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Avoiding Inappropriate Medication Prescription in Older Intensive Care Survivors
From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).
Abstract
- Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
- Methods: Review of the literature.
- Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
- Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.
Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.
Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].
Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].
Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.
Inappropriate Medications at ICU Discharge
Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].
A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].
One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1). 
When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].
Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].
Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].
The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].
Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].
Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].
Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].
Inappropriate Medications at Hospital Discharge
Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].
Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].
Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].
Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].
Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].
Inappropriate Medications: Where and How to Intervene?
Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).
Criteria for the Evaluation of Inappropriate Medications Prescription
Explicit criteria derived from expert reports or published reviews are available (Table 2).
Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79]. 
Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].
The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.
Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].
Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].
Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly
Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3. 
Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly
Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4). 
Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).
Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].
Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].
Conclusion
Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.
Corresponding author: Alessandro Morandi, MD, MPH, [email protected].
Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).
Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.
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From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).
Abstract
- Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
- Methods: Review of the literature.
- Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
- Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.
Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.
Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].
Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].
Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.
Inappropriate Medications at ICU Discharge
Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].
A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].
One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1).
When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].
Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].
Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].
The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].
Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].
Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].
Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].
Inappropriate Medications at Hospital Discharge
Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].
Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].
Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].
Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].
Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].
Inappropriate Medications: Where and How to Intervene?
Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).
Criteria for the Evaluation of Inappropriate Medications Prescription
Explicit criteria derived from expert reports or published reviews are available (Table 2).
Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79].
Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].
The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.
Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].
Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].
Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly
Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3.
Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly
Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4).
Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).
Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].
Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].
Conclusion
Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.
Corresponding author: Alessandro Morandi, MD, MPH, [email protected].
Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).
Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.
From the Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Marra), Division of Anesthesiology Critical Care Medicine, Vanderbilt University Medical Center, Nashville, TN (Dr. Hayhurst, Dr. Hughes, Dr. Pandharipande), Department of Clinical and Experimental Science, University of Brescia, Brescia, Italy (Dr. Marengoni), School of Medicine and Surgery,
University of Milano-Bicocca, Milan, Italy (Dr. Bellelli), and Rehabilitation and Aged Care Unit Hospital Ancelle, Cremona, Italy (Dr. Morandi).
Abstract
- Objective: To present an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examine possible strategies of intervention.
- Methods: Review of the literature.
- Results: Polypharmacy and inappropriate prescribing of medications in older persons may lead to a significant risk of adverse drug-related events and mortality. The intensive care unit (ICU) is often the place where potentially inappropriate medications (PIMs) are first prescribed. Common PIMs at ICU discharge are antipsychotics, benzodiazepines, opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension. Different classes of medications, typically intended for short-term use, are sometimes inappropriately continued after discharge from the hospital. At admission, potential risk factors for PIM are multiple morbidities, polypharmacy, frailty and cognitive decline; at discharge, a high number of pre-admission PIMs, discharge to a location other than home, discharge from a surgical service, longer length of ICU and hospital stay, and mechanical ventilation. Inappropriate prescribing in older patients can be detected through either the use of explicit criteria, drug utilization reviews, and multidisciplinary teams, including a geriatrician and/or the involvement of a clinical pharmacist.
- Conclusion: Use of PIMs may be common in critical patients, both on admission and at discharge from ICU. Therapeutic reconciliation is recommended at every transition of care (eg, at hospital or ICU admission and discharge) in order to improve appropriateness of prescription.
Key words: elderly; intensive care unit; inappropriate medications; antipsychotics.
Since older persons are often affected by multiple chronic diseases and are prescribed several medications, the quality and safety of prescribing these medications has become a global health care issue [1–4]. Polypharmacy and inappropriate prescribing of medications among the elderly is receiving significant attention in the medical literature [5,6]. Inappropriate medications in the elderly can lead to falls, cognitive impairment and delirium, poorer health status, and higher mortality [7–10]. Medications are considered potentially inappropriate when (a) the risks of treatment outweigh the benefits [11], (b) they are prescribed for periods longer than clinically indicated or without any clear indication, (c) they are not prescribed when indicated [12], and (d) they are likely to interact with other drugs and diseases. Medications included in this category are often referred to as potentially inappropriate medications (PIMs), as in some situations their use is justified; however, if the risk of harm from the drug is judged to outweigh the potential clinical benefit after an individual patient’s clinical circumstances are considered, these drugs are considered “actually inappropriate medications” (AIMs) [6].
Advancing age is associated with substantial pharmacokinetic and pharmacodynamics changes, such as altered distribution volumes and altered permeability of the blood-brain barrier, impaired liver metabolism and renal capacity, up- and down-regulation of target receptors, transmitters, and signaling pathways changes, impaired homeostasis, and increased risk of adverse drug reactions (ADRs) that lead to increased mortality and morbidity and higher health care costs [2,11,13–19]. Studies show that ADRs cause approximately 5% of hospital admissions in the general population, but the percentage rises to 10% in older persons [20].
