A Randomized, Controlled, Prehabilitation Intervention to Maximize Early Recovery (PRIMER) in Liver Transplantation

Abstract

Background and Aims:

Frailty and impaired functional status are associated with adverse outcomes on the liver transplant (LT) waitlist and after transplantation. Prehabilitation prior to LT has rarely been tested. We conducted a two-arm patient randomized pilot trial to evaluate the feasibility and efficacy of a 14-week behavioral intervention to promote physical activity prior to LT.

Methods:

Thirty patients were randomized 2:1 to intervention (n=20) vs. control (n=10). The intervention arm received financial incentives and text-based reminders linked to wearable fitness trackers. Daily step goals increased by 15% in 2-week intervals. Weekly check-ins with study staff assessed barriers to physical activity. Primary outcomes were feasibility and acceptability. Secondary outcomes included mean end-of-study step counts, short physical performance battery (SPPB), grip strength, and body composition by phase angle (PhA). We fit regression models for secondary outcomes with arm as the exposure adjusting for baseline performance.

Results:

Mean age was 61, 47% were female, median MELD-Na was 13. One third were frail or pre-frail by the liver frailty index (LFI), 40% had impaired mobility by SPPB, nearly 40% had sarcopenia by bioimpedance PhA, 23% had prior falls, and 53% had diabetes. Study retention was 27/30 (90%; 2 unenrolled from intervention, 1 lost to follow-up in control arm). Self-reported adherence to exercise during weekly check-ins was about 50%; most common barriers were fatigue, weather, liver-related symptoms. End of study step counts were nearly 1000 steps higher for intervention vs. control: adjusted difference 997, 95% CI 147–1847; p=0.02. On average, the intervention group achieved daily step targets 51% of the time.

Conclusion:

A home-based intervention with financial incentives and text-based nudges was feasible, highly accepted and increased daily steps in LT candidates with functional impairment and malnutrition.

INTRODUCTION

Patients with decompensated cirrhosis have high morbidity and mortality with adverse clinical outcomes partially mediated by liver-disease associated sarcopenia, and frailty, defined as progressive loss of physiologic reserve and increased susceptibility to stressors (e.g. falls, infections).(1–4) Liver transplant (LT) waitlist candidates are particularly vulnerable; 40–60% have sarcopenia and 25% are frail.(2) Furthermore, it is well-established that frailty and sarcopenia add to the predictive validity of the MELD score, particularly at lower values, (1, 4–6) and are associated with lower transplant waitlisting, increased pre-transplant mortality, becoming too sick for transplant, higher need for rehabilitation, higher readmissions and costs. (4, 7, 8) Even more concerning, studies have shown only partial reversal of sarcopenia (ranging from 6–28%) even for up to 3 years after LT.(4)

Although physical activity is beneficial for patients with advanced liver disease, most have low physical activity levels (9–11) Fatigue and hepatic encephalopathy (HE) contribute to sedentary lifestyle while limited access to safe physical activity programs may also play a role.(10) In patients awaiting LT, increased aerobic and exercise capacity has been shown to improve survival outcomes post-transplant, (12, 13) yet there is a dearth of data on tailored physical activity programs for cirrhosis. A recent study of a 12-week, home-based program for cirrhosis was safe and increased participant daily counts by almost 1000 steps on average, however, adherence to the recommended exercise videos was only 14%.(14)

There is an opportunity to increase physical activity through behavioral nudges in the setting of patients with advanced liver disease. Our group conducted a randomized intervention of home-based text messaging program with financial incentives and health engagement messages that increased physical activity among kidney and liver transplant recipients with 92% study retention and 74% adherence to target step goals.(15) We now present the results of a pilot study of a home-based, 14-week intervention utilizing principles of behavioral economics to assess feasibility, acceptability, and physical activity.

