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Clinical research study| Volume 124, ISSUE 12, P1136-1142, December 2011

Anticoagulation-associated Adverse Drug Events

DOI:https://doi.org/10.1016/j.amjmed.2011.06.009
Anticoagulation-associated Adverse Drug Events
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      Abstract

      Purpose

      Anticoagulant drugs are among the most common medications that cause adverse drug events (ADEs) in hospitalized patients. We performed a 5-year retrospective study at Brigham and Women's Hospital to determine clinical characteristics, types, root causes, and outcomes of anticoagulant-associated ADEs.

      Methods

      We reviewed all inpatient anticoagulant-associated ADEs, including adverse drug reactions (ADRs) and medication errors, reported at Brigham and Women's Hospital through the Safety Reporting System from May 2004 to May 2009. We also collected data about the cost associated with hospitalizations in which ADRs occurred.

      Results

      Of 463 anticoagulant-associated ADEs, 226 were medication errors (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both a medication error and ADR. Seventy percent of anticoagulant-associated ADEs were potentially preventable. Transcription errors (48%) were the most frequent root cause of anticoagulant-associated medication errors, while medication errors (40%) were a common root cause of anticoagulant-associated ADRs. Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. After an anticoagulant-associated ADR, most hospitalization expenditures were attributable to nursing costs (mean $33,189 per ADR), followed by pharmacy costs (mean $7451 per ADR).

      Conclusion

      Most anticoagulant-associated ADEs among inpatients result from medication errors and are, therefore, potentially preventable. We observed an elevated 30-day mortality rate among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further quality improvement efforts to reduce anticoagulant-associated medication errors are warranted to improve patient safety and decrease health care expenditures.

