Article Archive
November/December 2015

Focus on Adverse Drug Events
By Mark D. Coggins, PharmD, CGP, FASCP
Today's Geriatric Medicine
Vol. 8 No. 6 P. 8

Important Medication Safety Definitions
Adverse drug events (ADEs) are defined as "any injury that results from the use of a drug." This broad definition includes harm directly caused by the drug, including medication errors, adverse drug reactions (ADRs), allergic reactions, and overdoses, as well as harm from the use of the drug, including dose reductions and discontinuation of therapy.1 Any negative event occurring as a result of not using a medication or inadequate doses of medications that are known to provide benefit for a particular condition may also be considered an ADE.

ADRs are harm directly caused by a drug at normal doses during normal use.1

Medication errors may occur during prescribing, transcribing, dispensing, adherence, or monitoring of drug therapy, and may or may not result in harm. In all cases ADRs are ADEs; however an ADE that results from a medication dosing error does not become an ADR if the patient suffers no harmful effects.1

An allergy is defined by the US Department of Veterans Affairs as an ADR mediated by an immune response such as a rash or hives. A side effect is defined as "an expected and known effect of a drug that is not the intended therapeutic outcome." The term "side effect" tends to normalize the concept of drug-related injury; it has been recommended that this term should be avoided in favor of ADR.1

Major Public Health Concern
ADEs are associated with increased morbidity and mortality, prolonged hospitalizations, and higher health care costs. Older adults are particularly vulnerable to ADEs due to polypharmacy, comorbid conditions, and age-related changes such as altered absorption, altered drug distribution, reduced hepatic metabolism, reduced renal excretion, and altered neurophysiology, all of which affect pharmacokinetics and pharmacodynamics.2,3

The potential for ADEs is common regardless of setting. ADEs result in more than 700,000 emergency department visits each year, with nearly 120,000 patients hospitalized for further treatment after emergency visits for ADEs. Older adults, aged 65 and older, are twice as likely as others to visit emergency departments for ADEs and are nearly seven times more likely to be hospitalized following an emergency department visit.4 One in six hospital admissions of older adults occurs because of ADEs, a rate four times that of younger people. Hospital admissions because of ADEs increase to one in three for individuals aged 75 and older. While hospitalized, one in six older patients experiences at least one ADE. In community settings, one in five older adults is taking potentially inappropriate medications.5

Long term care (LTC) residents are at a particularly high risk for ADEs; the average LTC resident uses seven to eight different medications each month, with about one-third of residents receiving nine or more medications.6 In LTC centers, an estimated 2 million ADEs occur each year with at least 10 ADEs occurring each month in an average size center. One in seven LTC residents will be hospitalized as a result of an ADE.7

In an effort to increase recognition and prevention of ADEs in skilled nursing facilities, the Centers for Medicare & Medicaid Services (CMS) is piloting "Medication Adverse Drug Event" focus surveys. CMS noted that a review by the Office of Inspector General found that one in three skilled nursing facility (SNF) residents was harmed by an adverse event or temporary harm event within the first 35 days of an SNF stay and 37% of the adverse events were related to medication. The second most frequent cause of medication-related adverse events was excessive bleeding related to anticoagulant use, causing harm ranging from hospitalization to death.8

ADEs Are Often Preventable
Numerous studies show that many ADEs are preventable. In outpatient settings, approximately 30% of ADEs are potentially preventable with some studies showing up to 88% of hospital admissions for ADEs among the elderly are preventable.9 A study of ADEs in two large academic LTC centers in the United States and Canada found the overall rate of ADEs to be 9.8 per 100 resident months. Forty-two percent of the ADEs were determined to be preventable; however, of the more serious ADEs, 61% were classified as preventable. The more serious the ADE, the more likely it was to be considered potentially preventable. These rates were approximately four times higher than had been previously reported.6

Strategies to Prevent ADE Risk
• Exercise pharmacovigilance. This is defined as the science of and activities related to the detection, assessment, understanding, and prevention of adverse effects or any other drug-related problem. Prescribing medications for older adults is a complex process requiring extreme vigilance in order to ensure optimal medication utilization. Due to the complexity of medication use and distinguishing between symptoms of existing illness and possible ADEs, health care professionals should exercise pharmacovigilance in considering any new symptom presented by an older adult as being drug-related until proven otherwise.

• Implement a team approach. Medication optimization is most effective when there is a cooperative relationship among the physician, nurses, nurse aides, pharmacist, other health care professionals, patient, and family. A team approach promotes optimal use of medications, reduces ADEs, and promotes cost-effective drug prescribing practices. This collaboration provides better insight around the patient's needs, typical behaviors, and responses, while also increasing the number of people who can observe a patient before and after a medication is started.

