Revising and Resubmitting an NIH R01: Exercise Training to Reduce Claudication: Arm Ergometry versus Treadmill Walking

1. Revising and Resubmitting an NIH R01:Exercise Training to Reduce Claudication: Arm Ergometry versus Treadmill Walking Diane Treat-Jacobson, PhD, RN Associate Professor University of Minnesota School of Nursing

2. Acknowledgements • Co-Investigators • Jean Wyman, PhD, RN; Professor, Nursing • Arthur S. Leon, MD, MS; Professor, Kinesiology • Patricia Painter, PhD; Associate Professor • Ruth Lindquist, PhD, RN; Professor, Nursing • Daniel Duprez, MD, PhD; Professor, Medicine • Ulf Bronas, PhD; Clinical Assistant Professor • Kay Savik, MS; Statistician • Consultants • Mark Creager, MD; Professor of Medicine, Harvard Medical School, Brigham and Women’s Hospital • Judith Regensteiner, PhD, Professor of Medicine, University of Colorado Health Sciences Center

3. Objectives • Describe randomized clinical trial submitted to NHLBI • Discuss content of summary statement • Discuss approach to grant revision • Describe process of revising grant

4. Background and Significance • Peripheral arterial disease (PAD) is a progressive atherosclerotic disease • Affects approximately 9 million Americans • Symptoms of PAD are related to insufficient arterial blood flow, which results in debilitating, activity-induced, ischemic pain (claudication) • Associated with major limitations in mobility and physical functioning, and decreased quality of life.

5. Background and Significance • Efficacy of treadmill training to improve walking distance in patients with claudication is well established • Mechanisms by which exercise training improves walking include both local and systemic changes. However, the contribution of these changes has not been fully elucidated

6. What is the mechanism of improvement in walking distance? • Local conditioning effect – changes in muscle metabolism stimulated by exercising specific muscles affected by limited blood flow • Systemic effect – changes in central cardiovascular conditioning and/or vascular function, leading to improved walking ability

7. Conceptual Framework Pathophysiological Changes with Claudication Physiological Outcomes with Aerobic Training Arm Ergometry (Non-Ischemic) Treadmill Walking (Ischemic) • Arterial Flow • Skeletal Muscle Oxygenation • Cardiac Output • Endothelial Dysfunction • Inflammation • Thrombogenic Activity Cardiovascular Conditioning ? Skeletal Muscle Oxygenation Endothelial Dysfunction Inflammation Thrombogenic Activity • ? Cardiovascular Conditioning • Skeletal Muscle Oxygenation • Endothelial Dysfunction •  Inflammation •  Thrombogenic Activity Health and Functional Consequences Health and Functional Outcomes • Walking Ability • Functional Status • Quality of Life • Mood Walking Ability Functional Status Quality of Life Mood

8. Preliminary Data • The Exercise Training for Claudication Study • Primary Aim: To compare the effectiveness of 12 weeks of supervised arm ergometry and treadmill walking exercise training, alone or in combination, versus “usual care” controls to improve pain free and maximal walking distance (PFWD and MWD) in patients with lifestyle limiting claudication.

9. Change in Pain Free Walking Distance* Planned comparisons: Bonferroni Adjustment for Multiple Comparisons * Treat-Jacobson, Bronas, & Leon (in press)

10. Pain Free Walking Distance ** ** *12 and 24 week values adjusted for baseline PFWD and unsupervised exercise **p<.05 arm ergometry versus control

11. Change in Maximal Walking Distance* Planned Comparisons: Bonferroni Adjustment for Multiple Comparisons * Treat-Jacobson, Bronas, & Leon (in press)

12. Maximal Walking Distance ** ** *12 and 24 week values adjusted for baseline MWD and unsupervised exercise **p<.05 versus control (all exercise groups @ 12 weeks, arm ergometry & treadmill @ 24 weeks)

13. Specific Aim 1 • Determine the relative efficacy of 12 weeks of supervised treadmill (n=60) versus arm ergometry exercise training (n=60) versus “usual care” (controls) (n=30) in persons with claudication on pain free walking distance (PFWD) and maximal walking distance (MWD), controlling for unsupervised exercise.

14. Specific Aim 2 • Determine the relative effects of supervised arm ergometry or treadmill training versus controls on local and systemic factors contributing to improvement in walking distance, including the following: • 2a. Measures of endothelial function in both upper and lower extremities • 2b. Systemic physiologic measures associated with endothelial function, inflammation, and thrombosis • 2c. Cardiovascular function • 2d. Calf skeletal muscle oxygen saturation • 2e. Correlates of physiologic measures (a-d above)

15. Specific Aims 3- 5 • Determine the relative efficacy of supervised arm ergometry versus treadmill training versus “usual care” on functional and health status, mood, and quality of life. • Evaluate the extent to which training-induced improvements (a-d above) are maintained or improved 12 weeks following completion of a supervised exercise program. • Evaluate the response to exercise training measured in Aims 1 through 4 above, independently for women and men.

