Multiple Sclerosis and Related Disorders 39 (2020) 101887

Contents lists available at ScienceDirect

Multiple Sclerosis and Related Disorders

journal homepage: www.elsevier.com/locate/msard

Original article

Factors associated with therapeutic inertia among pharmacists caring for T

people with multiple sclerosis
Maria A. Terzaghif, Cedrik Ruizf, Iciar Martínez-Lópezb, Montserrat Pérez-Encinasc,
Fabien Bakdached, Jorge Maurinoe, Gustavo Saposnika,f,g,
⁎

a
Division of Neurology, Department of Medicine, St. Michael's Hospital, University of Toronto, Canada
b
Department of Pharmacy, Hospital Universitari Son Espases, Palma de Mallorca, Balearic Islands, Spain
c
Department of Pharmacy, Hospital Universitario Fundación Alcorcón, Alcorcón, Madrid, Spain
d
Medical Affairs, Neuroscience, Hoffmann-La Roche Limited, Mississauga, Canada
e
Medical Department, Roche Pharma, Madrid, Spain
f
Decision Neuroscience Unit, Li Ka Shing Institute, University of Toronto, Canada
g
Laboratory for Social and Neural Systems Research, Department of Economics, University of Zurich, Switzerland

ARTICLE INFO ABSTRACT

Keywords: Introduction: Pharmacists play a critical role on therapeutic decisions in multiple sclerosis (MS) care.
Multiple sclerosis Therapeutic inertia (TI) is defined as the lack of treatment initiation or escalation when there was evidence of
Pharmacists clinical and radiological disease activity. The aim of this study was to assess factors associated with TI among
Disease-modifying therapy pharmacists involved in MS care.
Decision-making
Methods: A multicenter, non-interventional, cross-sectional study involving hospital pharmacists in Spain was
Inertia
conducted. Participants answered questions regarding their standard practice, risk preferences, and management
of nine simulated MS case-scenarios. We created a score defined as the number of case-scenarios that fit the TI
criteria over the total number of presented cases (score range from 0–6). Similarly, an optimal treatment score
(OTS) was created to determine the degree of appropriate pharmacological decisions (ranging from 0-lowest to
9-highest). Candidate predictors of TI included demographic data, practice setting, years of practice, MS ex-
pertise, number of MS patients managed at hospital/year, participation in MS clinical trials, and participants’
risk preferences.
Results: Overall, 65 pharmacists initiated and completed the study (response rate: 45.5%). The mean age was
43.5 ± 7.8 years and 67.1% were female. Forty-two (64.6%) participants had specialization in MS manage-
ment. Overall, the mean TI score was 3.4 ± 1.1. Of 390 individual responses, 224 (57.4%) met the TI criteria.
All participants failed to recommend treatment escalation in at least one of the six case-scenarios. The mean OTS
was 4.1 ± 1.4. Of 585 individual responses, 264 (45.1%) met the optimal choice criteria. Only 40% of parti-
cipants (23/65) made five or more optimal treatment choices. Lower experience in dispensing MS drugs and lack
of specialization in MS were the most common factors associated with TI and optimal management. The mul-
tivariable analysis revealed that more years of experience (p = 0.03), being a co-author of a peer-reviewed
publication (p = 0.03), and specialization in MS (p = 0.017) were associated with lower TI scores (adjusted
R2 = 0.23).
Conclusion: Therapeutic inertia was observed in all pharmacist participants, affecting over fifty percent of MS
treatment choices. Continuing education and specialization in MS may facilitate therapeutic decisions in MS
care.

1. Introduction
Multiple sclerosis (MS) is one of the most common disabling con-
ditions affecting young adults. In the last decade, over a dozen disease-
modifying therapies (DMT) have been approved by regulatory agencies
with varying routes of administration and different safety and efficacy
profiles (Freedman et al., 2018; Rae-Grant et al., 2018). Escalation is
traditionally the most common therapeutic approach, where a first-line,
moderate-efficacy and safety DMT is started and then switched for more
effective agents (monoclonal antibodies) until evidence of disease

⁎
Corresponding author: St. Michael's Hospital, University of Toronto, 55 Queen St E, Toronto, Ontario, M5C 1R6, Canada.
E-mail address: saposnikg@smh.ca (G. Saposnik).

