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					SHiFT: Shiftwork Heart Failure Trial
       Dipanjan Banerjee, Paulina Essah, Nicole Jensky, Naila Khalil,
      Aurelia Macabasco-O'Connell, Michael McKee, Chrisandra Shufelt,
                           and Cristina Wassel.
      Congestive Heart Failure (CHF) represents a
       growing public health problem affecting 5 million
        Half a million new cases annually
        Increasing trend in the elderly
        One third of patients require frequent hospitalizations1
        66% die within 5-years of diagnosis
        $34.8 billion in direct costs in 2008

CDC Fact Sheet and AHA Heart and Stroke Statistics
1Shocken et al, Incidence and prevalence of Heart Failure when falling out of your
kayak (you’ll never get back in). Journal of the Truckee River. 2009;3:101-5.
          15 million US employees work in shifts
              shift work can lead to behavioral changes such as reduced
               physical activity, poor diet, and stress (reversed with pedometer
          Shift work, specifically night shift work, has been associated
           with adverse outcomes
              Cancers: breast and colorectal
              Ischemic heart disease
          A previous study has documented elevated serum BNP after
           8-weeks in night-shift workers as compared to day-shift
1Fulton   J et al. Pedometers can cure everything (even cancer). J Awesome Pedometers 2009;3:101-5.
Patel D. Shift work, light at night and risk of breast cancer. Occup Med (Lond). 2006 Sep;56(6):433.
                                                                Case-control and cohort studies
              Odds Ratio & 95% confidence interval               have demonstrated an
                                                                 association between night-shift
Burke et al 2005                                                 work and risk of CHF.
Goff et al 2007

Criqui et al 2006                                               To date no clinical trials have
                                                                 compared exposure to night-shift
Labarthe et al 2005                                              work and risk of developing
Heidenreich et al 2009                                           CHF.

Lewis et al 2005

                         0        1         2        3   4
   Reduce risk of CHF by rotating the schedule of shift-
   Increase work-years and quality-adjusted life years
   Target at-risk shift workers for primary prevention
    of cardiovascular disease
   Reduce total health care cost for employers and
Night-shift work increases the risk of CHF after 1 year.

We will conduct a randomized clinical trial with an intention-to-treat
        456 male and female auto-factory line workers
        ages from 40-65 years
        Ford Motors Company at 4 Assembly Plant factory sites in Michigan
        Randomized to one of three 8-hour work shift schedules:
             1) 7am-3pm shift
             2) 3pm-11pm shift
             3) 11pm-7am shift
Specific Aims
Primary and secondary outcomes will be assessed at 1-year
 Specific Aim 1:

       Compare echocardiographic changes suggestive of impaired
        cardiac function between shift groups (primary outcome)
   Specific Aim 2:
       Compare serial changes in serum BNP concentrations between
        shift groups
   Specific Aim 3:
       Compare change in functional capacity and other markers of CHF
        between shift groups
  Preliminary Studies
BNP and shiftwork: Burke Dog Chow Prospective Study1
    At a Purina assembly plant, BNP was measured in shift workers at baseline and
     after 8 week follow-up.
    Conclusion: 20% higher BNP levels in the night shift workers compared to the
     day shift workers. (p<0.038)

CHF hospitalization and shiftwork: King’s Beach Heart Failure Study2
    In a 12-year case-control study of 420 security guards working shift work,
     emergency room ICD-9 codes for CHF were reviewed.
    Conclusion: There was a 2.27 greater odds (95% CI, 1.65-3.31) for emergency
     room visits for CHF in night shift workers compared to day shift workers, after
     adjusting for cardiovascular risk factors.

1. Burke et al., J of Westminster Kennel Club, 2008; 86: 34-55.
2. Goff, D. et al. A Brief Interlude for Security Guards. TAHOE Journal. 2009: 75: 111-115.

 Ethnic Group                                                Female           Male        Total
 Hispanic or Latino                                          12               12          24
 Not Hispanic or Latino                                      216              216         432
                                                             228              228         456
 Racial Categories
 Asian                                                       3                3           6
 Native Hawaiian or Other Pacific Islander                   2                2           4
 African American                                            40               40          80
 White                                                       183              183         366
 Total                                                       228              228         456

 Minorities are targeted to represent 23% of the proposed study cohort,1
 including 5% Hispanic, 17% African-American, 1% Asian, and 1% Pacific Islander.

