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A Personalized Decision Aid to Help Women with Lupus Nephritis from Racially and Ethnically Diverse Backgrounds Make Decisions about Taking Immune-Blocking Medicines
Jasvinder Singh, MD,1 Jinoos Yazdany, MD, MPH2 Winn Chatham, MD1 Tara Rizvi, MD3 Liana Fraenkel, MD, MPH4 Graciela Alarcon, 1Kenneth Saag, MD 1 Robert Kimberly, MD1 Maria Suarez-Almazor, 5 Amye Leong, MBA,6 Leslie Hanrahan,7 Sandra Raymond,7 Elyse Reyes, Charity Morgan, PhD1 Nipam Shah, 1 Candace Green, 1 Alexa Meara, MD8 Rick Street, PhD 9 Laura Marrow,10 Brennda Caro,1 Jennifer Barton, MD,11 Jeffrey Sloan, PhD,12
1University of Alabama School of Medicine, Birmingham, AL 2University of California San Francisco Medical Center at Parnassus, San Francisco, CA 3Baylor College of Medicine, Houston, TX 4Yale University School of Medicine, Boston, MA 5University of Texas MD Anderson Cancer Center, Houston, TX 6Healthy Motivations Inc. Santa Barbara, CA 7Lupus Foundation of America, Washington, DC 8Ohio State University, Columbus, OH 9Texas A&M University System, College Station, TX 10Arthritis Foundation, Atlanta, GA 11Oregon State University, Portland, OR 12Mayo Clinic Minnesota, Rochester, MN
Original Project Title: Individualized Patient Decision Making for Treatment Choices among Minorities with Lupus PCORI ID: CE-1304-6631 HSRProj ID: 20143522 ClinicalTrials.gov ID: NCT02319525 _______________________________
To cite this document, please use: Singh J, Yazdany J, Chatham W, et al. (2019). A Personalized Decision Aid to Help Women with Lupus Nephritis from Racially and Ethnically Diverse Backgrounds Make Decisions about Taking Immune-Blocking Medicines. Washington, DC: Patient-Centered Outcomes Research Institute (PCORI). https://doi.org/10.25302/10.2019.CE.13046631
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Table of Contents
ABSTRACT ............................................................................................................................. 3 BACKGROUND ....................................................................................................................... 5 PARTICIPATION OF PATIENTS AND OTHER STAKEHOLDERS IN RESEARCH DESIGN, CONDUCT, AND DISSEMINATION OF FINDINGS ....................................................................................... 9
Study Intervention Development ............................................................................................................................ 12 Study Design, Population, and Setting: Randomized Trial ...................................................................................... 26 Randomized Trial Study Intervention ...................................................................................................................... 27 Baseline and Follow-up Study Visits ........................................................................................................................ 27 Outcome Measures ................................................................................................................................................. 28 Statistical Analyses .................................................................................................................................................. 31 Conduct of the Study ............................................................................................................................................... 32
RESULTS .............................................................................................................................. 33 1. Primary Outcome ................................................................................................................................................ 40 2. Primary Outcome ................................................................................................................................................ 42 3. Secondary Outcome ............................................................................................................................................ 43 4. Secondary Outcome ............................................................................................................................................ 44 5. Secondary Outcome ............................................................................................................................................ 44
DISCUSSION ........................................................................................................................ 51 Context for Study Result.......................................................................................................................................... 51 Generalizability of the Findings ............................................................................................................................... 55 Implementation of Study Results ............................................................................................................................ 55 Subpopulation Considerations ................................................................................................................................ 57 Study Strengths and Limitations.............................................................................................................................. 57 Future Research ...................................................................................................................................................... 59
CONCLUSION ....................................................................................................................... 61 ACKNOWLEDGMENTS .......................................................................................................... 62 REFERENCES ........................................................................................................................ 63
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Abstract
Background/Objective: Systemic lupus erythematosus (SLE) is a rare and sometimes fatal disease. Lupus nephritis inflammation of the kidney is a devastating complication of SLE and is often more common in racial/ethnic minorities. Immunosuppressive drugs can effectively treat lupus nephritis, but patients may be reluctant to use them due to concerns about side effects and lack of understanding of their potential benefits. We assessed whether a web-based, individualized, culturally tailored, computerized patient decision aid can improve decision making regarding using immunosuppressive drugs in women with lupus nephritis.
Methods: We developed a patient decision aid for immunosuppressive medication decision making based on formative work with 52 lupus nephritis patients (predominantly racial/ethnic minorities with low socioeconomic status) and systematic review, meta-analyses, and network meta-analyses. In a 6-month randomized controlled trial at 4 US centers, we recruited adult women, largely racial/ethnic minorities with low socioeconomic status, who were making decisions about starting or maintaining treatment of lupus nephritis flares, or who had a history of lupus nephritis flares and were at risk of future flares. Patients were randomized during a clinic visit to receive a patient decision aid on a tablet computer or a standard American College of Rheumatology (ACR) pamphlet that provided information about lupus and its treatment, including the use of immunosuppressive drugs. The study was conducted during clinic visits and outcome assessments occurred immediately after the intervention was administered. Coprimary outcomes were a change in decisional conflict assessed with a low literacy–version Decisional Conflict Scale (0-100; the higher the score, the more conflict was present) and the proportion with an informed choice regarding immunosuppressive drugs (concordance of the patients’ values and their choice for or against immunosuppressives based on an adequate knowledge of the drugs). Secondary outcomes included (1) the concordance between a patient’s desired and actual role in immunosuppressive drugs decision making using the control preference scale, (2) the patient perception of patient–physician communication and care processes using the Interpersonal Process of Care–Short Form (IPC-SF), and (3) the assessment of patient–physician communication by assessing the audiotaped physician–patient conversation about therapy options.
Results: Of the 301 women with lupus nephritis randomized, 3 patients withdrew consent and 298 received an individualized decision aid (n = 151) or the ACR pamphlet (n = 147, control arm). The mean age was 37 years, 35% had an annual income < $20 000, 36% had a high school education or less, the average health literacy score on the Short Assessment of Health Literacy was 16.8 (a score of 0-14 denotes low health literacy), 47% were African American, and 26% were Hispanic. Compared with those who received the pamphlet, patients who received the decision aid had a significantly larger reduction in decisional conflict (21.8 [SD, 30.9] versus
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12.7 [SD, 24.4]; p = 0.005). The group receiving the decision aid made informed choices regarding immunosuppressive drugs more frequently (41% versus 31%), although this did not meet statistical significance (p = 0.08). Sensitivity analysis that used an alternate definition of informed choice (positive versus negative values rather than the median score for values) showed that significantly more women in the decision aid group made an informed choice compared with those in the pamphlet group (50% versus 35%; p = 0.006). We noted no statistically significant differences in the secondary outcomes of concordance in the desired versus the actual role in decision making (94% versus 85%; p = 0.25) or the IPC-SF scores (83.6 [SD, 7.7] versus 83.1 [SD, 7.3]; p = 0.50). Using an audiotaped patient–physician conversation, the patient-centered communication by doctor showed a statistical trend toward significance in the decision aid versus the pamphlet group (5.1 versus 3.7; p = 0.06).
Conclusions: An electronic, individualized, culturally appropriate patient decision aid was effective in reducing the decisional conflict regarding choosing immunosuppressive drugs in an ethnically and socioeconomically diverse sample of women with lupus nephritis. Future studies should investigate whether this decision aid can be further enhanced to improve its efficacy, modified for other manifestations of lupus, or provided on a mobile platform, so that patients have even easier access to it. The Patient-Centered Outcomes Research Institute (PCORI) lupus nephritis decision aid will be available in the public domain.
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Background
Systemic lupus erythematosus (SLE), or lupus, is a rare chronic disease that primarily
affects young women, particularly during peak reproductive years.1,2 In the United States, 161
000 individuals have SLE, making it a rare disease, and if not treated appropriately, SLE has
devastating consequences.3 Approximately 35% of SLE patients present initially with nephritis
and 50% to 60% develop nephritis during the first 10 years.4,5 Among racial/ethnic minorities
lupus nephritis accounts for 2% of all end-stage renal disease in the United States.6 Lupus
nephritis is significantly more prevalent and has worse outcomes (e.g., > 3 times higher
mortality) in African Americans and Hispanics than in whites.7,84,4,5,9-15 Thus, racial disparities in
outcomes and high mortality make lupus an optimal disease for patient-centered outcomes
research. While the 2012 American College of Rheumatology (ACR) treatment guidelines for
lupus nephritis incorporated comparative effectiveness research (CER) data,16 a detailed
analysis of comparative toxicity was not completed. Strong evidence exists that the use of
immunosuppressive medications improves lupus outcomes when combined with
glucocorticoids,16 and may reduce the cumulative glucocorticoid dose and associated side
effects.17-19 However, immunosuppressive drugs used to treat lupus nephritis (mycophenolate
mofetil, cyclophosphamide, azathioprine, etc.)16 differ from each other significantly in their
toxicity (e.g., cancer risk, infections), effects on fertility, safety during pregnancy, administration
route, frequency of dosing, and cost. For example, mycophenolate is contraindicated for use in
pregnancy, whereas clinicians consider azathioprine (a less expensive medication) a relatively
safe option.20 Given the differences in toxicity and cost across treatment options, we believed
that it was critical to generate both patient perspectives21-23 (Aim 1) and CER data24-26 (Aim 2)
related to immunosuppressive drugs to enable informed decision making. In the current study,
patients were asked to weigh risks versus benefits differently depending on their values,
preferences, and knowledge of and aversion to risk, to enable development of a patient-
centered decision aid.
Patients are often faced with difficult decisions about how to treat newly diagnosed and
chronic lupus nephritis. Medication choice(s) depend not only on efficacy and drug-specific risk
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profiles, but also on cost. In addition, efficacy may differ by race and ethnicity. For example, a
subgroup analysis of an open-label randomized controlled trial (RCT)—the Aspreva Lupus
Management Study (ALMS)—found that, compared with whites and Asians, patients of other
races and ethnicities with lupus nephritis responded less favorably to cyclophosphamide as
induction therapy27; and while not differing by race, the response to mycophenolate was
superior to azathioprine as maintenance therapy for lupus nephritis.28 If the existing CER data
can be expanded (Aim 1) and simplified using a decision aid, this may help patients with lupus
nephritis through the complicated decision-making process regarding immunosuppressive
drugs (Aim 3). It should be noted that the example study above, ALMS, was limited by its being
an open-label design and inclusion of relatively few African Americans.27
Many minority patients do not receive quality health care, due in part to lower health
literacy and numeracy,29 poor physician–patient communication,30-33 high medication
nonadherence,34 low socioeconomic status,35,36 more barriers to health care access,37-39 and
more risk aversion to therapies.40-45 Since health literacy is the ability to understand, engage in,
and actively apply health information to improve health,46 poor health literacy can contribute
to poor health outcomes. In the United States, 41% of Hispanics, 24% of African Americans, and
9% of whites have inadequate health literacy skills, highlighting the disproportionate impact of
low health literacy on racial minorities.46 Numeracy is the ability to understand and use
numbers in daily life and, when inadequate, is associated with poor health outcomes.47,48
Compared with whites, studies have shown that African Americans have lower numeracy,
which may explain poor health outcomes in diseases such as diabetes,49 and poor management
of medications, as demonstrated in a study using a simulated HIV medication regimen.50
Previous studies have shown poor medication adherence is common in patients with lupus
nephritis, with racial minorities indicating less willingness to receive treatment for worsening
lupus.51-53 In qualitative studies, we described both facilitators22 and barriers23 to medication
decision making by patients with lupus nephritis, and that a decision aid could overcome these
challenges and present information tailored to health literacy and numeracy. A decision aid is
one potential solution for patients with low literacy and numeracy but is currently lacking for
lupus. A Cochrane systematic review54 that included studies in patients with low literacy
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showed that a decision aid helped patients comprehend accurate expectations of possible
benefits and harms, make choices that are more consistent with their informed values, and
participate more in decision making.54 Patients who were involved in making medical decisions
had better outcomes55,56 and were more satisfied than patients who were not involved.57-59
Many treatment decisions (for example, mycophenolate mofetil versus cyclophosphamide for
induction) in lupus nephritis have no single “best” choice and are preference sensitive due to
insufficient evidence about outcomes and/or the need to trade off known benefits and harms.