PATIENTS AND METHODS

I. STUDY DESIGN

The Prehabilitation Intervention to Maximize Early Recovery (PRIMER) post-Liver Transplantation was a single center, two-arm, block-randomized study focused on evaluating the feasibility, acceptability, and potential efficacy of the PRIMER intervention in improving physical function and reducing frailty in adult LT candidates. This was a patient-randomized study conducted for 14 weeks; 2 weeks baseline and 12-week active intervention. The study was unblinded to study staff but blinded to the study investigators. Participants in both arms received usual care, a personal fitness tracker, and personalized nutrition and physical activity recommendations from a physical therapist and registered dietitian. The intervention arm consisted of: a) financial incentives to meet daily step goals measured with the fitness tracker, b) participation in weekly “check-in” sessions with the study coordinator, c) text messages to promote medication adherence, and d) regular consultation with allied health team members including clinical dieticians and physical therapists as needed (Arm 2).

Patients were recruited at a single hepatology clinic at the University of Pennsylvania between February 2018 and December 2018. After confirming eligibility and obtaining informed consent, participants were randomized to one of two study arms. The two study arms were: Arm 1 – control, and Arm 2 an incentivized physical activity program. Patients were prospectively, followed for up to 12 months post-intervention to evaluate clinical outcomes such as transplantation and death. A secondary evaluation examined transplantation and death at 3 years. This study was approved by the University of Pennsylvania Review Board (protocol #828669) and was registered and clinicaltrials.gov (NCT03584646). All research was conducted in accordance with both the Declarations of Helsinki and Istanbul and written informed consent was obtained from all participants.

III. SETTING AND PARTICIPANTS

Participants were contacted by telephone 1–2 weeks prior to their outpatient clinic appointments to assess interest and eligibility. Enrollment occurred in-person during clinic appointments. Prior to randomization, a trained research coordinator conducted baseline assessments of physical function, frailty, and nutritional status via a standardized form. A physical therapist (DZ) and registered dietitian (KD) reviewed the baseline data to assess safety for a home-based exercise program and to determine individualized nutrition goals, respectively. The participants were followed remotely via SMS text, email, and telephone calls. There was a 2-week introductory period prior to the 12-week intervention to ensure familiarity with personal fitness trackers. At 14 weeks post enrollment, participants completed exit interviews about their experience with the intervention.

Eligibility Criteria

Eligible participants were 21 or older with a MELD-Na ≤25 and were either undergoing LT evaluation, were waitlisted for LT, or completed LT evaluation but were not yet waitlisted due to clinical stability. To participate they had to be English-speaking, own/use a smartphone, be able to provide informed consent, and be willing to participate in an exercise program. Lastly, eligible participants had to meet at least one of the following 4 at-risk criteria: 1) less than optimal performance on the Short Physical Performance Battery (SPPB) scale < 12, 2) pre-frailty or frailty (LFI≥3.2), 3) score below normal for age- and sex- adjusted dynamometer-measured grip strength in the dominant hand, or 4) malnutrition (score of B or C on abridged self-reported Patient-Generated Subjective Global Assessment (SGA)(7, 16). The criteria were chosen to be pragmatic and to identify patients more likely to benefit from the intervention. Participants were excluded if they were unable to provide informed consent, were hospitalized within the last 30 days, scored 0–3 points on the SPPB assessment (indicating inability to participate in a physical activity program), were deemed a high falls risk by a physical therapist, or were already enrolled in an exercise program with wearable devices or text alerts.

IV. ENROLLMENT AND RANDOMIZATION

Patients with upcoming clinic appointments were contacted via telephone and subsequently approached at outpatient clinic visits. Enrollment procedures included completion of signed informed consent, the Patient-Generated Subjective Global Assessment (PG-SGA), the Short Physical Performance Battery (SPPB), and grip strength assessment (kg) to establish eligibility. Enrollment, randomization, and subsequent messaging utilized Way to Health, an automated online platform developed by University of Pennsylvania that interfaces with smartphone and other wireless devices to facilitate clinical trials with remote monitoring and patient engagement strategies.(15) Eligible patients received personal fitness trackers (Nokia GO). All enrolled patients underwent baseline assessment of body composition using bioimpedance analysis (BIA) with the BodystatQuadscan 1500^® (Bodystat Ltd). Phase angle (PhA) derived from BIA was used to assess for sarcopenia in chronic liver disease; less than 5^th percentile for phase angle was used as a marker for sarcopenia.(17–20) Participants were block randomized into one of two arms with a block size of 6 and a 2:1 ratio for the intervention vs. control. End of study assessments included exit interviews, measures of weight, grip strength, body composition, and physical performance within 30 days of intervention completion. All participants received $20 for study enrollment and $30 for completion of exit surveys.