      Keywords

      Adverse drug events (ADEs), which comprise medication errors and adverse drug reactions (ADRs), represent a major source of harm among hospitalized patients and have been a driving force behind implementation of electronic health records, including computerized provider order entry.
      • Zaidenstein R.
      • Eyal S.
      • Efrati S.
      • et al.
      Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants.
      Pharmacoepidemiol Drug Saf. 2002; 11: 235-238
      , 
      • Silverman J.B.
      • Stapinski C.D.
      • Churchill W.W.
      • et al.
      Multifaceted approach to reducing preventable adverse drug events.
      Am J Health Syst Pharm. 2003; 60: 582-586
      , 
      • Piazza G.
      • Goldhaber S.Z.
      Computerized decision support for the cardiovascular clinician: applications for venous thromboembolism prevention and beyond.
      Circulation. 2009; 120: 1133-1137
      , 
      • Morimoto T.
      • Sakuma M.
      • Matsui K.
      • et al.
      Incidence of adverse drug events and medication errors in Japan: the JADE Study.
      J Gen Intern Med. 2010; 26: 148-153
      , 
      • Hug B.L.
      • Witkowski D.J.
      • Sox C.M.
      • et al.
      Adverse drug event rates in six community hospitals and the potential impact of computerized physician order entry for prevention.
      J Gen Intern Med. 2009; 25: 31-38
      , 
      • Classen D.C.
      • Jaser L.
      • Budnitz D.S.
      Adverse drug events among hospitalized Medicare patients: epidemiology and national estimates from a new approach to surveillance.
      Jt Comm J Qual Patient Saf. 2010; 36: 12-21
      One study reported that 6.5 medication-related adverse events occurred per 100 hospitalizations and estimated that more than one quarter of these events were the result of a medication error.
      • Bates D.W.
      • Cullen D.J.
      • Laird N.
      • et al.
      Incidence of adverse drug events and potential adverse drug events Implications for prevention. ADE Prevention Study Group.
      JAMA. 1995; 274: 29-34
      Medication errors are potentially preventable causes of ADRs that can occur at all stages of the medication process, including prescription, transcription, dispensing, and administration.
      • Poon E.G.
      • Keohane C.A.
      • Yoon C.S.
      • et al.
      Effect of bar-code technology on the safety of medication administration.
      N Engl J Med. 2010; 362: 1698-1707
      , 
      • Poon E.G.
      • Cina J.L.
      • Churchill W.
      • et al.
      Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy.
      Ann Intern Med. 2006; 145: 426-434
      , 
      • Leape L.L.
      • Bates D.W.
      • Cullen D.J.
      • et al.
      Systems analysis of adverse drug events ADE Prevention Study Group.
      JAMA. 1995; 274: 35-43
      , 
      • Grissinger M.C.
      • Hicks R.W.
      • Keroack M.A.
      • et al.
      Harmful medication errors involving unfractionated and low-molecular-weight heparin in three patient safety reporting programs.
      Jt Comm J Qual Patient Saf. 2010; 36: 195-202
      , 
      • Fanikos J.
      • Stapinski C.
      • Koo S.
      • et al.
      Medication errors associated with anticoagulant therapy in the hospital.
      Am J Cardiol. 2004; 94: 532-535
      Compared with nonpreventable events, potentially preventable ADEs have been shown to double the incremental additional length of stay and health care costs attributable to the event.
      • Bates D.W.
      • Spell N.
      • Cullen D.J.
      • et al.
      The costs of adverse drug events in hospitalized patients Adverse Drug Events Prevention Study Group.
      JAMA. 1997; 277: 307-311
      • •
        Most anticoagulant-associated adverse drug events (70%) are potentially preventable.
      • •
        Transcription errors comprise the most frequent root cause of anticoagulant-associated medication errors, and medication errors are a common root cause of anticoagulant-associated adverse drug reactions.
      • •
        After anticoagulant-associated adverse drug reactions, most hospitalization expenditures are attributable to nursing and pharmacy costs.
      • •
        Efforts to minimize anticoagulant-associated medication errors are warranted to improve patient safety and decrease hospitalization costs.
      Anticoagulant drugs, including warfarin, unfractionated heparin, and low-molecular-weight heparin, are among the most commonly implicated medications that cause ADEs in hospitalized patients.
      • Zaidenstein R.
      • Eyal S.
      • Efrati S.
      • et al.
      Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants.
      Pharmacoepidemiol Drug Saf. 2002; 11: 235-238
      , 
      • Morimoto T.
      • Sakuma M.
      • Matsui K.
      • et al.
      Incidence of adverse drug events and medication errors in Japan: the JADE Study.
      J Gen Intern Med. 2010; 26: 148-153
      , 
      • Classen D.C.
      • Jaser L.
      • Budnitz D.S.
      Adverse drug events among hospitalized Medicare patients: epidemiology and national estimates from a new approach to surveillance.
      Jt Comm J Qual Patient Saf. 2010; 36: 12-21
      , 
      • Grissinger M.C.
      • Hicks R.W.
      • Keroack M.A.
      • et al.
      Harmful medication errors involving unfractionated and low-molecular-weight heparin in three patient safety reporting programs.
      Jt Comm J Qual Patient Saf. 2010; 36: 195-202
      , 
      • Fanikos J.
      • Cina J.L.
      • Baroletti S.
      • et al.
      Adverse drug events in hospitalized cardiac patients.
      Am J Cardiol. 2007; 100: 1465-1469
      Despite implementation of computerized provider order entry, electronic medication administration records, and improved infusion pump technology (“smart pumps”), medication errors involving anticoagulant medications remain common.
      • Grissinger M.C.
      • Hicks R.W.
      • Keroack M.A.
      • et al.
      Harmful medication errors involving unfractionated and low-molecular-weight heparin in three patient safety reporting programs.
      Jt Comm J Qual Patient Saf. 2010; 36: 195-202
      , 
      • Fanikos J.
      • Stapinski C.
      • Koo S.
      • et al.
      Medication errors associated with anticoagulant therapy in the hospital.
      Am J Cardiol. 2004; 94: 532-535
      Elderly
      • Hanlon J.T.
      • Pieper C.F.
      • Hajjar E.R.
      • et al.
      Incidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay.
      J Gerontol A Biol Sci Med Sci. 2006; 61: 511-515
      , 
      • Hajjar E.R.
      • Hanlon J.T.
      • Artz M.B.
      • et al.
      Adverse drug reaction risk factors in older outpatients.
      Am J Geriatr Pharmacother. 2003; 1: 82-89
      and cardiac patients
      • Fanikos J.
      • Cina J.L.
      • Baroletti S.
      • et al.
      Adverse drug events in hospitalized cardiac patients.
      Am J Cardiol. 2007; 100: 1465-1469
      represent populations at particularly high risk for suffering anticoagulant-associated ADRs.
      To determine the clinical characteristics, types, severity, root causes, and outcomes of anticoagulant-associated ADEs, we performed a 5-year retrospective study of the Safety Reporting System at Brigham and Women's Hospital. We reviewed discrete ADEs that originated during hospitalization at Brigham and Women's Hospital. We also conducted an analysis of the cost associated with hospitalizations in which ADRs occurred.

