COVID-SAFER: Deprescribing Guidance for Hydroxychloroquine Drug Interactions in Older Adults

Sydney B. Ross, MSc; Marnie Goodwin Wilson, MD, MSc; Louise Papillon-Ferland, BPharm, MSc; Sarah Elsayed, BSc; Peter E. Wu, MD, MSc; Kiran Battu, BPharm; Sandra Porter, BPharm; Babak Rashidi, MD, MS; Robyn Tamblyn, PhD; Louise Pilote, MD, PhD; James Downar, MD, MPH; Andre Bonnici, BPharm; Allen Huang, MD; Todd C. Lee, MD, MPH; Emily G. McDonald, MD, MSc

Disclosures

J Am Geriatr Soc. 2020;68(8):1636-1646. 

In This Article

Discussion

We reanalyzed data from the MedSafer pilot and found that one in two older adults with polypharmacy in our cohort have a chronically prescribed medication that could potentially interact with hydroxychloroquine, half of which were PIMs that could be deprescribed. The number of medical conditions and associated polypharmacy of the cohort places them at high risk of complications from COVID-19 but also potentially at risk of harm from treatments. We identified several common drug classes, many of which are also PIMs, that would preclude many older adults from enrolling in a trial. A main finding was that many older adults were taking medications that carry a known risk of prolonging the QTc. This finding should caution against routine prescribing of QTc prolonging COVID-19 treatments outside of a clinical study because there is real potential for harm. Importantly, more than 50% of interacting drugs were identified as a PIM that could be proactively deprescribed, rendering the person more likely to be eligible for a trial and increasing the generalizability of study findings to this population.

In this analysis, we chose to focus on a specific drug, hydroxychloroquine. Of note, debate is ongoing regarding the safety of hydroxychloroquine for treatment of COVID-19, and studies into its efficacy are still ongoing. The risks associated with a medication such as hydroxychloroquine are likely higher for older adults with polypharmacy, especially given the common coadministration of QTc prolonging medications and the prevalence of underlying cardiac conditions.[41] Many patients in our cohort were also overprescribed oral hypoglycemic agents (HbA1c<7.5% or a history of hypoglycemia) that when co-prescribed with hydroxychloroquine could increase the risk of hypoglycemia. Older adults may have decreased oral intake as a result of COVID-19 infection and subsequent dehydration, electrolyte disturbances, nausea, and gastrointestinal upset, which are also common adverse effects of hydroxychloroquine and may further exacerbate severe cardiac dysrhythmias.[42]

We have identified medications that may interact with study drugs that could be deprescribed proactively or at the time of treatment (eg, off-label low-dose quetiapine for sleep and agitation). Others, if stopped abruptly, could lead to serious adverse drug withdrawal events or uncomfortable withdrawal symptoms (eg, methadone or higher doses of SSRIs).[43] Finally, some medications have long half-lives that require weeks to months to discontinue safely and avoid interactions. In this case, it may not be possible to stop the medication in time for treatment, and thus the risk of interaction will not be reduced (eg, azithromycin,[44] fluoxetine, and amiodarone). Of note, although there is a risk of potential interactions between medications, this does not necessarily mean there will be any clinical manifestations.

Currently, the use of antimalarials for the treatment or prevention of COVID-19 has extremely limited evidence.[27] If robust evidence demonstrating efficacy in the treatment of COVID-19 is established, some clinicians might opt to continue certain medications that cannot be stopped abruptly or where symptoms of withdrawal are thought to be significant. In most cases, this would involve judicious monitoring of the QTc and minimizing other risk factors (electrolyte abnormalities, bradycardia). Although cardiac monitoring is generally available for hospitalized patients, and perhaps at select nursing homes, this is likely not the case for most outpatients. Finally, it is important to consider the half-life of the treatment medication to know for how long symptoms should be monitored and when it is safe to restart medications (hydroxychloroquine, range = 20–120 days; mean = 40 days).[45–47] The risk of QTc prolongation may persist beyond the treatment period and remain clinically relevant for an unclear duration.

