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Optimizing Patient Outcomes: Clinical Use of the Cystic Fibrosis Pulmonary Guidelines Michael P. Boyle, MD, FCCP John Paul Clancy, MD Kristin A. Riekert, PhD Faculty Michael P. Boyle, MD, FCCP Associate Professor of Medicine Director, The Johns Hopkins Adult Cystic Fibrosis Program The Johns Hopkins University School of Medicine Baltimore, MD John Paul Clancy, MD Professor, Director, and Raymond K. Lyrene Chair in Pediatric Pulmonology The Children’s Hospital of Alabama University of Alabama at Birmingham Birmingham, AL Kristin A. Riekert, PhD Assistant Professor Co-Director, The Johns Hopkins Adherence Research Center Division of Pulmonary and Critical Care Medicine The Johns Hopkins University Baltimore, MD Disclosures Dr Boyle reports having no financial or advisory relationships with corporate organizations related to this activity. Dr Clancy reports having no financial or advisory relationships with corporate organizations related to this activity. Dr Riekert reports receiving grants/research support from Genentech, Inc. and Novartis Pharmaceuticals Corporation. Agenda I. Cystic Fibrosis (CF) Overview and Introduction (1 min) Michael P. Boyle, MD, FCCP II. Aggressive Treatment Strategies to Optimize Patient Outcomes (25 min) John Paul Clancy, MD III. Promoting Adherence and Increasing Life Span (25 min) Kristin A. Riekert, PhD IV. Optimizing Patient Outcomes: An Illustrative Case (Slide Presentation, 8 min) Michael P. Boyle, MD, FCCP V. Conclusion and Summary (1 min) Michael P. Boyle, MD, FCCP Learning Objectives Upon the conclusion of this activity, the participant should be able to: • Evaluate current and emerging therapies and the delivery mechanism of these therapies. • Recognize and identify adherence issues in patients with cystic fibrosis. The Johns Hopkins University School of Medicine takes responsibility for the content, quality, and scientific integrity of this CME activity. Accreditation & Credit Designation Statements ACCREDITATION STATEMENT— The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT— The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity. Educational Grant Johns Hopkins would like to acknowledge an educational grant from Novartis Pharmaceuticals Corporation which helped to make this activity possible. Optimizing Patient Outcomes: Clinical Use of the Cystic Fibrosis Pulmonary Guidelines Michael P. Boyle, MD, FCCP John Paul Clancy, MD Kristin A. Riekert, PhD Aggressive Treatment Strategies to Optimize Patient Outcomes John Paul Clancy, MD The Children’s Hospital of Alabama University of Alabama at Birmingham Overview • Changing the face of CF • Improving longevity • New challenges, new opportunities • Pulmonary treatment guidelines for adolescents and young adults • CFF panel (RTs, nurses, MDs, and CFF personnel) • Future and emerging strategies • Ion transport-active agents • New classes/delivery of antibiotics • Monitoring for pathogens CF = cystic fibrosis. • Adherence Cystic fibrosis pulmonary guidelines Chronic medications for maintenance of lung health Flume, PA et al. Am J Respir Crit Care Med V176. pp 957-969, 2007. Improving Longevity in CF Survival by birth cohort 100 1995–2004 Percent Surviving 98 96 1990–1994 94 92 1985–1989 90 88 86 84 82 1980–1984 80 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Age (Years) Reprinted with permission from Cystic Fibrosis Foundation Patient Registry. 2006 Annual Data Report. Bethesda, MD. Basic CF Care Paradigms • Coordinated Care • CF Care centers • Optimize: • Education • Nutrition • • • • Exocrine pancreas (and fat soluble vitamins) Endocrine pancreas Hepatobiliary disease GI ion transport • *Pulmonary care • Reproduction • Other CF Lung Disease – Macroscopic CF airway obstruction Photos – compliments of Carlos Milla. Example of growth curve - Nancy Pulmonary Care Rationale of Treatment Strategies • Disease manifestations and Targets: • • • • • CFTR (1) *Ion transport (2) *Clearance (3) *Antimicrobials (4) *Inflammation (5) Reprinted with permission from Advances in cystic fibrosis therapies Rowe, SM