 1Kumanyika  et al. Honda, Buick or Lamborghini? Culturally tailored approaches to choosing your car. Motor
 Trend, Aug 2009.
Inclusion/Exclusion Criteria
Inclusion                                   Exclusion
      Newly employed auto-factory line           Conditions likely to influence outcomes:
       workers                                     severe lung, renal (CrCl <30 ml/min),
      Women and men ages 40-65 years              hepatic or heart disease including CHF
      Competent to give informed consent         Recent hospitalization (<3mos) for CHF,
                                                   MI, CVA
                                                  Atrial Fibrillation
                                                  Prior non-cardiac illness with an estimated
                                                   life expectancy <4 years
                                                  Women who are breast feeding or who
                                                   are pregnant
                                                  Adherence or retention reasons:
                                                     Recent alcoholism or drug abuse
                                                     Psychiatric illness including severe
                                                        depression, dementia
                                                     Unwilling to complete follow-up
                                                        evaluation including repeat testing
          Senior/Key Person                 %       Salary      Requested     Fringe     Total
                                          Effort                  Salary

Dr. Dipanjan Banerjee (PI)                 20      196,700.00     39,200      12,740    51,940

Dr. Paulina Essah (co-PI)                  20      196,700.00     39,200      12,740    51,940

Dr. Nicole Jensky (co-PI)                  20      196,700.00     39,200      12,740    51,940

Dr. Naila Khalil (co-PI)                   20      196,700.00     39,200      12,740    51,940

Dr. Aurelia Macabasco-O'Connell (co-PI)    20      196,700.00     39,200      12,740    51,940

Dr. Michael McKee (co-PI)                  20      196,700.00     39,200      12,740    51,940

Dr. Chrisandra Shufelt (co-PI)             20      196,700.00     39,200      12,740    51,940

Dr. Cristina Wassel (co-PI)                20      196,700.00     39,200      12,740    51,940

                                 TOTAL                          313,600     101,920    415,520

         Total Salaries 3-year Budget                                                  1,246,560
            PERSONNEL                  %      Salary   Requested   Fringe     Total
                                     Effort              Salary
Research Statistician                 20      40,000     8,000     1,600      9,600

Site Project Manager (4)              100     54,000    216,000    43,200    259,200
                                                         (for 4)
                                      100     27,000    108,000    21,600    129,600
Site Study Coordinator (4)                               (for 4)
Research Assistant (2)                100     16,000    38,000     7,600     45,600
                                                         (for 2)


Echocardiograpy Technician           100%     39,200    39,200               39,200

Chronobiologist                      15%      90,000    13,500               13,500

                             TOTAL                                          496,700

      Total Salaries 3-year Budget                                          1,490,100
  Materials and Supplies                                          28,800

  Echocardiogram machine, 12-lead EKG, 6-minute walking test,     309,008
  BNP and serum markers

  Echo Core lab Reading                                           136,800

  Serum Marker Core lab                                           136,800

  Incentive Costs: $50 per patient visit                          114,000

                                                        TOTAL    775,408

  Total 3-year Direct Costs                                      3,512,068

  Total Indirect Costs (50%)                                     1,756,034

                                           TOTAL 3 Year Budget   5,268,102
    Baseline Data Collection
   Socio-demographic characteristics
       Age, gender, ethnicity, SES (income & educational level), health insurance,
        social/family history

   Medical Exam and History
       BP, HR, RR, height/weight/BMI, waist circumference
       Medical comorbidities: diabetes, hypertension, COPD, OSA, renal disease, stroke
       Medications: ACE-I, Beta-blockers, diuretics, statins, aspirin, anti-hyperglycemic
       Previous cardiac history

   Lab Tests: BNP, catecholamines, CRP, BARK-1 polymorphism, lipids
   Cardiac tests: Echocardiogram & Electrocardiogram
   6 minute walk test
   Various bio-behavioral measures: Nutrition, Physical Activity, Occupational Stress and
    Depression, Sleep Quality, Work Ability and Productivity
  Time 0
                                          Screening of new employees


                                  Night shift         Swing shift           Day shift
                                   N = 152             N = 152              N = 152

            Baseline exam                 Central Lab (3-4 hours total)

03 months

06 months              Questionnaires                              Lab Tests

09 months                               Echocardiogram & EKG
                                                Lab Tests
                                    Questionnaires & 6 min walk test
12 months
                                 Incident HF, hospitalizations, ER visits
      Table 1:
      Primary and Secondary Endpoints
           Variable                    Instrument      Baseline   3 mos   6 mos   9 mos   12 mos

Primary Outcomes
ECHO parameters (systolic and                             X                                 X
diastolic function)
Secondary outcomes
BNP, Catecholamines,            Core Lab                  X        X       X       X        X
Inflammatory markers – CRP.
Fasting Blood Sugar, Total
Cholesterol:, HDL, LDL, TG,
EKG                             EKG Machine               X                                 X
Blood Pressure, BMI             Welch Allen TR-2          X        X       X       X        X
waist circumference             ProCheck
                                SECA 770
                                Electronic scale
                                SECA 225 Hite-Mobile
                                Gulick tape measure
                                Portable Stadiometer
6 minute walk test              Medical Records           X                x                X
  Table 2: Biobehavioral Measures
       Variable               Instrument         Baseline   3 mos   6 mos   9 mos   12 mos