      Methods

      Patient Population

      Brigham and Women's Hospital is a 793-bed acute tertiary care facility providing medical and surgical care for patients with general medical, cardiothoracic, orthopedic, oncologic, neurologic, obstetric and gynecologic, neonatal, urologic, and gastrointestinal conditions. Brigham and Women's Hospital utilizes a Medical Informatics System that integrates an online medical record, computerized provider order entry, an electronic medication administration record, and an electronic safety reporting system. The Safety Reporting System is a voluntary computerized reporting system for ADRs and medication errors, which was instituted in May 2004.

      Data Collection

      We reviewed all inpatient anticoagulant-associated ADEs, including ADRs and medication errors, reported at Brigham and Women's Hospital through the Safety Reporting System from May 2004 to May 2009. Inpatient events for the purpose of our study were required to have originated during hospitalization at Brigham and Women's Hospital. We excluded reported anticoagulant-associated ADEs that took place in the Emergency Department, Operating Room, Cardiac Catheterization Laboratory, Cardiovascular Recovery Room, Post-Anesthesia Care Unit, and Neonatal Intensive Care Unit because medication administration records were not consistently computerized in these units during the registry period. We defined an ADR as a response to a drug normally used for prophylaxis or therapy of disease and that was noxious and unintended.
      • Nebeker J.R.
      • Barach P.
      • Samore M.H.
      Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting.
      Ann Intern Med. 2004; 140: 795-801
      A medication error was defined as an event that caused or led to inappropriate medication use or patient harm.
      • Nebeker J.R.
      • Barach P.
      • Samore M.H.
      Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting.
      Ann Intern Med. 2004; 140: 795-801
      A medication error that was discovered and corrected before reaching the patient was classified as a near miss. All isolated medication errors and ADRs that resulted from medication errors were considered potentially preventable.
      We searched the Safety Reporting System using Risk Monitor Pro (rL Solutions, Inc., Cambridge, Mass). We evaluated the patient characteristics, ADE type and severity, root cause, and outcomes of all anticoagulation-associated medication errors and ADRs. All patient records were reviewed for evidence of treatment with an anticoagulant medication. Hemorrhagic events were classified according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria for severe or life-threatening, moderate, or mild bleeding.
      An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction The GUSTO investigators.
      N Engl J Med. 1993; 329: 673-682
      We obtained 30-day follow-up for 100% of patients included in the registry.
      We included all anticoagulant medications administered for prophylaxis and treatment of thromboembolic events. ADEs associated with the use of the following anticoagulants were reviewed: unfractionated heparin, low-molecular-weight heparin, fondaparinux, warfarin, and direct thrombin inhibitors, such as argatroban, bivalirudin, and lepirudin. A multidisciplinary team, including physicians, pharmacists, and a hospital patient safety officer, reviewed all reported anticoagulant-related events and evaluated the root case of all ADEs.
      We also collected data about the cost associated with hospitalizations in which ADEs occurred. Because medication errors that do not culminate in an ADR do not add significant incremental cost to hospitalization, we included only ADRs in our cost analysis. ADRs that added significant incremental cost to hospitalization were distinguished from those that did not by consensus of a physician (GP), pharmacist (TNN), and patient safety officer (KF). While patients may have suffered multiple ADRs during a hospital admission, we analyzed costs incurred after the initial event. We utilized a software program for cost accounting that is capable of tabulating the cost associated with a patient admission (Transitions System Incorporated, Waltham, Mass). We sorted costs by the following categories: nursing, pharmacy, blood products, clinical laboratory, radiology, surgery, nonsurgical intervention, and anesthesia. We compared total and component costs of hospitalization for admissions in which an ADR occurred and added incremental expense with those for admissions in which an ADR occurred but was not determined to incur incremental cost.