Avoiding PIMs represents a strategy aimed at reducing drug-related mortality and morbidity. This article provides an overview of the phenomenon of inappropriate medication prescription in older critically ill patients and examines available strategies of intervention.
Inappropriate Medications at ICU Discharge
Though PIMs and AIMs may be identified at the time of hospital discharge, the intensive care unit (ICU) is often the place where these medications are first prescribed [21]. Acute hospitalization may increase PIM prescribing because of newly prescribed medications, the presence of multiple prescribers, inadequate medication reconciliation, and a lack of care coordination among inpatient providers or in the transition back to outpatient care [22)].
A known complication of critical illness and ICU stay is a significant increase in psychological symptoms, sleep cycle alterations, delirium, and cognitive impairment, which may be associated with increased prescription of specific PIMs, such as antipsychotics or benzodiazepines [6,23,24]. Despite the lack of reliable evidence supporting their use in the ICU, antipsychotic agents are used routinely in ICU patients [25] to treat a variety of conditions, such as substance withdrawal, agitation not responding to other therapies, or delirium. Results from a multicenter study of 164,996 hospitalizations across 71 academic medical centers in the US showed that 1 out of 10 ICU patients received an antipsychotic during their hospital stay [25]. Jasiak et al estimated that one-third of patients initiated on an atypical antipsychotic therapy for ICU delirium received a hospital discharge prescription for these medications, with a potential annual outpatient medication cost of approximately $2255 per patient [26].
One potential consequence of antipsychotic use in the ICU is their continuation after the transition to other clinical settings, including discharge from the hospital [27] (Table 1).
When examining the specific factors that may contribute to a patient being discharged on an antipsychotic, authors found that the specific antipsychotic used correlated with risk of continuation [27,30], with atypical antipsychotics having a greater likelihood of being continued than haloperidol [27,30]. Possible explanation for these results could be that physicians perceive less long-term risk from atypical agents, so may be more likely to continue them on discharge [30]. However, such an approach is not always safe. Indeed, although atypical antipsychotic agents tend to cause less tardive dyskinesia, they are known to be associated with similar rates of other adverse events compared with typical agents and have been linked to an increased risk of sudden cardiac death and pneumonia in the elderly [31,32].
Other factors independently associated with being discharged on a new antipsychotic medication were the severity of the acute illness as measured with the Acute Physiology and Chronic Health Evaluation II score at ICU admission (odds ratio [OR] 1 [95% confidence interval {CI}, 1.0–1.1]) and days treated with benzodiazepines (OR 1.1 [95% CI, 1.0–1.14]) [30]. Conversely, perhaps due to different practice patterns, Tomichek et al did not find an association between benzodiazepines administration and antipsychotic prescription at discharge in post hoc analyses [27].
Another possible reason for antipsychotic continuation may reside in the indication chosen [33]. Antipsychotic agents have sedative properties and they might be used to optimize sleep during hospitalization, despite the lack of evidence to support this indication [34]. Other factors potentially contributing to continuation of antipsychotics may include persistent delirium and agitation, newly diagnosed psychiatric illness, and difficulties experienced by physicians in deprescribing [35] with improper/incomplete medication reconciliation [33].
The continuation of antipsychotic therapy increased 30-day readmission rates in patients compared to those who had therapy stopped before discharge [33]. In addition to the well-described cardiac effects (prolonged QT interval), neuroleptic malignant syndrome and extrapyramidal symptoms may also occur, and longer-term use can predispose patients to metabolic disturbances, falls, and increase the risk of death in elderly patients with dementia [31].
Benzodiazepines and sedative hypnotics are commonly used to treat insomnia and agitation in older adults despite significant risk. Benzodiazepine administration was found to be an independent risk factor for a daily transition to delirium [36,37]. Pandharipande et al reported that every unit dose of lorazepam was associated with a higher risk for daily transition to delirium (OR 1.2, 95% CI 1.1–1.4, P = 0.003) [36] in critically ill patients. A more recent analysis found for every 5 mg of midazolam administered to a patient who is awake and without delirium, there is a 4% chance that this patient will develop delirium the next ICU day [37].
Given that the risk for benzodiazepine-associated delirium is dose-dependent, clinicians should use strategies known to reduce the daily number of benzodiazepines administered that often includes the use of a sedative associated with less delirium occurrence, such as dexmedetomidine or propofol [38]. Evidence has shown that long-term use of benzodiazepines has little benefit with many risks, including an increased susceptibility to spontaneous bacterial infection [39,40] and mortality in the setting of infection [41]. Nakafero et al showed that exposure to benzodiazepines was associated with increased occurrence of both influenza-like-illness–related pneumonia and mortality. Benzodiazepine use was associated also with increased occurrence of asthma exacerbation and with increased all-cause mortality during a median follow-up of 2 years in a cohort of asthmatic patients [42] as well with an increased risk of pneumonia and long-term mortality in patients with a prior diagnosis of community- acquired pneumonia [40]. Long-term use of benzodiazepines is also associated with increased risk of falls [43–45], cognitive impairment [46–48] and disability [49,50].