and Clancy, JP. Curr Opin Pediatr V18(6): pp 604-613, 2006. Timeline of CF Therapies From 1950’s to 2010: childhood ---> childhood and adult disease 1950 1960 1970 1980 1990 2000 CFTR DNase identified Sweat abnormalities Cl- AZM 2010 2020 2030 • Ion transport agents • CFTR modulators • Nebulized atbx Enzyme impermeability replacement Hypertonic Anti-PsA Airway clearance saline antibiotics NSAIDs Family-centered care Fat-full diet Inhaled tobramycin Complexity of Current CF Pulmonary Care Recombinant DNase Inhaled b2 agonists Inhaled steroids ? Inhaled colistin Azithromycin Leukotriene modifiers Systemic steroids TOBI Inhaled gentamicin Hypertonic saline Inhaled anticholinergics Anti-staphylococcal antibiotics Assessing the Evidence for Use of Current Pulmonary Therapies • Systematic reviews of original research • Modified systematic reviews • Existing Cochrane systematic reviews Strength of recommendations (A > B > C > D; I) Quality of data Reprinted with permission from Cystic Fibrosis Pulmonary Guidelines Chronic medications for maintenance of lung health Flume, PA et al. Am J Respir Crit Care Med V176. pp 957-969, 2007. Recombinant Human DNase + • Age > 6 yo • Moderate to severe disease (FEV1 <69%) • Ten RCT, 3 cross-over, six without comparator, Cochrane review (2005) • Total n = 3140 • Recommendation = A (strength of evidence good, benefit substantial) • Mild disease (FEV1 = 70%–89%) • Three RCT, one cross-over • Total n = 520 • Recommendation = B (strength of evidence fair, benefit moderate) Chronically Inhaled Tobramycin • PsA+ (persistent), and > 6 yo • Moderate to severe disease (FEV1 <69%) • Three RCT, one RCO, two 1-arm trials, Cochrane review (2006) • Total n = 679 • Recommendation = A (level of evidence good, net benefit substantial) • Mild disease (FEV1 = 70%–89%) • Two RCT (n = 202) • Recommendation = B (level of evidence fair, net benefit moderate) • Other inhaled antibiotics • Recommendation = I (level of evidence poor, net benefit small) Inhaled Tobramycin (300 mg BID) Phase III trial, 24 weeks randomized, placebo-controlled Reprinted with permission from Ramsey B, et al. N Engl J Med. 1999;340(1):23-30. Hypertonic Saline • Age > 6 yo • Three RCT, one cross-over trial, and six trials without comparators • Total n = 520 • Two RCT, two RCO compared with recombinant DNase • Total n = 284 • Cochrane review (2005) • Recommendation = B (level of evidence fair, net benefit moderate) Anti-inflammatory Agents • Inhaled corticosteroids (age > 6 yo) • • • • No asthma, no ABPA Five RCT, two RCO, Cochrane review (2006) Total n = 388 Recommendation = D (level of evidence fair, net benefit zero) • Oral/systemic corticosteroids (age 6–18 yrs) • • • • No asthma, no ABPA Three RCT, Cochrane review (2006) Total n = 354 Recommendation = D (level of evidence good, net benefit negative) • Oral/systemic corticosteroids (adults) • No asthma, no ABPA • One RCT (Total n = 20) • Recommendation = I (level of evidence poor, net benefit zero) Anti-inflammatory Agents (cont’d) • Oral nonsteroidal anti-inflammatory drugs (NSAIDS) • Three RCT, Cochrane review (2005) • Total n = 145 • Recommendation = B (level of evidence fair, net benefit moderate) • Leukotriene modifiers • Two RCO, one controlled trial • Total n = 64 • Recommendation = I (level of evidence poor, net benefit none) • Cromolyn • Two RCT, one clinical trial • Total n = 44 • Recommendation = I (level of evidence poor, net benefit none) Macrolides (chronic) • PsA+ (persistent), and > 6 yo • Two RCT, one crossover trial, one clinical trial, Cochrane review (2005) • Total n = 296 • Recommendation = B (level of evidence fair, net benefit substantial) Azithromycin in PsA+ CF Patients 4 * * * 2 100 OFF Azithromycin % Exacerbation-free FEV1 (% predicted) 6 Azithromycin 0 Placebo -2 OFF 80 60 Placebo 4 0 20 -4 0 28 84 Day 168 196 0 28 84 Day 168 196 Reprinted with permission from Azithromycin in patients with cystic fibrosis chronically infected with Pseudomonas aeruginosa: a randomized controlled trial. Saiman, L. et al. JAMA. Oct 1;290(13):1749-56, 2003. Anti-staphylococcal Antibiotics • Patients with