Similarly, there are preference-sensitive decisions for maintenance therapy for lupus nephritis,
including the choice between mycophenolate mofetil versus cyclophosphamide (following
azathioprine failure), calcineurin inhibitors such as cyclosporine/tacrolimus versus
cyclophosphamide (following azathioprine and mycophenolate mofetil failure), or
cyclophosphamide versus azathioprine (following mycophenolate mofetil failure). For others,
the benefits of a drug far outweigh its risks. For example, the use of glucocorticoids combined
with immunosuppressives is superior to glucocorticoids alone for induction—i.e., it is the
dominant choice (not preference sensitive), yet the rate of immunosuppressive use by patients
with lupus nephritis is low in the United States.60 A patient decision aid could facilitate
preference-sensitive decisions, such as the choice between immunosuppressives for induction
or maintenance therapy for lupus nephritis. Decision aids have been used successfully for
diabetes and osteoporosis,61,62 rheumatoid arthritis, and hepatitis C.63-66 Decision aids have
succeeded in improving outcomes in other inflammatory arthritis conditions67 when developed
for the target population.68 To our knowledge, no decision aid exists to assist patients with
lupus nephritis in treatment decision making. As part of Aims 3 and 4, we tested the hypothesis
that a decision aid that can help patients overcome literacy/numeracy challenges can improve
patient decision making and can lead to more informed choices by patients.
We conducted network meta-analyses (NMAs)69-71 to assess the efficacy and
harms/toxicity of lupus nephritis treatments to address the PCOR question “What are my
options and what are the potential benefits and harms of those options?” Second, we aimed to
develop an individualized decision aid for African American and Hispanic women with lupus
nephritis, for whom the disease is often more severe and outcomes are worse, by focusing on
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culture-specific barriers. Our central research question was whether the use of an
individualized, culturally tailored, patient-centered decision aid would reduce the conflict in
patient decision making and lead to more informed patient choice regarding
immunosuppressives for the treatment of lupus nephritis. Our study aims were the following:
Aim 1: To perform an evidence synthesis by systematic review and NMA. To assess
comparative effectiveness of various immunosuppressives compared with each other and with
glucocorticoids, corresponding to main induction and maintenance treatment decision points
(published24-26), using rigorous systematic review and NMA methods based on Agency for
Healthcare Research and Quality (AHRQ) recommendations72 and the Cochrane handbook,73
and building on the systematic review performed for the 2012 ACR lupus nephritis treatment
recommendations.16 After assessing heterogeneity across trials74 in patient characteristics, trial
methodologies, and treatment protocols, we conducted a Bayesian NMA75-77 for prespecified
outcomes.
Aim 2: To elicit patients’ perceptions of barriers to effective decision making for lupus
nephritis treatments, and their concerns regarding the risks and benefits of various
immunosuppressives compared with each other and with glucocorticoids through the nominal
group technique (NGT; results published21-23).
Aim 3: To develop and pilot test an interactive computerized decision aid based on CER
data and formative work with patients—largely racial/ethnic minorities of low socioeconomic
status—using an iterative process (a detailed protocol has been published78).
Aim 4: To conduct a multicenter, parallel arm, randomized trial comparing the usual
care for decision making against an individualized, culturally tailored patient decision aid in
women— largely racial/ethnic minorities with low socioeconomic status—making lupus
nephritis treatment decisions regarding immunosuppressives.
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Participation of Patients and Other Stakeholders in Research Design, Conduct, and Dissemination of Findings
We identified our key patients, patient advocacy organization, physicians, researcher,
and institutional stakeholders from various racial and socioeconomic backgrounds to assist with
the development and execution of this project. Our patient stakeholders included Ms. A
(anonymized as per instructions; CEO of Company A; master’s degree in business management;
trained in psychometrics and outcomes); Ms. B (anonymized; Master of Public Administration;
past director of patient programs and community programs at a patient advocacy organization;
bilingual). Our patient advocacy organization leaders included Sandra Raymond (president and
CEO of research, Lupus Foundation of America [LFA]), Leslie Hanrahan (vice president of
education and research, LFA), and Laura Marrow (director, partnerships liaison at the Arthritis
Foundation [AF]). Physician and researcher stakeholders included experts in lupus treatment
(Drs. Chatham, Yazdany, Alarcón) and those with expertise in decision aid development and/or
performing CER including NMA (Drs. Fraenkel, Winthrop, Wells, Suarez-Almazor, Barton,
Grossman, Saag, Singh, and Street). Institutions and organizations that served as key
stakeholders and assisted with the study development and conduct included the University of
Alabama (UAB) Department of Communication, University of California at San Francisco (UCSF),
AHRQ-supported UAB CERTs, and The Eisenberg Center.
We recruited our 2 patient stakeholders (Ms. A, Ms. B) based on their expertise, disease
experience, and experience serving as partners in patient-centered research. Ms. A and Ms. B
represent a key group of people for whom the study results are particularly relevant. Ms. A and
Ms. B played key roles in developing our study questions before submission, and throughout
the funding period. Patient and other key stakeholder engagement had a significant impact on
all aspects of the study quality and contributed heavily to the development of the decision aid.
We held stakeholder and investigator teleconference meetings monthly on Thursdays to discuss
key aspects of the project, from project inception through its conclusion. The stakeholder
committee was charged with finalizing the risks and benefits that were incorporated into the
decision aid, and all patient and clinician stakeholders engaged in a variety of activities,
including formulation of the study design, the NMA, pilot testing of the intervention (i.e.,
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individualized decision aids in English and Spanish), and patient recruitment and retention in
our trial. Previous experience of key stakeholders helped us meet new challenges during the
study conduct. The monthly meetings allowed interactions of investigators with other key
stakeholders. For example, stakeholders and investigators collaboratively reviewed and
provided feedback about plans for focus group techniques and discussed the results of patient
focus groups. We did not face any significant logistic or budgetary challenges in engaging
patients and stakeholders. Specific examples of key stakeholder involvement are as follows:
• Both researchers and patient partners were involved in creating the manuscript related
to facilitators of medication adherence and cognitive mapping (published21).
Researchers presented a preliminary document for review at one of the recent
stakeholder/investigator calls. All partners provided their feedback on the study design
as a group and later independently grouped concepts/statements as part of the
cognitive mapping. This iterative process was highly effective, allowing
researchers/clinicians and patient representatives to hear the differing opinions of their
peers. The resulting manuscript of cognitive mapping of medication decision-making
facilitators addressed the different views of all 3 groups.21
• Brennda Caro led and Drs. Suarez-Almazor, Alarcón, and Barton helped with the Spanish
translations that led to the development of the Spanish version of the decision aid. Dr.
Fraenkel helped the researchersdevelop the content of our lupus nephritis decision aid
for minorities based on the NGT results, using the rheumatoid arthritis decision aid as a
template. We eliminated from the decision aid several side effects important only to
physicians, but not patients (eg, low white cell counts and bone density values related to
glucocorticoids).
• Patient research partners (Ms. A and Ms. B) helped us design the study and participated
heavily in the development of the decision aid. Both participated in all of the activities of
our study by regular teleconferences and email exchanges.
Additionally, we were able to convene a group of key stakeholders and investigators at
the 2016 annual ACR meeting, at which panel discussions were held about further ideas on
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patient-centered research for lupus. The theme of the discussion was how to improve lupus
care. Discussion involved key Patient-Centered Outcomes Research Institute (PCORI)
investigators, stakeholders, and attending rheumatologists from sites such as Ohio State
University (OSU), and stakeholders shared ideas on initiatives started by their respective
organizations for better lupus care. The panel concluded that a multicomponent intervention
for the management of lupus was important from the patient perspective. Investigators have
actively engaged and enrolled their patients in this research project. It has helped study team
investigators understand how patient-centered research helps and empowers patients to make
informed decisions about their care for lupus nephritis. Investigators were motivated to
become a part of future outcomes research involving implementation of multifaceted
interventions for management of this condition. We discussed the methods to disseminate this
decision aid with the help of our stakeholder partners, LFA and AF, using one of the PCORI
dissemination grants.
Overall, patients enrolled in this trial liked the decision aid tool and found it very
informative. Most patients did not mind spending the extra time during their visits to
participate in the study, noting it helped them understand the treatment options as well as the
risks and benefits of those options. Patients shared positive experiences about the study
participation, the research study process and conduct, and the technology used (iPad self-
administered).
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Methods
Study Intervention Development
The study intervention in this 2-arm trial was a decision aid in English or Spanish
targeting patient knowledge and opinions about immunosuppressive drugs. The decision aid
content was based on information generated through qualitative work with our target
population,21,22,79 and further pilot tested in the patient population of interest. The decision aid
included information about benefits and harms that are relevant to patients with lupus
nephritis. A published study protocol provides further details about the decision aid.78 We
designed the decision aid educational tool to improve understanding of a large amount of
information and decision quality.
We achieved the lupus nephritis decision aid development in 3 steps: (1) nominal group
technique in the target population to understand barriers and facilitators to treatment decision
making related to lupus; (2) performance of systematic review and network meta-analysis to
derive the estimates of comparative effectiveness and harms of each treatment option for
preference-sensitive decisions; and (3) pilot testing, iterative modification, and finalization of
the decision aid in English and Spanish for the target population.
The following sections briefly describe the methods for the NGT21-23 and the NMA and
systematic reviews,24-26 which we have reproduced from our peer reviewed publications with
permission from the respective journals.22,24 Detailed methods of the NGT and the NMA and
systematic reviews for other outcomes are available in listed publications.
NGT to Define the Barriers and Facilitators of Medication Decision Making in Lupus
Nephritis
We used the NGT with patients with lupus to assess the barriers and facilitators to
medication decision making for the treatment of lupus.22,79 The NGT is a structured process
to elicit ideas from participants for a formative assessment. We conducted 8 NGT
meetings in English at 2 medical centers, UAB and UCSF, moderated by an expert NGT
researcher. Participants responded separately to 2 questions: (1) Barriers: “What sorts
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of things make it hard for people to decide to take the medicines that doctors prescribe
for treating their lupus kidney disease?”79 (2) Facilitators: “What sorts of things make it
easier for people to decide to take the medicines that doctors prescribe for treating their
lupus kidney disease?”22 In response to each of the 2 questions, patients nominated,
discussed, and prioritized (1) barriers and (2) facilitators to medication decisional
processes for lupus. In the section below, methods from our previous publication22 have
been replicated (with permission from the publisher).