Other common types of PIMs at ICU discharge were opioids, anticholinergic medications, antidepressants, and drugs causing orthostatic hypotension [6]. Of the anticholinergic AIMs, H2 blockers (61%) and promethazine (15%) were the most common [6]. Only 16% of opioids, 23% of antidepressants, and 10% of drugs causing orthostatic hypotension were found to be actually inappropriate after the patient’s circumstances were considered (eg, postoperative pain control, a new diagnosis of major depressive disorder) [6].
Inappropriate Medications at Hospital Discharge
Medications typically intended for short-term use during acute illness are sometimes continued after discharge without documented indication [51]. Poudel et al found that in 206 patients 70 years of age and older discharged to residential aged care facilities from acute care, at least 1 PIM was identified in 112 (54.4%) patients on admission and 102 (49.5%) patients on discharge [11]. Commonly prescribed PIM categories, at both admission and discharge, were central nervous system, cardiovascular, gastrointestinal, and respiratory drugs and analgesics [6,11,52,53]. Of all medications prescribed at admission (1728), 10.8% were PIMs, and at discharge, of 1759 medications, 9.6% were PIMs. Of the total 187 PIMs on admission, 56 (30%) were stopped, and 131 (70%) were continued; 32 new PIMs were introduced [11].
Morandi et al in 2011 conducted a prospective cohort study including 120 patients age ≥ 60 who were discharged after receiving care in a medical, surgical, or cardiovascular ICU for shock or respiratory failure. The percentage of patients prescribed at least 1 PIM increased from 66% at pre-admission to 85% at discharge. The number of patients with 0 PIMs dropped from 34% at preadmission to 14% at discharge, and the number of patients with 3 or more PIMS increased from 16% at preadmission to 37% at discharge. While it is possible that these drugs may be appropriate when started during an acute illness in the ICU (eg, stress ulcer prophylaxis with H2-antagonists in mechanically ventilated patients), most should have been discontinued at ICU and/or hospital discharge [21].
Inappropriate prescriptions of proton pump inhibitors (PPIs) in hospital and primary care have been widely reported [54,55]. In a study conducted by Ahrens et al in 31 primary care practices, for 58% (263/506) of patients discharged from 35 hospitals with a PPI recommendation in hospital discharge letters, an appropriate indication was missing. In 57% of these cases general practitioners followed this recommendation and continued the prescription for more than 1 month [54]. The strongest factor associated with appropriate and inappropriate continuation of PPI after discharge was PPI prescription prior to hospitalization [54]. Although PPIs are safe, they can cause adverse effects. PPI intake has been found to have a significant association with risk of community-acquired pneumonia [56,57], hip fractures [58], Clostridium difficile-associated diarrhea [55,61,62], and to reduce the therapeutic effects of bisphosphonates [59] and low-dose aspirin [60].
Unintentional medication continuation is not a problem isolated to a single drug class or disease [63]. Scales et al evaluated rates of and risk factors for potentially unintentional medication continuation following hospitalization in a population of elderly patients (≥ 66 years) [51]. They created distinct cohorts by identifying seniors not previously receiving four classes of medications typically used to treat or prevent complications of acute illness: antipsychotic medications; gastric acid suppressants (ie, histamine-2 blockers and proton pump inhibitors); benzodiazepines; and inhaled bronchodilators and steroids [51]. Prescription without documented indication occurred across all medication classes, from 12,209 patients (1.4 %) for antipsychotic medications to 34,140 patients (6.1 %) for gastric acid suppressants [51].
Several potential risk factors were considered. The relationship between multimorbidity and polypharmacy is well described in the literature, and several studies have identified a positive association between the number of drugs and the use of PIMs [64–66]. Conversely, Poudel et al did not find any association between polypharmacy and PIM use [11]. Associations were found between the use of PIMs, frailty status, and cognitive decline of patients at admission and at discharge [11], while no association was observed with age, gender, in-hospital falls, delirium, and functional decline [11,67]. Other potential risk factors of a high number of PIMs at discharge were a high number of pre-admission PIMs, discharge to a location other than home, and discharge from a surgical service [1,6,68,69]. Length of ICU stay and mechanical ventilation had a positive influence on the number of PIMs used by acutely ill older patients [11,63,69]. In the study of Scales et al, the greatest absolute risk factor across all medication groups was longer hospitalization. The increased OR for medication continuation after a hospitalization lasting more than 7 days ranged from 2.03 (95% CI 1.94–2.11) for respiratory inhalers to 6.35 (95% CI 5.91–6.82) for antipsychotic medications [51].
