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Evaluation of Discharge Medication Orders Following Automatic Therapeutic Substitution of Commonly Exchanged Drug Classes
Automatic therapeutic substitution (ATS) is a mechanism that, upon patient hospitalization, prompts the pharmacist to exchange an equivalent formulary drug for a nonformulary medication, typically without prescriber contact. In facilities utilizing ATS, there is the possibility that physicians and patients may be unaware of the substitution, potentially leading to drug–drug interactions, therapeutic duplication, and/or increased patient expense following discharge should the original regimen not be resumed. The purpose of this study was to determine the frequency with which hospitalized patients subjected to an ATS protocol were not returned to outpatient drug therapy.
A retrospective chart review of adult patients admitted to an academic medical center between January 1 and June 30, 2011, was conducted. Patients were included if they were admitted on angiotensin-converting enzyme (ACE) inhibitors, antidepressants, nonsedating antihistamines, histamine (H2) receptor antagonists, or proton pump inhibitors (PPIs), and were then prescribed a different agent via ATS. Admission and discharge medication reconciliation documents, dictated discharge summaries, and patient education documentation reports were reviewed for drug therapies and doses, as well as medication counseling evidence. The primary endpoint was the percentage of patients not returned to original outpatient therapy following ATS. Secondary endpoints included prescribing events in patients not returned to original therapy, the rate and source of drug therapy counseling at discharge, and the number of patients discharged on a potentially cost-prohibitive drug, defined as any drug available only as a branded product during the study period.
A total of 317 interventions were identified through review of pharmacy records. Of these, 47 patients (15%) were not returned to original outpatient therapy. Within this subsection, 15 patients (32%) were discharged on the substituted drug, eight patients (17%) resumed initial therapy but received a dosage adjustment from previous outpatient therapy, and three patients (6%) were discharged on a drug that was neither the substituted product nor the previous outpatient therapy. The remaining 21 patients had therapy discontinued (n = 12/47, 26%) or lacked documentation of discharge therapy (9/47, 19%). Nursing staff provided medication counseling to 288 of the 317 patients (91%). Overall, 51 patients (16%) were identified as receiving a cost-prohibitive drug.
Patients subject to ATS of commonly substituted drug classes were returned to their original outpatient drug therapy more than 85% of the time following inpatient hospitalizations, with similar rates of medication counseling at discharge. The prescribing of cost-prohibitive drugs has been identified as a potential area for pharmacist intervention at discharge.
Therapeutic interchange, or substitution, occurs when a prescribed drug is exchanged for an alternative agent that is therapeutically equivalent but differs in chemical composition. This alternative agent may be a generic drug, another drug within the same pharmacological class, or a drug from a different class with similar therapeutic effect and potency.1,2 While the terms therapeutic interchange and therapeutic substitution are often used synonymously, the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) 2011 Health Policy Statement considers these to be discrete processes, with interchange occurring after prescriber authorization and substitution occurring without prior prescriber authorization.2
Both therapeutic interchange and substitution may be implemented as a cost-savings mechanism in a variety of practice settings, including hospitals with established formularies, those with collaborative practice agreements, and those with pharmacy benefit contracts.2 Typically, drugs involved in therapeutic interchange or substitution belong to pharmacological classes with numerous, similar agents. A 2002 survey by Schachtner et al. identified the 11 medication classes most commonly involved with therapeutic interchange: histamine H2 receptor antagonists, proton pump inhibitors (PPIs), ant-acids, quinolones, potassium supplements, first-, second-, and third-generation cephalosporins, hydroxymethylglutaryl CoA (HMG-CoA) reductase inhibitors, insulin, and laxatives/stool softeners. Survey results reported savings realized through therapeutic interchange varied widely among institutions, from less than $10,000 to greater than $1 million annually.3 Despite the variability and potential costs associated with implementation, use of therapeutic interchange among American hospitals has increased significantly over the past 30 years, from 31% in 1982 to 92% in 2010.4,5
Examined from a clinical and humanistic perspective, the utilization of therapeutic substitution may inadvertently expose patients to situations that complicate care, either during hospitalization or after discharge. Facility procedure or protocol may not require prescriber notification in the event of therapeutic exchange, increasing the risk of confusion or drug–drug interactions during hospitalization. Following discharge, the patient or caregiver may experience uncertainty with the discharge medication regimen, as illustrated in a 2002 study by Sodorff and colleagues, which found that 36% of patients subject to PPI therapeutic interchange were unaware a change in therapy had occurred.6 This is problematic because patients may have a previous home supply available, may be provided with a new agent at discharge, or may acquire another agent based on insurance formulary preferences. Subsequent patient confusion may increase the likelihood of therapeutic duplication or omission, as well as potentially exposing the patient to the risk of additional drug interactions and adverse reactions if overlapping agents are used inappropriately for the same indication.