V. STUDY ARMS

Patients were randomized to one of two arms: control or intervention. Participants in both arms received the Nokia Go personal tracker device to log daily step counts and received personalized diet and physical activity recommendations based on their baseline physical and nutritional assessment. The personalized programs were designed by a licensed physical therapist (DZ) and registered dietitian (KD) with transplant expertise (Supplement S1, S2). Participants received tailored handouts modified by a physical therapist and dietitian via email or in person within 1 week of enrollment. Exercise instructions included upper, lower body exercises for strength and balance with links to sample videos. The nutrition handout included daily calorie, protein, sodium, general intake goals, and personalized advice based on current diet. Control arm participants were encouraged to walk “as much as possible” and to sync their step tracker daily.

Intervention Arm

The intervention arm received a home-based physical activity program supported by financial incentives for meeting walking goals and participating in weekly telephone check-ins, and text messages with medication reminders, and personalized nutrition and exercise recommendations. The intervention was paused during hospitalizations that occurred during the study period.

Walking goals

One of the exploratory objectives was to increase daily step counts; this was promoted with financial incentives. As optimal walking goals for patients with decompensated cirrhosis are unknown, average daily step counts were computed during the 2-week run-in period using at least 7 days of data, as per a previous study. (15) During each 2-week period of the intervention (6 periods in total), participants were asked to increase daily step counts by 15% over their previous baseline target. Participants were given a virtual account balance of $60 at the beginning of each 2-week active intervention period with the potential to earn $360. If participants met their goals, the account balance was maintained from day to day, however, if they did not meet the daily step goal, $3 was deducted from the virtual account balance. Daily text messages informed the participants whether they met the daily step goal on the previous day and the current account balance amount. An example of a sample message was: “Congratulations, you walked X number of steps yesterday and reached your target. Each day you meet your target you earn money. Your account currently holds $Y.”

Weekly check-ins

The pilot trial assessed the feasibility and acceptability of study intervention as well as proactive symptom monitoring. To this end, participants were incentivized an additional $9 per week to complete telephone check-in calls with the research coordinator (funds were deducted weekly if check-ins were missed). During the weekly check-ins, the research coordinator assessed any symptoms, concerns about the intervention and any barriers to walking or to following exercise or nutritional recommendations (Supplement S3).

Text message reminders

Participants received twice daily general medication adherence reminders, e.g., “Please take your morning/evening medications” via text and links to exercise videos.

VI. OUTCOMES

The primary outcomes were feasibility (% of patients that completed the intervention) and acceptability as measured by satisfaction on the exit survey (Supplement S4). Secondary outcomes included end of study step counts, end of study SPPB performance, grip strength, and body composition (PhA). Clinical outcomes such LT, death, or waitlist removal were evaluated at 12 months after study enrollment.

VII. STATISTICAL ANALYSES

Descriptive statistics were obtained for baseline variables. To compare sample characteristics between arms, ANOVA and Wilcoxon rank sum tests were used for continuous variables and Pearson chi-square tests or Fisher’s exact tests for categorical variables. For secondary outcomes, we fit linear regression models with robust standard errors for continuous variables (step counts, grip strength, SPPB) and logistic regression models for categorical outcomes (frailty by LFI, sarcopenia by PhA) with study arm as the primary exposure variable and adjusted for baseline performance. A total of 98% of participant-days had data, based on this and small sample size, multiple imputation was not pursued. All hypothesis tests were two-sided using a two-sided alpha of 0.05 as our threshold for statistical significance. Stata 15.1 (StataCorp, College Station, TX) was used to perform statistical analyses. The predetermined sample size for this feasibility pilot study was 30 and based on the size of the pilot grant.

RESULTS

Recruitment and Retention

The study enrollment details are shown in Figure 1. A total of 284 patients were assessed for eligibility and 150 were potentially eligible and were contacted via telephone or in person. A total of 33 participants underwent the screening visit; 2 did not meet any at risk criteria for frailty, impaired physical function or malnutrition and 1 did not like the device. A total of 30 participants were randomized (n=20, intervention, n=10 control). The retention rate was 27/30 (90%); one participant in the control arm was lost to follow-up and 2 unenrolled from the intervention arm. The intervention was paused and later restarted among 5 participants due to hospitalizations.