      Statistical Methods

      Descriptive statistics including baseline characteristics; variables related to ADEs and those pertaining to outcomes were stratified as continuous or binary. Continuous variables were presented as medians with interquartile ranges. Binary variables were presented as numbers and proportions. Cost variables were presented as means with standard deviations and were compared using a 2-sample t-test. All reported P-values were 2-sided, and a P-value of <.05 was considered statistically significant. All statistical analyses were performed using STATA version 9.2 (STATA Corp., College Station, Tex).

      Results

      Baseline Characteristics

      Patients who suffered anticoagulant-associated ADEs had a median age of 62 years (Table 1). Their median body mass index was 27.4 kg/m2. Patients who suffered anticoagulant-associated ADEs had a median length of stay of 13 days. Patients with anticoagulant-associated ADEs had a high frequency of medical conditions, such as atrial fibrillation, history of deep vein thrombosis or pulmonary embolism, heart failure, ischemic heart disease, chronic kidney disease, and stroke, that increase the risk of thromboembolism.
      Table 1Baseline Characteristics and Medical Conditions in Patients with Anticoagulation-associated Adverse Drug Events (ADEs) (n=463)
      Patients could have had more than 1 ADE.
      Baseline characteristic
       Median age on admission, years (interquartile range)62 (49-72)
       Age >75 years, n (%)92 (19.9)
       Male, n (%)246 (53.1)
       Median body mass index, kg/m2 (interquartile range)27.4 (23.8-33.1)
       Median length of stay, d (interquartile range)13 (7-23)
      Medical condition
       Hypertension, n (%)243 (52.5)
       Surgery in past 2 months, n (%)213 (46)
       Ischemic heart disease, n (%)140 (30.2)
       Atrial fibrillation, n (%)126 (27.2)
       Serum creatinine >1.5 mg/dL, n (%)125 (27)
       Deep vein thrombosis or pulmonary embolism, n (%)121 (26.1)
       Heart failure, n (%)106 (22.9)
       Diabetes, n (%)104 (22.5)
       Active cancer without metastases, n (%)74 (16)
       Status post heart valve surgery, n (%)68 (14.7)
       Chronic obstructive pulmonary disease, n (%)66 (14.3)
       History of stroke, n (%)45 (9.7)
       Active cancer with metastases, n (%)42 (9.1)
       Other thromboembolism, n (%)40 (8.6)
       History of cancer, n (%)34 (7.3)
       Dialysis, n (%)30 (6.5)
       Thrombophilia, n (%)16 (3.5)
      low asterisk Patients could have had more than 1 ADE.

      Characteristics of Anticoagulant-associated Adverse Drug Events

      In 250,725 admissions over the 5-year study period, there were 463 anticoagulant-associated ADEs reported. Of these anticoagulant-associated ADEs, 226 were medication errors (48.8%), 141 were ADRs (30.5%), and 96 (20.7%) involved both a medication error and ADR. Seventy percent of anticoagulant-associated ADEs were potentially preventable (Table 2). Unfractionated heparin (58%) and warfarin (21%) were the most commonly implicated drugs in anticoagulant-associated ADEs. An average of 1.4 anticoagulant-associated ADEs occurred per patient over the 5-year study period.
      Table 2Characteristics of Adverse Drug Events (ADEs) in Patients Receiving Anticoagulation (n=463)
      Patients could have had more than 1 ADE including both medication errors and ADRs.
      Characteristic of ADE
       Adverse drug reaction (ADR), n (%)141 (30.5)
       Medication error, n (%)226 (48.8)
       Combined medication error and ADR, n (%)96 (20.7)
       Near miss, n (%)33 (7.1)
       Potentially preventable ADE, n (%)322 (69.5)
      Anticoagulant associated with ADE
       Unfractionated heparin, n (%)270 (58.3)
       Warfarin, n (%)96 (20.7)
       Low-molecular weight heparin, n (%)44 (9.5)
       Argatroban, n (%)29 (6.3)
       Bivalirudin, n (%)18 (3.9)
       Lepirudin, n (%)3 (0.7)
       Fondaparinux, n (%)3 (0.7)
      ADR=adverse drug reaction.
      low asterisk Patients could have had more than 1 ADE including both medication errors and ADRs.