Of note, the optimal effective does of hydroxychloroquine is not known. Our referenced study uses a daily dose of 600 mg, but in practice doses are variable, and some jurisdictions may prescribe lower doses of 400 mg daily that may have an impact on the risk of drug interactions and of side effects. These considerations aside, for medications that are PIMs, their interactions with possible COVID-19 therapies are yet another reason to evaluate these medications for safe deprescribing immediately.[48] Any concern for abrupt discontinuation can be avoided by deprescribing in advance of acute illness.[48]

Although we used hydroxychloroquine as a test case, this should not be interpreted as an endorsement of the medication. The clinical scenario described here is not limited to hydroxychloroquine. Other treatments including but not limited to lopinavir-ritonavir, colchicine, and dapsone have also been proposed. These treatments similarly do not have significant evidence to support their use presently, but they also carry risks of serious drug-drug interactions.[48,49] Clinicians may be tempted and indeed are prescribing medications out of desperation to provide patients with some form of treatment for COVID-19, but caution and a rigorous review of possible interactions is warranted, especially in older adults with polypharmacy. Notably, this population will often be underrepresented in clinical trials and even if proven effective, harms may still outweigh benefits for some therapies. An individualized approach should always be taken. Presently, although some medications have shown promise, such as hydroxychloroquine and more recently remdesivir,[49] no medication for the treatment of COVID-19 has been proven effective, and so we would suggest that outside of a clinical trial, the potential harms of off-label prescribing likely outweigh benefits. In the meantime, it is important that we reduce the number of PIMs patients are taking because it may facilitate more treatment options once clinical evidence is established.

Strengths of this study include a large cohort of older adults from a multisite trial with polypharmacy, a thorough review of the literature to outline potential drug interactions, and clear instructions for medication management in the setting of drug interactions. This cohort also reflects the latest FDA recommendation that hydroxychloroquine should not be used outside of a clinical trial or a hospitalized setting.[14]

Our study also has several limitations. Because they were all hospitalized, the patients in this study likely represent those who are most likely to experience harm as a result of widespread prescribing of hydroxychloroquine. Future work should focus on finding safe and effective treatments in long-term care facilities where the burden of polypharmacy is high, there is an increased risk for COVID-19 exposure, and effective treatments may decrease the risk of hospitalization. We chose to focus on hydroxychloroquine as a test case to provide realistic examples of harm that could result from widespread prescribing. Reviewing all potential therapies and their subsequent drug-drug interactions was beyond the scope of this article. However, similar recommendations could be generated for other potential treatments and may be more complex. For example, interactions with lopinavir-ritonavir are more extensive than we have outlined for hydroxychloroquine.

Additionally, the clinical significance of the interactions identified vary with cardiac complications, with sudden death the most severe, whereas absolute risks of seizure or hypoglycemia are less well defined. All patients in our cohort were on at least five medications. This is the case for approximately 50% of older Americans.[24,25] For those on fewer medications, the risk of drug-drug interactions is less. However, this study only looked at interactions with home medications. Patients who are hospitalized may have an even higher risk of interactions because they receive additional treatments (eg, concurrent antibiotics that prolong the QTc, antipsychotics for the management of delirium, insulin, etc). Finally, although the population of patients we analyzed is Canadian, the problem of polypharmacy has been widely described in the United States and countries across the world, so the principles outlined in the discussion can be extrapolated to other jurisdictions.

In conclusion, polypharmacy has many unpredictable consequences. There are well-described harms (eg, falls, fractures, and cognitive impairment),[23] but we describe an emerging concern in the era of COVID-19. Patients may not be eligible for COVID-19 trials to study the effectiveness and safety of the medications under investigation. Others may be subject to harm as a result of off-label prescribing due to the risk of drug-drug interactions. Now more than ever, we should examine the medication lists of older adults with a focus on medication optimization and stopping PIMs, particularly those that may interact with potential COVID-19 therapies.

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