Integrating multiple co-morbidities in guidelines

Holger Schünemann
Professor and Chair, Dept. of Clinical Epidemiology & Biostatistics
Professor of Medicine
Michael Gent Chair in Healthcare Research
McMaster University, Hamilton, Canada

Madrid, February 21, 2013 (recorded slides)

Integrating multiple co-morbidities in
guidelines

Acknowledgment
Mr. W. Wiercioch
Dr. Pablo Alonso
Co-authors

Disclosure
• No direct/personal for-profit payments to me or my
research group
• Co-chair of GRADE working group
• Cochrane Collaboration
– Co-convenor of the Applicability and Recommendations
Methods Group
– Various other functions
• IQWiG Scientific Board

Content
1. Intro to considering multiple co-morbidities
2. How important are multiple comorbidities for guidelines?
3. How have other organizations involved in the
development of guidelines for single chronic disease
approached the problem of multiple comorbidities?
4. What are the implications of multiple comorbidities for
pharmacological treatment?
5. What are the potential changes induced by multiple
comorbidities in guidelines?
6. What are the implications of considering a population of
older patients with multiple comorbidities in designing
clinical trials?

Intro to considering multiple co-
morbidities

Framing a foreground question

Population: Patients with COPD
Intervention: Respiratory rehabilitation
Comparison: No respiratory rehabilitation
Outcomes: Mortality, hospitalizations,
resource use, adverse
outcomes

Schunemann, Hill et al., The Lancet ID,
2007

Importance of multiple comorbidities for
guidelines
• COPD commonly exists in patients who often have
multiple comorbidities:
– e.g. heart failure, coronary artery disease,
hypertension, diabetes mellitus, metabolic syndrome,
cancer, depression
• These comorbidities affect the epidemiology,
pathophysiology, and care of COPD, as well as
that of the comorbid disease(s)
• For example, COPD and cardiovascular disease
(a non-respiratory comorbidity):
– Symptoms of COPD and comorbidities may overlap
– Underlying pathology may be shared
– Treatments may interact
– Natural history of conditions may be altered

Relation between PICO and
available evidence

PICO

Indirectness - population
Outpatient respiratory
rehabilitation in patients with
COPD

COPD and heart
COPD and heart failure
failure

No concerns about directness (transferability) Concerns about directness
No lowering of confidence Lower confidence 
Same recommendation Separate recommendation

Indirectness - population
Outpatient respiratory
rehabilitation
in patients with COPD

COPD and heart
failure
Is the effect the same
in patients who also
have heart failure

No concerns about directness (transferability) Concerns about directness
No lowering of confidence Lower confidence 
Same recommendation Separate recommendation

Determinants of confidence:
GRADE
• Any evidence 
• 5 factors that can lower confidence
1. limitations in detailed study design and execution
(risk of bias criteria)
2. Inconsistency (or heterogeneity)
3. Indirectness (PICO and applicability)
4. Imprecision
5. Publication bias
• 4 factors can increase confidence
1. Randomization
2. large magnitude of effect
3. opposing plausible residual bias or confounding
4. dose-response gradient

Lowering confidence in RCTs
Table: GRADE's approach to rating quality of evidence (aka confidence in effect estimates)
For each outcome based on a systematic review and across outcomes (lowest quality across the outcomes critical for decision making)
1. 2. 3.
Establish initial Consider lowering or raising Final level of
level of confidence level of confidence confidence rating
Study design Initial Reasons for considering lowering Confidence
confidence or raising confidence in an estimate of effect
in an estimate across those considerations
of effect  Lower if  Higher if*

High Risk of Bias Large effect High
Randomized trials
confidence 
Inconsistency Dose response
Indirectness All plausible Moderate
confounding & bias 
Imprecision  would reduce a
Low demonstrated effect Low
Observational studies Publication bias
confidence or 
 would suggest a
spurious effect if no Very low
effect was observed


*upgrading criteria are usually applicable to observational studies only.

1. How important are multiple comorbidities for
guidelines? K

ey questions
development of guidelines for single chronic
disease approached the problem of multiple
comorbidities?
3. What are the implications of multiple
comorbidities for pharmacological treatment?
4. What are the potential changes induced by
multiple comorbidities in guidelines?
5. What are the implications of considering a
population of older patients with multiple
comorbidities in designing clinical trials?