      Characteristics of Anticoagulant-associated Medication Errors

      The most frequent type of anticoagulant-associated medication errors were missed medication doses (25%) and wrong rate or frequency (23%) (Table 3). Transcription errors (48%) were the most frequent root cause of anticoagulant-associated medication errors, followed by memory lapses (16%).
      Table 3Types and Root Causes of Anticoagulant-associated Medication Errors (n=323)
      Type of medication error
      Patients may have had more than 1 medication error type.
       Missed dose, n (%)79 (24.5)
       Wrong rate or frequency, n (%)75 (23.2)
       Medication not discontinued when ordered, n (%)31 (9.6)
       Extra dose, n (%)26 (8.1)
       Wrong dose, n (%)23 (7.1)
       Wrong time of administration, n (%)17 (5.3)
       Failure to act on laboratory result, n (%)17 (5.3)
       Known allergy or contraindication, n (%)13 (4)
       Wrong route, n (%)10 (3.1)
       Medication expired, n (%)8 (2.5)
       Wrong patient, n (%)7 (2.2)
       Wrong drug, n (%)7 (2.2)
       Preparation error, n (%)6 (1.9)
       Wrong technique of administration, n (%)3 (0.9)
       Medication administered without an order, n (%)2 (0.6)
       Inadequate monitoring, n (%)1 (0.3)
      Root cause of medication error
       Transcription error, n (%)155 (48)
       Memory lapse, n (%)52 (16.1)
       Infusion or parenteral administration problem, n (%)28 (8.7)
       Rule violation, n (%)19 (5.9)
       Lack of knowledge about drug, n (%)18 (5.6)
       Faulty drug identity checking, n (%)17 (5.3)
       Drug preparation error, n (%)12 (3.7)
       Drug stocking or delivery problem, n (%)9 (2.8)
       Faulty interaction between services, n (%)7 (2.2)
       Lack of information about the patient, n (%)4 (1.2)
       Faulty dose checking, n (%)1 (0.3)
       Known allergy or contraindication, n (%)1 (0.3)
      low asterisk Patients may have had more than 1 medication error type.

      Characteristics of Anticoagulant-associated Adverse Drug Reactions

      The most frequent anticoagulant-associated ADRs were abnormal coagulation studies (72%), any bleeding (25%), and thrombocytopenia (18%) (Table 4). Seventy-two percent of all ADRs were associated with at least one occurrence of excessive anticoagulation, such as a super-therapeutic international normalized ratio or activated partial thromboplastin time. Seventeen percent of anticoagulant-associated ADRs culminated in transfusion of at least one unit of packed red blood cells. Undetected predisposing conditions (58%), such as a previously unknown drug allergy, and medication errors (40%) comprised the most common root causes of anticoagulant-associated ADRs.
      Table 4Characteristics and Root Causes of Adverse Drug Reactions (ADRs) (n=238)
      Characteristic of ADR
       Abnormal coagulation studies, n (%)172 (72.3)
       Occurrences of excessive anticoagulation during hospitalization, n (%)171 (71.9)
       Any bleeding event, n (%)59 (24.8)
        Occult bleed21 (8.8)
        Bleeding event related to surgery14 (5.9)
        Hematoma8 (3.4)
        Any gastrointestinal bleeding6 (2.5)
        Decrease in hematocrit6 (2.5)
        Retroperitoneal hemorrhage3 (1.3)
       Median length of stay post bleeding event, days (interquartile range)9 (5-20)
       Blood transfusion administered, n (%)40 (16.8)
       Blood transfusion administered with 48 hours after surgery, n (%)13 (5.5)
       Treatment of bleeding ADR, n (%)
        Vitamin K10 (4.2)
        Protamine2 (0.8)
        Fresh frozen plasma11 (4.6)
        Surgery6 (2.5)
        Catheterization laboratory1 (0.4)
       GUSTO bleeding classification, n (%)
        I19 (8)
        II32 (13.5)
        III8 (3.4)
       Thrombocytopenia, n (%)43 (18.1)
        Heparin-induced thrombocytopenia, n (%)31 (13)
       Any thromboembolic event, n (%)16 (6.7)
        Deep vein thrombosis6 (2.5)
        Pulmonary embolism6 (2.5)
        Myocardial infarction1 (0.4)
        Stroke2 (0.8)
        Other arterial thromboembolic event1 (0.4)
       Thromboembolic ADR requiring treatment, n (%)8 (3.4)
       Treatment of thromboembolic ADR, n (%)
        Catheterization laboratory3 (1.3)
        Interventional radiology procedure1 (0.4)
        Surgery2 (0.8)
      Root cause of ADR
       Undetected predisposing condition, n (%)138 (58)
       Medication error, n (%)94 (39.5)
       Drug-drug interaction, n (%)3 (1.3)
       Patient medication non-adherence, n (%)2 (0.8)
      GUSTO=Global Use of Strategies to Open Occluded Coronary Arteries study.

