January/February 2020

Medication Monitor: Decreasing Adverse Drug Events
By Jacques Turgeon, BPharm, PhD, and Veronique Michaud, BPharm, MSc, PhD
Today’s Geriatric Medicine
Vol. 13 No. 1 P. 8

Many patients benefit from taking multiple medications, as various classes of drugs are proven effective for improving life quality and expectancy. Numerous clinical trials involving patients with specific diseases have demonstrated the value of such medications. Therefore, polypharmacy, or the simultaneous use of multiple drugs, may be necessary for some people, especially older adults, who often have more than one chronic disease. However, taking multiple medications also greatly increases a person’s risk of suffering from drug-drug interactions, multidrug interactions, and side effects.1,2 Such conditions are often very serious and can be life-threatening.

Medication use in the United States, especially among older people, has gotten to the point at which millions of people are overloaded with too many prescriptions and are experiencing significant harm as a result. The Centers for Disease Control and Prevention on a regular basis releases the major causes of death in the United States. In the most recent 2017 report, the Center for Drug Evaluation and Research reveals that adverse drug events (ADEs) and the inappropriate use of drugs (included in the Unintentional Injuries category) are now the third leading cause of death, behind only heart disease and cancer.3 In April 2019, the Lown Institute released a report, “Medication Overload: America’s Other Drug Problem,” which presented the following eye-opening statistics4:

• Five million older adults sought medical attention for ADEs in 2018.
• Forty-two percent of older adults take five or more prescription medications.
• There has been a 300% increase in polypharmacy over the past 20 years.
• Seven hundred fifty hospitalizations occur every day due to ADEs in older adults.
• Sixty-two billion dollars have been spent on unnecessary hospitalizations over the last 10 years.
• It’s projected that 150,000 premature deaths will occur over the next 10 years due to ADEs.

These are some of the facts that Americans are facing on a daily basis. As much as we appreciate the usefulness of medications to improve life expectancy, we should also consider the hidden side of pharmacological tools as they often induce undesirable effects or unexpected adverse events.

There are multiple reasons why even the appropriate prescription of drugs with demonstrated positive outcomes—from clinical trials—could lead to polypharmacy and inappropriate use. First, the culture of prescribing can lead to pressure on the medical community to prescribe when a patient is physically present in a physician’s office. There are a growing number of direct-to-consumer drug advertisements by the pharmaceutical industry, providing hope and easy solutions to complicated conditions. Patients will visit their physicians’ offices and expect to leave with a solution. Second, drug rebates and adherence are often the centerpieces of programs from health insurances and governmental agencies. While this makes sense—if patients cannot afford or do not take their medications, they cannot realize the expected benefits—it also favors polypharmacy and increases the risk of multidrug interactions and side effects. While “heavily promoted” adherence may sometimes be associated with improved patient outcomes, it also has a direct and positive impact on revenues for the pharmaceutical industry. Furthermore, treatment guidelines from scientific communities have suggested that the use of more than one drug or potent high-dose medication is needed to achieve treatment goals and expected outcomes. Once again, these conditions increase the risk of polypharmacy in patients with multiple chronic diseases, and use of maximal doses—such as with high-intensity (potency) statins to lower LDL cholesterol—may not always be the appropriate strategy in patients with polypharmacy and in the frail elderly.

The next concern lies with the fragmentation of care with isolated prescribing patterns. Who is the chef d’orchestre for the management of patients’ drug regimens? Is the primary care physician entitled to review drugs prescribed by the cardiologist, the nephrologist, the endocrinologist, the psychiatrist, and the rheumatologist in a depressed and anxious patient with metabolic syndrome and rheumatoid arthritis? Who manages severe multidrug interactions, dose adjustments, and interruption of treatments when the primary care physician prescribes antibiotics for a urinary tract infection or pneumonia? Finally, who is considering the variability in drug response—positive outcomes (mean values) observed in clinical trials with select patients that do not apply to every single individual—due to genetic or environment factors including lack of systematic deprescribing approaches? This is important, as deprescribing is very attractive but must be done with great care and caution not to destabilize patients, especially in the context of underlying multidrug interactions.