We recruited patients from the lupus clinics at the University of Alabama at Birmingham
and the University of California at San Francisco. All patients met American College of
Rheumatology classification criteria for systemic lupus erythematosus and had a clinical
diagnosis of lupus nephritis (based on renal biopsy and/or laboratory tests).
We convened 8 NGT meetings including lupus nephritis patients who had received
treatment at UAB or UCSF lupus clinics. An expert NGT researcher (R.S.) conducted and
moderated all NGT meetings in English between February and April 2014. The Institutional
Review Boards at UAB and UCSF approved this study. All patients provided written, informed
consent.
The NGT meeting is a facilitated data collection activity, structured to promote even and
equal subject participation by minimizing the loss of information. Evidence shows that the NGT,
when used correctly, elicits a greater volume of novel and higher-quality responses to a
carefully articulated question than less structured group data collection approaches such as
focus groups and brainstorming.80,81 Moreover, by using the verbatim responses that are
concisely documented on a flipchart as participants present them to the group, the NGT
eliminates a potential source of investigator-induced interpretive bias resulting from
transcribing and coding audio or video recordings.
The purpose of the NGT meetings was to tap into patients’ unique insights, knowledge,
and lived experiences to identify different factors that facilitated their decision-making process
regarding prescribed lupus medications. The NGT leader (R.S.), along with a team member
(H.Q.), started the sessions with a brief explanation of the purpose and the NGT process.
Patients then worked independently for about 5 minutes to develop their own lists of brief
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statements/phrases in response to the NGT question.
Patients were encouraged to think broadly about the types of factors that enhanced the
likelihood of deciding to take the medications prescribed for their condition. This ensured that
each panel generated a wide array of responses. After 5 minutes of working on their own,
patients were invited to present their responses to the group. To promote open disclosure,
increase response volume, and ensure all patients had an equal opportunity to present
responses, we used a “round-robin” participation format. This format involved having each
patient, in turn, articulate a single response without providing any rationale, justification, or
explanation for his or her response and without discussion or debate from other members in
the group. All responses were immediately recorded verbatim on a flipchart to help participants
recollect previously nominated responses. We continued until no further responses could be
generated. All responses were then discussed in a nonevaluative fashion to ensure that they
were understood from a common perspective and, potentially, to obtain additional insights.82
Patients were asked to silently review the full list of responses generated during the
meeting and to independently select 3 facilitators that they perceived as the most influential to
their decision making regarding lupus nephritis medication. Patients recorded their selected
responses on index cards and prioritized the influence of each of their selections from 1 (least
influential) to 3 (most influential). The votes reflecting these priorities were tabulated across
patients in each NGT panel to determine the perceived relative influence of medication
decision-making facilitators and the level of agreement among patients regarding these
perceptions.
A brief questionnaire was administered to the patients at the conclusion of each NGT
meeting to obtain basic demographic data, education level, and disease duration, and whether
the patient needed assistance in reading materials. Data from this questionnaire were analyzed
at the group level and not linked with individual responses generated during the NGT meetings.
NMA and Systematic Review of Medications Used for the Treatment of Lupus Nephritis
We performed the NMA and systematic review for several benefit and harm outcomes,
which we identified from NGT with patients with lupus nephritis. We published the results in 3
15
peer reviewed manuscripts focused on the following outcomes: (1) serious infections25; (2)
malignancy, herpes zoster, gastrointestinal side effects (gastrointestinal upset, diarrhea, etc),
nausea, alopecia, mycobacterial infections, hyperglycemia/diabetes, avascular
necrosis/osteonecrosis, mortality, amenorrhea, cytopenia, and urinary bladder toxicity
(including hemorrhagic cystitis and hematuria)26; and (3) renal remission/response, renal
relapse/flare, amenorrhea/ovarian failure, and cytopenia.24
In the section below, we describe the methods from our previous publication,24 which
have been replicated from the publication (with permission from the publisher). We chose to
describe methods for only a select few outcomes, rather than all outcomes, since (1) methods
were similar (or in some cases the same) for other outcomes with minor exceptions, as noted
below; and (2) most estimates for the outcomes described in the paper24 were used in the
patient decision aid. In the other 2 papers describing outcomes from the systematic
reviews,25,26 rankograms were not presented.
We used rigorous methods for the systematic review and NMA based on the Agency for
Healthcare Research and Quality (AHRQ) recommendations,72 the Cochrane handbook,83 and
the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
The Institutional Review Board at the University of Alabama at Birmingham approved the study.
The need for informed consent was waived for this systematic review, since no human subjects
were involved. The study protocol was registered in PROSPERO, CRD42016032965
(http://www.crd.york.ac.uk/PROSPERO/).
This systematic review included randomized controlled trials or controlled clinical trials
of immunosuppressive drugs or corticosteroids for lupus nephritis, published in English, that
reported any safety or efficacy outcome. Included medications were corticosteroids ([PRED],
cyclophosphamide [CYC], mycophenolate mofetil [MMF], azathioprine [AZA], cyclosporine,
tacrolimus, or rituximab). Belimumab studies could not be included in this systematic review
since these studies included patients with lupus, and only a small proportion had active lupus
nephritis. A Cochrane systematic review of belimumab for lupus is underway.84 There were no
restrictions regarding medication dose or the duration of medication use.
16
Experienced librarians (J.J. and T.R.) updated 2 systematic reviews16,85 from their search
end dates (August 2010 and April 2012, respectively) to September 2013 using the PubMed
database. The search used the following terms:
(Lupus[text word] OR “Lupus Vulgaris”[MeSH] OR “Lupus Erythematosus,
Cutaneous”[MeSH] OR “Lupus Erythematosus, Systemic”[Mesh]) AND (“Kidney
Diseases”[MeSH] OR nephropath*[text word] OR Transplants[MeSH] OR Transplantation[MesH]
OR transplantation[subheading] OR transplant*[text word] OR “Kidney”[Mesh] OR Kidney*[text
word] OR Renal*[text word] OR “End Stage Renal Disease”[text word] OR ESRD[text word] OR
Glomerulonephr*[text word] OR “GN”[text word] OR “crescentic GN”[text word]) NOT
(“animals”[MeSH] NOT “humans”[MeSH]).
Raw data abstracted for the ACR lupus nephritis guidelines systematic review16 were
obtained (courtesy Dr. Jennifer Grossman [J.G.], see acknowledgment section), or were
abstracted from the Revman tables of the Cochrane Systematic Review.85 A librarian (C.H.) also
performed a search for all lupus trials for harms (for conditions other than lupus nephritis) in
PubMed and SCOPUS from inception to February 2014, based on an a priori assumption that
treatment-related harms may not depend on whether kidney is involved. Examination of data
from this search revealed little additive data for harms, but added clinical heterogeneity related
to differences in patient population. Therefore, after careful consideration of pros and cons, we
decided not to use these data in analyses.
We defined the PICO (patient, intervention, comparator, outcome) for our systematic
review and NMA as follows:
P: Adults 18 years or older, meeting the 1987 American College of Rheumatology
Classification criteria for systemic lupus erythematosus,86 who have lupus nephritis.
I: Immunosuppressant drug alone or in combination with other immunosuppressant
drugs or biologics (such as rituximab) or corticosteroids. We categorized medication
doses as low dose (LD), standard dose (SD), or high dose (HD).
C: Placebo or another immunosuppressive with or without biologic.
O: Benefit and harm outcomes (renal remission/response, renal relapse/flare, fertility,
bone marrow suppression), defined as follows.
17
We assessed benefits based on 2 composite outcomes: (1) renal remission/response
(indicating success of therapy), including complete renal remission,27 partial renal
remission,87,88 and renal response; and (2) renal relapse/flare (indicating failure of therapy),
including renal relapse89 and renal flare. We assessed harms based on 2 composite outcomes:
(1) ovarian failure/amenorrhea, including ovarian failure and amenorrhea; and (2) bone
marrow toxicity (cytopenia), including leucopenia.
Two trained abstractors (A.O, A.B) independently reviewed abstracts and titles,
abstracted data in duplicate directly into Microsoft Excel sheets, and assessed the risk of bias
according to the Cochrane risk of bias tool.90 We examined the following domains as low or
high risk of bias or unclear risk (lack of information or uncertainty about potential for bias):
randomization sequence generation, allocation sequence concealment, blinding of participants,
personnel and outcome assessors, incomplete outcome data (primary outcome data reporting,
dropout rates and reasons for withdrawal, appropriate imputation of missing data, an overall
completion rate ≥ 80%), and selective outcome reporting and other potential threats to validity
(considering external validity, e.g., relevant use of cointerventions, bias due to funding source).
An adjudicator (J.S.) resolved any disagreements not resolved by consensus. An expert
rheumatologist (J.S.) and an expert in lupus (J.G.) examined for similarity of studies prior to
performing evidence synthesis by the examination of similarity of study population and
interventions.
We designated doses as follows: (1) CYC: SD: 0.5 through 1.0 gm/m2 intravenously (IV) q
month for 6 to 12 months or 2 through 2.5 mg/kg orally (PO) daily over 3 to 6 months; HD: dose
higher or duration longer than SD; LD: dose lower or duration shorter than SD, including the
EURO-lupus dose, 500 mg IV q 14 days for 6 doses (mean 3 g); (2) AZA: SD: 1 to 3 mg/kg PO
daily; HD: > 3 mg/kg PO daily; (3) LEF: 1 mg/kg PO qd for 3 d then 30 mg PO qd for 6 months;
and (4) PRED: SD: prednisone/methylprednisolone 1 gm/m2 IV q month for 6 months or
prednisone 60 mg PO qd 1 to 3 months then tapered over 3 to 12 months as tolerated; HD:
prednisone/methylprednisolone 1gm/m2 qd IV 3 times, then 1 dose q month for 1 year or
18
prednisone 1mg/kg daily for 4 to 8 weeks (or unspecified period). When dose is not specified,
medication dose is the standard dose.
We used Bayesian mixed treatment comparison (MTC) meta-analyses75-77 to assess the
comparative effectiveness of one immunosuppressive drug versus another and
immunosuppressive drugs versus corticosteroids. We conducted a Bayesian MTC meta-analysis
using a binomial likelihood model using WinBUGS software (Cambridge, UK: MRC Biostatistics
Unit), which allows inclusion of data from multiarm trials.91,92 We conducted random-effects
NMA and assessed model fit and the choice of model (random versus fixed effects) based on
the assessment of the deviance information criterion and the comparison of residual deviance
to the number of unconstrained data points.91,93
We assigned vague priors, such as N (0, 1002) for basic parameters throughout91 and
informative priors for the variance parameter based on Turner et al.94 We evaluated the model
diagnostics including trace plots and the Brooks-Gelman-Rubin statistic to ensure model
convergence.91,95 We fit 3 chains in WinBUGS for each analysis, with 40 000 iterations, and a
burn-in of 40 000 iterations.95,96 Both MTC and traditional meta-analysis require studies to be
sufficiently similar in order to pool their results. We investigated heterogeneity, where
warranted, with subgroup analyses and meta-regressions.92,97 We examined consistency–
inconsistency plots for evidence of inconsistency, and chose the appropriate model for our
analyses. We obtained point estimates using odds ratios (ORs) and 95% credible intervals (CrI)
using Markov Chain Monte Carlo methods. We conducted transformation of the OR to relative
risk and risk difference to allow ease of interpretation for clinicians and patients. We assessed
the quality of evidence as recommended in a recent study.98
We performed sensitivity analysis by limiting analyses to partial/complete remission
rather than combining this with renal response for the composite renal remission/response. We
constructed staircase diagrams, another pictorial way to visualize comparisons of various
treatments against each other. We constructed rankograms to model the probabilities of the
treatment rankings, representing the best to the worst ranks.