CF (most studies in children, including < 6 yo) • Use of prophylactic antibiotics in Sa (+) patients • Three RCTs, one crossover trial • Cochrane review (2006) • Total n = 306 • Recommendation = D (level of evidence fair, net benefit negative) Bronchodialators • Patients > 6 yo • b2 adrenergic agonists • Fourteen RCO (mix of nebulized/MDI) • Total n = 257 • Recommendation = B (level of evidence good, net benefit moderate) • Anticholinergics • Five RCO • Total n = 79 • Recommendation = I (level of evidence poor, net benefit none) Summary (patients over age 6 yrs) • Class A recommendations (substantial benefit) • Recombinant DNase • Inhaled tobramycin (PsA +) • Class B recommendations (moderate benefit) • • • • NSAIDs (ibuprofen) Macrolides (azithromycin) Bronchodialators (b2 adrenergic receptor agonists) Hypertonic saline (7%) • Class D recommendations (no benefit or potential harm) • Oral corticosteriods ( 6–18 yrs, chronic) • Inhaled corticosteroids • Anti-staphylococcus antibiotics (chronic) • Class I recommendations (insufficient information) • Leukotriene antagonists, oral corticosteroids (adults), anticholinergics, N acetyl cysteine, and cromolyn Pediatric CF Care Trends – Influence on Young Adult Care • Relationship between PsA infection and lung function • Inverse • PsA eradication strategies • Various antibiotic approaches • Development of a ‘new’ young adult CF population • Lack chronic (mucoid) PsA infection • Careful monitoring • Aggressive intervention for new infections Starner T and McCray P. Ann Intern Med. 2005;143:816-822. Infection with Pseudomonas aeruginosa and Progression of CF Lung Disease Lung Function 100% Irreversible Lung Damage Inflammation Transient Bacterial Infection Uninfected Chronic Bacterial Infections Mucoid/Biofilm Bacterial Infection Eradication Time Adapted from Starner T and McCray P. Ann Intern Med. 2005;143:816-822. Slide compliments of France Foundation. Prevalence of Respiratory Infections in CF Patients Over Ages prevention management Reprinted with permission from Cystic Fibrosis Foundation Patient Registry. 2006 Annual Data Report. Bethesda, MD. Age-Specific Prevalence of P. aeruginosa from Birth to Age 16 No PsA Nonmucoid PsA only Mucoid PsA +/Nonmucoid PsA Reprinted with permission from Li Z, et al. JAMA. 2005;293(5):581-588. Association of Mucoidy with Decline in FEV1 % Predicted Non-mucoid Pa (+) Pa(-) mucoid Pa (+) Reprinted with permission from Li Z, et al. JAMA. 2005;293(5):581-588. Early Pseudomonas Infection Control (EPIC) Phase 4 – closed to enrollment • Randomized, double-blind, placebocontrolled, safety and efficacy study QT: quarterly treatment PsA +: treatment only when quarterly cultures are + for P. aeruginosa • 54 US Centers • 300 CF patients 1–12 years old Tobramycin + Ciprofloxacin Tobramycin + Placebo Month 0 3 QT QT QT QT QT QT PA+ PA+ PA+ PA+ PA+ PA+ QT QT QT QT QT QT PA+ PA+ PA+ PA+ PA+ PA+ 6 9 12 15 18 • Primary Outcome: Proportion of recurrent Pa positive cultures (18 months) • Time to occurrence of pulmonary exacerbations Available at: http://www.ClinicalTrials.gov/ct2/show/NCT00097773. Accessed March 2008. Slide compliments of France Foundation. Summary – Pulmonary Treatment Guidelines • Many options available • Address many aspects of CF lung disease • Strength of recommendations varies • Key features: • Pseudomonas aeruginosa status • Chronic management • Emerging eradication strategies • Few head to head comparisons • Burden of care increasing (accelerating) • Optimal outcomes ► adherence strategies Promoting Adherence and Increasing Life Span Kristin A. Riekert, PhD The Johns Hopkins University Composite Medication Possession Ratio (MPR) Reprinted with permission from Riekert KA, et al. Pediatr Pulmonol. 2007;S30:405. Emerging Adulthood (aged 18–25 years) • Identity exploration • Role transitions • Changes in residence, relationships, work, finances, becoming a parent, etc. • Feeling “in-between” adolescence and adulthood • Greater acceptance of responsibility for one’s self • Greater autonomy in decision making Social Support and Adherence Odds Ratio Functional Support Practical Emotional 3.6 1.83 Family Functioning Cohesiveness Conflict 3.03 2.35 Family Structure Married Living with someone vs. alone 1.27 1.38 Except for conflict, odds ratio=odds of being adherent if score on variable is high. DiMatteo MR, et al. Health Psychol. 