https://doi.org/10.1016/j.msard.2019.101887
Received 2 September 2019; Received in revised form 1 December 2019; Accepted 7 December 2019
2211-0348/ © 2019 Elsevier B.V. All rights reserved.
M.A. Terzaghi, et al.
progression is observed (Prosperini et al., 2012; Ontaneda et al., 2019).
As a result, health care providers caring for MS patients face more
complex therapeutic decisions when considering individual targets,
including relapses, new brain or spinal cord lesions, brain atrophy, and
cognitive impairment (Ontaneda et al., 2019).
Pharmacists play a key role as decision-makers by facilitating access
and recommending DMT according to the existing drug-policy
(Schultz et al., 2016; Banks et al., 2019). In many countries, approval
by the pharmacist either working in a hospital setting or at the gov-
ernment level is critical given their decisive influence on the trajectory
of care with direct consequences on patients’ outcomes (e.g. suboptimal
therapy or under treatment associated with disease progression)
(O´Connor et al., 2005; Saavedra-Mitjans et al., 2018; Tang et al., 2016;
Ziemssen et al., 2016). Therapeutic Inertia (TI) refers to the absence of
treatment initiation or intensification when therapeutic goals are unmet
(O´Connor et al., 2005; Okonofua et al., 2006). The prevalence of TI in
MS care is associated with several factors including education and ex-
perience with MS therapies (Saposnik et al., 2017; Saposnik and
Montalban, 2018). Interestingly, there is a limited amount of studies
evaluating the therapeutic decisions made by pharmacists.
In the present study, we aimed to evaluate the prevalence of TI and
factors associated with optimal therapeutic choices among pharmacists
caring for MS patients.
2. Methods
We conducted a non-interventional, cross-sectional web-based study
which targeted pharmacists from public hospitals who were actively
involved in therapeutic decisions in MS in Spain from August 24, 2018
to January 30, 2019 (ATTRIBUTE-MS Study). The study was approved
by the Research Ethics Board of Hospital Clínico San Carlos (Madrid,
Spain). Informed consent was obtained from all participants.
Participants answered questions regarding their standard practice,
individual risk-preferences, and the management of nine simulated MS
case-scenarios (n = 585 individual responses). Case-scenarios were
created by a team of MS experts, pharmacists and members with ex-
pertise in regulatory affairs according to the current available best
practice recommendations and drug-policy regulations in Spain
(García-Merino et al., 2017). Case-scenarios included treatment initia-
tion or escalation for participants using first (e.g. beta interferons,
glatiramer acetate) and second-line therapies (e.g. cladribine, fingo-
limod, monoclonal antibodies) with either relapsing remitting or pri-
mary progressive MS (Tramacere et al., 2015; García-Merino et al.,
2017; Montalban et al., 2017).
We also assessed participants’ risk preferences and tolerance to
uncertainty as potential factors that may influence therapeutic deci-
sions as tested in previous studies (Gerrity et al., 1995; Dohmen et al.,
2011; Saposnik et al., 2016; Almusalam et al., 2019). We also evaluated
willingness to take risks and tolerance to uncertainty using two stan-
dardized surveys. The German Socio-Economic Panel (SOEP) is a vali-
dated survey that evaluates willingness to take risks in different do-
mains (financial matters, health, driving, occupation, etc.)
(Dohmen et al., 2011). We used questions of the form: “How would you
rate your willingness to take risks in the following areas…?”. Areas in-
cluded financial matters, driving, occupation, etc. and responses could
range from 0 (completely unwilling) to 10 (completely willing). The second
survey measured tolerance to uncertainty in patient care, using the
reaction to uncertainty test. It includes five questions to be rated from 0
to 5 that when added gives a total score (Okonofua et al., 2006). Low
tolerance to uncertainty was defined as values below the median of the
total score. Further details of the protocol were published elsewhere
(Saposnik et al., 2017).
Finally, we evaluated participants’ agreement with the concept of
shared decision making while presenting advantages (e.g. patients’
participation, accounting for patients’ preferences) and disadvantages
(e.g. biased information, limited understanding) together. Participants
2
Multiple Sclerosis and Related Disorders 39 (2020) 101887
were asked to rate their level of agreement on a scale ranging from 0
(completely disagree) to 10 (completely agree).
2.1. Participants
Practicing pharmacists actively involved in the care of patients with
MS from Spain were invited to participate in our study by the Spanish
Society of Hospital Pharmacy (Sociedad Española de Farmacia
Hospitalaria-SEFH). Pharmacists whose practice was primarily in caring
for MS patients were classified as ‘MS specialists’. Participants were
paid 150 euros on completion of the study acknowledging the time and
effort they provided to collaborate in the research.
2.2. Definitions
Disease activity was defined as a clinical relapse plus the presence of
new brain lesions in follow-up magnetic resonance imaging (MRI) scans
with at least one gadolinium-enhancing T1 lesion (Bermel et al., 2013;
Sormani et al., 2013; Prosperini et al., 2014). The use of these defini-
tions combining a clinical relapse and MRI activity is consistent with
recent evidence regarding the risk of treatment failure among patients
receiving interferon beta (Tramacere et al., 2015). Recent meta-analysis
confirmed that alemtuzumab, fingolimod, natalizumab, and ocreli-
zumab are the best available choices for preventing clinical relapses in
patients with relapsing-remitting MS (Li et al., 2019). The current
landscape of DMT for the treatment of relapsing-remitting MS includes
first-line therapies (beta interferons, glatiramer acetate, dimethyl fu-
marate, and teriflunomide) and second-line agents (alemtuzumab, fin-
golimod, natalizumab, ocrelizumab) (Montalban et al., 2018; Rae-
Grant et al., 2018). For the present study, we used this treatment
scheme as per current clinical practice.
2.3. Outcome measures
The primary outcome of the study was TI defined as a continuous
and binary measurement. We created a score defined as the number of
case-scenarios that fit the TI criteria over the total number of presented
cases (score range from 0–6). The prevalence of TI was defined as
participants not escalating treatment when indicated in at least one out
of six presented case-scenario (binary outcome). The rationale for this
criterion was based on the potential impact in this patient population
(e.g. 17% of the therapeutic decisions leading to TI).
Optimal management, a secondary outcome, included treatment
discontinuation due to side effects or the appropriate selection of
therapeutic options for each of the presented case-scenarios. We created
the optimal treatment score (OTS) to determine the degree of appro-
priate pharmacological decisions (ranging from 0 (lowest) to 9 (highest).
2.4. Statistical analysis
The primary analysis assessed the prevalence and factors associated
with TI. We included the following explanatory variables: age, gender,
MS patients seen per week, practice setting (academic vs non-aca-
demic), general pharmacist vs. pharmacist specialized in MS, co-au-
thorship in a peer-reviewed publication within the last year (yes/no),
tolerance to uncertainty (above/below the median), willingness to take
risks in all domains (above/below the median in SOEP survey), and
agreement with shared decisions making.
We used parametric tests (t-test and Fisher exact-test) to compare
continuous and categorical variables between groups. Linear regression
analysis was used to determine the association of exploratory variables
with the TI and OTS scores, respectively. A multivariable logistic re-
gression analysis with backward selection was completed to determine
the association between pharmacists’ characteristics and TI and optimal
management.
All tests were 2-tailed, and p-values < 0.05 were considered
M.A. Terzaghi, et al. Multiple Sclerosis and Related Disorders 39 (2020) 101887