Importance of multiple comorbidities for
guidelines
• Increase in the prevalence of multiple
comorbidities with advanced age
– 33% in 65-69 year-old age group, and ≥50% in 85+
year-old age group, have 3 or more chronic
conditions
• Multiple comorbidities influence the clinical
manifestations and natural history of a chronic
disease
• Multiple comorbidities must be taken into account
in considering diagnosis, assessment of severity,
prognosis, and management of a chronic disease
(i.e. the topics covered in a clinical guideline)
• Implementing single disease guidelines presents a
challenge to clinicians treating the average
population of patients with multiple comorbidities

guidelines? K

ey questions
comorbidities?

Approaches of other organizations in
addressing problem of multiple comorbidities
• Recent guidelines for COPD:
– Acknowledge the importance of considering multiple
comorbidities in diagnosis, prognosis, and management
– Acknowledge the lack of evidence and specific guidance for
clinicians to make these considerations
– Provide few recommendations on how to modify care based
on multiple comorbidities
• Recent guidelines for other common chronic diseases
– CHF, hypertension, and diabetes mellitus guidelines address
poorly some comorbidities, including COPD, one at a time,
failing to address coexistence of multiple comorbidities at the
same time
– Underrepresentation of individuals 80 years and older
– Few adequately address issues directly related to elderly
patients with comorbidities

• There are some examples of collaborative guideline
development that may serve as a model for future work
• European Society of Cardiology participating in joint
development of cardiovascular disease prevention
recommendations with 9 other societies
• American Geriatrics Society/California HealthCare Foundation
guideline for care of the older patient with diabetes mellitus:
– Selected six chronic conditions common in people with
diabetes mellitus and reviewed literature on each topic
– Limited availability of data specific to older adults for most
topic areas
– Extrapolation of findings based on data for persons of younger
ages
– Example Recommendation Statement: “The older adult who
has diabetes mellitus is at increased risk for major depression
and should be screened for depression during the initial
evaluation period (first 3 months) and if there is any
unexplained decline in clinical status. (IIA)” Brown AF, Mangione CM, Saliba D, Sarkisian CA.
Guidelines for improving the care of the older
person with diabetes mellitus. J Am Geriatr Soc
2003;51:S265–S280.


• All chronic disease guidelines should have
a separate section on comorbidities, with a
summary of basic recommendations on
diagnosis, assessment of severity, and
treatment of each comorbid condition that
can be derived from other high-quality
guidelines or developed de novo

guidelines? K

ey question
comorbidities?

Implications of multiple comorbidities for
pharmacological treatment

• Primary focus on the management of a single
disease may inadvertently lead to
undertreatment, overtreatment, or
inappropriate treatment:
– Excess medication administration from adding
treatments for the same condition when other
causes are not considered and there is a lack of
response to therapy
– Therapeutic efficacy of a medication is often
evaluated for treatment of a single index condition
and the medication may have unanticipated
effects on patients with other illnesses

• Problem of adverse effects of
pharmacological agents in patients with
COPD:
– Systemic steroids are recommended for
treatment of exacerbations of COPD, but
increase risk of hyperglycemia in patients with
COPD and diabetes mellitus, and may worsen
osteoporosis
– Beta-blockers are recommended for treatment
of CHF, but can exacerbate respiratory
symptoms in patients with COPD who also
have asthma

• Strategies can be used to account for possible effect
modification and interaction of different
pharmacological agents:
– Demonstrate whether the effects will differ in the
population for whom the recommendation is intended
from that in whom the evidence is obtained
– Or, demonstrate that there is evidence of an interaction
between different interventions that would change the
benefit-downside profile compared with when the
interventions are administered alone
• Key Message: Evidence that is less direct,
compared with evidence that directly supports the
recommendations, influences the confidence in how
the obtained effects relate to the population of
interest.

Population indirectness:
Does the recommendation apply to the
population treated/managed by the
decision maker?

Relative effect Assumed & described
applies? baseline risk estimate
Interaction? May be related if from same
evidence base applies?
Risk group correct (same
features)?