Study Intervention Content Finalization and Pilot Testing
19
We performed iterative testing of the decision aid content. Examples from various
sections of the decision aid are provided in Figures 1 through 6. The decision aid for each
scenario provided information about lupus in general and how lupus affects kidneys, general
information about the medication (medication formulation, route of administration, costs of
medication, dosage), information about comparative risks and benefits about the 2
immunosuppressive drugs being compared, a final summary of the information provided, and
information on patient resources and patient support groups. The decision aid also provided 3
optional modules: benefits and side effects of using glucocorticoids, lupus and pregnancy, and
lupus and breast-feeding. We ensured the cultural sensitivity of the tool by developing the
content and the structure of the tool based on our qualitative work with predominantly African
American and Hispanic women (English- and Spanish-speaking) with lupus nephritis (but also
white and Asian women)21,22,79; pilot-testing both English- and Spanish-language versions in this
target group; making the decision aid understandable to people with low literacy, numeracy,
and graphical literacy; and keeping the decision aid at a sixth- to eight-grade reading level. The
control intervention consisted of the American College of Rheumatology pamphlet with
information about lupus, lupus nephritis, and its treatment.
20
Figure 1. Screen Shot of Lupus Nephritis Decision Aid: Introduction Section
21
Figure 2. Screen Shot of Lupus Nephritis Decision Aid: Example of Comparison of a Benefit (Prevention of Kidney Failure) of Treatment Choices
22
Figure 3. Screen Shot of Lupus Nephritis Decision Aid: Example of Comparison of a Harm/Toxicity (Shingles) Related to the Treatment Choices for Lupus Nephritis
23
Figure 4. Screen Shot of Lupus Nephritis Decision Aid: Example of Potential Concerns Related to the Use of Immunosuppressive Drugs During Pregnancy
24
Figure 5. Screen Shot of Lupus Nephritis Decision Aid: Example of Other Concerns Related to Medications Based on Qualitative Work With Patients With Lupus Nephritis
25
Figure 6. Screen Shot of Lupus Nephritis Decision Aid: An Example of a Summary Slide
26
Study Design, Population, and Setting: Randomized Trial
This was a multicenter, parallel 2-arm, prospective randomized trial comparing an
individualized computerized decision aid tool to an educational pamphlet (usual care). A
published study protocol provides details.78 Patients with lupus nephritis attending
rheumatology or nephrology clinics at the 4 sites (UAB, UCSF, OSU, and Baylor College of
Medicine) were recruited over 2 years starting in January 2015. Each site has a weekly lupus
clinic and has been actively engaged in lupus research. A multisite study conducted with
geographically diverse centers ensured the representativeness of the study population and the
generalizability of our study findings. The PIs of each lupus clinic were our study
coinvestigators, who helped us develop the recruitment and retention plan, with a focus on
racial and ethnic minorities. We developed our intervention and all assessment forms in both
English and Spanish and included experienced translators as coinvestigators. Study coordinators
at each site were bilingual and/or nonwhite or had extensive experience with recruiting
minorities in studies. A list with hospital clinic appointments of lupus patients, their gender, and
their race/ethnicity was generated each month using the International Classification of
Diseases, code 710.0. We screened this list on a weekly basis to identify potentially eligible
individuals, and then discussed potential study eligibility of the individuals with their lupus care
provider before their visit. Study inclusion criteria were (1) adult women (≥ 18 years) of any
race/ethnicity with lupus nephritis and (2) currently having a flare of lupus nephritis and
considering a change or initiation of an immunosuppressive medication (current flare; including
new incident lupus cases) or patients with a history of lupus nephritis and at risk for a future
lupus nephritis flare (future flare). Exclusion criteria were (1) men, (2) lupus but no nephritis, (3)
current lupus nephritis flare but medication change not considered, (4) end-stage renal disease
on dialysis, and (5) renal transplant or candidate for a renal transplant. Patients were recruited
at the time of their regular clinic visits. All primary and secondary outcome assessments were
patient reported and completed during the baseline visit, to eliminate the burden of additional
study visits. Patients were provided a check for $70 for completing the baseline study
procedures, which usually took 45 to 90 minutes.
27
Randomized Trial Study Intervention
The randomized trial compared the decision aid in English or Spanish against an ACR
pamphlet in this 2-arm trial.
Arm 1, Study Arm: Individualized computerized decision aid for immunosuppressive
drugs for lupus nephritis (for the 4 most common scenarios, i.e., immunosuppressive drug
choice decision points: mycophenolate mofetil versus cyclophosphamide for induction therapy
or the 3 maintenance therapy scenarios; see background section), developed specifically for
this study, with a focus on racial/ethnic minorities from a diverse socioeconomic background.
Patients randomized to the intervention group viewed the tool on a tablet computer. Patients
were prompted to write down questions for their physicians about their treatment choices. The
computerized decision aid was programmed once a scenario was chosen by the coordinator per
the guidance of the referring physician based on the most likely 2 choices (or a provider in the
future); the decision aid shows only that comparison. Therefore, individualization of this web-
based touchscreen tool was achieved at multiple levels by (1) allowing subjects to stop, go back,
and review the presentation, depending on their understanding of the decision aid content; (2)
providing optional links to the management of the adverse effects of medications; (3) providing
3 optional sections, 1 each on glucocorticoids, pregnancy, and lactation, to be viewed based on
its relevance; and (4) making selection of 1 of the 4 treatment scenarios by the physician, based
on individual patient treatment choices for lupus nephritis, each of which provided a different
sets of comparisons.
Arm 2, Control Arm: The control intervention was an ACR pamphlet with information
about lupus, lupus nephritis, and its treatment.99
Baseline and Follow-up Study Visits
After obtaining written informed consent and the physician’s designation of the
treatment scenario, patients were randomized to either the decision aid or the pamphlet group
in a 1:1 ratio (stratified by study site and language) using the Research Electronic Data Capture
tool.100 Baseline assessments were then administered including the Rapid Estimate of Adult
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Literacy in Medicine–Short Form,101 the Short Assessment of Health Literacy,102 measures of
graphical and numeric literacy, and the measures of primary outcomes including the Decisional
Conflict Scale103 and informed choice (details in the section on outcome measures below;
knowledge, patient values, and choice of the immunosuppressive drug for lupus
nephritis).104,105 Questionnaires were modified slightly for patients with future lupus nephritis
flare, who were asked to answer questions thinking about a future flare and a decision at that
point in time. After the completion of the preintervention assessment, the intervention was
administered. This was followed by an audiotaped conversation between patients and
physicians (secondary outcome) for patients with current lupus nephritis flares only, who
agreed to recording of the conversation. The postintervention questionnaire measured
coprimary outcomes (decisional conflict and informed choice) and 2 secondary outcomes (i.e.,
the control preference scale106-108 and Interpersonal Process of Care–Short Form) for all
patients.109
We kept follow-up assessments to a minimum due to the nature of the study and to
minimize missing data. At 3 months, study subjects responded again to the IPC-SF
questionnaire either during a routine clinic visit or via phone (if no clinic visit), or via mail (if not
reachable via phone and not seen in the clinic). This was the only study assessment after the
initial visit. The study coordinator extracted laboratory, medication, and other clinical data on
exploratory outcomes (cumulative glucocorticoid dose, serum creatinine, spot
protein/creatinine ratios, renal remission, and missed appointments) at 6 months using
Electronic Health Record (EHR) clinical care data at each study site for patients currently
experiencing lupus nephritis flare.
Outcome Measures
Coprimary Outcome Measures
Decisional Conflict Scale (DCS), low literacy version: The DCS is a patient self-
administered, validated measure of decisional conflict, most commonly used as the primary
outcome in RCTs of decision aids.110,111 The low literacy version consists of 10 items with 3
29
response categories (yes, unsure, no) with overall scores ranging from 0 (no decisional conflict)
to 100 (extreme decisional conflict), available in English and Spanish.112 We scored responses as
yes = 0; unsure = 2; no = 4. We summed 10 items and multiplied them by 2.5 to provide a score
ranging from 0 to 100. Decisional conflict represents a state of uncertainty about a choice or
course of action and is more likely in situations involving high-stakes choices with important
potential gains and losses, value tradeoffs in choosing one selection or one course of action
(versus the alternative), or uncertain outcomes. We chose the DCS scale based on our
intervention and the formative work showing significant doubts and decisional conflict
regarding immunosuppressive drugs in lupus patients.
Informed choice: We assessed informed choice by using a validated multidimensional
model of informed choice104,105 that individually assesses and then combines 3 constructs:
values regarding immunosuppressive drugs, knowledge about immunosuppressive drugs, and
treatment choices. We assessed informed choice after each patient had viewed the decision aid
or the ACR pamphlet at the baseline study visit before any treatment decision making. We
assessed values with a list consisting of patients’ views regarding immunosuppressive drugs as a
treatment option and their side effects generated by our study team based on patient concerns
regarding immunosuppressive drugs. The values statements consisted of both positive and
negative values about immunosuppressive drugs, mixed in a random order, with responses
ranging from strongly disagree to strongly agree. We scored positive and negative value
statements with appropriate signs (+ or –) and aggregated this into a total score. A higher total
score indicated more positive values regarding using immunosuppressive drugs, and we used a
median score to classify values as positive versus negative regarding using immunosuppressive
drugs. We assessed knowledge related to immunosuppressive drugs for lupus nephritis using 20
questions. We considered patients to have adequate knowledge if they answered at least 75%
of questions correctly. We assessed choice based on response to a single item on a nominal
scale with anchors of “start vs. don’t start immunosuppressives” and “uncertain” in the middle
and 15 circles, asking each patient’s choice in response to the question, “If your doctor asked
you right now to make a choice about immunosuppressives, please show where you would be
on the scale below by choosing a circle below.” Informed choice referred to a choice that is
30
based on accurate knowledge and is concordant with one’s values. A higher proportion of
patients with an informed choice is optimal. Table 1 provides details for this outcome. We
performed a sensitivity analysis for informed choice by reclassifying subjects according to net
score (positive or negative) on value statements, comparing value statements favorable toward
immunosuppressives with those not favorable, rather than the median score; we classified
those with a net positive score as favoring immunosuppressives and those with a net negative
score as against immunosuppressives.
Table 1. Classification Criteria for Informed Choice Willing to Take Immunosuppressive Drugs Not Willing to Take Immunosuppressive
Drugs Values Values Knowledge Favor
immunosuppressives Against immunosuppressives
Favor immunosuppressives
Against immunosuppressives
Adequate Informed choice - - Informed choice Not adequate
- - - -
- Represents a choice that was not informed; subjects who did not make a decision were considered to be in a the “not informed choice” group
Secondary Outcome Measures
Control preferences scale: This validated measure assessed patient participation in
decision making for only those patients with a current flare. The scale assessed how much
decision-making control a patient would like to have versus control actually experienced by
each patient. It distinguishes between those who feel involved in the decision versus those who
do not.106-108 The measure included 5 responses corresponding to 5 control options: active,
active shared, collaborative, passive shared, and passive. We categorized these roles as active
(combining active and active shared), collaborative, or passive (combining passive and passive
shared).113-115 We examined the concordance between the desired and the actual role played
by each patient with a current lupus nephritis flare.