16. Walking Distance - PFWD & MWD via graded treadmill test Upper body fitness - Graded arm ergometry test Arterial Flow - Arm and leg flow-mediated vasodilation (FMD) Skeletal Muscle Oxygenation - Near Infrared Spectroscopy (NIRS) at rest and during exercise Cardiovascular Functioning - Non-invasive cardiac output; oxygen consumption; BP - during both arm and treadmill testing Concept - Measure

17. Endothelial Dysfunction/injury - FMD, ADMA, von Willebrand factor; soluble P-selectin, soluble thrombomodulin Inflammation - HS C-reactive protein, interleukin-6 Thrombosis - Fibrinogen, TPA Community-based walking impairment - Walking Impairment Questionnaire Health Status – SF-36 PAD-Specific Quality of life - PAD Quality of Life Questionnaire Mood - Profile of Mood States (POMS) Concept - Measure

18. Concept - Measure Nonsupervised Physical Activity • Physical Activity Monitoring – Accelerometer for 1 week periods during weeks 1, 5, 11, 23 • Exercise records – Daily exercise records kept for 1 week periods during weeks 1, 5, 11, 23

19. Power Analysis/Sample size • Power Analysis was based on secondary outcome of change in flow-mediated vasodilation (FMD). • Major analysis a repeated measures analysis of covariance using a random coefficient model analysis • Sample size adjusted to allow for separate analysis of men and women • N= 150; arm ergometry: n=60 (30 m, 30 f); treadmill: n= 60 (30 m, 30 f); control n=30 (15 m, 15 f). • Plan to over-sample by 10% to account for dropouts (total n =165)

20. Inclusion Age > 18 years Resting ABI < 0.90 or 20% drop in post-exercise ABI Lifestyle limitation due to claudication Ability to complete study procedures Exclusion Uncontrolled hypertension or diabetes Recent peripheral or coronary revascularization procedure Fontaine stage 3 (rest pain) or 4 (tissue loss) Unstable heart disease Walking limited by factors other than claudication Entry Criteria

21. Study Design Intervention Period 12 weeks Follow-up Period 12 weeks Screening Period 2-3 weeks Treadmill Training (n=60) 3x/week for 12 weeks 12 Week follow-up (Monthly Phone Calls) Randomization Arm Ergometry (n=60) 3x/week for 12 weeks 12 Week follow-up (Monthly Phone Calls) Control (n=30) Brief Visit 1/week for 12 weeks 12 Week follow-up (Monthly Phone Calls) Pre-Screening Screening 1 Screening 2 Baseline 1 Baseline 2 6 Week Visit (2 day) 12 Week Visit (2 day) 24 Week Visit (2 Day)

22. Schedule of Measurements

23. Exercise Training Locations • Participants have a choice of exercise training locations • University of Minnesota (Minneapolis) • Fairview Southdale (Edina) • Fairview Ridges (Burnsville) • United Hospital (St. Paul) • Possible to add additional sites if needed

24. Exercise Groups • Supervised 3 times/week for 12 weeks • Sessions 70 minutes in length, 5 minutes warm-up, 60 minutes of exercise, 5 minutes cool down • Recording of exercise outside supervised setting (weeks 1, 5, 11, 23)

25. Treadmill Exercise Program • Treadmill walking • Speed: 2.0 mph • Intensity increased when participants can exercise for 8 minutes without reaching moderate claudication level (rating: 3-4 out of 5) • Grade increased by 1% increments • After 10% grade is reached, increase speed at 0.1 MPH intervals • Time: 60 minutes including rest periods

26. Upper Body Exercise Program • Arm Ergometry • Watts start at one level below maximal test • 2 minutes exercise, 2 minutes rest • Gradually increase watts, exercise-rest intervals throughout program as tolerated • Time: 60 minutes including rest periods

27. Control Group • Instructed to continue ‘usual care’ • Provided specific written walking instructions • Weekly follow-up at the U of M site

28. Post-Training Assessment • Re-assessment of all outcome variables • 6 weeks • 12 weeks • 24 weeks (12 weeks after completion of 12 week visit)

29. Statistical Analysis Plan • Appropriate descriptive statistics • Logarithmic transformation of variables with skewed distribution • Intention to treat analysis • Longitudinal data analysis using random coefficient models • Model rate of change individually • Model predictors and covariates of rates of change • Allows for nonlinear rates of change

30. Other Issues Addressed • Recruitment Plan • Protocol Adherence • Participant Burden

31. R01 Submission • First submission February, 2007 (first electronic submission cycle) • Clinical and Integrative Cardiovascular Sciences Study Section • Primary Assignment • NHLBI • Secondary Assignment • NINR • NIA

32. R01 Submission • Study section review June 9, 2007 • Score available June 12, 2007 (while on vacation) • Priority Score 225 • Percentile Ranking 37.5% Ouch!

