Optimizing Patient Outcomes: Clinical Use of the Cystic Fibrosis
Pulmonary Guidelines Michael P. Boyle, MD, FCCP John Paul Clancy,
MD Kristin A. Riekert, PhD Slide 2 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 Childrens
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
Faculty Slide 3 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.
Disclosures Slide 4 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 Agenda Slide 5 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. Learning Objectives Slide 6 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. Accreditation & Credit Designation Statements Slide 7
Johns Hopkins would like to acknowledge an educational grant from
Novartis Pharmaceuticals Corporation which helped to make this
activity possible. Educational Grant Slide 8 Optimizing Patient
Outcomes: Clinical Use of the Cystic Fibrosis Pulmonary Guidelines
Michael P. Boyle, MD, FCCP John Paul Clancy, MD Kristin A. Riekert,
PhD Slide 9 Aggressive Treatment Strategies to Optimize Patient
Outcomes John Paul Clancy, MD The Childrens Hospital of Alabama
University of Alabama at Birmingham Slide 10 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 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. CF = cystic fibrosis. Slide 11 Improving Longevity in CF
Survival by birth cohort Age (Years) 80 82 84 86 88 90 92 94 96 98
100 1234567891011121314151617181920 Percent Surviving 19801984
19851989 19901994 19952004 Reprinted with permission from Cystic
Fibrosis Foundation Patient Registry. 2006 Annual Data Report.
Bethesda, MD. Slide 12 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 Slide 13 Photos
compliments of Carlos Milla. Example of growth curve - Nancy CF
airway obstruction CF Lung Disease Macroscopic Slide 14 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. Slide 15 Sweat abnormalities
Airway clearance Family-centered care Enzyme replacement Anti-PsA
antibiotics Fat-full diet Cl - impermeability 1950196019701980 1990
2000 201020202030 CFTR identified DNase AZM Hypertonic saline Ion
transport agents CFTR modulators Nebulized atbx NSAIDs Timeline of
CF Therapies From 1950s to 2010: childhood ---> childhood and
adult disease Inhaled tobramycin Slide 16 Complexity of Current CF
Pulmonary Care Recombinant DNase TOBI Hypertonic saline Inhaled
colistin Inhaled gentamicin Inhaled steroids Azithromycin
Anti-staphylococcal antibiotics Inhaled 2 agonists Inhaled
anticholinergics Leukotriene modifiers Systemic steroids ? Slide 17
Assessing the Evidence for Use of Current Pulmonary Therapies
Systematic reviews of original research Modified systematic reviews
Existing Cochrane systematic reviews 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. Quality of data Strength of
recommendations (A > B > C > D; I) Slide 18 Recombinant
Human DNase Age > 6 yo Moderate to severe disease (FEV 1
Chronically Inhaled Tobramycin PsA + (persistent), and > 6 yo
Moderate to severe disease (FEV 1 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) Slide 22 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 618 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) Slide
23 Anti-inflammatory Agents (contd) 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) Slide
24 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) Slide 25 Day 0 2884168 196 0 20 4040 60 80 100
% Exacerbation-free Placebo Azithromycin OFF 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. 2884168196 -4 -2 0 2 4 6 Day Placebo Azithromycin * * * OFF
FEV1 (% predicted) Azithromycin in PsA+ CF Patients Slide 26
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) Slide 27 Bronchodialators Patients > 6 yo
2 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) Slide 28 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 ( 2 adrenergic receptor agonists)
Hypertonic saline (7%) Class D recommendations (no benefit or
potential harm) Oral corticosteriods ( 618 yrs, chronic) Inhaled
corticosteroids Anti-staphylococcus antibiotics (chronic) Class I
recommendations (insufficient information) Leukotriene antagonists,
oral corticosteroids (adults), anticholinergics, N acetyl cysteine,
and cromolyn Slide 29 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. Slide 30 Time Uninfected Lung Function 100 %
Transient Bacterial Infection Eradication Chronic Bacterial
Infections Mucoid/Biofilm Bacterial Infection Inflammation
Irreversible Lung Damage Adapted from Starner T and McCray P. Ann
Intern Med. 2005;143:816-822. Slide compliments of France
Foundation. Infection with Pseudomonas aeruginosa and Progression
of CF Lung Disease Slide 31 Reprinted with permission from Cystic
Fibrosis Foundation Patient Registry. 2006 Annual Data Report.