Searching for a Solution
Health economic studies demonstrate that for every dollar spent on prescription medication, more than another dollar is spent trying to address problems caused by the medication.5 This type of health care spending is not sustainable. How can we identify and develop suitable approaches to support health care professionals in their quest to resolve the issues associated with ADEs? The following are strategies that may help:

• Explore integrated, scientifically based methods that may offer ways to prevent and decrease ADEs. Proposed solutions, derived from basic and clinical research in academic environments, embrace a step-by-step strategy that relies on comprehensive patient data paired with a constantly evolving knowledge base about current drugs on the market. Once the information is gathered, detailed analysis of each medication comprising a drug regimen is analyzed for specific pharmacological characteristics such as anticholinergic burden, sedative burden, the presence of noncompetitive and competitive inhibition between substrates for specific CYP450 isoforms, the risk of drug-induced long QT syndrome, calculation of relative odds ratio for side effects using large databases, pharmacogenomic information, and renal function.6-8

• Have a central hub of a patient’s information and clinical variables via electronic records, e-prescribing, and appropriate data registry.

• Utilize drug claim data as the most reliable and timely source of drugs taken by a patient as well as a proxy to deduce their active disease states.

• Use risk stratification to better identify and concentrate efforts on patients at high risk of ADEs.

• Apply an identifier/calculator of medication risk (a medication risk score) so that every actor on a patient medication condition, including the patients themselves, can easily identify the level of risk for ADEs.

• Flag patients with a high medication risk score so they can receive special attention on preventing hospitalizations, emergency department visits, and major side effects.

• Use a clinical decision support system that computes all this information at the point of care, alerting health care professionals to potential risks and providing evidence-based guidance on the most appropriate way for patients to take the medications they need while avoiding ADEs.

• Reorganize care teams, ensuring that clinical pharmacists should be at the forefront of this approach because they have the most relevant training and are experts in providing pharmaceutical care.

The Result
Such an approach can be applied to various programs such as the Program of All-Inclusive Care in the Elderly, health care organizations offering services to Medicare/Medicaid patients, payers and at-risk organizations offering services to working or commercial populations, and new Center for Medicare & Medicaid Innovation initiatives toward medication safety. In all of these, specific attention should be given to identified high-risk patients based on their complete drug regimens. Pharmacists should be at the center of such programs aimed at avoiding drug-drug interactions, side effects, and targeted therapy management, and apply interventions such as deprescribing, dose adjustments, and changing drugs or time of administration. Such an approach shall demonstrate very positive return on investment as hospitalizations and emergency department visits associated with inappropriate use of drugs represent an important portion of medical expenditures in high-risk patients with polypharmacy. But most important, however, is that the interventions improve patients’ quality of life and life expectancy.

— Jacques Turgeon, BPharm, PhD, is chief scientific officer of Tabula Rasa HealthCare (TRHC); a professor emeritus at Université de Montréal in Montreal, Canada; a fellow of Canadian Academy of Health Sciences in Canada; and a fellow of Académie Nationale de Médecine in France.

— Veronique Michaud, BPharm, MSc, PhD, is chief operation officer of TRHC Precision Pharmacotherapy Research & Development Institute and an adjunct professor of the faculty of pharmacy at Université de Montréal.

References
1. Think it through: managing the benefits and risks of medicines. FDA website. https://www.fda.gov/drugs/drug-information-consumers/think-it-through-managing-benefits-and-risks-medicines. Updated June 18, 2018.

2. Doan J, Zakrzewski-Jakubiak H, Roy J, Turgeon J, Tannenbaum C. Prevalence and risk of potential cytochrome P450-mediated drug-drug interactions in older hospitalized patients with polypharmacy. Ann Pharmacother. 2013;47(3):324-332.

3. Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States, 2017. NCHS data brief no 328. Centers for Disease Control and Prevention website. https://www.cdc.gov/nchs/products/databriefs/db328.htm. Updated November 29, 2018.

4. Lown Institute. Medication overload: America’s other drug problem. https://lowninstitute.org/wp-content/uploads/2019/04/medication-overload-lown-web.pdf. Published April 2019.

5. Watanabe JH, McInnis T, Hirsch JD. Cost of prescription drug-related morbidity and mortality. Ann Pharmacother. 2018;52(9):829-837.

6. Turgeon J, Michaud V. Clinical decision support systems: great promises for better management of patient’s drug therapy. Expert Opin Drug Metab Toxicol. 2016;12(9):993-995.

7. Zakrzewski-Jakubiak H, Doan J, Lamoureux P, Singh D, Turgeon J, Tannenbaum C. Detection and prevention of drug-drug interactions in hospitalized elderly: utility of new cytochrome p450-based software. Am J Geriatr Pharmacother. 2011;9(6):461-470.

8. Cicali B, Michaud V, Knowlton CH, Turgeon J. Application of a novel medication-related risk stratification strategy to a self-funded employer population. Benefits Quarterly. 2018;2nd quarter:49-55.