protocol across multiple sites (6 inpatient rehabilitation units across 3 provinces) throughout Canada. This establishes a model for future clinical trials of stroke recovery to be conducted within Canada.
Stroke recovery dosing trials do need to consider how to systematically determine the dose to be tested. This trial chose to pragmatically double and quadruple the dose of usual care. While the results provide some cause for optimism that dose of aerobic exercise may be important for stroke recovery, simply doubling the dose did not consistently lead to a doubling of the training effect. This has also been observed in the context of upper limb training trials post-stroke.5 Adopting a systematic discovery pipeline approach has been identified as an international consensus-based recommendation.6 This approach,7 similar to that applied for drug treatment development, seeks to identify the dose range before determining the optimal (or effective) dose. Implementing such an approach could meaningfully advance our understanding of dose and move us closer to identifying more efficacious stroke recovery interventions.
References:
1. Ward NS. Restoring brain function after stroke – bridging the gap between animals and humans. Nat Rev Neurol. 2017;13:244-255.
2. Stinear CM, Lang CE, Zeiler S, Byblow WD. Advances and challenges in stroke rehabilitation. Lancet Neurol. 2020;19:348-360.
3. Klassen TD, Dukelow SP, Bayley MT, Benavente O, Hill MD, Krassioukov A, Liu-Ambrose T, Pooyania S, Poulin MJ, Schneeberg A, et al. Higher doses improve walking recovery during stroke inpatient rehabilitation. Stroke. 2020;51:2639-2648.
4. Lohse KR, Pathania A, Wegman R, Boyd LA, Lang CE. On the reporting of experimental and control therapies in stroke rehabilitation trials: A systematic review. Arch Phys Med Rehabil. 2018;99:1424-1432.
5. Lang CE, Strube MJ, Bland MD, Waddell KJ, Cherry-Allen KM, Nudo RJ, Dromerick AW, Birkenmeijer RL. Dose response of task-specific upper limb training in people at least 6 months poststroke: A phase ii, single-blind, randomized, controlled trial. Annals of Neurology. 2016;80:342-354.
6. Bernhardt J, Hayward KS, Dancause N, Lannin N, Ward N, Nudo RJ, Farrin AJ, Churilov L, Boyd L, Jones TA, et al. A stroke recovery trial development framework: Consensus-based core recommendations from the second stroke recovery and rehabilitation roundtable. International Journal of Stroke. 2019;14:792–802.
7. Dalton EJ, Churilov L, Lannin NA, Corbett D, Hayward KS. Dose articulation in preclinical and clinical stroke recovery: Refining a discovery research pipeline and presenting a scoping review protocol. Frontiers in Neurology. 2019;10:1148.
