Pulmonary Rehabilitation-2009 - Moving Forward Richard Casaburi, Ph.D.,M.D. Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center Torrance, California, USA Disclosures: Grants/Consultation for Boehringer-Ingelheim, Forest, Astra Zeneca, Novartis, Inogen, Pfizer, GlaxoSmithKline, Osiris, Roche
Pulmonary Rehabilitation ‌the standard of care for COPD patients debilitated by their disease
38 pages of EVIDENCE! Chest 2007, 131:4S-42S
Evidence Based Rehabilitation Guidelines Evidence Grades: 1,2 - Strength of Recommendation based on balance of risks and benefits A,B,C - Strength of Evidence based on supporting evidence
Evidence Based Rehabilitation Guidelines for COPD Pulmonary rehabilitation: • Both low- and high-intensity exercise training produce clinical benefits- 1A • improves the symptom of dyspnea - 1A • improves health-related quality of life - 1A These benefits are generally of greater magnitude than for any other COPD therapy
Evidence Based Rehabilitation Guidelines for COPD Pulmonary rehabilitation: • reduces the number of hospital days and other measures of health care utilization - 2B • induces psychosocial benefits - 2B
Chest 2007, 131:4S-42S
Rehabilitation in COPD Why is rehabilitation poorly funded…and therefore poorly available?
• Inadequate lobbying • Inadequate evidence of benefit
2008 - A Good Year for Pulmonary Rehabilitation in the United States • Pulmonary Rehabilitation achieves Assembly status in the ATS • Federal legislation establishing pulmonary rehabilitation as a covered service under Medicare is passed
Details of coverage decision being worked out by CMS implementation in January 1, 2010
Rehabilitation in COPD Why is rehabilitation poorly funded…and therefore poorly available?
• Inadequate lobbying • Inadequate evidence of benefit
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?
Ann Int Med, 2008
Change in CRQ Dyspnea at 3 months
Ann Int Med, 2008
54
Change in 6MWD at 3 months
44 34 24 14 4 -6 Home-Based
Center-Based
Ann Int Med, 2008
Respir Med, 2007
Respir Med, 2007
Respir Med, 2007
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?
Better Exercise Tolerance Better LongTerm Outcomes (e.g., survival)
Better Exercise Tolerance
More Active During Daily Life
Better LongTerm Outcomes (e.g., survival)
Better Exercise Tolerance
More Active During Daily Life
Better LongTerm Outcomes (e.g., survival)
Better Exercise Tolerance ?
More Active During Daily Life
Better LongTerm Outcomes ? (e.g., survival)
Do more active COPD patients survive longer? • Garcia-Aymerich et al. Thorax, 2006 – 2386 Danish COPD patients completed activity questionnaire – Followed for 12.0±5.9 years for mortality and other outcomes
Do more active COPD patients survive longer? • Garcia-Aymerich et al. Thorax, 2006 – 2386 Danish COPD patients completed activity questionnaire – Followed for 12.0±5.9 years for mortality and other outcomes
• Ringbaek et al., Clin Rehabil, 2005 – 226 Danish LTOT patients completed activity questionnaire – Followed for mean of 8 years for mortality
Are self-ratings of activity reliable?
No long-term studies of influence of objectively assessed activity on prognosis in COPD
Is activity level increased by rehabilitation? • • • •
Sewell et al., Chest - 2005 Walker et al., Thorax -2008 Steele et al. JCR -2008 Pitta et al. Chest -2008
Is activity level increased by rehabilitation? • • • •
Sewell et al., Chest - 2005 YES Walker et al., Thorax -2008 YES Steele et al. JCR -2008 NO Pitta et al. Chest -2008 MAYBE
Pitta et al., Chest, 2008
Is activity level increased by rehabilitation? • • • •
Sewell et al., Chest - 2005 Walker et al., Thorax -2008 Steele et al. JCR -2008 Pitta et al. Chest -2008 Differences in Activity Monitoring Technology and Duration May Explain Differences in Results
Is activity level increased by rehabilitation? • • • •
Sewell et al., Chest - 2005 Walker et al., Thorax -2008 Steele et al. JCR -2008 Pitta et al. Chest -2008
2 days 2 days 6 days 5 days
Differences in Activity Monitoring Technology and Duration May Explain Differences in Results
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?
• 209 completed rehabilitation program • 18 died in one-year follow-up period • 49 failed to continue through 1-year evaluation (non-completers)
Number Needed to Treat to Improve SGRQ by a Clinically Important Amount for 1 Year ~ 1.6 N=142 Completers
N=49 Noncompleters
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Promising Approaches
n=93
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Promising Approaches
Combined Effects of Exercise Training and 30% Oxygen Breathing in Non-hypoxemic COPD 30
* *
Time (min)
25 20 15
** *
*
*
*
10
Air-pre Oxygen-pre Air-post Oxygen-post
5 0 Oxygen Training
Before
After
Air Training
Before After
Emtner et al., AJRCCCM, 2003
Time (min)
Increase in Constant Work Rate Test Endurance after Exercise Training 16 14 12 10 8 6 4 2 0
*
38% greater gain in endurance air and oxygen breathing tests
Oxygen Air training training group group
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Promising Approaches
Anabolic steroids Casaburi R, Bhasin S Cosentino L. et al. Effects of testosterone replacement and resistance training in men with COPD. Am. J. Respir. Crit. Care Med. 170:870-878,2004.
