Abstract
Background:
We developed the Strength Training Intervention (STRIVE), a home-based exercise program targeting physical function in patients with cirrhosis. In this pilot study, we aimed to evaluate the safety and efficacy of STRIVE.
Methods:
Eligible were adult patients with cirrhosis at 3 sites. Patients were randomized 2:1 to 12 weeks of STRIVE, a 30-minute strength training video plus a health coach or standard of care (SOC). Physical function and quality of life were assessed using the Liver Frailty Index (LFI) and Chronic Liver Disease Questionnaire (CLDQ), respectively.
Results:
58 and 25 were randomized to STRIVE and SOC arms, respectively: 43% women, median age was 61y, MELDNa was 14; 54% were Child B/C. Baseline characteristics were similar in the STRIVE vs. SOC arms except for rates of hepatic encephalopathy (19 vs. 36%). LFI @ 12 weeks was available in 43 STRIVE and 20 SOC participants. After 12 weeks, median LFI improved from 3.8 to 3.6 (ΔLFI −0.1) in the STRIVE arm and 3.7 to 3.6 (ΔLFI −0.1) in SOC arm (p=0.65 for ΔLFI difference). CLDQ scores improved from 4.6 to 5.2 in STRIVE participants (ΔCLDQ 0.38) and did not change in SOC participants (4.2 to 4.2; ΔCLDQ −0.03) [p=0.09 for ΔCLDQ difference]. One patient died (SOC arm) of bleeding. Only 14% of STRIVE participants adhered to the strength training video for 10 to 12 weeks. No adverse events were reported by STRIVE participants.
Conclusions:
STRIVE, a home-based structured exercise program for patients with cirrhosis, was safely administered at 3 sites, but adherence was low. While all participants showed minimal improvement in LFI, STRIVE was associated with a substantial improvement in quality of life.
INTRODUCTION
Physical frailty is prevalent in patients with cirrhosis, particularly among those with hepatic decompensation awaiting liver transplantation, with over 80% displaying at least some degree of physical frailty (as measured by the Liver Frailty Index). Physical frailty has emerged as a critical determinant of mortality in this population,1 and is strongly associated with disability and symptom burden.2 Importantly, it is also the sole predictor of physical robustness after liver transplantation.3 Given that it is potentially modifiable through exercise, physical frailty represents a key target for intervention to improve outcomes and quality of life in liver transplant candidates.
There now exist sufficient data demonstrating that certain factors that contribute to physical frailty improve with activity-based interventions. In multiple trials including over 150 patients with cirrhosis, exercise interventions improved frailty-related metrics such as cardiopulmonary exercise capacity, six-minute walk-test distance, body composition, and/or health-related quality of life (hrQOL).4–7 However, all of these studies involved supervised, center-based exercise interventions, and as such, are limited in their generalizability to individuals who cannot access such resources either due to the long distance from their transplant center or limited available resources. Furthermore, these studies largely focused on low MELD patients with cirrhosis with a low likelihood of hepatic decompensation. There is, therefore, a great unmet need for home-based, exercise interventions targeting physical frailty in patients with hepatic decompensation, who represent those at highest risk of mortality due to physical frailty.
To address this unmet need, we developed the Strength Training Intervention (STRIVE), a 12-week, home-based structured exercise program specifically for patients with decompensated cirrhosis. The design of this program was guided by the Information-Motivation-Behavioral Skills conceptual model for modifying individual health behaviors. The IMB framework postulates that individuals who are knowledgeable about the harms of physical inactivity, motivated to engage in activity, and empowered with effective behavioral skills will take action to improve their physical health.8 Using this framework, we established a 3-component intervention (Figure 1) consisting of an initial visit (information), a health coach (motivation), and a structured exercise program (behavioral skills).
Figure 1.