Influenced by the confidence in the estimate of the
baseline risk estimate that was assumed when
modeling?
Risk of bias, imprecision, publication bias,
inconsistency, upgrading criteria apply

Potential changes induced by multiple
comorbidities in guidelines
• Underlying Question: How should
physicians make treatment recommendations
for people with multiple comorbidities,
particularly if they are elderly?
– Clinical decision-making in such patients requires
estimation of the often subtle balance of benefits
and harms, i.e. the net benefits or net harms
– This frequently involves considerable uncertainty,
and requires estimation of a baseline risk over a
given time period
– Values and preferences patients place on
treatment options and outcomes
• Patient-oriented guidance must incorporate
these judgments

Potential changes induced by multiple
comorbidities in guidelines
To address these issues, comorbidities could be considered in all
disease guidelines in several aspects:
1. Explicitly discussing whether patients with the most
common comorbidities were included in the disease-
specific trials
– Is the patient, to whom the study results are being applied,
sufficiently like, or exchangeable to, the average patient in the
trial?
– When high-quality randomized studies are available, the
evidence will frequently be indirect for the multi-morbid
population, and the quality of evidence may be downgraded
– Review of the evidence in layers considering both people with
and without multiple comorbidities, as well as people of different
ages
2. Considering the absolute risk reduction from therapy for
a patient with multiple comorbidities
– Recognize that a person with multiple comorbidities may be at
either higher or lower absolute risk than the ‘average’ person
– Is it known whether the relative benefit of therapy increases or
decreases in people with each combination of the multiple

Implications of considering a population with
multiple comorbidities in designing clinical trials
• Patients in clinical trials do not adequately
reflect the true population of people with any
chronic disease in terms of the burden of
multiple comorbidities
– Older patients and patients with multiple
comorbidities are specifically excluded from most
clinical trials
– The number of trials with explicit age exclusions
for older patients has decreased, but exclusions
for comorbidities have increased
• Exclusion and inclusion criteria are less
important than who is the ‘average’ patient in a
trial. Few exclusion criteria may still not prevent
few people with comorbidities being enrolled
and results will be of questionable relevance.

Implications of considering a population with
multiple comorbidities in designing clinical trials

• Key Message: Developing recommendations for patients with
multiple comorbidities requires careful consideration of the
directness of evidence
Fails to reflect diversity
of the population

Broadly representative of
the population in terms of
risk, responsiveness, and
vulnerability

Individuals who benefit
much more from treatment
than average members of
the population

From: Kravitz RL, Duan N, Braslow J. Evidence‐based medicine, heterogeneity
of treatment effects, and the trouble with averages. Milbank Q 2004;82:661–687.

Summary
Framework for Development of Multiple Comorbidity
Clinical Practice Guidelines and Patient Involvement
Step How Example for COPD
1. Define all problems for a Ask patients or review the literature Primary concern: Dyspnea,
given patient depression, swelling of legs?
2. Which outcome is of Use tools to elicit values and preferences Ranking techniques, e.g.
greatest importance (e.g. ranking exercises, visual analog comparing dyspnea with
to a patient with multiple tools) fatigue and hospitalizations
co‐morbidity (described in detail)
3. Define possible options Literature search (focus on SR), expert LABA, diuretics, beta‐blockers,
to intervene input on what might work antidepressants
4. Evaluate whether ‐ Evaluate subgroup effects/ ‐ LABAs may be worse in
benefits or downsides heterogeneity patients with dyspnea
differ across ‐ Did trials include subgroups and are from COPD and CHF
populations (in particular subgroup effects credible? ‐ Treatment of dyspnea
those with different ‐ Evidence that biology differs? leads to improvement in
comorbidity) ‐ Judgement about directness of evidence depression
5. Evaluate greatest net ‐ Systematically judge expected benefits ‐ Beta‐blockers with greatest
benefit across populations against potential downsides after net benefit in pop. of interest
based on evidence profiles considering various interventions ‐ Treatment of depression
and present to panel ‐ Explain to patients second largest net benefit
making recommendations ‐ LABA and diuretic net benefit
and to patients smaller than beta‐blockers

Integrating multiple co-morbidities in guidelines

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