Patient–physician communication and care processes: We used the IPC-SF, an 18-item
validated patient-reported measure of patient–physician communication and care processes,
31
available in English and Spanish.109,116-119 The IPC-SF score ranges from 18 (worst) to 90 (best);
higher scores represent better patient–physician communication and care processes.
Analysis of an audiotaped physician–patient interaction: For the current flare patients
only, we recorded the patient–physician discussion about immunosuppressives and used the
Active Patient Participation Coding Scheme, a validated instrument, to assess indicators and
facilitators of patient participation.120 We coded 3 types of speech acts (question asking,
assertive responses, and expressions of concern) as active patient participation, because they
may influence a doctor’s behavior as well as the content and structure of the consultation.121-124
We coded physician communication using speech acts such as supportive talk and partnership
building. We summed these units (range 0 to infinity) for each interaction to create a frequency
for the degree of active participation.
Acceptability and feasibility of the decision aid: We assessed information quality and
quantity, presentation style, and usefulness of the decision aid using a validated acceptability
survey62 on a 4-point scale ranging from excellent to poor. We assessed feasibility of the
decision aid versus the pamphlet and the study procedures with a self-administered
questionnaire.125 Patients rated the feasibility of the decision aid versus the pamphlet by
responding to the statement “the education guide was easy to use” on a 5-point Likert scale
(strongly agree to strongly disagree).
Clinically meaningful difference: We considered a 10% difference between study arms in
the proportion of patients achieving a favorable or unfavorable outcome as clinically
meaningful. We designated a 5% difference in proportions as “possibly” clinically meaningful.
Statistical Analyses
Sample size calculation: Our study had an 80% power to assess the treatment effect for
the coprimary outcomes, with an estimated enrollment of 200 patients, after allowing for a
10% loss to follow-up. We anticipated that 100 African American and 100 Hispanic/Caucasian
women with lupus nephritis should be enrolled. We anticipated the ability to detect a medium
effect size difference (effect size = difference between 2 means/standard deviation of the data;
according to Cohen small, medium, and large effect sizes correspond to 0.2, 0.5, and 0.8,
32
respectively126) between group means on decisional conflict (range 0-100) using a 2-sample t
test and 2-tailed type 1 error rate of 0.05 (hypothesis 1)112,127 and a 15% absolute difference in
the proportion of patients with informed choice using a 1-sided type 1 error rate of 0.05
(hypothesis 2).128
Analysis of outcomes measures: We compared baseline characteristics including
demographic variables between the decision aid and pamphlet groups. We compared primary
and secondary outcome measures using student t test or analysis of variance or comparison of
proportions. For continuous measures, we checked the normality assumption using normal
probability plots; for any measures that showed possible departures from normality, we used
the Wilcoxon rank sum test (a nonparametric test) to verify results. No conclusions differed by
method (parametric versus nonparametric test). Therefore, we report the results of the
parametric tests for easy interpretation of the study results. We performed sensitivity analysis
for informed choice by reclassifying subjects according to net score (positive or negative) on
value statements, instead of the median, comparing value statements favorable toward
immunosuppressives with those not favorable. We considered a 2-sided P value < 0.05
significant. We stratified variables based on language (English or Spanish) and study site and
compared them using a chi-square test or Fisher’s exact test. We conducted all statistical
analyses conducted using SAS, Version 9.4 ([computer program] Cary, NC).
Conduct of the Study
We made the following major protocol amendments due to a recruitment shortfall: (1)
We added 2 additional sites, Baylor University and Ohio State University, to allow us to reach
our target goal; (2) we enrolled patients with current flare or at risk of future flare, since the
total number of patients making treatment decisions for a current flare only was fewer than
estimated; and (3) we enrolled Caucasian and Asian women to increase the generalizability of
the study findings and potentially make this decision aid relevant to all women with lupus
nephritis.
33
Results
We conducted a systematic review, meta-analysis, and NMA to assess the comparative
efficacy and harms of immunosuppressive drugs (Aim 1); performed a nominal group technique
with primarily minority women with lupus nephritis to prioritize barriers and facilitators to
immunosuppressive drug decision making (Aim 2); and iteratively modified and finalized our
decision aid by testing it in women with lupus nephritis (Aim 3).
Detailed results of the NMA and systematic review have been published.24-26 This study
provided comparative estimates for benefits and harms of immunosuppressive drugs in lupus
nephritis for our decision aid. We provide a brief summary below. We included 65 RCTs that
met the inclusion and exclusion criteria. Significantly lower risk of end-stage renal disease
(ESRD; 17 studies) was seen with cyclophosphamide (CYC; odds ratio 0.49, 95% credible interval
0.25-0.92) or CYC + azathioprine (AZA; OR 0.18, 95% CrI 0.05-0.57) compared with standard-
dose glucocorticoids, and with high-dose (HD) CYC (OR 0.16, 95% CrI 0.03-0.61) or CYC + AZA
(OR 0.10, 95% CrI 0.03-0.34) compared with high-dose glucocorticoids. High-dose
glucocorticoids were associated with higher risk of ESRD compared with CYC (OR 3.59, 95% CrI
1.30-9.86), AZA (OR 2.93, 95% CrI 1.08-8.10), or mycophenolate mofetil (MMF; OR 7.05, 95% CrI
1.66-31.91).26 No differences were noted between medications for the risk of malignancy (15
studies). The risk of herpes zoster versus glucocorticoids (17 studies) was as follows, OR (95%
CrI): MMF, 4.38 (1.02-23.87); CYC, 6.64 (1.97-25.71); tacrolimus [TAC], 9.11 (1.13-70.99); and
CYC + AZA, 8.46 (1.99-43.61). We concluded that renal benefits and the risk of herpes zoster
were higher for immunosuppressive drugs versus glucocorticoids. In another systematic review,
we compared the risk of serious infections with various drugs in lupus nephritis (32 RCTs with
2611 patients provided data). Tacrolimus was associated with significantly lower risk of serious
infections compared with glucocorticoids, CYC, MMF, and AZA, with odds ratios (95% CrI) of
0.33 (0.12-0.88), 0.37 (0.15-0.87), 0.34 (0.18-0.81), and 0.32 (0.12-0.81), respectively.25 We also
found that MMF treatment followed by AZA (MMF-AZA sequential treatment) was associated
with significantly lower risk of serious infections compared with CYC LD, CYC HD, CYC-AZA, or
HD glucocorticoids, with odds ratios (95% CrI) of 0.09 (0.01-0.76), 0.07 (0.01-0.54), 0.14 (0.02-
0.71), and 0.03 (0.00-0.56), respectively. Sensitivity analyses confirmed these findings. We
34
concluded that tacrolimus and MMF-AZA combination each were associated with a lower risk of
serious infections compared with other immunosuppressive drugs or glucocorticoids for lupus
nephritis. In another analysis, we assessed the rates of renal remission/response (37 trials; 2697
patients), renal relapse/flare (13 studies; 1108 patients), amenorrhea/ovarian failure (8 trials;
839 patients), and cytopenia with immunosuppressive drugs (16 trials; 2257 patients). CYC LD
and CYC HD were less likely than MMF-AZA, CYC LD, CYC HD, and plasmapheresis less likely
than cyclosporine to achieve renal remission/response.24 TAC was more likely than CYC LD to
achieve renal remission/response. MMF and CYC were associated with lower odds of renal
relapse/flare compared with glucocorticoids and MMF was associated with a lower rate of renal
relapse/flare than AZA. CYC was more likely than MMF and glucocorticoids to be associated
with amenorrhea/ovarian failure. Compared with MMF, CYC, AZA, CYC LD, and CYC HD were
associated with a higher risk of cytopenia. We used these estimates in the decision aid tool to
depict the comparative benefits and harms of various immunosuppressive medications, as
applicable to a given comparison/scenario for induction or maintenance therapy.
We incorporated themes generated from NGTs into our decision aid. Since we recruited
a similar target patient population for the NGT as we aimed for in the trial (racially/ethnically
diverse with diverse socioeconomic status and literacy level), themes and content generated
were culturally appropriate. An NGT expert moderated 8 patient group meetings at
Birmingham and San Francisco, in which 52 women with lupus nephritis participated (27 African
American, 13 Hispanic, and 12 Caucasian). The average age was 40.6 years (standard deviation
(SD) = 13.3), and the mean disease duration was 11.8 years (SD = 8.3); 36.5% had at least some
college education, and 55.8% had difficulty in reading health materials (Aim 1).
Detailed results of the NGT have been published.21-23 Briefly, participants (n = 52)
responded to the question “What sorts of things make it easier for people to decide to take the
medicines that doctors prescribe for treating their lupus kidney disease?” and generated 280
decision-making facilitators.22 Of these, 102 (36%) facilitators were perceived by patients as
having relatively more influence in decision-making processes than others. Prioritized
facilitators included effective patient–physician communication regarding benefits and harms,
patient desire to live a normal life and improve quality of life, patient concern for their
35
dependents, experiencing benefits and few/infrequent/no harms with lupus medications, and
medication affordability (Aim 2). In a similar NGT (n = 51), participants with lupus nephritis
responded to the question “What sorts of things make it hard for people to decide to take the
medicines that doctors prescribe for treating their lupus kidney disease?”23 The most salient
perceived barriers were known/anticipated side effects (15.6%), medication expense/ability to
afford medications (8.2%), and the fear that the medication could cause other diseases (7.8%).
We discussed these barriers in detail and incorporated them into the development of the
decision aid. These barriers and facilitators guided the content of the decision aid. For example,
we included slides on medication cost in the decision aid and focused the content on the key
side effects of these medications identified by patients during the NGT to be most relevant to
women with lupus nephritis. We also focused benefits on relevant aspects (dialysis, patient-
relevant benefits) identified by patients in the NGT, rather than benefits and harms that are
relevant to providers only, such as decreased white cell counts and improvement in laboratory
measures of proteinuria. We also included 3 optional sections, 1 each on glucocorticoids,
pregnancy, and breast-feeding, based on the additional concerns identified from the NGT. After
finalization of our decision aid content, we tested it iteratively in 19 subjects with lupus (mean
age 39 years). We made edits, word substitutions, and corrections as suggested by patients.
Three patients reviewed a pre–pilot test version of the decision aid website for color and the
ease of use. They suggested a change in the background color and the exclusion of a navigation
bar; we made both changes before the finalization of the electronic version of the decision aid
(Aim 3).
We performed a randomized trial of the decision aid versus the pamphlet (Aim 4). In the
section below, we provide results using tables adapted from clinicaltrials.gov as per instructions
including the CONSORT flow chart (Figure 7) and a study flow diagram showing the study
procedures (Figure 8).