2004;23(2):207-218. Adherence Typologies Erratic Adherence Patient understands and agrees with therapy but has difficulty consistently maintaining regimen "I try to take my medicine regularly but I'm too . . . " • • • • • Busy Forgetful/disorganized Stressed/family chaos Out of medicine Regimen too complex Unwitting Nonadherence Patient and provider mistakenly believe that the patient is adherent "But I thought I was taking my medicine right . . ." • • • • Misunderstands regimen Poor device technique Language barriers Cognitive deficits Poor Knowledge • Many patients and family members do poorly on a standardized measure of CF knowledge • Average score parents = 79% • Average score teens = 61% • For example: How many knew that fat contains more calories that carbohydrates or proteins? 16% of parents 19% of teens Quittner, A. L., Drotar, D, and Ievers-Landis, C. Improving Adherence in Adolescents with Cystic Fibrosis: Comparisons of Family Therapy & Psychoeducation. Paper presented at the Society of Pediatric Psychology National Conference on Child Health Psychology, Charleston SC. 2004. Poor MDI/DPI Technique % Good Technique Patients 28–681 House staff 43–652,3 Physicians 653 4–472 Nurses Respiratory Therapists Pharmacists 85–922,3 624 MDI=metered dose inhaler, DPI=dry powder inhaler. 1. Fink JB, Rubin BK. Respir Care. 2005;50(10):1360-1374. 2. Interiano B, Guntupalli KK. Arch Intern Med. 1993;153(1):81-85. 3. Guidry et al. Chest. 1992;101(1):31-33. 4. Kesten S, et al. Chest. 1993;104(6):1737-1742. “Intelligent” Nonadherence Patient deliberately alters or discontinues therapy "I don’t need to take my medicine because I . . ." • Don’t think the therapy makes a difference to my health • Feel fine/better = don’t need it • Am concerned about sideeffects • Fear addiction/drug resistance Beliefs About Asthma Medication1,2 Parents of children Adult patients Hard to take meds when feel fine 32.2 45.9 Hard to remember to get refills 13.9 35.7 Nothing I can do to stop an attack 30.8 43.9 Even if take meds, will still have sx 62 54.1 Benefits of meds make side effects worth it 51 51.5 Taking meds makes me worry more about asthma 32.7 19.4 Sx = symptoms. Riekert KA, et al. Am J Respir Crit Care Med. 2003;167:A155. Riekert KA, et al. Am J Respir Crit Care Med. 2004;169:A328. Additional Risk Factors • Depression • OR=3.03 (95% CI, 1.96–4.89)1 • Poor integration of CF into personal identity • Healthy versus sick versus “normal”2,3 1. DiMatteo MR et al. Arch Intern Med. 2000;160(14):2101-2107; 2. Badlan K. Health Soc Care Community. 2006;14(3):264-270; 3. Lowton K, Gabe J. Sociol Health Illn. 2003;25(4):289-319. What Can the CF Clinician Do? Assessing Adherence • Objective measures (eg, medication refill history) are most valid • Patient/family-report • Overestimates adherence • HIGH SPECIFICITY FOR REPORT OF NONADHERENCE!!! • Open-ended and direct questions better • POOR = Any problems with your medicines? • GOOD = How have you been taking your dornase alpha? • BETTER = Which, if any meds, have you been taking? . . . How do you use [name med]? Pediatric Adherence with Inhaled Steroids 96 Twice a day 71 90 Three times/day 34 69 Four times/day 18 0 20 40 Recorded 60 80 100 Reported Coutts JA, et al. Arch Dis Child. 