Inappropriate Medications: Where and How to Intervene?
Early detection of PIMs may prevent adverse drug events and improve geriatric care in older adults [13,70]. PIM prevalence can often be a useful indicator of prescribing quality [2]. Appropriate interventions and an improved quality of prescribed medications require appropriate assessment tools to decrease the number of patients discharged on these medications [71,72]. Medication reconciliation is the process of avoiding inadvertent inconsistencies within a patient’s drug regimen, which can occur during transitions in different setting of care [73]. A multidisciplinary team should be involved in the medication reconciliation at each care transition to reevaluate medications use according to the clinical conditions, cognitive/functional status and the coexistence of geriatric syndromes (eg, dementia, malnutrition, delirium, urinary incontinence, frailty) (Figure).
Criteria for the Evaluation of Inappropriate Medications Prescription
Explicit criteria derived from expert reports or published reviews are available (Table 2).
Beers criteria PIMs have been found to be associated with poor health outcomes, including confusion, falls, and mortality [7,75,78]. The STOPP (Screening Tool of Older Person’s potentially inappropriate Prescriptions) and START (Screening Tool to Alert doctors to the Right Treatment) are evidence-based sets of criteria that were developed in Ireland and updated in October 2014, including some of the new criteria for direct oral anticoagulants, drugs affecting or affected by renal system and anti-muscarinic/anticholinergic agents [79].
Several other sets of criteria have been published to identify PIMs, such as the FORTA (Fit for the Aged) and the PRISCUS [86] criteria. FORTA allows a disease-related evaluation revealing over-treatment and under-treatment, and medications are graded as follows: A, indispensable drug, clear-cut benefit in terms of efficacy/safety ratio proven in elderly patients for a given indication; B, drugs with proven or obvious efficacy in the elderly, but limited extent of effect or safety concerns; C, drugs with questionable efficacy/safety profiles in the elderly which should be avoided or omitted in the presence of too many drugs or side effects; D, avoid in the elderly, omit first, refer also to negative listings. Negative lists such as PRISCUS, which provide an explicit listing of drugs, independent of the diagnosis, are easy to use. On the other hand, constant updates are needed, and such lists carry the risk of an assumption that drugs not listed would be appropriate in every case [87]. Both sets of criteria have in common that they refer to long-term medication and drugs frequently used during the inpatient stay, such as antibiotics, are hardly taken into account [87].
The Medication Appropriateness Index measures overall prescribing quality through 10 separate but interrelated domains [8]. Three components are used to detect PIMs: indication, effectiveness, and duplication. However, it does not give any precise guidance in relation to specific medicines and therefore has limited application for objectively defining PIMs.
Another prescribing quality assessment tool is the Inappropriate Prescribing in the Elderly Tool (IPET), which consists of a list of the 14 most prevalent prescription errors identified from an extensive list of inappropriate prescription instances drawn up by an expert Canadian Consensus Panel [88,89].
Another approach to assess the appropriateness of drugs prescribed for older people is the use of Drug Utilization Reviews (DURs) [16]. DURs use consensus opinion by drug therapy experts to define standards or explicit criteria for a single drug, class of drugs, or group of drugs [16]. DURs typically use retrospective information from large, nonclinical administrative databases to identify problems such as dosage range, duration, therapeutic duplication, and drug interactions [90, 91]. Monane et al [92] evaluated a program designed to decrease the use of PIMs among the elderly through a computerized online DUR database. Computer alerts triggered telephone calls to physicians by pharmacists to discuss a potential problem and any therapeutic substitution options. From a total of 43,007 telepharmacy calls generated by the alerts, they were able to reach 19,368 physicians regarding 24,266 alerts (56%). The rate of change to a more appropriate therapeutic agent was 24% (5860), but ranged from 40% for long half-life benzodiazepines to 2% to 7% for drugs that theoretically were contraindicated by patients’ self-reported history [92].
Computerized Support Systems to Reduce Inappropriate Prescribing in the Elderly
Other potential solutions for reducing inappropriate medications may include continuing medical education, electronic medical records surveillance, routine clinical evaluation, and/or improved hand-off communication between discharging and accepting providers. Incorporating this assessment of medication appropriateness into the medication reconciliation process when patients are discharged or transferred out of the ICU has the potential to enhance patient safety [21,93]. A randomized controlled trial conducted by Raebel et al [94] reported the effectiveness of a computerized pharmacy alert system plus collaboration between health care professionals for decreasing potentially inappropriate medication dispensing in elderly patients. Another study showed that computer-based access to complete drug profiles and alerts about potential prescribing problems reduced the occurrence of potentially inappropriate prescriptions [95]. A summary of these studies is shown in Table 3.
