Physical Activity to Improve CV Health in Women: a Pragmatic Trial

Women’s Health Initiative Strong & Healthy The WHISH Trial

CCC-lead PI: Marcia Stefanick, Ph.DBehavioral Science Director: Abby King, Ph.D.

Stanford University School of Medicine

DCC Multiple-PI: Andrea LaCroix, Ph.D.(lead) Charles Kooperberg, Ph.D., FHCRC

(Fred Hutchinson Cancer Research Center)

Clustered R01s ≥ $500K/yrPAR-13-128 (Investigator Initiated Multi-Site Clinical Trials - Collaborative RO1).

WHISH Trial

Primary Hypothesis An intervention designed to improve levels of aerobic physical activity based on national (DHHS*)

recommendations for older U.S. adults, combined with muscle strengthening, balance and flexibility exercises, and reduced sedentary behavior, will reduce major CV events (CV death, MI, stroke) in older (WHI) women, compared to “usual activity” controls over ~4 years of follow-up

Physical Activity Guidelines Advisory Committee(2008). Report of the Physical Activity Guidelines Advisory Committee, 2008. Washington, DC: U.S. Department of Health and Human Services. http://www.health.gov/paguidelines/guidelines/chapter5.aspx

*

WHISH Trial

Primary Aim Conduct a pragmatic trial in approximately 52,500 women enrolled in the WHI Extension Study, for whom CV outcomes are available, randomized to a centralized, tailored physical activity intervention or “usual activity” (observational control comparison).

Primary Safety Aim Evaluate whether an intervention based on DHHS-recommended levels of physical activity for older American adults increases the risk of total clinical fracture, hip fracture, falls, or non-CVD mortality over ~4 years

WHISH Trial

Secondary Aim Evaluate whether this tailored, PA intervention reduces risk of selected PA-linked secondary outcomes, potentially ameliorable through regular physical activity, of importance to maintaining independence in older women

Secondary Hypotheses Women randomized to the WHISH PA intervention (compared to observational control) will have: Lower rates of venous thromboembolic events (VTE)

and peripheral artery disease (PAD); Less loss of physical function including higher rates of

ongoing mobility (and independence)

Secondary Safety AimEvaluate whether increased PA increases CABG or PCI

WHISH Trial

Eligible based on existing data

Intervention

Consent

WHISH PA Interventiondeliver mail-based + website ± IVR (phone) + live advisor, PRN

Follow, per original protocolno

yes

no

yes

Based on Zelen. N Eng J Med 1979

Randomized Consent Design for the WHISH trial

Randomize

Follow, per original protocol

Follow, per original protocol

Inclusion: Alive; WHI MRC or linked to CMS (Medicare administrative data)

Exclusions: recent (past 6 months) CV event; dementia; living in a nursing home; self-reported inability to walk

Control

WHISH Trial

Assumptions in randomized consent design Existing data are adequate for primary eligibility

determination Original consent and protocol covers

Re-approach for additional studies All outcome ascertainment procedures

Control arm represents “standard of care” Randomization is ethical Power calculations account for

Lack of adherence/cross-over Dilution of effect from non-consenters

Fraction consenting to intervention expected to be high Primary analysis based on ITT principle, includes:

non-consenters those found to be ineligible after randomization

WHISH Trial

Pragmatic Trial considerationsRandomized Consent Design* in well-characterized cohort

(WHI infrastructure creates tremendous efficiencies**)Scientific Advantages:

Increases external validity (no/limited Hawthorne effect in control arm)

Provides estimates of effectiveness, rather than efficacyPractical advantages

Avoids resentful demoralization in control groupSimplifies recruitment/consent and reduces associated costs

Intervention based on National Recommendations (DHHS) and Publicly Available Resources (NIA Go4Life®) to be delivered by widely used Technology (interactive voice response, IVR + telephone) – pilot tested in small WHI sample; will offer two levels of consenting

Outcomes collected in WHI: ~20,000 in Medical Records Cohort (MRC) + additional 32,500 linked to CMS records; NDI searches

*Adamson et al, Contemporary Clin Trials 2006;27:305-319.

**

WHISH Trial

WHISH Intervention – in brief Goals per DHHS (2008) PA Guidelines for older adults

Consent mailings to women assigned to Intervention will include basic recommendations/goals and Go4Life® pamphlet (exercises)

Go4Life® Written Materials, DVD, Websitepublicly available evidence-based exercise and physical activity

materials developed by the National Institute on Aging “Full Consent” reinforced and individualized by means of an

algorithm-driven telephone- delivered interactive voice response (IVR) system managed centrally at Stanford, with “light (human) touch” (telephone and mailed materials), as neededWeekly for 6 weeks, Bi-monthly for 6 weeks, then Monthly

“Mailings Only” consent option (2-4x/yr) – may become “Full” Special materials for women who use walkers, canes, wheelchairs,

and to deal with injuries & rehabilitation

National (& Regional) Community Facilities/Resources, e.g. Senior Centers, Ys (Silver Sneakers), Special Programs

WHISH Trial

http://go4life.nia.nih.gov/

On Go4Life website: can watch exercise videos, submit personal exercise success stories, print educational tip sheets, use interactive tools in MyGo4Life section to make an exercise plan and track progress over time.