The three components of the Strength Training Intervention for Liver Transplant Patients (STRIVE-LT) based on the Information-Motivation-Behavioral Skills conception model for modifying individual health behaviors.8
In this randomized clinical trial, we aimed to evaluate the safety of, adherence to, and effect of STRIVE in patients with cirrhosis at 3 centers in the United States. We hypothesized that, in patients with decompensated cirrhosis, STRIVE would: 1) be safe, 2) could be feasibly administered in the home setting, and 3) improve physical frailty.
METHODS
Setting, participants, and randomization scheme
At 3 U.S. centers (University of California San Francisco, Duke University, Johns Hopkins Medical Institute), we conducted a randomized controlled trial of STRIVE compared to enhanced standard-of-care in patients with end-stage liver disease. Inclusion criteria were: 1) age ≥18 years, 2) diagnosis of cirrhosis, 3) laboratory MELD score ≥12 (to increase the acuity of illness given that prior studies focused largely on low MELD patients, and 4) access to either a home Digital Versatile Disc (DVD) player or home internet to play the exercise video. Exclusion criteria were: 1) any limitation that precluded exercise (e.g., physical disability impairing balance), as determined by the participant’s primary hepatologist, 2) non-English speaking, as the video-based exercise program was only available in English, and 3) known variceal hemorrhage within 3 months of enrollment. Participants meeting eligibility criteria who were scheduled for a clinic visit for routine clinical care were identified based on pre-screening of clinic schedules, then selected at random (picking out names from a hat at UCSF; based on availability of study personnel at Duke and Johns Hopkins) and enrolled at a rate of no more than 1 participant per week.
Eligible participants were randomized in a ratio of 2 to the intervention and 1 to the control arm. Prior to study initiation, random assignments were generated using a computerized randomization scheme at the coordinating site, placed into sequentially numbered, opaque, sealed envelopes, and distributed to each site. Once an eligible participant enrolled in the study, provided signed informed consent, and completed all baseline assessments (e.g., baseline frailty assessment, baseline surveys, and collection of demographic and laboratory data), the envelope was opened to reveal the randomization assignment (in sequential order).
Study arms
At enrollment, prior to randomization, all participants were provided a personal activity tracker (Fitbit Alta). Data from the personal activity tracker were wirelessly uploaded and aggregated using the Fitabase software platform.
Control arm
The control arm was intended to consist of participants under their usual standard of care. None of the participating sites had implemented formal standardized exercise recommendations or programs during the study period. However, it is known that some degree of physical activity benefits all individuals, regardless of clinical condition; what is unknown is how best to deliver such exercise. To maintain clinical equipoise, we provided participants randomized to the control arm with written instructions for exercise based on formal recommendations from the 2008 Physical Activity Guidelines for Americans: Active Older Adults (Chapter 5: http://health.gov/paguidelines/guidelines/chapter5.aspx) developed by the U.S. Office of Disease Prevention and Health Promotion. These guidelines have previously been studied as an exercise-based intervention in liver transplant patients.9
Intervention arm
STRIVE is a 12-week, home-based, structured exercise program that was developed specifically for patients with decompensated cirrhosis. Based on the IMB framework for modifying individual behaviors, STRIVE consists of 3 components (Figure 1):
Initial visit (Information). The health coach provided information on the impact of frailty on outcomes. At the initial visit, s/he guided participants through the exercise video (see below) to determine the starting resistance band level, to demonstrate proper positioning during the exercises, and to provide instruction on adjusting resistance. The individual exercises were also provided on paper in a binder as a reference for the participant.
Health coach (Motivation). The health coach called the participant once per week to provide motivation—using a semi-structured script—to encourage program adherence. On a weekly basis for 12 weeks, new step goals were provided, increasing step goals by 500 steps per day above the daily average from the week prior.
Strong for Life™ video (Behavioral skills). Developed for sedentary older adults, this 30-minute video consists of 11 exercises, some of which utilize resistance bands (Therabands©), incorporating movement patterns associated with daily functional activities.10 Participants were “prescribed” Strong for Life™ a minimum of three times per week and provided Therabands© at three different resistance levels. This “dose” (three times per week) resulted in significant functional improvement in a randomized clinical trial of older adults after hip fracture.11 The Strong for Life™ video was selected for STRIVE-LT for its safety in frail older adults (therefore safe for frail patients with cirrhosis),10 validated efficacy at improving physical function,11 and ease of use at home (increasing acceptability, adherence, and generalizability). Permission to use this video for STRIVE-LT was obtain by personal communication with Dr. Alan Jette.