Figure 1.

Study Flow Diagram

Baseline Characteristics

Table 1 shows baseline participant characteristics in total and by study arm. The mean age was 61 (SD 7.4) years, 53% of participants were male, 27 (90%) were White and 3 (10%) were Black; the majority were married. The mean MELD-Na score was 13 (SD) with 37% of the patients on the active LT waitlist and the rest completed evaluation but had not yet been waitlisted. The median body mass index (BMI) was 27 kg/m². One third met criteria for frailty by sex-, age-adjusted grip strength measurement and about one third were frail or pre-frail by LFI. Nearly 40% had impaired mobility by SPPB (<10) and greater than half had PhA⁰ less than the 5^th percentile, i.e. concerning for sarcopenia. The most common liver disease complications were ascites and hepatic encephalopathy. Medical comorbidities were common with about half with a history of diabetes. A total of 7 (23%) patients had a history of falls. No statistically significant differences were noted in baseline characteristics by arm, however, 5 (50%) of patients in the control arm had HCC compared to 3 (15%) of the intervention arm (p=.05).

Table 1.

Baseline characteristics of PRIMER study participants

Variable	All Participants N = 30	Control N = 10	Intervention N = 20
Age, Mean (SD)	61 (7)	63 (6)	60 (8)
Male, n (%)	16 (53)	6 (60)	10 (50)
Black, n (%)	3 (10)	1 (10)	2 (10)
White, n (%)	27 (90)	9 (90)	18 (90)
Married, n (%)	19 (63)	6 (60)	13 (65)
MELD-Na, Mean (SD)	13 (4)	13 (3)	14 (5)
Waitlisted, (%)	11 (37)	4 (40)	7 (35)
BMI, Mean (SD) [Median]	28 (6) [27]	28 (6) [28]	28 (6) [27]
Frailty, physical function, malnutrition
Frail by hand grip strength, n (%)	9 (30)	3 (30)	6 (30)
LFI, Mean (SD) [Median]	4.0 (0.4) [4.2]	4.2 (0.5) [4.2]	4.0(0.4) [4.0]
Pre-frail/frail by LFI (≥3.2), n (%)	29 (97)	10 (100)	19 (95)
SPPB total, Mean (SD) [Median]	9.6 (1.5) [10]	9.4 (1.8) [10]	9.7 (1.3) [10]
Impaired mobility by SPPB (<10), n (%)	11 (37)	4 (40)	7 (35)
PhA⁰, Mean (SD) [Median]*	4.4 (0.8) [4.3]	4.3 (0.8) [4.4]	4.3 (0.9) [4.3]
PhA⁰ < 5th percentile), n (%)*	15 (56)	5 (63)	10 (53)
Cirrhosis Complications
Ascites, n (%)	27 (90)	9 (90)	18 (90)
History of GI bleed, n (%)	13 (43)	5 (50)	8 (40)
HE on lactulose +/rifaximin, n (%)	20 (67)	5 (50)	15 (75)
History of SBP, n (%)	6 (20)	1 (10)	5 (25)
HCC**, n (%)	8 (27)	5 (50)	3 (15)
Medical Comorbidities
Atrial fibrillation, n (%)	3 (10)	2 (20)	1 (5)
Diabetes on insulin, n (%)	9 (30)	3 (30)	6 (30)
Diabetes not on insulin, n (%)	7 (23)	3 (30)	4 (20)
Hypertension, n (%)	16 (53)	5 (50)	11 (55)
CAD, n (%)	6 (20)	2 (20)	4 (20)
COPD, n (%)	4 (13)	3 (30)	1 (5)
Dyslipidemia, n (%)	12 (40)	5 (50)	7 (35)
History of Falls, n (%)	7 (23)	2 (20)	5 (25)

Abbreviations: MELD-Na- model for end stage liver disease sodium, BMI- body mass index, SPPB – short physical performance battery, LFI- liver frailty index, PhA – phase angle assessed by biompedanceGI – gastrointestinal, HE - hepatic encephalopathy; SBP- spontaneous bacterial peritonitis, HCC – hepatocellular carcinoma, CAD – coronary artery disease, COPD- chronic obstructive pulmonary disease, SD – standard deviation