      Outcomes of Anticoagulant-associated Adverse Drug Events

      Death within 30 days of anticoagulant-associated ADEs occurred in 11% of patients. In-hospital death occurred after 5.6% of anticoagulant-associated ADEs, while death after discharge but within 30 days of the ADE was observed in 5% (Table 5). A rehabilitation center stay was frequently required (40%) after an admission in which an anticoagulant-associated ADE occurred. Patients who suffered anticoagulant-associated ADEs had a high rate of re-hospitalization within 30 days of the ADE (17.5%).
      Table 5Outcomes of Adverse Drug Events (ADEs) (n=463)
      Outcome
       In-hospital death, n (%)26 (5.6)
       Death after discharge but within 30 days of ADE, n (%)23 (5)
       Death due to thromboembolism, n (%)4 (0.9)
       Death due to bleeding event, n (%)1 (0.2)
       Discharge status, n (%)
        Home236 (51)
        Rehabilitation center186 (40.2)
        Hospice13 (2.8)
        Acute care facility2 (0.4)
        Deceased26 (5.6)
       Readmission within 30 days of ADE, n (%)81 (17.5)

      Cost Analysis of Anticoagulant-associated Adverse Drug Reactions

      Most hospitalization expenditures after an anticoagulant-associated ADR were attributable to nursing costs (mean $33,189 per ADR) followed by pharmacy costs (mean $7451 per ADR) (Table 6). ADRs that were determined to add incremental expense were associated with significant increases in total hospitalization cost (mean $118,429 vs $54,858, P=.02) as well as cost after the ADR (mean $89,733 vs $23,680, P=.004) compared with ADRs in which no incremental cost was determined to be incurred (Table 7). ADRs that were determined to add incremental cost to hospitalization were associated with significant increases in costs of nursing, pharmacy, blood products, clinical laboratory, and radiology.
      Table 6Cost Associated with Adverse Drug Reactions (ADRs)
      Patients may have suffered multiple ADRs during a hospital admission. Costs incurred were analyzed after the initial event.
      Mean ($)±SD
      Costs are rounded to the nearest US dollar.
      Overall and departmental costs
       Total hospitalization88,842±166,708
       Hospitalization pre-ADR29,851±49,264
       Hospitalization post-ADR58,991±146,065
       Nursing33,189±81,236
       Pharmacy7451±21,878
       Blood products2318±9235
       Clinical laboratory2001±5069
       Radiology1864±4175
       Surgical225±1349
       Interventional procedure210±1485
       Anesthesia46±257
      Drug-related costs
       Argatroban1570±7097
       Bivalirudin1102±5879
       Thrombolytic therapy87±579
       Low-molecular weight heparin49±154
       Unfractionated heparin35±64
       Lepirudin34±327
       Warfarin23±45
       Fondaparinux14±76
       Aprotinin4±51
       Vitamin K2±6
       Desmopressin2±12
       Protamine1±6
       Aminocaproic acid0±1
      ADR=adverse drug reaction.
      low asterisk Patients may have suffered multiple ADRs during a hospital admission. Costs incurred were analyzed after the initial event.
      † Costs are rounded to the nearest US dollar.
      Table 7Incremental Cost Associated with Adverse Drug Reactions (ADRs)
      Patients may have suffered multiple ADRs during a hospital admission. Costs incurred were analyzed after the initial event.
      No Incremental Cost (n=85)Incremental Cost (n=74)P-Value
      Overall and departmental costs (Mean±SD)
      Costs are rounded to the nearest US dollar.
       Total hospitalization54,858±115,659118,429±196,840.02
       Hospitalization pre-ADR31,178±58,17228,696±40,265.75
       Hospitalization post-ADR23,680±65,28389,733±185,395.004
       Nursing14,008±42,45749,888±101,194.005
       Pharmacy2830±924311,473±28,123.01
       Blood products548±17033858±12,359.02
       Clinical laboratory902±24692957±6406.01
       Radiology798±22282792±5158.002
       Surgical0±0421±1828.0496
       Interventional procedure0±0393±2019.1
       Anesthesia0±087±348.03
      Drug-related costs (Mean±SD)
      Costs are rounded to the nearest US dollar.
       Argatroban231±14412735±9486.03
       Bivalirudin70±3662001±7946.04
       Thrombolytic therapy24±205142±766.2
       Lepirudin0±063±446.23
       Low-molecular weight heparin53±18345±125.72
       Unfractionated heparin27±6741±60.14
       Warfarin15±4330±47.04
       Fondaparinux0±426±102.03
       Aprotinin0±08±69.35
       Vitamin K1±53±7.01
       Desmopressin0±03±17.17
       Protamine0±03±8.003
       Aminocaproic acid0±00±1.21
      low asterisk Patients may have suffered multiple ADRs during a hospital admission. Costs incurred were analyzed after the initial event.
      † Costs are rounded to the nearest US dollar.