33. Summary Statement • Primary and Secondary reviews were quite different • Primary Reviewer more negative • Secondary Reviewer more positive • It took a while to appreciate the positive comments of the second reviewer in light of the first reviewer’s remarks

34. Summary – The good news • PI is new investigator but has sufficient experience to be able to successfully conduct proposed work • Good publication productivity • Excellent supportive environment • Important area of investigation is proposed • Statistical analyses and methodologies are appropriate

35. Summary – The Bad News • Multiple methodological concerns with Aim 2 • Limited data presented that studies are feasible • Multiple variables proposed • Interference in blood markers by other factors • FMD difficult in leg • Perception that work may reiterate what is already known

36. Reviewer #1 Major Concerns (To be changed) • Aim 2 has plethora of endpoints (particularly blood markers) • Didn’t like use of NIRS for skeletal muscle O2 • Had concerns about being able to do FMD in the leg

37. Reviewer #1 Major Concerns (to be addressed) • Expressed concern about confounding variables – smoking, diabetes, recommended stratifying by these variables • Expand limitation section • Discuss statistical analysis plan by aim

38. Reviewer #1 Major Concerns (could be clarified) • Concern about testing being done at multiple sites • Stated that this work had been done before • Mentioned isometric hand exercise • Aims not different from pilot study • Suggested skeletal muscle biopsies or measurement of circulating endothelial progenitor cells

39. Reviewer # 1 • Investigators • Qualified to lead such an investigation • Although not an exercise physiologist, she has enlisted the help of experts in that area • Environment • “The environment and team assembled by the PI are impressive” • Innovation • Not very high, methodologies have been done before although in smaller samples • NIRS innovative • Budget • Excessive – Many personnel/Co-Investigators • Cost for testing and equipment questioned

40. Reviewer #2 • Significance - High • PAD major public health problem • Exercise shown to improve function, QL, and possibly co-morbid conditions • Potential negative effects of leg training • “Large scale comprehensive trial comparing these 2 interventions needs to be done”

41. Reviewer #2 • Approach • Comprehensive approach to screening, pre-testing, intervention, post-testing • Demonstrated they can conduct trial • Needed expertise and infrastructure in place

42. Reviewer #2 • Approach • Limitations with FMD and NIRS • Suggested instead using reactive hyperemia via venous occlusion plethysmography to measure structural changes in the lower extremity • The inclusion of psychosocial data is an important component… and the investigators should be commended for including it

43. Reviewer #2 • Innovation • Important question that begs for the type of trial outlined • Investigator • Clearly capable of conducting study • Excellent support from a variety of skilled co-investigators • Environment - Outstanding • Budget • Should be adjusted to reflect the likely replacement of FMD and NIRS with peak reactive hyperemia measures

44. Reviewer #2 - Summary Overall Evaluation: This is a proposal from a very strong young investigator backed by an outstanding team at an outstanding institution. There are no major structural problems with the application in terms of the question asked, the intervention proposed, and a number of the key outcome measures. However, this reviewer feels strongly that there are significant limitations with the FMD and NIRS approaches and that the peak calf reactive hyperemia studies suggested may be much more useful in addressing the key hypotheses and physiologic issues of interest in this application. The above comments are made in the most positive possible context and are designed to improve this application.

45. Other Reviewer Comments • Suggested increase sample size based on number expected to be lost at 24 weeks (versus only 12 weeks)

46. Revision

47. Specific Aim 1 • Determine the relative efficacy of 12 weeks of supervised treadmill (n=60) versus arm ergometry exercise training (n=60) versus “usual care” (controls) (n=30), and 12 weeks of follow-up (24 weeks), in persons with claudication on pain free walking distance (PFWD) and maximal walking distance (MWD), adjusting for unsupervised exercise, smoking and diabetes status.

48. Specific Aim 1 • Combined previous Aim 1 and 4. • Added covariates of smoking and diabetes in response to concerns from reviewer 1 and as a compromise to the suggestion of stratification by these variables

49. Specific Aim 2 • Determine the relative effects of supervised arm ergometry or treadmill training versus controls on selected factors that contribute to improvement in walking distance, including the following: • 2a. Resting, submaximal and peak limb blood flow (venous occlusion plethysmography). • 2b. Cardiovascular function (peak oxygen consumption, cardiac output, resting blood pressure). • 2c. Correlates of physiologic measures.

50. Specific Aim 2 • Replaced FMD and NIRS with peak reactive hyperemia via venous occlusion plethysmography • Co-Investigators (Painter and Duprez) and both consultants have expertise with this technique • More literature on the use of this method in PAD, including exercise trials • Removed blood markers from Aims and included a smaller number of markers as supporting data