Table 1 specialization in MS management. The mean (SD) agreement with

Socio-demographic characteristics and risk preferences of the sample. shared decision making was 7.6 (1.8), with 39 (60.0%) participants
N = 65 given rates equal to or higher than 8. Main sociodemographic char-
acteristics and risk preferences of the sample are shown in Table 1.
Age, mean ± SD, in years 43.5 ± 7.8 The mean (SD) TI score was 3.4 (1.1). Of 390 individual responses,
Gender, n (%)
224 (57.4%) met TI criteria. All participants failed to recommend
Female 41 (63.1)
Years of experience, mean ± SD 16.0 ± 7.4
treatment escalation in at least one of the six case-scenarios that as-
MS specialty, n (%) 42 (64.6) sessed TI. Main outcome measures are summarized in Table 2.
Practice Setting, n (%) During our assessment of management, the mean optimal treatment
Academic 52 (80) score (OTS) was 4.1 ± 1.4. Of 585 individual responses, 264 (45.1%)
Position, n (%)
met the optimal choice criteria (Table 2). Only 40% of participants (23/
Pharmacist Head 17 (26.1)
Number of MS patients managed at hospital per year, mean ± 261.7 ± 215.8 65) made five or more optimal treatment choices. Tolerance to un-
SD certainty (p = 0.26), willingness to take risks in different domains
Participation in MS clinical trials, n (%) 13 (20) (p = 0.27), or agreement to shared decisions (p = 0.23) were not as-
Co-author of a peer-reviewed publication in the last year, n 51 (78.5)
sociated with TI. Similar findings were observed for OTS.
(%)
Willingness to take risks: SOEP survey, median (25–75th) 19 (12–25)
The most common factors associated with TI included lower ex-
Tolerance to uncertainty, median (25–75th) 23 (16–29) perience in dispensing MS drugs and lack of specialization in MS.
Shared decision-making, mean ± SD 7.6 ± 1.8 Participants risk preferences were not associated with TI. The multi-
variable analysis revealed that more years of experience in dispensing
MS = Multiple sclerosis; SD = Standard deviation; SOEP = German Socio- MS drugs (p = 0.03), being a co-author of a peer-reviewed publication
Economic Panel.
(p = 0.03), and specialization in MS (p = 0.017) were associated with
lower TI scores (Table 3, Fig. 1). The adjusted R2 was 0.23. Tolerance to
Table 2
uncertainty, willingness to take risks in different domains and agree-
Summary of main outcome measures.
ment with shared decision making were not associated with TI or OTS.
Outcome Measures