Study assessments and data collection
All participants underwent the following assessments at baseline and at 12 weeks following completion of the 12-week STRIVE program:
Physical frailty. This was assessed using the Liver Frailty Index, which consists of 3 performance-based measures: grip strength, chair stands, and balance.12 The Liver Frailty Index was calculated using the on-line calculator available at: https://liverfrailtyindex.ucsf.edu. We have previously described high inter-rater reliability of the Liver Frailty Index (intra-class correlation coefficient = 0.93).13 We have also previously demonstrated that changes in the Liver Frailty Index are predictive of mortality in patients with cirrhosis;14 we have suggested change of 0.2 and 0.5 in the Liver Frailty index to define moderate and substantial clinically important differences in the Liver Frailty Index, respectively.3
Quality of life (QOL). This was assessed by the disease-specific Chronic Liver Disease Questionnaire.15
Assessments were administered by trained study personnel at each site who were blinded to the participant assignment.
Additional data were collected at baseline including participant demographics and laboratory tests (that were collected as part of routine clinical care in patients with decompensated cirrhosis). Participants were asked about any inpatient hospitalized days and reasons for hospitalizations on a weekly basis. The presence of ascites was recorded if documented in the physical exam of the patient’s hepatologist on the day of the enrollment visit. The presence of hepatic encephalopathy was recorded if the patient took 45 seconds or longer to complete the Numbers Connection Test A that was administered at enrollment; this 45-second threshold was determined based prior studies comparing healthy controls with individuals with hepatic encephalopathy.16 We have previously described sensitivity analyses demonstrating the robustness of the Liver Frailty Index to predict mortality regardless of method to ascertain hepatic encephalopathy in this population.1
Statistical analysis
Characteristics were reported as medians with interquartile ranges (IQR) or percentages for (1) all participants randomized in the trial and (2) among participants having a 12 week assessment (+/− 6 weeks) each stratified by intervention and control arms. To assess for differences between participants with and without a 12 week assessment, we also compared descriptive characteristics between these two groups. Differences were compared using Wilcoxon rank sum or chi-square tests, as appropriate. Our sample size of 83 participants (58 treatment and 25 controls) had >99% power to detect a difference of 0.5 between groups. Adherence was evaluated among participants randomized to the intervention arm with a 12 week assessment by quantifying the weeks where the Strong for Life and step goals were met.
Statistical analyses were performed using SAS (v9.4, SAS Institute, Cary, NC) and Stata (v15.0, StataCorp, College Station, TX). The Institutional Review Boards at each of the participating sites approved this study.
RESULTS
Comparison of baseline characteristics by group
A total of 83 participants enrolled in this randomized controlled trial: 58 (70%) were randomized to STRIVE-LT and 25 (30%) were randomized to the control arm. Sixty-two were enrolled from one site, 12 from a second site, and 9 from a third site. There were more women in the STRIVE-LT arm than in the control arm (50% versus 28%). Baseline characteristics in those randomized to STRIVE-LT versus the control groups were otherwise clinically similar. Notably, median baseline MELDNa score (12 versus 13) and the proportion with Child Pugh B/C (53% versus 54%) were similar between the two groups. MELDNa at 12 weeks was also similar between the two groups (15 versus 15).
Comparison of outcomes by group
A total of 43 / 58 (74%) STRIVE-LT and 20 / 25 (80%) control patients completed the full 12 week intervention and had a 12 week assessment of frailty. Baseline characteristics between those who did and did not have a 12 week assessment were similar except for % with HCC (44 vs. 20%). One patient randomized to the control arm died within the 12 week study period secondary to gastrointestinal bleeding presumed to be variceal; none in the intervention arm died within the 12 week intervention period. The remaining individuals who did not have a Liver Frailty Index assessment due to their inability or unwillingness to come in within the specific time frame of 12 weeks (+6 weeks).