Patient counseling prior to discharge has been extensively studied in the literature and was recently examined as a component of the medication reconciliation process. Karapinar-Carkit et al. found that medication reconciliation plus patient counseling yielded interventions in 97% of patients, versus 87% with medication reconciliation alone.7 While this study, conducted in the Netherlands, did not include cost barriers as an intervention, the potential exists for identifying cost barriers during patient counseling at discharge. Cost has been recognized as a barrier to medication adherence in numerous patient populations, including the chronically ill and those recently discharged from the hospital.8,9 Additionally, studies have indicated the use of branded medications can lead to cost-related nonadherence.10,11
While the prevalence and implications of discharge discrepancies have been extensively reported in medication reconciliation literature, there remains a paucity of data related to therapy transitions among patients following therapeutic interchange or substitution during hospitalization. The purpose of this study was to determine the frequency with which patients hospitalized at an academic medical center and subjected to an automatic therapeutic substitution (ATS) protocol were not returned to original outpatient drug therapy.
A retrospective chart review of the adult inpatient population admitted to an academic medical center between January 1 and June 30, 2011, was conducted. Eligible individuals were at least 18 years old, were admitted on angiotensin-converting enzyme (ACE) inhibitors, antidepressants, nonsedating antihistamines, H2 receptor antagonists, or PPIs, and were subsequently prescribed an alternative agent via ATS. These five drug classes, previously approved for ATS by the Pharmacy and Therapeutics (P&T) committee, were selected for evaluation based upon overall frequency of use, potential health impact in the event of therapeutic duplication or omission, and cost disparity among formulary and nonformulary agents.
At the time the study was conducted, a combination of electronic patient records and paper medical charts was in use. Admission medication reconciliation was completed manually and included in the patient’s paper medical chart. During hospitalization, prescribers submitted prescriptions through use of computerized prescriber order entry (CPOE). Upon receiving an order suitable for ATS, the processing pharmacist would intervene and complete the order with the P&T-approved agent. Nursing staff was subsequently alerted to the change through an automated comment on the electronic medication administration record (eMAR), stating that a specific medication had been substituted from the original order. At discharge, nursing completed the paper discharge medication list; the patient signed for the list at the time of receipt. After providing the patient with the discharge medication list, nursing documented any patient education in a clinical software program. Medication counseling was recorded within this clinical software program solely as “medications,” with no indication of the individual drugs discussed; however, for this study it was assumed that all drugs on a patient’s discharge medication list were included in this counseling.
Electronic patient records and scanned paper medical charts were reviewed for admission and discharge medication reconciliation documents, dictated discharge summaries, and patient education documentation reports. Data collected included patient demographics; hospital service responsible for care; drug, strength, and dose at admission, following ATS, and at discharge; and documentation of counseling. Clinical software documentation specifically describing “medications” was considered evidence of discharge counseling, and it was assumed that counseling was provided for all drugs on the discharge summary.
The primary endpoint was the percentage of patients not returned to original outpatient therapy following ATS. Secondary endpoints included prescribing events (i.e., discharged on ATS drug, treatment discontinued, lack of documentation, dose changed, drug changed) in patients not returned to original therapy following discharge, with the purpose of determining why patients were not returned to original therapy. These patients were further evaluated by the service, either medical or surgical, responsible for their care during hospitalization and the medication class substituted upon admission. The rate and source of drug therapy discharge counseling was also assessed to see whether patients who had regimen changes were receiving appropriate instruction consistently. To determine whether patients were being prescribed therapies they might later be unable to afford, the number of patients discharged on a cost-prohibitive drug, defined as any drug available only as a branded product during the study period, was an additional secondary endpoint; the service treating these patients during hospitalization was also evaluated.