∆Leg Muscle Mass (kg)
∆Leg Muscle Strength (lb) 180
mean
± SE
mean ± SE
*
*
160
1.5
140
* ∆ Leg Press (lb)
∆ Leg Lean Body Mass (kg)
2.0
1.0
* 0.5
*
120 100
*
80 60 40
0.0
20 0
-0.5 P+NE
T+NE
P+E
T+E
P+NE
T+NE
P+E
T+E
N=47
• Fiber hypertrophy documented for both resistance training and testosterone • Mediators of muscle anabolism increased
Wide use of testosterone unlikely because of potential side effects: • Fiber hypertrophy documented for both • virulization in women resistance training and • prostate stimulation testosterone in men • Mediators of muscle anabolism increased Selective androgen receptor modulators (SARMs), now entering clinical trials, are likely to overcome these problems
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Promising Approaches
Electrical Muscle Stimulation •
• •
•
Surface electrodes stimulate a motor nerve to induce repeated muscle contractions All studies small (n=15 to 18) Two of three studies showed increases in muscle strength and endurance vs. control group One study showed muscle stimulation, when added to exercise training, yielded additional strength, but not endurance, improvement
Electrical Muscle Stimulation •
Surface electrodes stimulate a motor nerve to induce repeated muscle contractions All studies small (n=15 to 18) Two of three studies showed increases in muscle strength and endurance vs. control group One study showed muscle stimulation, when added to exercise training, yielded additional strength, but not endurance, improvement
Larger studies needed to define • • benefits and refine techniques •
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Promising Approaches
In ventilation feedback training, a computerized system encourages slowerdeeper breathing pattern 33 patients completed VF training vs training alone Less dynamic hyperinflation and trend for better exercise tolerance in VF group
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Evidence of Lack of Benefit
Interval training Recent COPD Studies •
•
•
•
•
Varga J, Porszasz J, Boda K, et al. Supervised high intensity continuous and interval training vs. self-paced training in COPD. Respir Med 2007; 101:2297-2304 (n=71) Arnardottir RH, Boman G, Larsson K, et al. Interval training compared with continuous training in patients with COPD. Respir Med 2007; 101:1196-1204 (n=60) Puhan MA, Busching G, Schunemann HJ, et al. Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2006; 145:816-825 (n=98) Mador MJ, Krawza M, Alhajhusain A et al. Interval training versus continuous training in patients with COPD. J Cardiopulm Rehabil 2009; 29:126-132. (n=21) Nasis IG, Vogiatzis I, Stratakos G, et al. Effects of interval-load versus constant-load training on the BODE index in COPD patients. Respir Med 2009 (in press) (n=42)
Interval training Recent COPD Studies •
•
•
Varga J, Porszasz J, Boda K, et al. Supervised high intensity continuous and interval training vs. self-paced training in COPD. Respir Med 2007; 101:2297-2304 (n=71) Arnardottir RH, Boman G, Larsson K, et al. Interval training compared with continuous training in patients with COPD. Respir Med 2007; 101:1196-1204 (n=60) Puhan MA, Busching G, Schunemann HJ, et al. Interval versus continuous high-intensity exercise in chronic obstructive pulmonary disease: a randomized trial. Ann Intern Med 2006; 145:816-825 (n=98) Mador MJ, Krawza M, Alhajhusain A et al. Interval training versus continuous training in patients with COPD. J Cardiopulm Rehabil 2009; 29:126-132. (n=21) Nasis IG, Vogiatzis I, Stratakos G, et al. Effects of interval-load versus constant-load training on the BODE index in COPD patients. Respir Med 2009 (in press) (n=42)
Decent sized studies!
Interval training not found superior to constant work rate training in any • of them.