Among the 63 participants (43 STRIVE-LT and 20 control participants) with a 12 week assessment, baseline Liver Frailty Index was 3.8 in STRIVE-LT participants and 3.7 in participants randomized to the control group (p=0.95). Liver Frailty Index was also similar at 12 weeks in the 2 groups (3.6 versus 3.6; p=0.70), with no significant difference in the median change in Liver Frailty Index over 12 weeks (−0.1 versus −0.1; p=0.65). A substantially greater proportion of participants in the STRIVE-LT arm experienced a 0.2 unit (21 vs. 5%) and 0.5 unit (12% vs. 0%) improvement in the Liver Frailty Index, although these differences did not meet statistical significance. Median CLDQ score increased from 4.6 at baseline to 5.2 at 12 weeks in STRIVE-LT participants with a median increase in 0.4 over 12 weeks. Among those randomized to the control arm, median CLDQ remained the same at 4.2 from baseline to 12 weeks [p=0.09 for the difference in the 12-week change in CLDQ scores between the two groups]. The average number of steps per day in the STRIVE-LT group was numerically higher than in the controls (4451 versus 3569), but this difference was not statistically significant (p=0.37). No adverse events were reported related to the STRIVE-LT intervention, including injuries, muscle strains, falls, or variceal bleeding.
Adherence and logistical challenges
Participants reported adhering to the recommended Strong for Life frequency a median of 5 (IQR 1–8) weeks over the 12 week period. Only 6 / 43 (14%) participants randomized to the STRIVE arm adhered to the recommended Strong for Life frequency of three times per week for at least 10 of the 12 weeks. Among those who met this goal, median (IQR) Liver Frailty Index decreased from 3.93 (3.76–4.04) at baseline to 3.75 (2.98–3.97) at 12 weeks compared to 3.66 (3.24–4.35) at baseline to 3.55 (3.13–4.15) at 12 weeks.
With regards to use of the personal activity tracker, 35 / 43 (81%) participants were able to sync their Fitbit at least 10 out of the 12 week intervention. Participants randomized to STRIVE met their personalized step goal a median of 7 (IQR 3–12) weeks. Only 14 / 43 (33%) participants met their personalized step goal at least 10 of the 12 weeks.
DISCUSSION
We report results from a multi-center randomized clinical trial evaluating the safety and feasibility of a 12-week home-based structured strength training program in patients with cirrhosis, the largest trial to date in this population. While we found that exercise in a home-based setting was safe, participants enrolled in the STRIVE arm did not experience a clinically meaningful improvement in their physical frailty scores at the end of the 12-week intervention. This was no different than those enrolled in the control arm. While the average number of steps per day during the 12-week study period among participants in the STRIVE arm was nearly 1,000 steps per day higher than in the control arm, this difference was not statistically significant. The STRIVE program resulted in a trend toward improvement in self-reported quality of life, whereas participants enrolled in the control arm did not report any significant change in their quality of life during the 12 week study period (but the between-group difference was not statistically significant).
While there are a number of studies that have evaluated exercise programs in patients with cirrhosis,17 our study offers essential lessons to the community that substantially add to our understanding of exercise in patients with cirrhosis. These lessons are grouped into the following 3 major categories:
Feasibility of administering a home-based intervention.
The majority of studies in this population have evaluated supervised exercise programs conducted at centers with specialized personnel to oversee the training programs. While supervised studies where one can maximize adherence are essential to demonstrate the direct impact of exercise on outcomes in this population, they are not readily generalizable or scalable given wide-spread resource limitations. Developing effective home-based programs is essential to maximizing accessibility of exercise programs that have been recommended by several groups of experts.18–20 Three-quarters of those randomized to the STRIVE arm were able to complete baseline and 12-week assessments after randomization. However, adherence to this home-based intervention was low, despite efforts to engage patients through a weekly health-coach. These preliminary data are essential to inform the design of future exercise-based randomized clinical trials in this population.