Exercise & Physical Activity: Your Everyday Guide from the National Institute on Aging

120-page guide describes the benefits of exercise and physical activity for older adults

Workout to Go: A Sample Exercise Routine from the National Institute of Aging at NIH

Featured exercises include:

Hand Grip Wall Push-Up Overhead Arm Raise Back Leg Raise Side Leg Raise Toe Stand Stand on One Foot Heel-to-Toe Walk Balance Walk Ankle Stretch Back Stretch Thigh Stretch Shoulder and Upper Arm Stretch

Go4Life DVD—Everyday Exercises from the NIA

How to set exercise goals and stick to them. Includes sample exercises for endurance, strength, balance, flexibility & list of resources.

WHISH Trial

Background: The use of interactive voice response (IVR)

technology for healthcare applications and for medical and psychological research is growing.

Health-related IVR examples include:Follow up of patients after hospital dischargePeer support to patients with chronic heart failureIncrease of medication adherenceWeight loss promotion in pre-diabetic patientsPhysical activity in older adults (CHAT, King et al, 2007)

Physical activity in WHI participants – WHISH pilot

WHISH Trial

218 Community-dwelling Under-activeAdults ages ≥ 55 yrs, randomized to:

Community Health Advice by Telephone:CHAT Project

Telephone Advice by (IVR)

COMPUTER

Attention-Control

arm

Telephone Advice by

HUMAN

Assessments at 0, 6, 12, & 18 mos.

King, Friedman, Marcus, et al., Health Educ Res, 2002

WHISH Trial

MV

PA

(kc

al/k

g-1/d

ay-1)

Baseline 6 mo. 12 mo.

*Intervention > control, p < .01; †Intervention > control, p = .05

0

.80

.95

1.10

1.25

1.40

1.55

1.70

1.85

*

Control

Automated Advice

Human Advice

†

CHAT TrialModerate-Vigorous PA (7-day PAR)

*

*

King AC et al., Health Psychol, 2007

18 mo.

(N.S.)

Mean age 61 + 6 yrs

(range:53-78)67% women

86% white

WHISH Trial

WHISH Pilot Study Design

Baseline PA Assessment

IVR Reports: Minutes

Steps Strength

Balance/Flexibility

Follow-up PA Assessment

IVR Calls

Enrollment Welcome Packet Orientation 1 2 3 4 5 Follow-up Interview

27 WHI former Diet Trial participants - average age: 75 years (66 – 92)Baseline Physical Activity (by telephone interview*)

F34: walking outside home ≥ 10 min w/o stopping; moderate/strenuous exerciseQ: Strengthening exercises and Balance/Flexibility ≥ 2x/wk (Y/N)

Welcome Packet: NIA Go4Life®, Omron Pedometer, IVR instructions

Participants increased PA significantly between baseline and follow-up (mean change (min/week): 79 ± 116, p<.001).

WHISH Trial

WHISH PA Monitoring Intervention Arm

Mailings Only (+website)- simple calendars (pre-paid postcards). “Full” - IVR phone contact (PA type & amount, pedometer steps)based on Adherence, tailored behavioral augmentations are built

into interventionVanguard cohort will be studied with SMART trial design, for

optimization of intervention

Both Arms (self-report) short OPACH PA questionnaire mailed to WHISH participants in

annual WHI Form 33 (WHI outcomes) mailings; first mailing prior to initiating the intervention (baseline) and then annually.

Subset of Both Arms (Objective PA Monitoring) ~1000 from each arm, randomly selected among OPACH/WHISH

participants for 7-day accelerometry (B, 6-, 18- and 24-months)

WHISH Trial

Outcomes, Events needed Intention to Treat (ITT) comparison of clinical events

Expect ~52,500 to meet eligibility criteria In MRC or linked to CMS at trial outset (i.e. Outcomes/Data

being collected as a fn. of enrollment in WHI Extension Study)Exclusions: recent (past 6 months) CV event; dementia; living in

a nursing home; self-reported inability to walk

Expect 80% of Intervention arm to consent 60% to “full” intervention; 20% to “mailings only”

Anticipating 10-12% effect size observational studies suggest 25-30% reduction in CV events

WHI: currently observed annualized rates: 0.90%/yr, suggests a ~ 4 year follow-up is needed

WHISH Trial

WHISH Outcomes Collected within the Scope of the Ongoing WHI Extension Study

WHISH Trial

Outcomes, Events (continued) WHI Analyses have demonstrated reliability of CMS data for MI and

stroke (kappa~0.75), and other CV events (Hlatky et al; Burwen et al)

We have ~80% power for finding a significant treatment effect if true effect size is ~12.5% and 90% if true effect size is ~14.5% If trial were extended one year (using a no cost extension): ~80% power for ~11% true effect size, and 90% if the effect size is a little under 13%.

With 44 months follow up (2019)

Expected number of CV Events

With 56 months follow up (2020)

Expected number of CV Events

Effect Control

Intervention

Power

Control

Intervention

Power

10% 940 847 60.9%

1191 1073 71.1%

11% 940 838 69.4%

1191 1062 79.2%

12% 940 829 77.0%

1191 1050 85.8%

13% 940 820 83.4%

1191 1039 91.0%

14% 940 810 88.6%

1191 1027 94.5%

15% 940 801 92.5%

1191 1015 96.9%

WHISH Trial

Anticipated timeline for proposed trial

Activity Yr 10-6 mo

Yr 16-12

Yr 2

Yr 3

Yr 4

Yr 5

Finalize IVR and Intervention Materials X  

IRB approvals (FHCRC, Stanford) X  Screening, Randomization, Consenting (DCC) X  

Initiate Intervention in Vanguard cohort X

Intervention Adoption Phase (3 months) X X

Intervention Optimization and Maintenance   X X X X X

Study closeout         X

Analyses/publication of final manuscripts         X