SPPB score < 10 indicates a mobility limitation

PhA⁰ percentile based on age-, sex-, and BMI-adjusted norms

^*data available for N=27 (N=8 intervention, N=19 control)

^**p=.05 for between group difference

Feasibility & Acceptability

Exit survey responses are shown in detail in Supplement S5. Among the 18 intervention participants that completed the study, all 18 (100%) agreed that the exercise recommendations were helpful and easy to perform; whereas 67% of the control arm participants agreed (p=0.03). A total of 7 (78%) of participants in the control arm, and 11 (61%) in the intervention arm agreed that nutrition recommendations were helpful. Most (80–90%) felt that the fitness tracker device was easy to use, that they would continue with the study longer if given the opportunity, and that they would continue with the study after transplant. A total of 15 (83%) in the intervention arm agreed that text messages about steps count goals and medication reminders were helpful, and 17 (94%) agreed that weekly check-is with study staff were helpful. During the weekly check-ins, about half of the patients reported reaching recommended exercise goals and nutrition goals, most rated their energy level as medium, and their liver disease symptoms or any mental confusion as mild or none. One third noted some discomfort with exercises and physical activity. The most common barriers to exercise were related to fatigue or weather and rarely due to pain or liver disease symptoms. Patients reported that they highly valued the weekly check-ins with the study coordinator to discuss their symptoms and questions about exercise and nutrition recommendations.

Study Fidelity and Protocol Adherence

A total of 2031 out of 2268 (90%) of participant-days had complete data for analysis, however, adherence to wearing personalized fitness trackers throughout the entire study period was 93% in the intervention group and 73% in control. Figure 2 shows percent adherence to daily step count goals over each two-week interval in the intervention arm. The mean participant-level adherence to daily step goals in each two-week interval was 51% (SD 35); median was 50% (IQR: 18–85%) and the adherence was generally stable within each two-week interval. Individual level adherence over the entire study interval was 51% (SD 27), median 50% (IQR:27–71%).

Figure 2.

Percent adherence to daily step count goals over each two-week interval among participants who completed the intervention

Intervention costs

The total cost of the financial incentives was $4940; this included incentives for completion of baseline and exit assessments for participants who completed the study as well as those who dropped out. A total of $3621 was paid out in financial incentives for meeting walking goals and participating in weekly check-ins with study staff.

Secondary Outcomes

Table 2 shows the baseline, end of study, and changes in secondary outcomes among the 27 participants who completed the study. On average, the participants in the control arm (M:2632, SD [1599] walked 707 daily steps more than in the intervention arm (M:1925, SD [757]) at baseline. However, in the last two-week interval of the study, mean daily steps were 481 steps lower (SD 834) from baseline in control and 614 steps SD (1306) higher in intervention (p=0.03). Figure 3 shows daily steps in each two-week interval. In regression models adjusted for baseline steps, end of study step counts were nearly 1000 steps higher for intervention vs. control: adjusted difference=997, 95% CI 147–1847 (p=0.02). On average, participants in both arms had improvement in LFI by 0.2 points with no differences by arm. A total of 80% of participants in each arm had a clinically meaningful improvement LFI (decrease in 0.3 or greater). Physical function by SPPB and PhA (markers of sarcopenia) were largely unchanged from baseline to end of study. During 12 months of follow-up after enrollment, a total of 8 participants underwent LT during the study (5 in control and 3 in intervention); there were 3 non-injurious falls during the study (2 in the control and 1 in the intervention group); no deaths were reported during the study. A secondary analysis showed that there were no significant differences in death (1 in control, 3 in intervention) or transplantation (5 in control, 4 in intervention) by study arm at 3 years of follow-up.

Table 2.