We also faced major challenges to the logistics of using personal activity trackers for this study. Despite use of an on-line, real-time, mobile health collection tool for the data from the personal activity trackers, management of the personal activity tracker was time-consuming and labor-intensive for our study team. Participants frequently forgot to charge their device or forgot to wear their device, limiting use of the data from the device as either an accurate activity monitor or an effective motivator of behavior. While other studies in cirrhosis populations have successfully incorporated personal activity trackers into their interventions,21,22 identifying characteristics (e.g., younger individuals, higher baseline activity23) of individuals who will respond well to personal activity trackers is necessary to consider their use in future interventions.
Safety.
This study establishes that programs that encourage strength training and increased physical activity in the home environment without direct supervision by a trained physiotherapist can be done safely. STRIVE participants did not report any injuries or falls related to participation in the intervention. Although one patient enrolled in our trial died of a presumed gastrointestinal bleed, this patient had been randomized to the control arm.
Efficacy.
We were disappointed that STRIVE did not lead to a reduction in physical frailty scores after 12 weeks. Average step count was numerically higher in participants randomized to STRIVE compared to those randomized to the control arm, but this difference did not meet statistical significance. It is possible that this program, which was based on a program for frail older adults and designed with safety as the utmost priority, was not sufficiently rigorous for this non-geriatric, non-frail population. In addition, adherence rates were quite low, raising the possibility that the STRIVE program could have resulted in clinically meaningful improvements in physical function had participants strictly adhered to the program. A better understanding of the modifiable barriers to exercise adherence—such as fatigue, poor control of portal hypertensive complications, or pain24—for each individual patient and the development of personalized strategies to overcome these barriers is critical to enhancing efficacy of exercise interventions. Exploration of the barriers to and facilitators of adherence to an exercise program would need to be explored prior to designing and implementing future iterations of the STRIVE-LT program.
We were encouraged, however, by the improvement in self-reported quality of life at the end of the 12 week intervention, whereas the control group experienced no change during the same study period. This speaks to the range of the potential benefits of programs such as STRIVE-LT to patients’ well-being and emphasizes the importance of capturing patient-reported outcomes in future exercise interventions to more fully understand how they impact patients’ lives. It is possible that improvement in quality of life and other mental health benefits might ultimately translate to better clinical outcomes even in the absence of improvement in the Liver Frailty Index, and future studies should be designed to capture a broader spectrum of benefits outside of physical frailty alone.
We acknowledge the following limitations to our study. Our study was designed to understand the effect of the STRIVE program as a whole and not its individual components. Whether one component (e.g., information, health coach, or Strong for Life video) contributed more than the others to improvements in self-reported quality of life will need to be teased out in future studies. The majority of patients were recruited from a single site; however, this is the first multi-center study to evaluate exercise in cirrhosis and is important to highlight issues related to conducting such trials in this population. Lastly, adherence rates were low, so we were unable to determine whether the lack of improvement of STRIVE was related to the program itself or due to adherence. But this issue with adherence mimics the real-world experience with implementing exercise programs in this population and underscores the necessity of incorporating strategies to enhance adherence in future iterations of the STRIVE program.
There is no doubt that exercise is critical in the management of patients with cirrhosis. To date, there are a number of studies that have demonstrated positive effect of exercise in this population but few that have presented the challenges of implementing this exercise programs that can be scaled to the cirrhosis population at large. Here we offer lessons learned from our randomized clinical trial of STRIVE that can enhance future iterations of this program and inform the design of clinical trials testing exercise programs in patients with decompensated cirrhosis.
Table 1.