A total of 317 eligible patients were identified for chart review.
Patient counseling, as recorded by nursing staff, was noted in 288 of 317 patient charts (91%). A total of 29 patients (9%) who were subjected to ATS lacked documentation of medication counseling, including 20 patients returned to original outpatient therapy and two patients who received either dose or therapy changes. Post-ATS drug therapy was unidentified at discharge in the remaining seven patients.
A total of 51 patients (16%) were discharged on cost-prohibitive medications. Medical service lines treated 33 of these individuals (30 insured, three uninsured), with surgical services responsible for the remaining 18 patients. Escitalopram (Lexapro, Forest Laboratories) was the cost-prohibitive therapy recorded most frequently at discharge, documented for 45 insured patients and two uninsured patients. Esomeprazole (Nexium, AstraZeneca) was the discharge therapy for one insured and one uninsured patient. One patient was discharged on bupropion HBr (Aplenzin, Sanofi) and one patient on dexlansoprazole (Dexilant, Takeda). Four of the 47 patients not returned to original therapy (9%) were discharged on a cost-prohibitive ATS medication, two on esomeprazole and two on escitalopram.
Utilization of therapeutic interchange and substitution has tripled during the past 30 years, and utilization rates will likely remain high as health care systems attempt to balance expanded services and increasingly limited budgets.4,5 Agreements vary between institutions, ranging from less formal arrangements between providers and pharmacists to intricate protocols developed through P&T committees. Protocols should be reviewed periodically for appropriateness and should not supersede the clinical judgment of the provider or pharmacist.12 When implementing formulary policies related to therapeutic interchange or substitution, it is also important to recognize the relationship with timely and accurate medication reconciliations and patient counseling to positively impact patient outcomes.13
Medication reconciliation during transition of care has been extensively discussed in the literature and its importance is underscored by continued inclusion in the Joint Commission National Patient Safety Goals.14 Patients transitioning from hospital care to their standard care who experience discharge medication discrepancies are at an increased risk for discomfort, clinical deterioration, and potential harm related to confusion in changing medication regimens.1,15 Additionally, these patients frequently experience delays in starting a medication due to incomplete or inaccurate prescriptions.15 Because ATS leads to a change in patient medication regimens, there is the potential for it to contribute to these problems.
In this study, 15% of patients were not returned to their original outpatient medication regimen following ATS. This rate is at the low end of the range of identified studies evaluating medication discrepancies at discharge, which have reported rates varying from 14% to 71%.15–19 Institution-specific factors that may have influenced the discrepancy rate following ATS include the automatic generation of paper drug discharge summaries based on admission medication records and the ability to compare electronic admission and discharge medication orders side by side.
Despite limited literature on the impact of ATS on discharge prescribing, some information from medication discrepancy investigations can be informative in regard to ATS protocols. Chua et al. and Galt et al. reviewed PPI discrepancies at discharge related to therapeutic interchange. Chua et al. suggested that patients’ confusion regarding discharge medications could lead to compliance issues, therapy omission, or therapy duplication. Galt et al. concluded that most patients would not notice a discordance unless they were filling a new prescription or deciding to use a home drug supply.16,17 Coleman et al. studied medication use in geriatric patients one to three days after discharge, identifying anticoagulants, diuretics, ACE inhibitors, lipid-lowering agents, and PPIs as the drug classes most often involved in discrepancies. “Nonintentional nonadherence,” incomplete or inaccurate prescriptions, and duplication were frequently contributing factors, and patients with at least one identified discrepancy were found to have a higher 30-day rehospitalization rate compared with patients with no discrepancies.18
Patient education during therapeutic interchange and transition of care has been identified as an area for pharmacist intervention to reduce therapeutic duplication.1,2 Guidelines recommend patients be made aware of the interchange and any anticipated impact related to the interchange, while being monitored for unexpected reactions. In addition, patients should be counseled that the new therapy is a replacement within, not an addition to, their current medication regimen. Finally, while it is suggested that patient preference be taken into consideration during therapeutic interchange, it is specifically recommended that mechanisms be in place to permit exceptions to therapeutic interchange as indicated.1,12
These results showed that 91% of patients subjected to ATS received counseling prior to discharge, a finding that may also have contributed to the high rate of patients who were returned to original therapy at discharge. While the overall rate of counseling is notable, attention should be paid to those patients who did not receive counseling, particularly the seven patients whose discharge therapy was unknown and the two patients with dose or therapy changes. Additional research to investigate causality between patient counseling and discharge therapy following ATS may be warranted.