Step counts, physical function, frailty, and body composition at baseline and end of study

Variable	Total N = 27	Control N = 9	Intervention N = 18	P-value
Daily Step Counts
Baseline daily step counts, Mean (SD) [Median]	2186 (1166) [2030]	2632 (1599) [2273]	1925 (757) [2004]	0.48
End of study daily step counts, Mean (SD) [Median]	2395 (1490) [2379]	2150 (1213) [1740]	2539 (1650) [2578]	0.65
Δ Daily step counts, Mean (SD) [Median]	208 (158) [16.9]	−481 (834) [−267]	614 (1306) [425]	0.03
Frailty
Baseline LFI, Mean (SD) [Median]	4.1 (0.4) [4.2]	4.2 (0.5) [4.2]	4.0 (0.3) [4.1]	0.15
Baseline Pre-frail/frail LFI (≥3.2), n (%)	25 (93)	8 (89)	17 (94)	0.46
End of study LFI, Mean (SD)/[Median]	3.8 (0.4)/[3.8]	4.0 (0.5)/[4.2]	3.7 (0.4)/3.8	0.13
Δ LFI, Mean (SD) [Median]	−0.2 (0.3)/[−0.1]	−0.2 (0.2)/[−0.1]	−0.2 (0.4)/[−0.2]	0.96
Physical Function
SPPB total, Mean (SD) [Median]	9.5 (1.5)/[10]	9.4 (1.8)/[10]	9.5 (1.3)/[10]	0.94
End of study SPPB, Mean (SD) [Median]	10.4 (1.5)/[10.5]	10.1 (1.7)/[10]	10.5(1.5)/[11]	0.49
Δ SPPB, Mean (SD)[Median]	0.92 (1.0)/[1]	0.92 (1)/[1]	0.78 (1.1)/[1]	0.76
Body Composition *
Baseline PhA⁰, Mean (SD)/[Median]	4.4 (0.9) [4.3]	4.3 (0.8) [4.4]	4.5 (0.9) [4.3]	0.71
Baseline PhA⁰ < 5th percentile), n (%)	14 (58)	5 (63)	9 (56)	0.78
End of study PhA⁰, Mean (SD)/[Median]*	4.5 (1.2)/[4.5]	4.0 (0.8)/[4.0]	4.7 (1.3)/[4.7]	0.19
Δ PhA⁰, Mean (SD)/[Median]	0.02 (1.1)/[−.05]	−0.3 (0.8)/[-0.10]	−0.2 (1.2)/[0]	0.50

Abbreviations: BIA – bioelectrical impedance analysis; BMI – body mass index; LFI – liver frailty index; PhA – phase angle; SD - standard deviation;

^*measures available in 24 participants at baseline and 22 participants at end of study

Figure 3.

Steps counts by study arm by each two-week interval

DISCUSSION

Frailty and impaired physical function are common and associated with adverse waitlist and pos-transplant outcomes. Unfortunately, decompensated cirrhosis directly exacerbates frailty, sarcopenia, and functional status over time. Prehabilitation interventions could help LT candidates gain or maintain function, however, evidence for effective interventions is largely lacking. Supervised programs are costly and labor-intensive; therefore, home-based programs are of intense interest. A recent systematic review of 8 prehabilitation studies found that only 2 were of moderate quality evidence. Most studies had low sample size and modest effects.(21) PRIMER was one of the first known studies to deploy a home-based, pragmatic trial leveraging principles of behavioral economics and demonstrating feasibility, acceptability, and safety. The study had high completion rates (90%) and 51% adherence to walking goals. Participants were largely satisfied with an intervention that had a high degree of automation, except for weekly telephone check-ins with the study staff. There were no serious adverse events such as injurious falls or other injuries related the study. Brief baseline physical and nutritional assessments were completed by a trained physical therapist and registered dietitian remotely without significant added time or the need for in-person assessments.

Our study fills an important gap towards developing home-based prehabilitation intervention for patients on the LT waitlist who continue to be functionally independent and for those with decompensated cirrhosis. A recent meta-analysis identified only 8 prospective prehabilitation studies, only 2 were randomized-controlled trials with a sample size of 17 and 21, respectively.(21) An additional recent multi-center trial called STRIVE-LT randomized 63 participants into a 12-week program that included a wearable fitness tracker, health coaching, and exercise videos. Only 14% of participants reported adherence to 3 times weekly exercises and only 33% met personalized step goals 10 out of 12 weeks of the study, underscoring the difficulties in engaging this patient population in exercise.(14) In the current PRIMER study, participants met 51% of their daily step goals. Financial incentives may play an important supplementary role to increase adherence to prehabilitation recommendations.