Interdisciplinary Teams to Reduce Inappropriate Prescribing in the Elderly
Some studies evaluated the effect of multidisciplinary teamwork in improving inappropriate medication prescribing in the elderly (Table 4).
Pharmacists in hospitals can play a significant role in the initiation of changes to patient’s therapy and management [11] (Table 5).
Mattison et al recently emphasized that studies of PIMs should determine scenarios in which it is appropriate to prescribe PIMs, moving beyond simply labeling some medications as “potentially inappropriate,” since some PIMs are appropriately prescribed in specific clinical situations [109]. Morandi et al showed that the positive predictive value (PPV) depends on the drug type. Thus, when developing a screening system, one cannot be concerned only with high negative predictive value (NPV), one must consider PPV as well [6]. Screening tools that include medication classes with low PPV will generate false positive “flags” or warnings, which could lead to misguided clinical decisions [6]. The fact that many PIMs are not AIMs also reveals the value of using a multidisciplinary team to identify AIMs from lists of PIMs generated when discharge medication lists are screened [6,110]. Thus, a multidisciplinary team is needed to consider the clinical context to distinguish PIMs from AIMs [6]. Of course, such a team is not available in some settings; when resources are limited, knowledge of which PIMs are most likely AIMs (ie, have high PPVs) could guide the development of computer-based decision support systems or other surveillance approaches that are efficient in that particular setting [6].
Approaches for optimizing prescribing in this population mainly depend on patient needs and comorbidities and most available data are derived from randomized controlled trials involving a single drug. Such trials do not take into account the confounding effects of multiple comorbidities and patient preferences. Therefore, approaches for optimizing prescription management that are available for and validated in younger patients are not applicable to elderly subjects [3,111].
Conclusion
Clinicians should seek to identify and discontinue AIMs at 3 important transitions during a critically ill elderly patient’s hospital course: at the time of hospital or ICU admission; at ICU discharge; and at hospital discharge. The patient’s clinical situation should be reviewed at every transition points, ideally by a multidisciplinary team of clinicians, to judge the appropriateness of each PIM [6]. After the hospital discharge, patient’s medications should be then reviewed by a multidisciplinary team and/or by the primary care physician according to the final discharge destination (ie, home, nursing home, rehabilitation) by using any of the validated tools. Regardless of the approach, it is clear that standardized care processes, including enhanced clinical decision support, are necessary to ensure that physicians do not continue exposing our patients to unnecessary medications and harm after discharge.
Corresponding author: Alessandro Morandi, MD, MPH, [email protected].
Funding/support: Dr. Pandiharipande is supported by National Institutes of Health HL111111 (Bethesda, MD) and by the VA Clinical Science Research and Development Service (Washington, DC) and the National Institutes of Health AG027472 and AG035117 (Bethesda, MD).
Financial disclosures: Dr. Pratik Pandharipande has received a research grant from Hospira Inc in collaboration with the NIH.
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67. Ruggiero C, Dell’Aquila G, Gasperini B, et al. Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project. Drugs Aging 2010;27:747–58.
68. Onder G, Landi F, Cesari M, et al. Inappropriate medication use among hospitalized older adults in Italy: results from the Italian Group of Pharmacoepidemiology in the Elderly. Eur J Clin Pharmacol 2003;59:157–62.
69. Harugeri A, Joseph J, Parthasarathi G, et al. Potentially inappropriate medication use in elderly patients: A study of prevalence and predictors in two teaching hospitals. J Postgrad Med 2010;56:186–91.
70. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med 2010;170:1648–54.
71. Dimitrow MS, Airaksinen MS, Kivela SL, et al. Comparison of prescribing criteria to evaluate the appropriateness of drug treatment in individuals aged 65 and older: a systematic review. J Am Geriatr Soc 2011;59:1521–30.
72. Levy HB, Marcus EL, Christen C. Beyond the beers criteria: A comparative overview of explicit criteria. Ann Pharmacother 2010;44:1968–75.
73. Marengoni A, Nobili A, Onder G. Best practices for drug prescribing in older adults: a call for action. Drugs Aging 2015;32:887–90.
74. Poudel A, Hubbard RE, Nissen L, Mitchell C. Frailty: a key indicator to minimize inappropriate medication in older people. QJM 2013;106:969–75.
75. American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227–46.
76. Beers MH, Ouslander JG, Rollingher I, et al. Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine. Arch Intern Med 1991;151:1825–32.
77. Blanco-Reina E, Ariza-Zafra G, Ocana-Riola R, Leon-Ortiz M. 2012 American Geriatrics Society Beers criteria: enhanced applicability for detecting potentially inappropriate medications in European older adults? A comparison with the Screening Tool of Older Person’s Potentially Inappropriate Prescriptions. J Am Geriatr Soc 2014;62:1217–23.
78. Stockl KM, Le L, Zhang S, Harada AS. Clinical and economic outcomes associated with potentially inappropriate prescribing in the elderly. Am J Manag Care 2010;16:e1–10.