Diet                  Block FFQ                     X        X       X       X        X
Physical Activity     Duke Activity Status          X                X                X

Occupational Stress   Occupational Stress           X                X                X

Depression                                          X                X                X
Sleep Patterns
                      Epworth Sleepiness Scale
                                                    X                X                X
                                                    X                X                X
                      Quality of Worklife
Work Productivity     Questionnaire

                                                    X                X                X
Outcome Parameters
  Primary outcomes: Echocardiogram parameters
       Can be measured serially, non-invasively and portably
       Current gold standard to assess cardiac function and extensive track record in research studies
          and clinical realm
       Systolic function is associated with mortality and morbidity 1
       Diastolic function is associated with mortality and morbidity2
       Core lab will read echos, blinded to study group (two echocardiographers, 3rd employed when >
          10% disagreement between first two)

  Secondary outcomes
       Brain Natriuretic Peptide (BNP) Levels: change quickly in response to ventricular stretch, cheap
         and can be measured serially
       Serum catecholamine levels
       β – adrenergic receptor polymorphism (BARK-1)
       Serum samples will be frozen and sent to a core lab will perform biomarker assays
       6 minute walk test
       Physical activity/dietary questionnaires
       All cause mortality, incident heart failure, myocardial infarction (Data Safety Monitoring Board)

   1Picard   et al. Assessment of Left Ventricular Function by Echocardiography: A Technique in Evolution. JASE 2008: 14-21.
   2Lester et al. Unlocking the mysteries of diastolic function: deciphering the Rosetta Stone 10 years later. J Am Coll
   Cardiol. 2008 Feb 19;51:679-89
Echocardiographic Parameters

      Diastolic Function
        Most likely echo parameter to show changes in study time period
        Biologic plausibility that shift work could lead to worsening diastolic
        Study powered to assess % change in E/E’ ratio (E/E’ T0 – E/E’ T12/ E/E’
          T0 x 100) as 10 outcome
        Measures
                E/E’ ratio: least load dependent, 38% improvement in one study at 12
                 months with cardiac resynchronization therapy1
                E’
                E/A ratio: most studied, but dependent on volume status
                P/H ratio: innovative marker that also incorporates cost-effectiveness2
                Change in grade of systolic function (>= 1 grade increase over study period)
  1Jansen,  Improvement in diastolic function and left ventricular filling pressure induced by
  cardiac resynchronization therapy AHJ 2007; 843-849
  2 Heidenreich   P et al. P/H ratio: it just sounds better than the E/A ratio. JASE 2009;3:101-5.
Echocardiographic Parameters

         Systolic Function
           Unlikely to show changes in ejection fraction in study time period due to
             low rate of change and inter-observer variability
           Biologic plausibility that shift work could lead to worsening systolic
           % change in LV mass index (LVMI T0 – LVMI T12/ LVMI T0 x 100 )
           Measures
                 Left ventricular mass index: powerful predictor of cardiovascular morbidity
                  and mortality, validated in multi-ethnic cohorts1
                 Left ventricular size
                 Tissue Doppler Index: independent predictor of mortality in general
                 Ejection fraction: most studied parameter, but least likely to reveal significant
  1Chal et al. Ethnicity-Related Differences in Left Ventricular Function, Structure and Geometry: A Population Study
  of UK Indian Asians and European Whites. Heart 2009
  2 Mogelvang et al. Cardiac Dysfunction Assessed by Echocardiographic Tissue Doppler Imaging Is an Independent

  Predictor of Mortality in the General Population Circulation. 2009;119:2679-2685
 Serum biomarkers

      Elevated BNP levels in patients without heart failure predict a higher probability of
       death, and heart failure events (hospitalization)
      Levels < 100 pg/ml are known to impart significant risk1
      Rapid increase/decrease in levels in response to ventricular stress

 Serum catecholamines
      Implicated in pathogenesis of heart failure
      Predictive of mortality and response to treatment in patients with heart failure2
      Increased with psychologic/physiologic stress
      Interact with genetic polymorphisms to increase cardiovascular risk3,4
1Wang   et al, NEJM 2004;350:655-63
2 Latiniet al The comparative prognostic value of plasma neurohormones at baseline in patients with heart failure
enrolled in Val-HeFT European Heart Journal 2004 25:292-299
3 Frantz et al. Baseline and serial neurohormones in patients with congestive heart failure treated with and without

bucindolol: results of the neurohumoral substudy of the Beta-Blocker Evaluation of Survival Study (BEST). J Card
Fail. 2007;13:437-44.
4 O’Donnell et al. I will GWAS anything you could possibly imagine. J Craig Venter 2009;3:101-5.
 Type                # of Questions      Measures            Prior Heart          Scoring             Validity
                                                             Failure Study