Therapeutic inertia, number of individual responses 390 4. Discussion

Individual responses that meet TI criteria, n (%)
TI Score, mean ± SD
Optimal Management, number of individual responses
OTS Score, mean ± SD
Individual responses that meet optical choice criteria, n (%)
Number of pharmacists that made five or more optimal treatment
choices, n (%)
OTS = Optimal treatment score; SD = Standard deviation; TI = Therapeutic
inertia.
significant. We used STATA 13 (College Station, TX: StataCorp LP) to
conduct all analyses.
3. Results
Overall, 143 pharmacists were invited to participate and 65 in-
itiated the study (response rate: 45.5%). Sixty-five participants com-
pleted the study (completion rate: 100%). The mean age (SD) was 43.5
(7.8) years and 67.1% were female. Forty-two (64.6%) participants had
224 (57.4)
3.4 ± 1.1
585 Pharmacists play an essential role in the management of MS patients
4.1 ± 1.4 by contributing to the selection and dispensation of DMTs, and coun-
264 (45.1) selling patients and their families about administration, dosing, and
23 (40) risks of different side effects (Miller et al., 2012; Habibi et al., 2016;
Schultz et al., 2016; Banks et al., 2019). As a result, the intervention of
pharmacists in the circle of care has a relevant impact on outcomes
measures and quality of life of MS patients (Tang et al., 2016;
Banks et al., 2019). In the present study, we assessed pharmacists’
therapeutic choices to better understand factors influencing their de-
cision-making process. We found that more than half (57.4%) of in-
dividual responses met TI criteria. Moreover, all participants did not
recommend treatment escalation in at least one case-scenario when
there was evidence of clinical relapses and radiological progression. We
were able to determine that years of experience, being a co-author of a
scientific publication and MS specialization were factors associated
with lower TI scores. Furthermore, when assessing the optimal man-
agement of MS patients, we found that less than half (40%) of parti-
cipants made five or more optimal treatment choices. Willingness to

Table 3
Variables associated with the outcomes of interest.
A. Variables associated with TI score.
Measure Coefficient 95% CI p-value

Years of experience −0.66 −0.13, 0.03

−0.007
Co-author of a scientific −0.67 −1.29, −0.06 0.03
publication
Pharmacist specialization in −0.64 −1.16, −0.12 0.017
MS
CI = Confidence interval; MS = Multiple sclerosis. Interpretation: higher years of experience as a pharmacist, specialization in MS, and being a co-author of a peer-reviewed
publication were associated with higher TI scores (higher therapeutic inertia) after adjustment for age, gender, volume of MS patients seen per year.

B. Variables associated with optimal treatment decisions.

Measure Coefficient 95% CI p-value

Years of experience 0.072 0.01–013 0.016

Co-author of a scientific publication 1.20 0.44–1.98 0.003
Pharmacist specialization in MS 0.805 0.16–1.44 0.015
CI = Confidence interval; MS = Multiple sclerosis. Interpretation: higher years of experience as a pharmacist, specialization in MS and being a co-author of a peer-reviewed publication
were associated with optimal therapeutic decisions after adjustment for age, sex, volume of MS patients seen per year.