Characteristics of the 83 participants in this randomized controlled trial.
| Characteristics* | All n=83 | By Study Arm | ||
|---|---|---|---|---|
| STRIVE-LT n=58 (70%) | Control n=25 (30%) | |||
| Female | 43% | 50% | 28% | |
| Age, years | 61 (55–65) | 62 (56–66) | 61 (42–72) | |
| Race/Ethnicity | White | 83% | 96% | 68% |
| Black | 10% | 0% | 14% | |
| Asian | 6% | 4% | 7% | |
| Other | 2% | 2% | 2% | |
| Height, cm | 170 (165–178) | 170 (163–175) | 173 (168–180) | |
| Body mass index, kg/m2 | 28 (26–33) | 28 (26–33) | 28 (26–33) | |
| Etiology of liver disease | Chronic hepatitis C | 37% | 36% | 40% |
| Alcohol | 21% | 19% | 24% | |
| Non-alcoholic fatty liver disease | 12% | 10% | 16% | |
| Autoimmune/cholestatic | 18% | 21% | 12% | |
| Other | 12% | 14% | 8% | |
| Hepatocellular carcinoma | 39% | 36% | 44% | |
| Hypertension | 48% | 48% | 48% | |
| Diabetes | 33% | 36% | 24% | |
| Coronary artery disease | 5% | 5% | 4% | |
| Baseline MELDNa | 14 (11–19) | 12 (6–32) | 13 (6–23) | |
| MELDNa at 12 weeks | 15 (11–17) | 15 (6–24) | 15 (11–17) | |
| Albumin, g/dL | 3.3 (2.8–3.7) | 3.4 (2.8–3.8) | 3.0 (2.8–3.6) | |
| Ascites | 22% | 21% | 25% | |
| Hepatic encephalopathy | 24% | 19% | 36% | |
| Child Pugh B/C | 54% | 53% | 54% | |
Median (IQR) or %
Table 2.
Results of physical activity, physical frailty, and quality of life assessments at baseline and at 12-weeks.
| Assessment* | By Study Arm | p-value | |
|---|---|---|---|
| STRIVE-LT n=43 | Control n=20 | ||
| Liver Frailty Index, baseline | 3.8 (3.2–4.4) | 3.7 (3.4–4.2) | 0.95 |
| Liver Frailty Index, 12 weeks | 3.6 (3.0–4.2) | 3.6 (3.2–3.9) | 0.70 |
| Change in Liver Frailty Index from baseline to 12 weeks | −0.1 (−0.4–0.1) | −0.1 (−0.4–0.1) | 0.65 |
| % with ≥0.2 unit improvement in Liver Frailty Index | 21% | 5% | 0.15 |
| % with ≥0.5 unit improvement in Liver Frailty Index | 12% | 0% | 0.17 |
| Average steps per day | 4451 (2898–6202) | 3569 (2442–5441) | 0.37 |
| CLDQ, baseline | 4.6 (3.4–5.8) | 4.2 (3.5–5.0) | 0.42 |
| CLDQ, 12 weeks | 5.2 (3.8–5.9) | 4.2 (3.3–5.5) | 0.09 |
| Change in CLDQ from baseline to 12 weeks | 0.4 (−0.1–0.9) | 0.0 (−0.4–0.4) | 0.09 |
Median (IQR) or %
Acknowledgements:
We would like to thank Fitbit, Inc for their sponsorship of the personal activity trackers, Performance Health for their sponsorship of the Theraband resistance bands, and Dr. Alan Jette for his permission to use the Strong for Life video in the intervention.
Financial support: This study was funded by NIH K23AG048337 (Lai), NIH R01AG059183 (Lai), NIH P30DK026743 (Lai, Dodge), NIH K24DK101828 (Segev), and the Mendez National Institute of Transplantation Foundation (Lai, McAdams-Demarco, Kappus). These funding agencies played no role in the analysis of the data or the preparation of this manuscript.
List of abbreviations:
- CLDQ
Chronic Liver Disease Questionnaire
- SOC
standard of care
- STRIVE
strength training intervention
Footnotes
Clinical Trial Number: NCT02367092
Disclosures: The authors of this manuscript have no conflicts of interest to disclose as described by American Journal of Gastroenterology.
Writing Assistance: None.
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