Although liver disease-specific data are lacking, a recent meta-analysis in the general population showed that taking more steps per day was associated with lower all-cause mortality (up to 6000–8000 daily steps among adults 60 or older)(22) and thus represents an important behavior to target with home-based interventions. Our study shows low baseline physical activity with daily step counts below 3000 even among ambulatory patients with at intermediate MELD-Na scores (median of 13). The intervention was effective at increasing daily steps by about 1000/day in the intervention relative to control. Importantly, the control arm lost 400 daily steps on average over 12, possibly related to progressive decline, whereas the intervention group gained about 600 hundred by the end of the study. We also found that both groups had improvements in LFI by 0.2 points by average. Studies have shown that as little as 0.1 worsening in LFI was associated with increased waitlist mortality and 0.3-point improvement may be associated with improved survival, therefore, staving off a worsening in frailty status could be considered a “win” among patients on the waitlist (23, 24). A recent report from the multicenter Functional Assessment in Liver Transplantation (FrAILT) consortium showed that LT recipients with pretransplant frailty were more likely to exhibit physical frailty after LT, had lower odds of employment and had lower self-reported physical functioning. Only 5% of frail pretransplant recipients were robust at 1 year post-transplant, highlighting the need to developed tailored pre-transplant interventions.(25)

Behavior change is difficult and notoriously so in the setting of decompensated liver disease whereby patients suffer from weakness, fatigue, anhedonia, impaired mobility in addition to symptoms of cramping, and volume overload. A growing body of evidence supports the use of small financial incentives to promote physical activity among healthy adults as well as those with chronic conditions such as solid organ transplant recipients and patients with ischemic heart disease.(15, 26, 27) To our knowledge, this is the first study to use financial incentives for prehabilitation among LT candidates. We used the principle of loss aversion, which is a more potent behavioral lever than a positive incentive.(28, 29) A total of $3621 was paid out in financial incentives for 20 intervention participants (including those who dropped out) in this 12-week study with a little over $200 in incentives per completed patient. Although a formal cost analysis was beyond the scope of the study and labor costs were not directly measured, the program has the potential to be cost-saving by preventing even a single hospitalization or by helping maintain waitlist candidacy for a single LT patient. Formal cost-effectiveness analyses should be performed in future studies of behavioral interventions in LT.(30)

This study had several limitations. Our pilot study design was single center with a small sample size and among only English-speaking participants. We largely encouraged walking behaviors, but we propose that future studies should test multi-component interventions that specifically incentivize weight bearing exercise and protein supplementation, which have been shown to be effective in combating sarcopenia. There is the potential for missing data and measurement error, however, we report results of intention-to-treat analyses. There is potential to overestimate adherence to exercise via self-report. We acknowledge that technology uptake is variable and a smartphone-paired intervention may not have uniform uptake among LT candidates.

It is important to discuss the feasibility of financial incentives in real-world settings and who could be responsible for them; viable options include large employers, hospitals, and payers. Multiple large employers have rolled out employee wellness programs with financial incentives to encourage biometric screening, participation in wellness coaching and exercises classes; some of the interventions were associated with increased physical activity.(31) Among hospitals there is a growing movement of “paying for health programs” where hospital assist patients with social needs such as food and transportation; if prehabilitation can reduce transplant length of stay, subsidizing physical activity and wellness for transplant recipients would add value and make financial sense. Large payers are moving towards value-based purchasing contracts and could similarly pay for programs that would reduce acute care and rehabilitation facility use after LT. We underscore that incentive in our study was modest, about $400 for perfect adherence during a 12-week program – this is a small price to pay relative to a single extra rehabilitation or readmission day.

Conclusion:

A behavioral rehabilitation intervention among LT candidates was feasible, safe, had high retention and patient satisfaction. The intervention was effective in increasing physical activity among highly sedentary LT candidates. Future studies should pair physical activity and protein supplementation interventions in larger, multi-center cohorts that investigate clinical endpoints such as post-LT length of stay, readmissions, muscle mass, frailty and physical function.

Abbreviations:

BMI

Body Mass Index

SPPB

Short Physical Performance Battery

BIA Lean

Bioelectrical Impedance lean body mass Value

BIA PA

Bioelectrical impedance phase angle

LFI

Liver Frailty Index Value