Comment by Dr. Daniel Selchen – St. Michael’s Hospital, Toronto, Ontario
An estimated 70% of clinicians managing multiple sclerosis experience therapeutic inertia when faced with the decision to escalate therapy, according to a series of studies conducted by Saposnik and colleagues. This delay in the use of more effective therapies may result in worse clinical outcomes.
Therapeutic inertia is a term coined a decade ago and refers to the tendency for clinicians not to start a treatment when one is needed, or to maintain status quo despite evidence of treatment ineffectiveness or worsening disease (Okonofua et al. Hypertension 2006;47:345-351).
This issue was examined in the prospective DIScUTIR MS study, which used case vignettes to investigate clinical decision-making in MS (Saposnik et al. Front Neurol 2017;8:65; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5331032/pdf/fneur-08-00065.pdf). Participants also completed surveys about their aversion to ambiguity in financial and clinical areas and risk preferences in different domains.
A total of 135 neurologists (mean age 39.5 years) in Spain participated; 96 completed the surveys. Two-thirds of respondents’ practices focused on MS care. Clinicians had worked a mean 14 years in practice, seeing an average of 20 MS patients per week.
Participants were given a series of clinical scenarios, with most of the vignettes describing candidates for treatment escalation. Ongoing disease activity was defined as >1 relapse + >1 Gd+ T1 lesion. The sensitivity analysis included the modified Rio criteria, which use the measures of 1 relapse in the first year on treatment (1 point), 2 relapses in the first year on treatment (2 points), 5 new T2 lesions (1 point), or the combination to stratify risk; and the European Medicines Agency criteria, which require >1 relapse in the previous year and either >9 T2 lesions or >1 Gd+ lesion before escalating to a second-line agent.
Therapeutic inertia was defined as failure to intensify therapy in at least one scenario where escalation was clinically and/or radiologically indicated. Overall, therapeutic inertia was present in 68.5% of participants, and was more common among general neurologists (81.3%) compared to MS specialists (62.5%). Similar results were seen when the modified Rio criteria were used. However, therapeutic inertia was less common among MS specialists (20.3%) and general neurologists (46.9%) when EMA criteria were used. One interpretation could be that these findings reflect the relative degree of clinicians’ agreement with treatment escalation recommendations, or their sensitivity to reimbursement criteria.
The study also examined how clinician uncertainty influenced therapeutic inertia. Uncertainty was defined as comprising risk and ambiguity, with risk applying to known probabilities, and ambiguity applying to unknown probabilities. Thus, risk aversion would be when a clinician chooses an option with the lowest known probability of harm. Ambiguity aversion would be a preference for events with known probability (even if unfavourable) over events with unknown probability, e.g. a high incidence of known adverse events (e.g. injection site reactions, GI upset) vs. unknown long-term treatment-related adverse events.
The study found that 27.1% of clinicians demonstrated total aversion to unknown probabilities. In the scenario where the ambiguous option had a 50% unknown probability, 73.7% of clinicians chose the known probability. Interestingly, participants with high aversion to ambiguity in the financial (but not health) domain were significantly more likely to demonstrate therapeutic inertia. Therapeutic inertia was also more likely among those with low tolerance to uncertainty.
Implications in practice
These findings highlight several conundrums in MS care. Therapeutic inertia is more likely in clinicians averse to uncertainty, and MS is a disease of uncertainty. In the clinician’s risk assessment, the probabilities of treatment-related adverse events are known; the clinical course of MS is awash in ambiguity. And factors that would help clinicians evaluate risks and benefits with a greater sense of the probabilities involved – weighting of risk factors for progression, biomarkers of clinical worsening or treatment response, long-term outcomes with different DMTs – have not been established.
The result is what could be considered the widespread undertreatment of MS. For example, 43% of relapsing-onset MS patients in the Halifax database who were seen during the treatment era (1998-2010) never received a DMT (Brown et al. PLoS One 2014;9:e105123). In part this can be attributed to risk aversion on the part of patients. As Saposnik and colleagues noted, patients with a low risk of progression may be less willing to choose more effective but riskier treatments; those same treatment-associated risks may be acceptable in patients at high risk of early disability (Saposnik & Montalban. Front Neurol 2018;9:174; free full text at www.ncbi.nlm.nih.gov/pmc/articles/PMC5869922/pdf/fneur-09-00174.pdf). This appeared to be the case in the Halifax database analysis, in which the annual EDSS change was greater in treated versus untreated RMS patients (0.204 vs. 0.155), suggesting that untreated patients had milder disease and a lower risk of progression. In the EMPOWER study, side effects (32.9%) were rated by patients as a more important consideration than prevention of disease progression (10.0%) or relapse prevention (8.3%) (Arroyo et al. BMJ Open 2017;7:e014433).