Cost-prohibitive drugs were received by 16% of the patient population at discharge. Although 94% of patients receiving these agents were insured, the true financial burden on individual patients remains unknown. Of concern are the 6% of patients discharged on a cost-prohibitive medication with no insurance coverage. Identifying these patients prior to discharge and providing counseling on available options, whether financial or pharmacological, is vital in preventing loss to follow-up within this population. The high rate of insured patients in this study is aligned with the overall patient population at this facility, where approximately 92% are insured through private insurers, Medicaid, or Medicare (
The current trend toward integrated computer software and CPOE may limit the generalizability of these results for some institutions, particularly those with fully integrated ordering and records systems that provide automated substitution and reconciliation. At the time this study was conducted, ATS was performed manually by a pharmacist during order processing. ATS has since been integrated and is available to the prescriber when the order is placed, prior to pharmacy processing. However, small medical centers may not be capable of, or interested in, transitioning to larger, more integrated computer systems such as these, and may continue to rely on manual substitution and reconciliation. Alternatively, for some institutions, software communication issues may prevent the integration of ordering and records systems, which may also create a heavier reliance on manual substitution and reconciliation. Additionally, while the sample size was relatively small in this six-month review, it is reasonable to expect future studies to find an even smaller sample size: Decreased ATS discrepancies could result as fully integrated ordering and records systems utilize automated substitution and reconciliation processes.
This study was limited by its single-center setting and use of retrospective chart review, relying on accurate documentation and data collection. Pharmacy records used to identify the patient population should provide highly reproducible results, as these rely less on manual documentation and thereby reduce the potential for unintended exclusions, but the fact that the study included only one institution means that the external validity and effect size are likely compromised. The overall rate of conversion at discharge may have been impacted by limiting the investigation to five drug classes. Interestingly, the rate of discrepancy in PPIs following ATS was lower than the 27% to 49% PPI discrepancy rate reported by Chua and colleagues following therapeutic interchange.16 However, the current finding of 15% may be artificially high as a result of the relatively small sample size and the fact that discharge therapy was unknown in 19% of patients. A further limitation was the assumption that nurses counseled patients on all medications at discharge. This was not evaluated beyond reviewing whether nurses electronically indicated that they spoke with the patient about medications. The true rate of discharge counseling is therefore unknown; however, discharge counseling was evaluated in this manner to assess the necessity for further counseling based on current indicated rates. Further assessment is beyond the scope of this study. Conducting this study as a retrospective chart review prevented the investigators from exploring the incidence and impact of therapeutic duplication in patients who received ATS, and which interventions, if any, prevent therapeutic duplications from reaching this patient population following discharge.
Future studies should be prospective in nature in order to yield insight regarding the true rate of therapeutic duplication and any resulting adverse effects that occur in patients not returned to original outpatient therapy following ATS. An additional limitation to other institutions may be the high number of insured patients included in this analysis. In facilities with lower rates of patient insurance coverage, the impact of ATS might be smaller because uninsured patients may already be on the less expensive medications selected as the formulary option due to cost. Finally, by classifying cost-prohibitive drugs as brand-only products, it was assumed that these medications would be considerably more expensive than alternative agents available during the study period. However, these patients may have been enrolled in patient assistance programs, receiving drugs at reduced cost.
This study showed that the majority of patients subjected to ATS at an academic medical center were returned to their original outpatient therapy. Approximately one-third of patients who were not returned to their original outpatient therapy were prescribed the substituted drug at discharge. Medication counseling was provided by nursing staff to more than 90% of patients. Despite the high counseling rate, 16% of the patient population was discharged on cost-prohibitive medications, identifying an area for additional pharmacist intervention at this institution.
