Is There a Time-Sensitive Window in Patients With Stroke to Enhance Arm Recovery With Higher Intensity Motor Therapy?

Abstract

HomeStrokeVol. 53, No. 5Is There a Time-Sensitive Window in Patients With Stroke to Enhance Arm Recovery With Higher Intensity Motor Therapy? Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBIs There a Time-Sensitive Window in Patients With Stroke to Enhance Arm Recovery With Higher Intensity Motor Therapy? Sean I. Savitz, MD Sean I. SavitzSean I. Savitz Correspondence to: Sean I. Savitz, MD, Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, 6431 Fannin St, Houston, TX 77030. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4637-1790 Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, Houston. Search for more papers by this author Originally published25 Apr 2022https://doi.org/10.1161/STROKEAHA.121.037402Stroke. 2022;53:1823–1825Rehabilitation medicine in stroke continues to grapple with fundamental issues surrounding optimal dosing, frequency, and timing of treatment after injury. One of the foremost authorities working in this field was Alex Dromerick, who recently passed away in August of this past year. Before his death, Alex and his team at MedStar National Rehabilitation Hospital completed the CPASS (Critical Period After Stroke Study),1 the focus of this emerging therapies review.For >20 years, we have known that the brain after stroke displays heightened responsiveness to behavioral experience in time-sensitive windows.2 Rehabilitation therapy initiated early after stroke in rodents leads to greater functional gains compared with delayed treatment.2 Our colleagues designed CPASS to recapitulate these animal studies in patients and determine if there is a similar time sensitive window in humans.In the CPASS trial, the investigators randomized patients with ischemic stroke and arm impairment (primarily ischemic) to receive 20 extra hours of upper limb rehabilitation initiated at different times after stroke: <30 days (acute), 2 to 3 mo (subacute), or 6 months (chronic). The fourth randomized group was allocation to usual and customary care (control) in which no additional motor training was intentionally provided in the context of the trial. The primary end point was the change in the action research arm test (ARAT) at 1 year, a well-validated functional measure of the arm. The patients in each of the allocated groups had similar age, severity on the National Institutes of Health Stroke Scale, and days after stroke at the time of randomization.Patients randomized to the subacute period achieved statistically significant improvement on ARAT compared with the control group (6.87±2.63 points, P=0.009), which passed the threshold for a minimal clinically important difference. Compared with the control group, patients randomized to the acute group also achieved a statistically significant improvement (+5.25±2.59 points, P=0.043) but did not reach the minimal clinically important difference threshold. Finally, there was no difference in ARAT change between the chronic and control group. Thus, the authors concluded that intense motor therapy provided at 2 to 3 months was the most effective among the different time windows at promoting arm recovery.Overall, this trial was a remarkable effort carried out by one of the best in our field and is a fitting tribute to a leader whom we dearly miss. Strengths of the study include (1) providing a standardized regimen that was designed with input from the latest clinical trials; (2) tailoring the therapy to the individual needs of the patient in a shaping protocol; (3) incorporating minimal clinically important difference in the primary end point analyses; (4) minimal loss to follow-up; and (5) manipulation check to assure that patients indeed received 20 hours or nearly 20 hours of therapy. The most important conclusion from this trial is that additional hours of intense motor training enhances arm recovery after stroke compared with usual care and that patients can tolerate higher amounts of therapy. If extra hours of motor therapy enhance recovery when applied at 2 to 3 months after stroke, consider the ramifications. Most patients in this time frame are in the community receiving minimal outpatient rehabilitation. The results, if replicated in larger studies, should galvanize the medical community and federal regulators to create the infrastructure and provide the resources necessary for intense motor therapy to become the standard of care for arm impairment in this time frame after stroke. New adjunctive treatments could then be designed to amplify even further arm recovery in conjunction with upper limb rehabilitation.As with all clinical trials, there are always issues for further consideration. The biggest challenge of this study was that the authors were investigating 2 different topics—(1) the difference between patients who received the experimental treatment versus standard of care and (2) the differences in treatment effect of the experimental intervention when applied at different time points. The study design and statistical analysis plan did not enable the investigators to fully differentiate whether the receipt of the extra motor training mediated the treatment effect on enhanced arm recovery or if the effect was related to the timing of the intervention. To further address the timing, the investigators would have to contrast the different time windows themselves of the active groups, but this analysis was not in the publication and, if performed, would likely have shown no differences with a frequentist approach, especially given the sample size per group.A second issue concerns the primary end point analysis and sample size. The study’s protocol, published in 2015,3 identified raw ARAT scores at 1-year poststroke as the primary outcome measure, and the sample size was calculated on the basis of this original primary end point. However, the analysis plan that the authors presented involved a comparison of groups based on ARAT change from randomization to 1 year.As a third issue, designing the control group in a rehabilitation trial is often a point of debate. Dr Dromerick often spoke about the challenges of control groups in rehabilitation trials. Usual and customary care represents whatever rehabilitation therapy patients receive either through insurance or through