1992;67(3):332-333. Good Communication is Key • Establish rapport • Open-ended questions • Reflective listening • Normalize nonadherence • Identify motivation to change Strategies for Improving Adherence Erratic Adherence • Query barriers and problem-solve • Simplify and tailor regimen • Behavioral strategies • • • • Self-monitoring (eg, diaries) Cueing (eg, toothbrush, pillbox) Reminders (eg, cell phone) Linking to established habits or pleasurable activities • Reinforcement • Encourage accessing social support Strategies for Improving Adherence Unwitting Nonadherence • Provide and review written treatment plan at each visit • Ask patient to repeat dosing instructions • Review device technique • Provide CF education • Encourage accessing social support Strategies for Improving Adherence • Include patient in decision-making “Intelligent” Nonadherence • Provide personalized feedback on relationship between adherence and health outcomes • Provide CF education • Link therapy with personal goals Look for “Turning Points” • Often occurs during emerging adulthood • • • • First hospitalization Going away to college Beginning of a new romantic relationship Becoming a parent • Can serve as a teachable moment • Elicit these events during clinical encounter Summary • Emerging adults are at risk for nonadherence • Time of significant yet normative life changes • Query patient adherence every visit • Be skeptical of self-report, but remember, a report of any nonadherence is true • Identify factors contributing to nonadherence • Match counseling strategies to identified barriers Optimizing Patient Outcomes: An Illustrative Case Michael P. Boyle, MD, FCCP The Johns Hopkins University School of Medicine Case History • Ryan, 19-year-old young man with CF • Genotype dF508/dF508 • Baseline FEV1 75%– 80% of predicted • Chronically infected with mucoid P. aeruginosa Case History “My parents always remind me how grateful I should be that I only have mild CF” “I find just staying active is the most important thing to keep me healthy” Case History Other medications: • Inhaled dornase alpha once a day • Azithromycin 250 mg orally each day • Pancreatic enzymes with each meal • Vitamins • First hospitalization last year to receive intravenous antibiotics for an exacerbation • Subsequently prescribed chronic inhaled tobramycin for 28 days every other month Case History • Now in first semester at local University • Missed last scheduled clinic visit because preparing for a math exam – now over 4 months since last visit • Parents noted increased night time cough and encouraged him to be seen • FEV1 today 74% of predicted • States: “I’m fine – the cough bothers my parents more than it bothers me” Treatment Options A. Oral antibiotic and add hypertonic saline B. Oral antibiotic, add hypertonic saline and extra daily session of airway clearance C. Assess treatment adherence and tell him he needs to do better job of taking meds D. Something else? “Intelligent” Nonadherence Patient deliberately alters or discontinues therapy Which, if any, of the medications have you been taking? Ryan’s Actual Regimen: Enzymes, vitamins, azithromycin, occasional dornase alpha and “getting to the gym” "I don’t need to take my medicine because . . ." • convinced he only has “mild” CF • feels fine = doesn’t need it • doesn’t think the prescribed therapy is the most effective way to maintain health Strategies for Improving Adherence “Intelligent” Nonadherence • Include patient in decision-making • Provide personalized feedback on relationship between adherence and health outcomes • Provide CF education • Link therapy with personal goals Treatment • Reviewed graph of FEV1 values for last five years showing decline • Obtained chest CT and reviewed images with Ryan so he could see presence of bronchiectasis, mucous plugging, and cystic changes Treatment • Prescribed oral ciprofloxacin and inhaled tobramycin, and proposed an experiment assessing FEV1 before and after use of medication • Scheduled follow-up in three weeks to reevaluate clinical status, support his decision for adherence, and provide further education Follow-up Visit • Taking medications • FEV1 79% of predicted • Symptoms resolved • Determined to make medications more of a priority in the future. Summary: Improving Patient Outcomes Treatment Guidelines • Early, aggressive therapy to optimize and maintain lung function • Particular attention to initial P. aeruginosa • Close monitoring of nutritional status and growth Summary: Improving Patient Outcomes Understanding the Role of Adherence • Assessing adherence • Recognizing different types of nonadherence • Utilizing treatment strategies specific for the type of nonadherence