Transcript Optimizing Patient Outcomes: Clinical Use of the Cystic

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