their own funds. While the number of hours of standard therapy were not quantified in CPASS, we know from Catherine Lang’s study, as described in the publication, that patients with stroke typically on average receive 36 min/day of outpatient therapy, which translates to 4.2 hours in a 7-day period.4 Thus, 20 extra hours likely was a substantially higher amount of therapy. The amount of additional therapy outside the context of the trial that randomized patients received before, during, and after the intervention was also unknown, which could have affected the results. However, the randomized nature of the study partially addresses this issue.Beyond the limitations, there are several interesting observations from the graphs on the temporal trajectories of the individual patients on the ARAT scores out to 1 year. First, across all groups, substantial numbers of patients achieved excellent recovery of the arm before the intervention was even applied in all the groups including the control group. Second, the rate of recovery appears different in the various treatment groups; in the acute phase, there was a rapid acceleration in recovery, in the subacute group, less acceleration, and in the chronic group, even less acceleration (though these could be artifacts of systematically differential measurement across conditions). However, no assessments were made around 60 days in the chronic and control groups, and it is therefore possible that we would see a similarly steep increase in ARAT score in the initial weeks poststroke in these groups as well. These results suggest that future studies should consider obtaining ARAT scores consistently at the same time points in all groups and more frequently in the 1- to 6-month time frame after stroke to better understand if there are different rates of acceleration and the bidirectional effects of accelerated recovery with high intensity motor interventions. It would be important to determine what the differences are among patients who achieved rapid improvement versus those who did not improve up to 1 year. To that end, perhaps the blood draws in the study could be utilized to develop predictive biomarkers.Some important points also need to be made about the ARAT score as the primary outcome measurement in the trial. The ARAT score is an excellent measurement of arm function, but the results clearly show that patients encountered a ceiling effect even before the intervention was applied. ARAT cannot be used to differentiate between behavioral restitution and compensation. Was the 6-point difference in the subacute group a true difference in motor impairment or masked by compensation strategies? To that end, it would have been very helpful to apply biomechanics (kinetics and kinematics) to quantify changes in the quality of movement to assess actual neurological repair.5 These points lead to the larger issue that we need to measure both activities and impairments (eg, Fugl-Meyer) of the arm to better study whether patients with stroke have sensitive periods of recovery. Measurements of impairment would also have been important to assure that the groups were equal at baseline before randomization. Last, the small differences shown in the trial between the acute and subacute groups could be the result of inter-item scaling properties of the ARAT. Overall, these limitations illustrate the need to include additional measurements to determine if patients benefited from the intervention.A final point that needs to be made concerns the public health messaging around this trial. While it might be tempting to think that CPASS proves that intense motor training is optimal in the subacute period of stroke, further studies will be needed to support this hypothesis in which different time frames are compared among each other in the analysis plan. Therefore, the results from this study must be interpreted with caution for each of the time frames studied. Unfortunately, dangerous interpretations of the results have surfaced in the media. As an example, there is no evidence from this trial that provision of rehabilitation therapy at higher intensities within 30 days after stroke is harmful. Furthermore, while this trial provides information about the effect of 20 additional hours of motor training in the chronic setting, an observational study suggests that much higher doses of upper limb rehabilitation in this time frame might lead to substantial gains in functional improvement.6 Randomized trials are needed to test the efficacy of substantially higher doses of upper limb rehabilitation in chronic stroke survivors.In summary, CPASS is an important advancement forward for stroke rehabilitation medicine and clearly deserves a replication study in a phase 3 multicenter trial to ascertain if there is an optimal time window after stroke to apply intense motor therapy. We also need trials to determine optimal dosing of motor therapy in different time windows after stroke. Timing may actually be everything, not only for reperfusion therapy, but also for rehabilitation.Article InformationSources of FundingNone.Disclosures As an employee of the institution (UTHealth), Dr Savitz has served in the following roles: as a site investigator in clinical trials sponsored by industry companies- Athersys, ReNeuron, San Bio, KM Pharma, Abbvie for which UT-HEALTH receives payments on the basis of clinical trial contracts; as an investigator on clinical trials supported by NIH grants, Department of Defense, Let’s Cure CP, the TIRR Foundation, and the Cord Blood Registry Systems; as a principal investigator or co-investigator on NIH funded grants in basic science and clinical research; as principal investigator for an imaging analysis center for clinical trials sponsored by SanBio and ReNeuron. In his capacity as a UTHealth employee, Dr Savitz has provided consulting services on behalf of UTHealth to ReNeuron, Lumosa, Deck Therapeutics, KM Pharma, Neurexcell, Abbvie, Neurastasis and ArunA. All compensation from such consulting arrangements have been paid to UTHealth.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Sources of Funding and Disclosures, see page 1825.Correspondence to: Sean I. Savitz, MD, Institute for Stroke and Cerebrovascular Disease, University of Texas Health Science Center, 6431 Fannin St, Houston, TX 77030. Email sean.i.[email protected]tmc.edu