3
M.A. Terzaghi, et al.
Fig. 1. Observed vs. predicted probability of the outcomes of interest.
Derived from linear regression analysis after adjusting for age, gender, years of experience, expertise in MS, and volume of MS patients per year.
take risks in different domains, tolerance to uncertainty and agreement
with shared-decision making were not associated with the outcomes of
interest.
Previous studies and a meta-analysis also tested the role of phar-
macists in improving chronic medical conditions (i.e.: improving blood
pressure control) and limiting therapeutic inertia. The World Health
Organization has been promoting pharmacist-driven protocols since
2005 as part of its integrated chronic disease prevention and control
program. For example, a Canadian study showed over two-fold im-
proved odds in reaching blood pressure targets among patients with
hypertension (Tsuyuki et al., 2015). Similar findings were observed
with a team approach involving pharmacists and nurses compared to
usual care (McLean et al., 2008). Other studies were tested with self-
blood pressure monitoring at home (Margolis et al., 2013). Pharmacists-
lead interventions not only showed clinical benefits, but also cost-sav-
ings (Polgreen et al., 2015). A recent meta-analysis comprising 39
randomized controlled trials involving pharmacist interventions
showed greater improvements in blood pressure among programs
4
Multiple Sclerosis and Related Disorders 39 (2020) 101887
targeting patients’ education, feedback to physician, and manage
medications suggesting that integrated approaches results into better
care and outcomes (Santschi et al., 2014).
To the best of our knowledge, our study is the first to identify the
need for education of pharmacists regarding the management of pa-
tients with MS. Increasing awareness and measuring the magnitude of
the problem are the first steps to design educational programs and in-
terventions to optimize the management of this group of patients.
Improving our understanding of the process of therapeutic choices
can help us develop educational tools that may ultimately lead to better
care and reducing of management errors (O'Connor et al., 2005). This
area of research has been neglected for years, especially when con-
sidering the role of pharmacists in the approval process, dispensing of
DMTs, and counselling of MS patients. The practical implications of
suboptimal management and therapeutic inertia may lead to poorer
clinical outcomes, including greater disability and lower quality of life
among MS patients (Giovannoni et al., 2017; Cerqueira et al., 2018;
Ontaneda et al., 2019). Therapeutic inertia is a common occurrence
M.A. Terzaghi, et al.
among healthcare providers who treat chronic medical conditions (e.g.
hypertension, diabetes, hypercholesterolemia) (Cooke et al., 2012;
Mata-Cases et al., 2018). Previous studies from our group revealed that
60 to 90% of neurologists caring for MS patients have TI
(Almusalam et al., 2019).
The most important areas for improvement suggested by our study
include pharmacists’ education and training in DMTs, and revision of
drug policy approval of MS agents. Efforts made in these two areas
would assist in optimizing MS care and possibly ameliorate suboptimal
therapeutic decisions among pharmacists.
Our study has a few limitations that should be mentioned. Firstly,
our sample size is small and may not represent a comprehensive as-
sessment of pharmacists’ decisions from across Spain. However, we do
not believe our sample was biased as pharmacists from all hospitals had
equal opportunities to participate in the study. Secondly, treatment
choices may have been influenced by the current drug policies in each
regional community. Additionally, we cannot rule out the possibility of
residual confounding despite the comprehensive adjustment in the
analysis.
Despite these limitations, our study represents a snapshot of ther-
apeutic choices involving pharmacists who play an essential role in
DMT approval, dispensation and counselling for MS patients. Our re-
sults revealed that all pharmacists in this study had TI in at least one-
out-of-six treatment decisions and only 40% provided optimal man-
agement recommendations.
Future directions to be investigated would include an assessment of
knowledge (guideline-based, health policy) and knowledge-to-action
gaps among pharmacists working in the community and in other
countries. Additionally, it would be important to develop education
strategies targeting healthcare providers and policymakers regarding
the optimal management and consequences of TI and suboptimal
therapeutic decisions in MS care. A previous randomized controlled
trial showed a 70% reduction in therapeutic inertia in MS among
neurologists allocated to the traffic light system (TLS) intervention
compared to usual care (Saposnik et al., 2017b, Saposnik et al., 2019).
The TLS allows individuals to identify a color (i.e.: red as a warning
sign) match with an action (e.g. change the strategy, escalate treat-
ment) (Saposnik et al., 2017b). We expect that tested educative inter-
ventions can be designed and implemented among pharmacists.
Declaration of Competing Interest
G.S. reported receiving grants and personal fees from Roche and
reported being supported by the Heart and Stroke Foundation of
Canada Career Award. F.B. and J.M. are employees of Hoffmann-La
Roche Limited Canada and Roche Farma Spain, respectively. The rest of
the authors declared no potential conflict of interest with respect to the
research, authorship, and/or publication of this article.
This study was funded by Roche Farma Spain (SL04845) and fa-
cilitated by NeuroEconoSolutions. Neither Roche Farma nor
NeuroEconSolutions were involved in the design, execution, analysis,
and interpretation or reporting of the results.
Acknowledgements
The authors are most grateful to all pharmacists participating in the
study.
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