36
37
38
Participant Flow Recruitment details Preassignment details Arm/group title Decision aid Pamphlet Total
(not public)
Arm/group description Participants received decision aid tool
Participants received the ACR lupus pamphlet
Period Title: Overall Study Started 153 148 301 Primary research completion 151 147 298 Completed 151 147 298 Not completed 2 1 3 Reason not completed Withdrew consent before
receiving intervention Withdrew consent before receiving intervention
Withdrawal by subject 2 1 3 (Not public) Not completed = 2
Total from all reasons =2 Not completed = 1 Total from all reasons = 1
Baseline Characteristics Arm/Group Title Decision Aid Pamphlet Total Overall Number of Baseline Participants 151 147 298 Age, categorical Measure type: count of participants Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
≤ 18 years 0 0%
0 0%
0 0%
Between 18 and 65 years
148 98.01%
146 99.32%
294 98.66%
≥ 65 years 3 1.99%
1 0.68%
4 1.34%
Age, continuous Mean (full range) Unit of measure: years
Number analyzed
151 participants
147 participants
298 participants
37.1 (19 to 69)
37.6 (19 to 66)
37.3 (19 to 69)
Sex: female, male Measure type: count of participants Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
Female 151 100%
147 100%
298 100%
Male 0 0%
0 0%
0 0%
Race/ethnicity, customized Measure type: number Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
Not answered
2 0 2 Asian
11 9 20
39
Hispanic/Latino
41 37 78 Non-Hispanic black
70 71 141
Non-Hispanic white
20 24 44 Other
7 6 13
Region of enrollment Measure type: number Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
United States
151 147 298 Decisional conflict[1] Mean (standard deviation) Unit of measure: units on a scale
Number analyzed
151 participants
147 participants
298 participants
33.37 (29.55)
37.48 (29.85)
35.4 (29.72)
[1] Measure description: The Decisional Conflict Scale is a patient self-administered, validated measure of decisional conflict—a state of uncertainty about a course of action. Scores range from 0 (no decisional conflict) to 100 (extremely high decisional conflict).
Knowledge about immunosuppressives[1] Measure type: number Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
Adequate knowledge
90 89 179 Inadequate knowledge
61 58 119
[1] Measure description: Patients were asked 20 true/false questions regarding lupus nephritis and immunosuppressive drugs. Patients answering at least 75% of questions correctly were considered to have adequate knowledge about immunosuppressives. Those answering fewer than 75% of questions correctly were considered to have inadequate knowledge.
Preintervention unresolved clinically significant decisional conflict[1] on Decisional Conflict Scale (score ≥ 25) Measure type: count of participants Unit of measure: participants
Number analyzed
151 participants
147 participants
298 participants
Unresolved conflict 85 93 178 Not unresolved conflict 66 54 120 [1]
Measure description: Unresolved conflict on the Decisional Conflict Scale is defined as a score of 25 or more. The Decisional Conflict Scale is a patient self-administered, validated measure of decisional conflict—a state of uncertainty about a course of action. Scores range from 0 (no decisional conflict) to 100 (extremely high decisional conflict).
Of patients, 68 (35 decision aid, 33 pamphlet) had current lupus flare; 107 (52 decision
aid, 55 pamphlet) were newly diagnosed.
40
1. Primary Outcome
Title: Change From Baseline in Decisional Conflict Scale Scores (Reduction)
Description Patient self-administered, validated measure of decisional conflict, most commonly used as the primary outcome in RCTs of decision aids (change score). The score ranges from 0 (no decisional conflict) to 100 (extreme decisional conflict). Decisional conflict represents a state of uncertainty about a choice or course of action and is more likely in situations involving high-stakes choices with important potential gains and losses, value tradeoffs in selecting a choice or a course of action (versus the alternative), or uncertain outcomes.
Time Frame Baseline and after viewing the decision aid or the standard pamphlet on the same visit as the intervention (preferred) but before treatment decision making (usually within 1 week)
Outcome Measure Data
Analysis Population Description All participants who received either the decision aid or pamphlet
Arm/Group Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed
151 147
Mean reduction (standard deviation) Unit of measure: units on a scale
21.80 (30.89) 12.69 (24.41)
Statistical Analysis 1 Statistical analysis overview
Comparison group selection Decision aid, pamphlet comments [Not specified] Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.005 Comments [Not specified] Method t test, 2 sided Comments [Not specified]
The effect size (Cohen’s d) for change in decisional conflict was 0.33. The proportion of
patients with unresolved clinically significant decisional conflict (score ≥ 25) postintervention
was greater in the pamphlet than in the decision aid group—44.2% versus 22.5% (p < 0.001).
Median (IQR) was 10 (45) for the decision aid group and 10 (25) for the pamphlet group.
Sensitivity Analysis: Change in Decisional Conflict Scale scores was almost normally
distributed (see Figure 9). For sensitivity analysis, we used the Wilcoxon rank sum test, a
41
nonparametric test, to compare change in DCS (in case of deviation from a normal distribution).
We found that the decision aid group had a significantly larger change in DCS compared with
the pamphlet group using the Wilcoxon rank sum test (p = 0.04).
Figure 9. Distribution of Change in DCS Scores
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2. Primary Outcome
Title Informed Choice (Validated Instruments for Values Regarding Immunosuppressives, Knowledge About Immunosuppressives, and Treatment Decision Making)
Description
Concordance between values related for or against starting immunosuppressive drugs with patients’ decision on (starting or not starting) immunosuppressive drugs, in those with adequate knowledge about benefits/harms of immunosuppressive drugs, assessed using validated instruments for values regarding immunosuppressive drugs, knowledge about immunosuppressive drugs, and treatment decision making (patient’s decision to start immunosuppressive drug)
Time Frame
After viewing the guide or standard pamphlet on the same visit as the intervention (preferred) but before treatment decision making (usually within 1 week)
Outcome Measure Data
Analysis Population Description All participants who received either the decision aid or the pamphlet
Arm/Group Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed 151 147
Measure type: number Unit of measure: participants
Row Title
Informed choice made 62 46 No informed choice 89 101
Statistical Analysis 1
Statistical analysis overview
Comparison group selection
Decision aid, pamphlet
Comments [Not specified] Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.08 Comments We compared informed choice versus no informed choice
made between the decision aid and the pamphlet groups. Method Chi-square Comments [Not specified]
Sensitivity Analysis: Using an alternate definition for patient values regarding
immunosuppressives (sensitivity analysis), more women in the decision aid group made an
informed choice compared with those in the pamphlet group (50.3% versus 34.7%; p = 0.006).
43
3. Secondary Outcome
Title Control Preferences Scale: Patient Participation in Decision Making Description This scale assessed how much decision-making control patients would like to have
versus what they actually experienced. There are 5 responses for 5 control options: active, active shared, collaborative, passive shared, and passive, which we collapsed into active (active, active shared), collaborative, and passive (passive shared, passive), as previously indicated (and prespecified). We assessed concordance between desired and actual role played by each patient. We present these data for patients with current flare only, since only they were making a decision about the immunosuppressive drugs; patients with past lupus flare were not included in the denominator.
Time Frame After viewing the guide or standard pamphlet on the same visit as the intervention (preferred) but before treatment decision making (usually within 1 week)
Outcome Measure Data
Analysis Population Description Only participants having current lupus nephritis and requiring immunosuppressive
medication change/initiation or participants with newly diagnosed lupus nephritis starting an immunosuppressive medication
Arm/Group Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed 35 33 Measure type: number Unit of measure: participants
Row Title
Concordance between roles 33 28 No concordance between roles 2 5
Statistical Analysis 1
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments We compared concordance between preferred and
actual roles versus no concordance between roles between decision aid and pamphlet.
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.252 Comments [Not specified] Method Chi-square Comments [Not specified]
44
4. Secondary Outcome
Title Patient Physician Communication (Interpersonal Processes of Care [IPC-SF]) Description
This was assessed using the IPC-SF, an 18-item validated patient-reported measure of patient–physician communication and care processes. The score ranges from 18 (worst) to 90 (best) and the scale is a patient-reported measure of patient–physician communication and care processes.
Time Frame
After viewing the guide or standard pamphlet on the same visit as the intervention (preferred) (usually within 1 week)
Outcome Measure Data
Analysis Population Description All participants who received either the decision aid or the pamphlet
Arm/Group Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed 149 147 Mean (standard deviation) Unit of measure: units on a scale
83.64 (7.69) 83.06 (7.28)
Statistical analysis overview Comparison group selection Decision aid, pamphlet
Comments [Not specified] Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis P value 0.504
Comments [Not specified] Method t test, 2-sided Comments [Not specified]
5. Secondary Outcome
Title Analysis of Audiotaped Physician–Patient Interaction (Using the Active Patient Participation Coding Scheme [APPC]): Doctor Patient-centered Communication
Description
We performed this by analyzing the audiorecorded patient–physician discussion in patients with current lupus nephritis flare. The APCC is a validated instrument to measure active patient participation. APCC assesses indicators and facilitators of patient participation. The unit of coding is the utterance, the oral analogue of a sentence. The range is 0 to unlimited. Patient participation is measured by the number of questions, number of concerns expressed, and act of assertiveness (e.g., preferences, introducing topics, making requests). These are active forms of participation because of their influence on clinician behavior and the structure and content of the consultation. The APPC also assesses clinician behaviors that facilitate and support patient participation,
45
partnership building, and supportive talk (e.g., reassurance, empathy). We present patient-centered communication by doctor/health care provider. Higher scores indicate better patient participation and communication.
Time Frame
After viewing the guide or standard pamphlet on the same visit as the intervention (preferred) (usually within 1 week)
Outcome Measure Data
Analysis Population Description Only participants having current lupus nephritis and requiring immunosuppressive
medication change/initiation or participants with newly diagnosed lupus nephritis starting an immunosuppressive medication, who also agreed to an audiorecorded conversation
Arm/Group Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed 16 17 Mean (standard deviation) Unit of measure: units on a scale
5.1 (2.1) 3.7 (1.9)
Statistical analysis overview Comparison group selection Decision aid, pamphlet
Comments [Not specified] Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis P value 0.06
Comments [Not specified] Method t test, 2-sided Comments [Not specified]
Acceptability
Title Acceptability (Number of Participants Rating Each Statement as “Excellent”)
Description We assessed acceptability of the decision aid (information quality and quantity, presentation style, and usefulness) using a validated acceptability survey on a 4-point scale ranging from excellent to poor (response options were excellent, good, fair, and poor). We compared the number of patients rating each of the five statements as excellent (versus other ratings) between the 2 treatment arms.
Time Frame After viewing the guide or standard handout on the same visit as the intervention (preferred) (usually within 1 week)
Outcome Measure Data
Analysis Population Description Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
46
Overall number of participants analyzed
151 147
Measure type: count of participants Unit of measure: participants
Row Title
Impact of lupus nephritis 74 49 Risk factors 64 40 Medication options 76 49 Evidence about medications 71 35 Studies about other patients 64 32
Statistical Analysis 1
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments Statistical analysis comparing the decision aid versus
pamphlet for patient rating of acceptability of information and presentation related to the impact of lupus nephritis
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.006 Comments [Not specified] Method Chi-square Comments [Not specified]
Statistical Analysis 2
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments Statistical analysis comparing the decision aid versus
pamphlet for patient rating of acceptability of information and presentation related to the risk factors
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.006 Comments [Not specified] Method Chi-square Comments [Not specified]
Statistical Analysis 3
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments Statistical analysis comparing the decision aid versus
pamphlet for patient rating of acceptability of
47
information and presentation related to the medication options
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.003 Comments [Not specified] Method Chi-square Comments [Not specified]
Statistical Analysis 4
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments Statistical analysis comparing the decision aid versus
pamphlet for patient rating of acceptability of information and presentation related to the evidence about medications
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value < 0.001 Comments [Not specified] Method Chi-square Comments [Not specified]
Statistical Analysis 5
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments Statistical analysis comparing the decision aid versus
pamphlet for patient rating of acceptability of information and presentation related to the evidence about other patients
Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value < 0.001 Comments [Not specified] Method Chi-square Comments [Not specified]
Feasibility
Title Feasibility (Number of Participants Rating the Feasibility of Using Decision Aid or Pamphlet—Referred to as Education Guide in This Statement)
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Description We assessed feasibility of the decision aid versus pamphlet using a single statement: “The education guide was easy to use.” Patients rated this on a 5-point ordinal scale ranging from strongly agree to strongly disagree (response options were strongly agree, agree, neither agree nor disagree, disagree, strongly disagree). We compared the number of patients between the 2 treatment arms.