• Increase awareness of high-risk medications. ADEs can occur with any medication, including over-the-counter medications and herbal remedies, making it difficult to predict which medication will result in an ADE for an individual patient. However, in general we know that certain risk factors such as increasing age, polypharmacy, comorbid conditions, and certain medication classes have been identified as consistently causing potential ADEs, which makes closely monitoring them a priority (see Table 1).

High-risk medications include anticoagulants, diabetes agents (insulin and oral agents), narcotics (opioids), anti-infectives, antineoplastics, sedatives (benzodiazepines), and antipsychotics.

Those medications requiring laboratory monitoring due to narrow therapeutic windows as with anticoagulants such as warfarin, diabetic medications, and seizure medications (phenytoin) and digoxin are commonly implicated as creating a high risk for potential ADEs.

The CMS drug utilization review criteria target eight prescription drug classes: digoxin, calcium channel blockers, angiotensin-converting enzyme inhibitors, H-2 receptor antagonists, NSAIDs, benzodiazepines, antipsychotics, and antidepressants, and focus on four types of prescribing problems: inappropriate dosage, inappropriate duration of therapy, duplication of therapies, and potential for drug-drug interactions. NSAIDs and benzodiazepines were the implicated the drug classes with the most potential problems among older adults in the community.10

A systematic review of nine international studies attributed most preventable medication-related admissions to antithrombotic medications, diuretics, and NSAIDs.11 In another study, two-thirds of all medication-related admissions to the hospital involved antithrombotic and antidiabetic medications, almost always by unintentional overdose.12 In a prospective study of 1,225 hospital admissions related to ADEs, 20 of 28 deaths were due to gastrointestinal or intracranial bleeding and five were due to renal failure.13

In LTC, preventable ADEs have been most frequently associated with atypical antipsychotics and warfarin therapy. In a 12-month observational study of 25 SNFs with 490 LTC residents taking warfarin, 720 ADEs were noted, with 625 of the events considered minor, 82 serious, and 13 life threatening; 57% of the serious events were considered preventable.14

ADEs Occur at All Phases of the Medication Utilization Process
Medication utilization involves a number of complex processes that can be grouped into five phases: assessment, prescribing, dispensing, administration, and monitoring. Each of these phases presents an opportunity for ADEs, making it appropriate to target all phases to impact potential ADEs. See Table 2 for clinical interventions that may indicate an ADE.

Recognize Signs and Symptoms of Possible ADEs
Educating team members on how to recognize potential side effects and triggers of ADEs is important (see Table 3).

Confusion, oversedation, delirium, and hemorrhagic and gastrointestinal events have been noted as the most common ADEs in a number of studies involving LTC facilities.

Orthostatic hypotension as well as falls and associated skeletal fractures increase with age and are attributed to multiple causes, including medication side effects, polypharmacy, and comorbid medical conditions.

Failure to recognize evidence-based guidelines that suggest avoiding excessive blood pressure lowering (eg, goal blood pressure guidelines of < 140/90 mmHg for older adults) increases the risk of falls and other ADEs. The use of psychoactive medications including antipsychotics, antidepressants, benzodiazepines, and sedative/hypnotics in older adults should be limited to reduce the risk of falls.

Medication Reconciliation
The health care team should review the current medication reconciliation process to improve communication during care transitions in all patient care settings. Transitions in care between hospital and nursing home or between institutional setting and home are common sources of medication errors and confusion leading to ADEs. Improving the accuracy and increasing the frequency of medication reconciliation whenever there is a medication change and with every transition of care settings can help reduce ADEs. This practice helps to avoid medication errors such as omissions, duplicate therapies, dosing errors, or drug interactions, while improving compliance and adherence patterns and improving discontinuation of unnecessary medications.

Communicating medication order changes between health care team members including the patient, family, and nursing assistants is critical because many ADEs occur near the onset of a new medication or dosage change. With this information, all team members will be in a better position to monitor for and report changes in a patient's condition with an increased urgency around evaluating medications as a potential cause.

Reduce the Number of Prescribers
Taking steps to streamline the prescribing process utilizing fewer prescribers can have a significant impact on improving patient safety. The number of prescribers has been shown to be an independent risk factor for ADEs, with each additional prescriber increasing the risk of ADEs in older adults by 29%.15

Decrease the Number of Medications
Medications should be discontinued when the indication no longer exists or where risk outweighs benefit. Some preventive and other therapies may no longer be beneficial to patients with short life expectancies. The appropriateness of these therapies should be reconsidered when other medical conditions develop that impact a patient's long-term prognosis, unless the therapies are thought to increase comfort.

Additionally, new medications should be prescribed sparingly to help limit the number of an older adult's medications because each new medication adds more than one ADE each year, and taking six or more medications increases this risk fourfold.

Another consideration to reduce the number of medications being used by an older adult is to avoid treating side effects of one medication with another medication; for example, starting an antihistamine for opioid-induced pruritus even when the symptoms are likely associated with the initiation of a new medication. Instead, the drug causing the side effect may be replaced with a different therapy.