Bethesda, MD. prevention management Prevalence of Respiratory
Infections in CF Patients Over Ages Slide 32 Reprinted with
permission from Li Z, et al. JAMA. 2005;293(5):581-588. No PsA
Nonmucoid PsA only Mucoid PsA +/- Nonmucoid PsA Age-Specific
Prevalence of P. aeruginosa from Birth to Age 16 Slide 33 Reprinted
with permission from Li Z, et al. JAMA. 2005;293(5):581-588. Pa(-)
Non-mucoid Pa (+) mucoid Pa (+) Association of Mucoidy with Decline
in FEV1 % Predicted Slide 34 Available at:
http://www.ClinicalTrials.gov/ct2/show/NCT00097773. Accessed March
2008. Randomized, double-blind, placebo- controlled, safety and
efficacy study 54 US Centers 300 CF patients 112 years old Primary
Outcome: Proportion of recurrent Pa positive cultures (18 months)
Time to occurrence of pulmonary exacerbations QT: quarterly
treatment PsA +: treatment only when quarterly cultures are + for
P. aeruginosa Month 0 3 6 9 12 15 18 Tobramycin + Ciprofloxacin QT
PA+ QT PA+ Tobramycin + Placebo QT PA+ QT PA+ Slide compliments of
France Foundation. Early Pseudomonas Infection Control (EPIC) Phase
4 closed to enrollment Slide 35 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
Slide 36 Promoting Adherence and Increasing Life Span Kristin A.
Riekert, PhD The Johns Hopkins University Slide 37 Composite
Medication Possession Ratio (MPR) Reprinted with permission from
Riekert KA, et al. Pediatr Pulmonol. 2007;S30:405. Slide 38
Emerging Adulthood (aged 1825 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 ones self
Greater autonomy in decision making Slide 39 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. Slide 40 Adherence Typologies Slide 41 Erratic
Adherence Patient understands and agrees with therapy but has
difficulty consistently maintaining regimen Slide 42 "I try to take
my medicine regularly but I'm too... " Busy Forgetful/disorganized
Stressed/family chaos Out of medicine Regimen too complex Slide 43
Unwitting Nonadherence Patient and provider mistakenly believe that
the patient is adherent Slide 44 "But I thought I was taking my
medicine right..." Misunderstands regimen Poor device technique
Language barriers Cognitive deficits Slide 45 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. Slide 46 Poor MDI/DPI Technique % Good
Technique Patients2868 1 House staff4365 2,3 Physicians65 3
Nurses447 2 Respiratory Therapists8592 2,3 Pharmacists62 4
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. Slide 47 Intelligent Nonadherence Patient
deliberately alters or discontinues therapy Slide 48 "I dont need
to take my medicine because I..." Dont think the therapy makes a
difference to my health Feel fine/better = dont need it Am
concerned about side- effects Fear addiction/drug resistance Slide
49 Beliefs About Asthma Medication 1,2 Parents of children Adult
patients Hard to take meds when feel fine32.245.9 Hard to remember
to get refills13.935.7 Nothing I can do to stop an attack30.843.9
Even if take meds, will still have sx6254.1 Benefits of meds make
side effects worth it 5151.5 Taking meds makes me worry more about
asthma 32.719.4 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. Slide 50 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. Slide 51 What Can the CF Clinician
Do? Slide 52 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]? Slide 53 Pediatric Adherence with Inhaled Steroids
Coutts JA, et al. Arch Dis Child. 1992;67(3):332-333. Slide 54 Good
Communication is Key Establish rapport Open-ended questions
Reflective listening Normalize nonadherence Identify motivation to
change Slide 55 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 Slide 56 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 Slide 57 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 Slide 58 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 Slide 59 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 Slide 60 Optimizing Patient Outcomes: An
Illustrative Case Michael P. Boyle, MD, FCCP The Johns Hopkins
University School of Medicine Slide 61 Case History Ryan,
19-year-old young man with CF Genotype dF508/dF508 Baseline FEV 1
75% 80% of predicted Chronically infected with mucoid P. aeruginosa
Slide 62 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 Slide 63 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 Slide 64 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 FEV 1 today 74% of predicted States: Im fine the
cough bothers my parents more than it bothers me Slide 65 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? Slide 66 Intelligent
Nonadherence Patient deliberately alters or discontinues therapy
Slide 67 Ryans Actual Regimen: Enzymes, vitamins, azithromycin,
occasional dornase alpha and getting to the gym Which, if any, of
the medications have you been taking? Slide 68 "I dont need to take
my medicine because..." convinced he only has mild CF feels fine =
doesnt need it doesnt think the prescribed therapy is the most
effective way to maintain health Slide 69 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 Slide 70 Treatment Reviewed graph of
FEV 1 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 Slide 71
Treatment Prescribed oral ciprofloxacin and inhaled tobramycin, and
proposed an experiment assessing FEV 1 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 Slide 72 Follow-up Visit Taking medications FEV 1
79% of predicted Symptoms resolved Determined to make medications
more of a priority in the future. Slide 73 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
Slide 74 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