79. Hill-Taylor B, Sketris I, Hayden J, et al. Application of the STOPP/START criteria: a systematic review of the prevalence of potentially inappropriate prescribing in older adults, and evidence of clinical, humanistic and economic impact. J Clin Pharm Ther 2013;38:360–72.
80. Barry PJ, Gallagher P, Ryan C, O’Mahony D. START (screening tool to alert doctors to the right treatment)--an evidence-based screening tool to detect prescribing omissions in elderly patients. Age Ageing 2007;36:632–8.
81. Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony D. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther 2008;46:72–83.
82. Haag JD, Davis AZ, Hoel RW, et al. Impact of pharmacist-provided medication therapy management on healthcare quality and utilization in recently discharged elderly patients. Am Health Drug Benefits 2016;9:259–68.
83. Gillespie U, Alassaad A, Hammarlund-Udenaes M, et al. Effects of pharmacists’ interventions on appropriateness of prescribing and evaluation of the instruments’ (MAI, STOPP and STARTs’) ability to predict hospitalization--analyses from a randomized controlled trial. PLoS One 2013;8:e62401.
84. Petrarca AM, Lengel AJ, Mangan MN. Inappropriate medication use in the elderly. Consult Pharm 2012;27:583–6.
85. Lavan AH, Gallagher P, Parsons C, O’Mahony D. STOPPFrail (Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy): consensus validation. Age Ageing 2017;46:600–7.
86. Holt S, Schmiedl S, Thurmann PA. Potentially inappropriate medications in the elderly: the PRISCUS list. Dtsch Arztebl Int 2010;107:543–51.
87. Wickop B, Harterich S, Sommer C, et al. Potentially inappropriate medication use in multimorbid elderly inpatients: differences between the FORTA, PRISCUS and STOPP ratings. Drugs Real World Outcome 2016;3:317–25.
88. Naugler CT, Brymer C, Stolee P, Arcese ZA. Development and validation of an improving prescribing in the elderly tool. Can J Clin Pharmacol 2000;7:103–7.
89. Barry PJ, O’Keefe N, O’Connor KA, O’Mahony D. Inappropriate prescribing in the elderly: a comparison of the Beers criteria and the improved prescribing in the elderly tool (IPET) in acutely ill elderly hospitalized patients. J Clin Pharm Ther 2006;31:617–26.
90. Knapp DA. Development of criteria for drug utilization review. Clin Pharmacol Ther 1991;50(5 Pt 2):600–2.
91. Lipton HL, Bird JA. Drug utilization review in ambulatory settings: state of the science and directions for outcomes research. Med Care 1993;31:1069–82.
92. Monane M, Matthias DM, Nagle BA, Kelly MA. Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer. JAMA 1998;280:1249–52.
93. Kaur S, Mitchell G, Vitetta L, Roberts MS. Interventions that can reduce inappropriate prescribing in the elderly: a systematic review. Drugs Aging 2009;26:1013–28.
94. Raebel MA, Charles J, Dugan J, et al. Randomized trial to improve prescribing safety in ambulatory elderly patients. J Am Geriatr Soc 2007;55:977–85.
95. Tamblyn R, Huang A, Perreault R, et al. The medical office of the 21st century (MOXXI): effectiveness of computerized decision-making support in reducing inappropriate prescribing in primary care. CMAJ 2003;169:549–56.
96. Dalleur O, Boland B, Losseau C, et al. Reduction of potentially inappropriate medications using the STOPP criteria in frail older inpatients: a randomised controlled study. Drugs Aging 2014;31:291–8.
97. Schmader KE, Hanlon JT, Pieper CF, et al. Effects of geriatric evaluation and management on adverse drug reactions and suboptimal prescribing in the frail elderly. Am J Med 2004;116:394–401.
98. Crotty M, Halbert J, Rowett D, et al. An outreach geriatric medication advisory service in residential aged care: a randomised controlled trial of case conferencing. Age Ageing 2004;33:612–7.
99. Allard J, Hebert R, Rioux M, et al. Efficacy of a clinical medication review on the number of potentially inappropriate prescriptions prescribed for community-dwelling elderly people. CMAJ 2001;164:1291–6.
100. Spinewine A, Swine C, Dhillon S, et al. Effect of a collaborative approach on the quality of prescribing for geriatric inpatients: a randomized, controlled trial. J Am Geriatr Soc 2007;55:658–65.
101. Elliott RA, Woodward MC, Oborne CA. Improving benzodiazepine prescribing for elderly hospital inpatients using audit and multidisciplinary feedback. Intern Med J 2001;31:529–35.
102. Saltvedt I, Spigset O, Ruths S, et al. Patterns of drug prescription in a geriatric evaluation and management unit as compared with the general medical wards: a randomised study. Eur J Clin Pharmacol 2005;61:921–8.