Approved ATS Conversions by Medication Class
|Antidepressants||Bupropion HBr||Bupropion HCl SR||≤ 200 mg daily = q.a.m.|
|• 174 mg, 348 mg||1:0.86||201 mg–449 mg daily = b.i.d.|
|• 522 mg||1:0.88||≥ 450 mg daily = t.i.d.|
|Bupropion HCl IR||1:1|
|Bupropion HCl XL||1:1|
|Venlafaxine IR||Venlafaxine XR
|• 50 mg, 100 mg||1:0.75|
|• 200 mg||1:1.13|
|• 37.5/75/150 mg||1:1|
|• 60 mg, 120 mg||1:0.083|
|• 180 mg||1:0.056|
|H2 receptor antagonists||Cimetidine||Famotidine||Daily, b.i.d., or q.h.s. permitted|
|• 200 mg–800 mg (daily or b.i.d.)||1:0.05|
|• 300 mg q.i.d.||1:0.025|
|PPIs||Dexlansoprazole||Esomeprazole||1:0.67||Daily or b.i.d. permitted|
IR = immediate release; XL/XR = extended release; SR = sustained release; q.a.m. = once daily in the morning; b.i.d. = twice daily; t.i.d. = three times daily; q.i.d. = four times daily; q.h.s. = bedtime
aBased on total daily dose of ordered drug
bCaptopril excluded from ACE inhibitor ATS protocol
cMaximum lisinopril 40 mg daily
|Age, mean, years||59||58||60||40|
|Male, n (%)||150 (47)||109 (49)||41 (44)||7,956 (46)|
|Race/ethnicity, n (%)|
|Caucasian||233 (73)||157 (70)||76 (81)||9,543 (56)|
|African-American||81 (25)||63 (28)||18 (19)||6,423 (37)|
|Other/not reported||3 (< 1)||3 (1)||0||1,192 (7)|
|Insurance, n (%)|
|Insured||301 (94)||210 (94)||91 (97)||15,831 (92)|
|Uninsured||15 (5)||12 (5)||3 (3)||1,327 (8)|
|Not reported||1 (< 1)||1 (< 1)||0||0|
Prescribing Events of Discharged Patients by Hospital Service Line
|Not returned to original therapy, n (%)||33 (15)||14 (15)||47 (15)|
|Discharged on ATS medication||9 (4)||6 (6)||15 (5)|
|Therapy discontinued||8 (4)||4 (4)||12 (4)|
|Therapy unknown at discharge||8 (4)||1 (1)||9 (3)|
|Discharged on different dose||6 (3)||2 (2)||8 (3)|
|Discharged on alternative agent||2 (< 1)||1 (1)||3 (< 1)|
|Discharged on cost-prohibitive agent||33 (15)||18 (19)||51 (16)|
Analysis of Discharge Therapy Following ATS
|Age, mean, years||59||59||59||59|
|Male, n (%)||129 (48)||21 (45)||24 (47)||126 (47)|
|Race/ethnicity, n (%)|
|Caucasian||200 (74)||33 (70)||40 (78)||193 (73)|
|African-American||67 (25)||14 (30)||11 (22)||70 (26)|
|Hispanic||2 (< 1)||0||0||2 (< 1)|
|Not reported||1 (< 1)||0||0||1 (< 1)|
|Insurance status, n (%)|
|Insured||256 (95)||45 (96)||48 (94)||253 (95)|
|Uninsured||13 (5)||2 (4)||3 (6)||12 (5)|
|Not reported||1 (< 1)||0||0||1 (< 1)|
|ACE inhibitor||91 (34)||11 (23)||0||102 (38)|
|Antidepressant||72 (27)||5 (11)||48 (94)||29 (11)|
|PPI||54 (20)||6 (13)||3 (6)||57 (21)|
|Antihistamine||32 (12)||1 (2)||0||33 (12)|
|H2 antagonist||21 (8)||3 (6)||0||24 (9)|
|Unknown/discontinued||0||21 (45)||0||21 (8)|
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