 Duke Activity       6                   Physical function   Yes                  Categorical         Yes
 Status Index                                                                     0-58.2 METS         Fair sensitivity
 (DASI)   1                                                                                           and specificity

 Block FFQ 2,3       110                 26 Nutrients        Yes                  Categorical         Yes
                                         Energy Intake                                                Moderate
                                                                                                      sensitivity and

1.   Arena, et al. Using the Duke Activity Status Index in Heart Failure. Journal of Cardiopulmonary Rehab. 2002; 22 (2);
2.   Subar et al. Comparative Validation of the Block, Willett, and National Cancer Institute Food Frequency
     Questionnaires. Nutrtional Epi. American Journal of Epidemiology Vol. 154, No. 12 : 1089-1099
3.   Anderson C et al. Sometimes chocolate cake is ok (just lie on the questionnaire). J Otis Spunkmeyer 2009;3:101-5.
     Type                # of Questions       Measures             Prior Heart          Scoring             Validity
                                                                   Failure Study

     Occupational        48                   Occupational         No                   Scalar              Yes
     Stress                                   Stress                                    (categorical)
     Assessment 1

     Epworth             8                    Waking hour          Yes                  Dichotomous         Yes
     Sleepiness                               Sleepiness                                0-9 (normal)        Highly sensitive
     Scale 2,3                                                                                              and specific
                                                                                        >9 (abnormal)

1.   Rajna Golubic et al. Work-related stress, education and work ability among hospital nurses. Journal of Advanced Nursing
     (online), July 2009
2.   A Staniforth et al. Nocturnal desaturation in patients with stable heart failure Heart. 1998; 79(4): 394–399
3.   Carnethon M, Burke et al. Art of gambling at the faculty tables in Tahoe: how to win 5 grants in 5 days. J R01 Grants
     Type               # of Questions      Measures            Prior Heart          Scoring             Validity
                                                                Failure Study

     Quality of         4 sections with     Work                No                   Scalar              Yes
     Worklife 1         4-10 questions      Productivity                             (categorical)

     PHQ-9 2            9                   Depression          Yes                  Categorical         Yes
                                                                                     0-9 (normal)        Highly sensitive
                                                                                                         and specific
                                                                                     10 or above

1.     Layer et al., The effect of cognitive demands and perceived quality of work life on human performance in
       manufacturing environments. International Journal of Industrial Economics 2009; 39 (2), 413-421
2.     Kurt Kroenke, MD et al. The PHQ-9 Validity of a Brief Depression Severity Measure
       J Gen Intern Med. 2001; 16(9): 606–613.
3.     Smile, Jack. Ensuring happy fellows in Tahoe through PHQ-9. Inter Moodiness Journal
   Stratified randomization within each of four
   Block randomization for treatment, block size of
    3x2 = 6
   Generate assignments on a random uniform [0,1]
     <0.33, shift A, 7am-3pm
     0.34-0.67, shift B, 3pm-11pm

     >0.67, shift C, 11pm-7am
    Sample sizes
•   Primary outcome – powered for change in E/E’ ratio
    – Mean 16, SD 6

    – 10% difference, 80% power, α=0.051

    – About n=132 per group, total n=396

    – n=456 (152 per group), assuming 15% drop out

    – Will be able to detect 10% difference for other echo
       parameters described previously
•   Secondary outcome – change in brain natriuretic peptide (BNP)
    – Mean 10 pg/ml, SD 16

    – With above sample size, can detect ~5 pg/mL difference
       between any 2 groups
    1Feldman   et al. I’m more redneck than Howard. J Dixie 2009;3:101-5
Statistical Analysis
   One way ANOVA for change in diastolic
    dysfunction (primary outcome)1
   Secondary outcomes with multiple measures over
    the study period (i.e. 0, 3, 6, 9, and 12 months)
    will use growth curve modeling to examine the
   Will control for covariates that are different
    between groups despite randomization

1Howard   et al. No, I am. (Letter) J Dixie 2009;3:101-5
Strengths                               Limitations
 Rigorous design with randomization     Using a surrogate endpoint

 Temporal nature of shift work and
                                           instead of a hard endpoint such
    CHF can be established                 as incidence of CHF
                                         Generalizability to other
 Novel risk factors tested in CHF
                                           populations of shift workers
 Providing the estimates of relative
                                         Potential selection bias:
    and absolute risk of surrogate
    markers of CHF                           Healthy worker effect
                                             Recruitment bias with
                                               participants unwilling to do
                                               the night shift
                                         Limitation of diagnosis and
                                           treatment of diastolic
                                           dysfunction by echocardiogram
   Our study group leaders and faculty

   Fellow Fellows, Fellow Families

   The Parsons

   Mike Criqui and David Goff

   The elusive Bears of Granlibakken