103. Hanlon JT, Weinberger M, Samsa GP, et al. A randomized, controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in elderly outpatients with polypharmacy. Am J Med 1996;100:428–37.
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107. Belfield KD, Kuyumjian AG, Teran R, et al. Impact of a collaborative strategy to reduce the inappropriate use of acid suppressive therapy in non-intensive care unit patients. Ann Pharmacother 2017;51:577–83.
108. Crotty M, Rowett D, Spurling L, et al. Does the addition of a pharmacist transition coordinator improve evidence-based medication management and health outcomes in older adults moving from the hospital to a long-term care facility? Results of a randomized, controlled trial. Am J Geriatr Pharmacother 2004;2:257–64.
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65. Gallagher PF, Barry PJ, Ryan C, et al. Inappropriate prescribing in an acutely ill population of elderly patients as determined by Beers’ Criteria. Age Ageing 2008;37:96–101.
66. Montastruc F, Duguet C, Rousseau V, et al. Potentially inappropriate medications and adverse drug reactions in the elderly: a study in a PharmacoVigilance database. Eur J Clin Pharmacol 2014;70:1123–7.
67. Ruggiero C, Dell’Aquila G, Gasperini B, et al. Potentially inappropriate drug prescriptions and risk of hospitalization among older, Italian, nursing home residents: the ULISSE project. Drugs Aging 2010;27:747–58.
68. Onder G, Landi F, Cesari M, et al. Inappropriate medication use among hospitalized older adults in Italy: results from the Italian Group of Pharmacoepidemiology in the Elderly. Eur J Clin Pharmacol 2003;59:157–62.
69. Harugeri A, Joseph J, Parthasarathi G, et al. Potentially inappropriate medication use in elderly patients: A study of prevalence and predictors in two teaching hospitals. J Postgrad Med 2010;56:186–91.
70. Garfinkel D, Mangin D. Feasibility study of a systematic approach for discontinuation of multiple medications in older adults: addressing polypharmacy. Arch Intern Med 2010;170:1648–54.
71. Dimitrow MS, Airaksinen MS, Kivela SL, et al. Comparison of prescribing criteria to evaluate the appropriateness of drug treatment in individuals aged 65 and older: a systematic review. J Am Geriatr Soc 2011;59:1521–30.
72. Levy HB, Marcus EL, Christen C. Beyond the beers criteria: A comparative overview of explicit criteria. Ann Pharmacother 2010;44:1968–75.
73. Marengoni A, Nobili A, Onder G. Best practices for drug prescribing in older adults: a call for action. Drugs Aging 2015;32:887–90.
74. Poudel A, Hubbard RE, Nissen L, Mitchell C. Frailty: a key indicator to minimize inappropriate medication in older people. QJM 2013;106:969–75.
75. American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2015 updated Beers criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc 2015;63:2227–46.
76. Beers MH, Ouslander JG, Rollingher I, et al. Explicit criteria for determining inappropriate medication use in nursing home residents. UCLA Division of Geriatric Medicine. Arch Intern Med 1991;151:1825–32.
77. Blanco-Reina E, Ariza-Zafra G, Ocana-Riola R, Leon-Ortiz M. 2012 American Geriatrics Society Beers criteria: enhanced applicability for detecting potentially inappropriate medications in European older adults? A comparison with the Screening Tool of Older Person’s Potentially Inappropriate Prescriptions. J Am Geriatr Soc 2014;62:1217–23.
78. Stockl KM, Le L, Zhang S, Harada AS. Clinical and economic outcomes associated with potentially inappropriate prescribing in the elderly. Am J Manag Care 2010;16:e1–10.
79. Hill-Taylor B, Sketris I, Hayden J, et al. Application of the STOPP/START criteria: a systematic review of the prevalence of potentially inappropriate prescribing in older adults, and evidence of clinical, humanistic and economic impact. J Clin Pharm Ther 2013;38:360–72.
80. Barry PJ, Gallagher P, Ryan C, O’Mahony D. START (screening tool to alert doctors to the right treatment)--an evidence-based screening tool to detect prescribing omissions in elderly patients. Age Ageing 2007;36:632–8.
81. Gallagher P, Ryan C, Byrne S, Kennedy J, O’Mahony D. STOPP (Screening Tool of Older Person’s Prescriptions) and START (Screening Tool to Alert doctors to Right Treatment). Consensus validation. Int J Clin Pharmacol Ther 2008;46:72–83.
82. Haag JD, Davis AZ, Hoel RW, et al. Impact of pharmacist-provided medication therapy management on healthcare quality and utilization in recently discharged elderly patients. Am Health Drug Benefits 2016;9:259–68.