In consequence, many RRMS patients begin and end their treatment regimen with a first-line agent. Indeed, one of the most commonly-prescribed agents is glatiramer acetate, which is the only DMT not indicated to slow progression, reinforcing the notion that a known safety record is a more important consideration than the unknown risk of worsening disease.
The therapeutically inert may be moved to action as new research unwraps some of the ambiguities of MS. Big data from population studies, database analyses and network meta-analyses will better define the benefits of more effective therapies compared to the status quo. No evidence of disease activity (NEDA) has provided an indication of the degree of disease suppression that can be achieved. Novel endpoints, such as clinical disability improvement (CDI), have shown that some agents may produce improvements in functioning. For example, in an analysis of patients in the CARE-MS II study, 45.4% of alemtuzumab-treated patients demonstrated disability improvement, with gains on all seven EDSS functional systems (Giovannoni et al. Neurology 2016;87:1985–1992). In the real-world setting, mean EDSS scores showed improvement at one year in alemtuzumab patients treated at the University of British Columbia MS clinic (Yong et al. ECTRIMS 2017; abstract P681).
Numerous biomarkers of disease progression are now being examined, which may remove some of the ambiguity about who is at risk of early disease worsening. Therapeutic inertia may become less common once the risks of MS are better characterized, and the probabilities of long-term benefits and risks associated with different treatment approaches are better quantified.
Dr. Daniel Selchen: The concept of therapeutic inertia is very important for understanding treatment dynamics associated with current MS care. Treating MS was very simple until about 10 years ago. Therapeutic choices were limited to two categories of injectable therapies which were mildly efficacious but extremely safe. We are now operating in a market that includes the two categories of injectables as well as four oral agents and three monoclonal antibodies delivered by infusion. The treatments involve multiple different mechanisms of action, therapeutic targets, levels of efficacy and risk. Ten years ago, uncertainty was primarily with regard to whether to treat or not. Now, with much more effective but riskier agents, uncertainty relates to treatment escalation and complex risk-benefit analyses. This is of course in the context of a disease characterized by significant uncertainty in terms of the natural history of individual patients.
The result has been an epidemic of under-treatment. Gustavo Saposnik’s work on therapeutic inertia gives us a framework for understanding this phenomenon. Risk avoidance is an important part of the practice of medicine, but when it comes at the cost of inadequate treatment in what is frequently in the long term a debilitating disease, it is highly problematic.
Saposnik’s work illustrates that lack of knowledge of the appropriate intervention is only one small part of the problem. His research demonstrates that clinicians do not act, even when they know that they probably should. The aversion to uncertainty appears at times to be cognitively paralysing.
The other fascinating and frequently ignored part of this equation is the extent that the individual physician’s personality affects therapeutic decision making. It is most interesting, but not surprising, that physicians who cannot tolerate ambiguity in financial matters are much more likely to exhibit therapeutic inertia. This suggests that it is incumbent on physicians to examine not only their patients’ belief systems and tolerance for risk, but also to be conscious of the baggage they bring to the table in terms of their own personalities and belief systems.
What are the solutions to this problem? It seems obvious that complexity combined with lack of knowledge will almost certainly increase ambiguity and aversion to risk. This implies that physicians who do not treat a significant number of MS patients should not be treating at all, as the motivation and ability to learn the vagaries of nine classes of treatments are unlikely to be present.
Another potential solution is shared decision-making, not just with the patient but with other colleagues. It would probably be valuable for many clinicians to have the opportunity to share the burden of uncertainty and ambiguity in some form of case conference setting for therapeutic decisions. Other disciplines do this regularly (e.g., tumour boards) and the technology now exists to make this manageable.
Continuing medical education focused on risks of disease (rather than just risk of treatment) and decision-making is obviously essential. With all their limitations, treatment recommendations and guidelines also have value.
It is incumbent on our community to try to understand and overcome the conundrum of therapeutic inertia to maximize the potential for optimal disease management for individual patients.