Full-pressure external counterpulsation was associated with greater improvements in cognition and activities of daily living than low-pressure treatment among patients with clinically diagnosed mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease, according to findings published in the American Journal of Alzheimer’s Disease & Other Dementias.
Researchers conducted a 12-month, multicenter, randomized, single-blind trial at 12 sites. The study included 190 patients aged 55 to 85 years who met 2011 National Institute on Aging–Alzheimer’s Association clinical criteria for mild cognitive impairment due to Alzheimer disease or mild Alzheimer disease. Eligibility was based on clinical diagnostic criteria, and the researchers noted that a fraction of participants were likely amyloid-negative.
Patients were randomly assigned in a 1:1 ratio to full-pressure external counterpulsation (ECP) or low-pressure treatment, with randomization stratified by clinical diagnosis and cardiovascular risk. Full-pressure ECP used cardiac-synchronized cuff inflation at 150 to 300 mmHg, with an average pressure of 240 mmHg. The control group received asynchronous compression at approximately 25 mmHg. The researchers stated that the low-pressure intervention was not an inactive control because low-pressure pneumatic compression may have physiological effects.
Both groups received 35 1-hour sessions over 7 to 12 weeks, followed by twice-weekly maintenance sessions through month 6. No treatment was administered during the final 6 months. Assessments were conducted at baseline and at weeks 6, 12, 18, 24, 36, and 52.
The primary efficacy outcome was the time-averaged Vascular Dementia Assessment Scale cognitive subscale (VADAS-cog) score, calculated from modeled values at weeks 12, 18, and 24. Bayesian analyses with multiple imputation estimated the probability that full-pressure treatment was superior to low-pressure treatment. The prespecified threshold for the primary endpoint was 97.9%. Frequentist mixed-model repeated-measures analyses were also performed.
The time-averaged VADAS-cog score improved by 9.95 points in the full-pressure group and 5.22 points in the low-pressure group. The posterior probability of superiority was 99.7%, meeting the prespecified primary endpoint. At 12 months, improvement from baseline was 9 points with full-pressure treatment and 3 points with low-pressure treatment.
The time-averaged ADAS-cog 14 score improved by 6.16 points with full-pressure treatment and 2.74 points with low-pressure treatment. The Mini-Mental State Examination, an exploratory outcome, improved by 1.68 points vs 0.19 points at 6 months.
Activities-of-daily-living scores improved by 2.57 points in the full-pressure group and declined by 0.49 points in the low-pressure group during the time-averaged assessment period. There was a statistically significant difference in baseline Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) scores, with mean scores of 72.4 in the low-pressure group vs 70.5 in the full-pressure group. At 12 months, scores remained 1.6 points above baseline in the full-pressure group and were 2.8 points below baseline in the low-pressure group. Each point on the scale indicates a change in ability or the level of caregiver assistance required.
Clinician-rated global change showed a statistically significant difference favoring full-pressure treatment at weeks 12, 24, 36, and 52. In addition, 63% of patients receiving full-pressure treatment and 44% receiving low-pressure treatment had improved or stable time-averaged scores on both the VADAS-cog and ADCS-ADL scale.
Patients, caregivers, and independent psychometricians who administered the functional, global-change, and Trail Making assessments were blinded to treatment assignment. However, site personnel who administered the VADAS-cog primary efficacy outcome, ADAS-cog 14, and Mini-Mental State Examination were not guaranteed to be blinded, introducing the potential for tester bias. Placebo and practice effects also could not be excluded.
Eighty-five of 95 patients assigned to full-pressure treatment and 77 of 95 assigned to low-pressure treatment completed the trial. Across 10,644 sessions, 30 adverse events considered probably or suspected to be device-related occurred in 22 patients. None were serious. Mild skin irritation or injury was the most common event and occurred in 16 patients, all in the full-pressure group. No patients discontinued treatment because of adverse events.
No brain edema or hemorrhage was identified relative to baseline on available follow-up magnetic resonance imaging. Amyloid-related imaging abnormalities were not a prespecified outcome, and follow-up imaging was incomplete. One patient in the low-pressure group developed a nonfatal intracerebral hemorrhage 1 month following the final treatment; investigators determined that the event was not treatment-related.
The researchers said the findings support further investigation of ECP in early Alzheimer disease but do not establish its role relative to or alongside established disease-modifying therapies.
“This study does not attempt to break down either the specific mechanism of improvement in individual patients, nor to determine whether the treatment influenced the ‘essential nature’ of AD or simply its overt clinical manifestations,” wrote lead author Jack E. Juni, MD, of Medical Device Development at Renew Research, LLC, in Farmington Hills, Michigan, and colleagues.
Renew Research funded the study and was responsible for its design and conduct; data collection, management, analysis, and interpretation; manuscript preparation, review, and approval; and the decision to submit the manuscript. Jack E. Juni, MD, and Drew Hill, MSE, were employed by Renew Research. Other researchers reported consulting, research, or financial relationships with Renew Research and other organizations. Full disclosures can be found in the published study.
Source:American Journal of Alzheimer’s Disease & Other Dementias