83. Gillespie U, Alassaad A, Hammarlund-Udenaes M, et al. Effects of pharmacists’ interventions on appropriateness of prescribing and evaluation of the instruments’ (MAI, STOPP and STARTs’) ability to predict hospitalization--analyses from a randomized controlled trial. PLoS One 2013;8:e62401.
84. Petrarca AM, Lengel AJ, Mangan MN. Inappropriate medication use in the elderly. Consult Pharm 2012;27:583–6.
85. Lavan AH, Gallagher P, Parsons C, O’Mahony D. STOPPFrail (Screening Tool of Older Persons Prescriptions in Frail adults with limited life expectancy): consensus validation. Age Ageing 2017;46:600–7.
86. Holt S, Schmiedl S, Thurmann PA. Potentially inappropriate medications in the elderly: the PRISCUS list. Dtsch Arztebl Int 2010;107:543–51.
87. Wickop B, Harterich S, Sommer C, et al. Potentially inappropriate medication use in multimorbid elderly inpatients: differences between the FORTA, PRISCUS and STOPP ratings. Drugs Real World Outcome 2016;3:317–25.
88. Naugler CT, Brymer C, Stolee P, Arcese ZA. Development and validation of an improving prescribing in the elderly tool. Can J Clin Pharmacol 2000;7:103–7.
89. Barry PJ, O’Keefe N, O’Connor KA, O’Mahony D. Inappropriate prescribing in the elderly: a comparison of the Beers criteria and the improved prescribing in the elderly tool (IPET) in acutely ill elderly hospitalized patients. J Clin Pharm Ther 2006;31:617–26.
90. Knapp DA. Development of criteria for drug utilization review. Clin Pharmacol Ther 1991;50(5 Pt 2):600–2.
91. Lipton HL, Bird JA. Drug utilization review in ambulatory settings: state of the science and directions for outcomes research. Med Care 1993;31:1069–82.
92. Monane M, Matthias DM, Nagle BA, Kelly MA. Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer. JAMA 1998;280:1249–52.
93. Kaur S, Mitchell G, Vitetta L, Roberts MS. Interventions that can reduce inappropriate prescribing in the elderly: a systematic review. Drugs Aging 2009;26:1013–28.
94. Raebel MA, Charles J, Dugan J, et al. Randomized trial to improve prescribing safety in ambulatory elderly patients. J Am Geriatr Soc 2007;55:977–85.
95. Tamblyn R, Huang A, Perreault R, et al. The medical office of the 21st century (MOXXI): effectiveness of computerized decision-making support in reducing inappropriate prescribing in primary care. CMAJ 2003;169:549–56.
96. Dalleur O, Boland B, Losseau C, et al. Reduction of potentially inappropriate medications using the STOPP criteria in frail older inpatients: a randomised controlled study. Drugs Aging 2014;31:291–8.
97. Schmader KE, Hanlon JT, Pieper CF, et al. Effects of geriatric evaluation and management on adverse drug reactions and suboptimal prescribing in the frail elderly. Am J Med 2004;116:394–401.
98. Crotty M, Halbert J, Rowett D, et al. An outreach geriatric medication advisory service in residential aged care: a randomised controlled trial of case conferencing. Age Ageing 2004;33:612–7.
99. Allard J, Hebert R, Rioux M, et al. Efficacy of a clinical medication review on the number of potentially inappropriate prescriptions prescribed for community-dwelling elderly people. CMAJ 2001;164:1291–6.
100. Spinewine A, Swine C, Dhillon S, et al. Effect of a collaborative approach on the quality of prescribing for geriatric inpatients: a randomized, controlled trial. J Am Geriatr Soc 2007;55:658–65.
101. Elliott RA, Woodward MC, Oborne CA. Improving benzodiazepine prescribing for elderly hospital inpatients using audit and multidisciplinary feedback. Intern Med J 2001;31:529–35.
102. Saltvedt I, Spigset O, Ruths S, et al. Patterns of drug prescription in a geriatric evaluation and management unit as compared with the general medical wards: a randomised study. Eur J Clin Pharmacol 2005;61:921–8.
103. Hanlon JT, Weinberger M, Samsa GP, et al. A randomized, controlled trial of a clinical pharmacist intervention to improve inappropriate prescribing in elderly outpatients with polypharmacy. Am J Med 1996;100:428–37.
104. Lipton HL, Bero LA, Bird JA, McPhee SJ. The impact of clinical pharmacists’ consultations on physicians’ geriatric drug prescribing. A randomized controlled trial. Med Care 1992;30:646–58.
105. Krska J, Cromarty JA, Arris F, et al. Pharmacist-led medication review in patients over 65: a randomized, controlled trial in primary care. Age Ageing 2001;30:205–11.
106. Brown BK, Earnhart J. Pharmacists and their effectiveness in ensuring the appropriateness of the chronic medication regimens of geriatric inpatients. Consult Pharm 2004;19:432–6.
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