Time frame After viewing the guide or standard handout on the same visit as the intervention (preferred) (usually within 1 week)
Outcome Measure Data
Analysis Population Description One patient from the pamphlet group did not respond to this question; therefore, valid
responses from the pamphlet were 146, not 147. Title Decision Aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
Overall number of participants analyzed
151 147
Measure type: count of participants Unit of measure: participants
Row Title
Strongly disagree 1 3 Disagree 1 13 Neither disagree nor agree 73 74 Agree 75 55 Strongly agree 1 1 Missing 0 1
Statistical Analysis 1
Statistical analysis overview
Comparison group selection Decision aid, pamphlet Comments The test of significance compared all the rows—i.e., all
response options for the statement. Type of statistical test Superiority or other (legacy) Comments [Not specified]
Statistical test of hypothesis
P value 0.006 Comments [Not specified] Method Chi-square Comments [Not specified]
49
Adverse Events Time frame 3 months Adverse event reporting description Source vocabulary name for table [Not specified] Collection approach for table default Nonsystematic assessment Arm/group title Decision aid Pamphlet
Arm/group description Participants received decision aid tool
Participants received the standard ACR pamphlet
All-cause Mortality Decision Aid Pamphlet Affected/at risk
(%)
Affected/at risk (%)
Total 1/151 (0.66%) 1/147 (0.68%)
Serious Adverse Events Decision Aid Pamphlet Affected/at risk
(%) # events
Affected/at risk (%)
# events
Total 1/151 (0.66%) 1/147 (0.68%) Vascular Disorders
Right ventricular failure[1]∗ 1/151 (0.66%) 1 0/147 (0%) 0 Subarachnoid hemorrhage[2]∗ 0/151 (0%) 0 1/147 (0.68%) 1 ∗ Indicates events were collected by nonsystematic methods. [1]
Decision aid: Patient with mitral regurgitation died due to right ventricular failure after cardiovascular operation (Day 53).
[2] Pamphlet: Subarachnoid hemorrhage from posterior circulation aneurysm. Patient died due to central herniation (Day 22).
Other (Not Including Serious) Adverse Events
Frequency threshold for reporting other adverse events
0%
Decision Aid Pamphlet Affected/at risk (%) #
events Affected/at risk (%)
# events
Total 0/151 (0%) 0/147 (0%)
6-month Outcomes (Exploratory)
We were unable to analyze any exploratory outcome in a meaningful way, due to the
sporadic availability and heterogeneity of these outcomes (laboratory values, medication use
data, etc.). This was related to the differences in clinical protocols, follow-up visit times, and the
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EHR systems, a passive data collection across each site as per clinical follow-up, and the
limitation of most exploratory outcomes to patients with current flares only.
Subgroup Analyses
Table. Subgroup Analyses of Outcomes by Race/Ethnicity Postintervention
Decision Aid Mean (SD) or n (%)
Postintervention Pamphlet Mean (SD) or n (%) P Value
Change in DCS Score
Non-Hispanic black (n = 141) 25.52 (3.71) 16.99 (3.18) < 0.001
Hispanic/Latino (n = 78) 13.5 (4.29) 6.76 (3.99) 0.07 Non-Hispanic white (n = 44) 30.25 (8.6) 12.29 (3.85) 0.002
Asian/other (n = 33) 19.17 (6.34) 7.44 (4.61) 0.05
Informed Choice
Non-Hispanic black 28 (40%) 20 (28.2%) 0.22
Hispanic/Latino 14 (35%) 12 (32.4%) 0.61
Non-Hispanic white 14 (70%) 5 (20.8%) 0.003
Asian/other 6 (33.3%) 9 (60%) 0.62
t test or chi-square test, as appropriate.
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Discussion
Context for Study Result
We found that an individualized, culturally tailored, computerized patient decision aid
improved decision making related to using immunosuppressive drugs in women with lupus
nephritis. Specifically, compared with viewing a standard ACR lupus information pamphlet,
women with lupus nephritis who viewed our computerized patient decision aid had a clinically
meaningful and statistically significant reduction in decisional conflict. Women with lupus
nephritis also had clinically meaningfully higher informed choice (41% versus 31%, a 10%
difference in proportions between arms) that was statistically nonsignificant (p = 0.08) in the
main analysis, and statistically significant and clinically meaningful in sensitivity analyses (50%
versus 35%; p = 0.006). There were no significant differences in the 2 secondary outcomes of
control preferences scale (concordance between desired role and actual role in decision
making) and IPC-SF, a patient-reported measure of patient–physician communication and care
processes. Patient-centered communication by the doctor/health care provider had a statistical
trend toward significance in the decision aid versus the pamphlet group in audiotaped
conversations with patients with current flare of lupus nephritis (p = 0.06). We also found that
the proportion of women with unresolved clinically significant conflict postintervention (score ≥
25) was statistically significantly lower in the decision aid group compared with the pamphlet
group—22.5% versus 44.2% (p < 0.001). When we examined coprimary outcomes by
race/ethnicity (subgroup analyses), we found that improvements in decisional conflict were
clinically meaningfully and statistically significantly higher in African Americans and Caucasian
women, and clinically meaningful with a nonsignificant statistical trend in Hispanic and
Asian/other women (small sample sizes; p = 0.075 and p = 0.053, respectively). Informed choice
did not show differences by race/ethnicity and was statistically not significant in this subgroup
analysis, likely related to small sample size.
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Comparison With Other Published Studies
A literature search with terms “decision aid” and “lupus or SLE” on January 28, 2017,
revealed 103 titles in PubMed. We found no studies that tested a decision aid in patients with
lupus nephritis, but found one related study.129 The authors of this related study tested the
validity and reliability of a decision board for lupus nephritis in 172 Brazilian lupus patients, 75%
of whom had taken or were taking some immunosuppressive drug.129 The decision board
consisted of 5 parts, each presented during different times in the patient clinic visit, including
general information related to lupus and lupus nephritis, information on 2 therapies
(cyclophosphamide and mycophenolate mofetil), most common side effects, patient
prioritization of the 3 worst side effects, and probability of each of the 3 side effects with
treatment options. The decision board was valid and reliable. Most patients easily understood
the content of the decision board. Patients with a higher education level showed a better
understanding. Patients favored oral medications and were most worried about cancer, hair
loss, and infections.129 The authors set a goal to “develop a decision-aid that will help clinicians
communicate.” We were unable to find any subsequently published studies of the development
or testing of a decision aid.
In the absence of published studies of decision aids in patients with lupus nephritis, we
examined relevant indirect evidence regarding other interventions used for medication
adherence (a related concept to medication decision making that we studied) in patients with
lupus and similar decision aid studies in other rheumatic conditions. For example, in a
randomized study of 50 lupus patients in India that excluded patients with “advanced” lupus
nephritis (“advanced” not defined in the article), patients were randomized to 3 counseling
sessions by the pharmacist and given a handout developed to improve patient knowledge
versus a single physician-led session at the second follow-up visit (control group).130 Medical
knowledge (p < 0.001) and the adherence to medication score (only 18% on
immunosuppressive drugs; P value not provided) improved significantly more in the group that
received the pharmacist counseling sessions with a handout versus the control group, although
only means were provided without standard errors or standard deviations.130 Study limitations
were that the results were described inadequately, it was a single-center study, a low
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proportion of patients were on immunosuppressives, and patients with advanced lupus
nephritis were excluded. A direct comparison to our study results is difficult, given the nature of
the intervention, study outcomes, country setting, and the type of patients. However, this study
provided some evidence that patient-centered education and counseling may improve lupus
outcomes.130
In another study, 41 patients with childhood-onset lupus were randomized in a 1:1 ratio
to receive text messages to improve their adherence to hydroxychloroquine. This study used
daily text messages before each patient’s scheduled time of medication intake to remind him or
her to take the medication (n = 19) or daily text messages to provide standard of care education
about hydroxychloroquine (n = 22).131 No significant difference in hydroxychloroquine
adherence was noted between groups (80% in each group). Our study was focused on
immunosuppressives, not hydroxychloroquine, and on medication decision making rather than
on medication adherence.
A recent systematic review of medication adherence in rheumatic conditions concluded
that interventions that were tailored to patients, delivered by the health care provider, and
directed at adherence were most likely to improve medication adherence outcomes.132 This
principle is consistent with the International Patient Decision Aid Standard (IPDAS) for the
development of effective decision aids,133 which we followed for the development of our lupus
nephritis decision aid. Tailoring to patients and using content that is easily understood by the
target population likely explains the higher efficacy of our decision aid compared with an
information pamphlet.
Implications of These Findings
We developed our decision aid intervention as a patient-focused intervention based on
IPDAS principles.133 We included benefit and harm data from a state-of-the-art NMA,69-71 and
based the content and messages of our lupus nephritis decision aid on the qualitative work with
patients with lupus nephritis similar to our target population.21-23 This information was
iteratively modified and finalized by constructive feedback from patients with lupus nephritis
who were similar to our target population. This study provides the proof that our individualized,
54
culturally tailored, computerized patient decision aid for medication decision making improved
decision making for immunosuppressive drugs in patients with lupus nephritis by reducing
decisional conflict. Patients were also more likely to make an informed choice using the
decision aid—41% versus 31%, a clinically meaningful difference that was statistically
nonsignificant (p = 0.08) for the main analysis. We used a 2-tailed analysis as a conservative
approach, but when viewed through the lens of a superiority perspective (as stated in our
original protocol78; also see the statistical analysis section above), a P value of 0.04 would be
the result. Thus, the effect for informed choice was alternatively statistically significant or
nonsignificant depending on whether a 1-sided or 2-sided test was used for the main analysis.
More important, the size of the effect (i.e., a 10% difference clinically in the proportion of
patients with favorable outcome is important simply because 10% more people are getting
help, and it is likely to impact clinical practice. Ultimately, the decision regarding the veracity of
the results will come with further review and perhaps more data. A statistically significantly
higher proportion of patients had informed choice in the sensitivity analysis, which was also
clinically meaningful (50% versus 35%; p = 0.006). Compared with the usual care group that
received the ACR lupus pamphlet, the decision aid group had higher knowledge scores
postintervention, which may be a mediator of the reduced decisional conflict.