Involve Patients/Family in Shared Decision-Making
Individualized prescribing decisions should be based on medical, functional, and social conditions; quality of life; and prognosis. Patients with several chronic health conditions should be asked often about ADEs because the odds of an event double with four or five conditions and triple with six or more.5

Improve Appropriate Prescribing
Consider avoiding medications listed on the Beers list of potentially inappropriate medications for older adults. The American Geriatrics Society released its second updated and expanded Beers Criteria in October 2015. The new update can be obtained at Three new medications and two new "classes" of medications have been added to the warning list. One of the additions is proton-pump inhibitors, often prescribed to patients living with acid reflux or stomach ulcers. Multiple studies support a link between these medications and an increased risk for bone loss, fractures, and serious bacterial infections. The Beers Criteria also provide separate guidance on avoiding 13 combinations of medications known to cause harmful drug-drug interactions, which can increase the risk of ADEs ranging from falls and fractures to urinary incontinence or medication toxicity. Also noted is a specific list of 20 potentially problematic medications to avoid or that may require dosage adjustments based on kidney function, which, if not addressed, could elevate the risk for everything from nausea and diarrhea to bleeding, problems with the central nervous system, changes in mental well-being, and bone marrow toxicity.

Utilize STOPP (screening tool of older adults' potentially inappropriate prescriptions) criteria: STOPP criteria identify five medication classes: proton-pump inhibitors, long-acting benzodiazepines, NSAIDs, nonselective beta blockers, and tricyclic antidepressants. These five categories of medications account for nearly 80% of the inappropriate prescribing detected by the STOPP criteria in the outpatient setting. Additionally, utilize START (screening tool to alert to right treatment) criteria, such as an ACE inhibitor in a patient with congestive heart failure.5

Reducing Patient Risks
Focusing on and reducing preventable ADEs remains a high priority focus in all health care settings. Reducing ADE risk can be achieved in a short timeframe through implementation of best evidence-based medication practice guidelines and improved collaboration between health organizations and health care providers. This can best be achieved through the incorporation of a multidisciplinary team approach with increased accountability by all members to implement safe medication practice steps with increased monitoring and reporting of ADEs.

— Mark D. Coggins, PharmD, CGP, FASCP, is senior director of pharmacy services for skilled nursing centers operated by Diversicare in eight states, and is a director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

1. VA Center for Medication Safety, VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. Adverse drug events, adverse drug reactions and medication errors: frequently asked questions. Published November 2006. Accessed October 1, 2015.

2. Zubenko GS, Sunderland T. Geriatric psychopharmacology: why does age matter? Harv Rev Psychiatry. 2000;7(6):311-333.

3. Jacobson SA, Pies RW, Katz IR. Clinical Manual of Geriatric Psychopharmacology. Washington, D.C.: American Psychiatric Publishing; 2007.

4. Medication safety program: adults and older adult adverse drug events. Centers for Disease Control and Prevention website. Updated October 2, 2012. Accessed September 28, 2015.

5. Pretorius RW, Gataric G, Swedlund SK, Miller JR. Reducing the risk of adverse drug events in older adults. Am Fam Physician. 2013;87(5):331-336.

6. Doshi JA, Shaffer T, Briesacher BA. National estimates of medication use in nursing homes: findings from the 1997 Medicare current beneficiary survey and the 1996 medical expenditure survey. J Am Geriatr Soc. 2005;53(3):438-443.

7. Handler SM, Hanlon JT. Detecting adverse drug events using a nursing home specific trigger tool. Ann Longterm Care. 2010;18(5):17-22.

8. Adverse events in nursing homes. Centers for Medicare & Medicaid Services website. Updated September 22, 2015.

9. Beijer HJ, de Blaey CJ. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies. Pharm World Sci. 2002;24(2):46-54.

10. Hanlon JT, Schmader KE, Boult C, et al. Use of inappropriate prescription drugs by older people. J Am Geriatr Soc. 2002;50(1):26-34.

11. Howard RL, Avery AJ, Slavenburg S, et al. Which drugs cause preventable admissions to hospital? A systematic review. Br J Clin Pharmacol. 2006;63(2):136-147.

12. Budnitz DS, Lovegrove MC, Shehab N, Richards CL. Emergency hospitalizations for adverse drug events in older Americans. N Engl J Med. 2011;365(21):2002-2012.

13. Pirmohamed M, James S, Meakin S, et al. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-19.

14. Gurwitz JH, Field TS, Radford MJ, et al. The safety of warfarin therapy in the nursing home setting. Am J Med. 2007;120(6):539-544.

15. Green JL, Hawley JN, Rask KJ. Is the number of prescribing physicians an independent risk factor for adverse drug events in an elderly outpatient population? Am J Geriatr Pharmacother. 2007;5(1):31-39.