•
Adjuncts to High Intensity Rehabilitative Exercise in COPD • • • •
Bronchodilators Supplemental oxygen Anabolic steroids Electrical muscle stimulation • Ventilation feedback
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle Lack training
Evidence of of Benefit
• • • • • •
Creatine Supplementation - During Pulmonary Rehabilitation • Fuld JP, Kilduff LP, Neder JA, et al. Creatine supplementation during pulmonary rehabilitation in chronic obstructive pulmonary disease. Thorax 2005; 60:531-537 (n=38) • Faager G, Soderlund K, Skold CM, et al. Creatine supplementation and physical training in patients with COPD: a double blind, placebo-controlled study. Int J Chron Obstruct Pulmon Dis 2006; 1:445-453 (n=23) • Deacon SJ, Vincent EE, Greenhaff PL, et al. Randomised controlled trial of dietary creatine as an adjunct therapy to physical training in COPD. Am J Respir Crit Care Med 2008 (n=100)
No evidence for additive effects on exercise endurance to date
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
Likely Impractical for Routine Use
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
82 COPD patients performed 4 endurance shuttle walk tests breathing •21% O2, 79% N2 •28% O2, 72% N2 •21% O2, 79% He •28% O2, 72% He AJRCCM, 2006
82 COPD patients performed 4 Problem with Heliox in endurance shuttle rehabilitation: must provide walk tests entire respired volume of breathing •21% O2, 79% N2
Heliox gas
•28% O2, 72% N2 •21% O2, 79% He •28% O2, 72% He AJRCCM, 2006
Adjuncts to High Intensity Rehabilitative Exercise in COPD • • • •
Bronchodilators Supplemental oxygen Anabolic steroids Electrical muscle stimulation • Ventilation feedback
Likely Impractical for Routine Use
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
n=29 Eur Respir J, 2006
Pressure support training: -requires 1:1 patient-to-therapist ratio -is uncomfortable for the patient
n=29 Eur Respir J, 2006
Adjuncts to High Intensity Rehabilitative Exercise in COPD • • • •
Bronchodilators Supplemental oxygen Anabolic steroids Electrical muscle stimulation • Ventilation feedback
Likely Impractical for Routine Use
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
One-legged exercise • Dolmage TE, Goldstein RS. Effects of one-legged exercise training of patients with COPD. Chest 2008; 133:370-376 (n=18) • Half trained with both legs for 30 minutes, half for 15 minutes with each leg; intensity increased as tolerated. • One-legged exercise group demonstrated better performance in incremental, but not constant work rate, exercise testing, than two-legged group
One-legged exercise • Dolmage TE, Goldstein RS. Effects of one-legged exercise training of patients with COPD. Chest 2008; 133:370-376 Solid physiologic rationale…but awkward (n=18) • Half trained with both legs for 30 minutes, Larger studies, perhaps with both half for 15 minutes with each leg; intensity increased asduration tolerated. increased intensity and session • One-legged demonstrated as tolerated, wouldexercise be ofgroup interest better performance in incremental, but not constant work rate, exercise testing, than two-legged group
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback Research Needed for Use in Special Populations
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Nutritional Supplementation Can optimizing nutritional support improve the benefits of rehabilitative exercise training?
Steiner MC, Barton RL, Singh SJ, et al. Nutritional enhancement of exercise performance in chronic obstructive pulmonary disease: a randomised controlled trial. Thorax 2003; 58:745-751 • •
85 COPD patients participating in a 7 week rehabilitation program were assigned to carbohydrate supplement vs. placebo Supplemented patients gained more fat weight, but did not have greater exercise tolerance gains
More targeted nutritional interventions might yield better results
Adjuncts to High Intensity Rehabilitative Exercise in COPD • • • •
Bronchodilators Supplemental oxygen Anabolic steroids Electrical muscle stimulation • Ventilation feedback
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation Research Needed • Inspiratory muscle training for Use in Special
Populations
• • • • • •
• 8 weeks endurance training • ± hyperpnea training via a rebreathing circuit • In hyperpnea training group – Respiratory muscle strength & endurance increased – No difference in exercise endurance between groups
Limit study to those with respiratory muscle weakness?
Adjuncts to High Intensity Rehabilitative Exercise in COPD • Bronchodilators • Supplemental oxygen • Anabolic steroids • Electrical muscle stimulation • Ventilation feedback
• • • • • •
Interval training Creatine Heliox breathing Non-invasive ventilation One-legged exercise Nutritional supplementation • Inspiratory muscle training
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?
Survival: the missing piece of the puzzle
Question: Why does the US spend ~ $3 billion annually to provide COPD patients with long-term oxygen therapy?
Answer: Because LTOT delivers an unequivocal survival benefit
Evidence considered conclusive despite: â&#x20AC;˘No confirmation since 1981 â&#x20AC;˘Based on a total of < 300 patients
Evidence Based Rehabilitation Guidelines for COPD Does pulmonary rehabilitation improve survival? â&#x20AC;&#x153;There is insufficient evidence to determine whether pulmonary rehabilitation improves survival. No recommendation is provided.â&#x20AC;? Evidence-Based Pulmonary Rehabilitation, Chest, 2007
Ries, A. L. et. al. Ann Intern Med 1995;122:823-832
Pulmonary Rehabilitationâ&#x20AC;&#x2122;s Mortality Trial â&#x20AC;&#x153;Expertsâ&#x20AC;? believe patients participating in rehabilitation live longer, but this possibility has never received an adequate test in a clinical trial. Therapies that improve survival have a high priority. We think that a clinical trial is practical and we are working to get it underway.
PRIMO Pulmonary Rehabilitation Impacts Mortality Outcomes
PRIMO • a ~ 10 center study, • ~ 800 patients discharged from the hospital following a COPD exacerbation, • patient accrual over ~ two years, • rehab vs. no-rehab, follow-up ~ 3 years • multiple outcomes, with mortality as primary outcome A Revised Application to NIH is Being Composed
Pulmonary Rehabilitation - Moving Forward • Can rehabilitation be administered at home? • Is activity level increased by rehabilitation? • Can the benefits of rehabilitation be maintained? • Can we make the exercise training component more effective? • Can we demonstrate a survival benefit?