To our knowledge, this is the first RCT of a patient-centered intervention for medication
decision making in lupus nephritis. Our finding that an individualized, computerized lupus
nephritis decision aid reduced decisional conflict related to immunosuppressive drugs and
possibly improved informed choice advances this field. We will make this decision aid available
in the public domain, as per instructions from the funder, PCORI. We plan to achieve this in
collaboration with our stakeholders, the Lupus Foundation of America and the Arthritis
Foundation.
The development of a lupus nephritis decision aid should help patients and providers
alike, since lupus nephritis is the most common manifestation of lupus,4,5 and has associated
morbidity of end-stage renal disease, in the United States.6 In addition, the rate of
immunosuppressive drug use by patients with lupus nephritis is low in the United States, at
34% in the Medicaid patient population.60 While we did not measure whether the use of a
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decision aid can improve adherence to immunosuppressive drugs, this can be addressed with
future research and tested in clinical settings. The decision aid will need careful modification to
focus it on this related, but separate, domain of inquiry; medication adherence was not the
focus of our investigation.
Generalizability of the Findings
We conducted this study at 4 major academic centers (West Coast, Deep South,
Southwest, and Northeast United States) that provided health care to patients with lupus in
urban and suburban settings. Therefore, our findings may not be generalizable to patients
receiving care in rural settings. While we oversampled for minority women (as lupus is more
common in racial/ethnic minorities, who also have worse outcomes related to the disease), to
improve the generalizability of study results we included all women with lupus nephritis seeking
health care in urban and suburban settings. Additionally, to improve the generalizability of our
decision aid, as well as all study materials, we developed and tested it in both English and
Spanish. The low rate of refusal to participate in this study by eligible patients (i.e., 19 of the
320 patients), inclusion of patients from both outpatient and inpatient settings, inclusion of
geographically diverse sites, and conduct of the research study during a regular scheduled clinic
visit improve the generalizability of our study findings. We did not include in this study patients
with renal transplant, dialysis, or anticipated renal transplant; therefore, our findings are not
generalizable to these patients.
Implementation of Study Results
The decision aid can guide the choice of immunosuppressive medications by women with
lupus nephritis for shared decision making about immunosuppressive drugs for either induction
or maintenance therapy in consultation with their health care provider, in outpatient and
inpatient settings. Our decision aid addresses 4 scenarios when the following drug choices are
considered for the treatment of lupus nephritis:
1. Induction therapy: Mycophenolate mofetil versus cyclophosphamide
2. Maintenance therapy: Mycophenolate mofetil versus cyclophosphamide
56
3. Maintenance therapy: Calcineurin inhibitors such as cyclosporine/tacrolimus versus
cyclophosphamide
4. Maintenance therapy: Cyclophosphamide versus azathioprine
The ideal time to provide this information might be after the lupus diagnosis has been
briefly discussed with the health care provider with the patient during an outpatient visit or
inpatient consultation using a touch-pad computer. Once the patient has reviewed the
information, the patient can ask questions of the health care provider about the information
and make a treatment decision concordant with her values and preferences. Another potential
use of this decision aid is to have patients view the module on corticosteroid benefits and risks
once they start receiving corticosteroids as a concomitant therapy. Young premenopausal
women with lupus nephritis can view the sections on pregnancy and breast-feeding to
understand the risks and benefits of these medications and be guided properly regarding future
planning related to conception.
In order to keep patient burden low and based on the main focus of the study to
develop a decision aid and to assess its efficacy in a randomized trial, we did not include any
qualitative or quantitative evaluation of barriers or facilitators for future implementation of the
decision aid. However, patients frequently shared their positive and negative experiences about
the study, which are summarized below and provide information about future potential
facilitators and barriers to its implementation.
Positive experiences (ie, potential facilitators): Patients shared their positive experiences
about study participation. Most patients told the research team members that the entire
research study process (informed consent, randomization, responding to surveys, follow-ups)
was very easy. They found that the technology used in this research was user-friendly.
Participants also reported that they were motivated to ask questions of their physicians about
treatment options for lupus nephritis and in general about lupus care after viewing this
information, which they were able to do before seeing their provider. Following the conclusion
of the study, we have received requests from patients for copies of the decision aid tool, so that
they can refer to it when they have questions before or after their visits with their attending
57
physicians. Some quotes from patients who were either involved in the development of the
decision aid content and/or pilot testing are as follows:
• “I wish I had this information when I had to make a decision about my lupus. It was
really difficult.”
• “This tool shows me what I want to know.”
• “I can actually understand what this says; sometimes the doctors are trying to tell you
something and you lose them, and get scared.”
• “Every lupus patient should get this tool.”
Negative experiences (ie, potential barriers): A few patients had difficulty navigating the
decision aid, both with using an iPad independently and with the decision aid graphical
representation of harms and benefits. Some patients noticed that it took a long time for them
during the clinic visit to navigate the decision aid. Many patients wondered if having a paper
copy of the decision aid in addition to the iPad version would help them make the best use of
this information.
Subpopulation Considerations
The improvement/reduction in decisional conflict was smaller in the Hispanic/Latino
subgroup and was not statistically significant. The reduction in decisional conflict was
statistically significant and clinically meaningful in all other racial/ethnic subgroups, including
African American, Caucasian, and Asian women with lupus nephritis. This indicated that the
Hispanic/Latino subgroup may not benefit as much from the use of the decision aid as the other
racial/ethnic groups. The magnitude of reduction in decisional conflict was slightly higher in
Caucasian women.
Study Strengths and Limitations
Our study had several strengths. We developed our decision aid based on IPDAS
principles.133 We based our estimates of benefits and risks of immunosuppressive drugs on an
58
updated systematic review, meta-analysis, and NMA.69-71 The design and the content of our
decision aid were based on qualitative work with patients with lupus nephritis similar to our
target population.21-23 We oversampled African Americans and Hispanic women, since
compared with Caucasian women, minority women have a higher prevalence of lupus, higher
lupus severity, and worse outcomes related to lupus, including higher mortality.7,8,14,134 Our
study was a multicenter randomized trial that recruited patients from 4 geographically diverse
medical centers, making our study population representative of female patients with lupus
nephritis in the United States. We developed the decision aid in English and Spanish. Our
decision aid takes just a short time to be viewed and it will be available in the public domain.
This will make the decision aid a practical tool available for use by any adult woman with lupus.
The decision aid can also be further modified to be contextually relevant.
Our study has several limitations. We assessed 2 coprimary outcomes, since they
captured 2 complementary aspects of decision making, related to our individualized decision
aid intervention. We do not know which component of the decision aid was responsible for
efficacy—i.e., the reduction in decisional conflict. Since lupus is a female-predominant disease,
we excluded males; therefore, these study findings cannot be generalized to men. Another
limitation is that, while the decision aid and outcome instruments are available in English and
Spanish, we lack the translation of materials into other languages. Translation can be done in
the future and will make this decision aid even more accessible for lupus patients who speak
and read languages other than English and Spanish. In order to reduce patient burden, we did
not assess patient satisfaction and quality of life in this study. These effects need to be
examined in future studies. It will also be important to see if a similar decision aid will improve
medication adherence. Our study was not designed to assess coprimary outcomes after
patient–physician interaction, or to examine long-term medication adherence, both of which
could have provided additional insights into shared patient decision making and/or medication
adherence. Future studies should consider examining these outcomes. We examined the effect
of the decision aid on outcomes immediately after the visit during which each patient used the
decision aid or control pamphlet. Our study was not designed to assess whether the
information retention was short lived and whether the desired improvement in patients’
59
decisional conflict or informed choice about immunosuppressives remained stable over weeks
or months.
Future Research
In an experimental setting, we found a computerized, patient self-administered lupus
nephritis decision aid was more effective than a standard lupus pamphlet in reducing decisional
conflict and improving informed choice about immunosuppressive drugs. Women with lupus
nephritis who are making treatment decisions related to immunosuppressive drugs currently
and patients who may face such a decision in the future can use this decision aid. Given the
active participation by patients and stakeholders in the research process, including the
development and the testing of this decision aid, we are confident that this tool can now be
disseminated widely to patients with lupus nephritis. While the effectiveness of the decision aid
has been established, a wider dissemination will need further work.
More work is also needed to figure out ways to make this tool accessible to all low-
income, rural, undereducated, and minority patients and caregivers who may have limited or
no access and/or knowledge related to computers. However, 57% of our trial participants had
an annual income < $40 000, 85% were racial/ethnic minorities, and 36% had a high school
education or less, indicating that we succeeded in enrolling underrepresented, disadvantaged,
minority female patients in our trial. However, more work needs to be done to make this tool
accessible to every female lupus patient. Therefore, we plan to target future modifications to
accommodate the elderly and additional underprivileged patient populations. More qualitative
work with study participants, responders, and nonresponders could provide insights for further
improvements to the tool. Such work includes continuing and expanding collaborative efforts
with our partners, the Lupus Foundation of America and the Arthritis Foundation, to
disseminate the decision aid, along with the following: (1) performing implementation research
to understand how to incorporate use of the decision aid into a busy clinical practice workflow;
(2) figuring out how to use social media and patient networks to further disseminate the
decision aid; and (3) developing alternate designs of the decision aid including, but not limited
60
to, smartphone applications for iPhone and Windows platforms. These steps can help ensure
that our decision aid is widely used and proves effective for patients with lupus nephritis. The
goal is to implement it in many more clinics across the United States, including more variations
in the type of practice (private practice versus academic centers), specialty (rheumatology
versus combined rheumatology–nephrology clinics), and location type (urban versus suburban
versus rural). Research is needed to assess barriers to implementation and how to overcome
them in unique settings and to make the use of a decision aid part of standard care of lupus
patients. Research and work are also needed to translate the decision aid into many more
languages. In addition, more work is needed to assess the reasons for lower efficacy of the
decision aid for Hispanic/Latino populations, and ways to improve its efficacy in this subgroup
and possibly other underserved populations.
61
Conclusion
This multicenter randomized study tested an individualized, culturally tailored,
computerized patient decision aid that addressed treatment induction and the failure of
maintenance therapy in patients with a flare of lupus nephritis. The decision aid was superior to
the standard ACR lupus pamphlet for the primary outcome: reducing decisional conflict about
immunosuppressive drugs in women from diverse racial/ethnic and socioeconomic
backgrounds. The lupus nephritis decision aid had higher acceptability and was easier to
understand than the standard ACR lupus pamphlet for patients.
The major strengths of our study were a randomized design as well as the negligible
number of patients without outcome data. The shortcoming was the lack of evidence about
how long the effect of the decision aid persisted. Based on these findings, we conclude that the
decision aid is ready for testing in additional settings and with further follow-up to measure the
persistence of the knowledge gained. This tool, available in English and Spanish, can facilitate
and improve shared decision making for lupus nephritis treatments in clinical practice and
should lead to higher patient satisfaction and engagement. Whether it might improve disease
outcomes remains to be seen.
62
Acknowledgments
We thank Jeffrey Foster, Mazin Khalil, Candace Green, and Diana Florence for proofreading this
report.
63
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Disclaimer:
The [views, statements, opinions] presented in this report are solely the responsibility of the author(s) and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute® (PCORI®), its Board of Governors or Methodology Committee.
Acknowledgement:
Research reported in this report was [partially] funded through a Patient-Centered Outcomes Research Institute® (PCORI®) Award (#CE-1304-6631) Further information available at: https://www.pcori.org/research-results/2013/personalized-decision-aid-help-women-lupus-nephritis-racially-and-ethnically