      Discussion

      We found that 48.8% of anticoagulant-associated ADEs were medication errors, 30.5% were ADRs, and 20.7% involved both medication errors and ADRs. Seventy percent of all reported anticoagulant-associated ADEs were potentially preventable. Transcription errors were the most common root cause of medication errors, while undetected predisposing conditions and medication errors were the most frequent root causes of ADRs. We noted high 30-day mortality (11%) in patients who experienced an anticoagulant-associated ADE during hospitalization. We observed high post-ADE hospitalization costs, largely attributable to nursing and pharmacy expenditures.
      We had implemented computerized provider order entry, an electronic medication administration record, “smart” infusion pumps, and barcode technology before the registry was instituted. Therefore, we were surprised to observe that 70% of anticoagulant-associated ADEs were potentially preventable and that 40% of related ADRs were due to medication errors. Our data corroborate previous reports demonstrating that a substantial proportion of ADEs are due to medication errors and therefore potentially preventable.
      • Morimoto T.
      • Sakuma M.
      • Matsui K.
      • et al.
      Incidence of adverse drug events and medication errors in Japan: the JADE Study.
      J Gen Intern Med. 2010; 26: 148-153
      , 
      • Hug B.L.
      • Witkowski D.J.
      • Sox C.M.
      • et al.
      Adverse drug event rates in six community hospitals and the potential impact of computerized physician order entry for prevention.
      J Gen Intern Med. 2009; 25: 31-38
      Computerized provider order entry,
      • Hug B.L.
      • Witkowski D.J.
      • Sox C.M.
      • et al.
      Adverse drug event rates in six community hospitals and the potential impact of computerized physician order entry for prevention.
      J Gen Intern Med. 2009; 25: 31-38
      improved infusion pump technology,
      • Grissinger M.C.
      • Hicks R.W.
      • Keroack M.A.
      • et al.
      Harmful medication errors involving unfractionated and low-molecular-weight heparin in three patient safety reporting programs.
      Jt Comm J Qual Patient Saf. 2010; 36: 195-202
      and implementing barcode technology
      • Poon E.G.
      • Keohane C.A.
      • Yoon C.S.
      • et al.
      Effect of bar-code technology on the safety of medication administration.
      N Engl J Med. 2010; 362: 1698-1707
      , 
      • Poon E.G.
      • Cina J.L.
      • Churchill W.
      • et al.
      Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy.
      Ann Intern Med. 2006; 145: 426-434
      reduce medication errors. However, our root cause analysis suggests that further improvements can be made to reduce anticoagulant-associated medication errors, particularly those due to transcription errors. While computerized provider order entry, “smart” infusion pump technology, electronic medication administration records, and barcode technology reduce the frequency of some transcription errors, human error may occur at transition points among these clinical tools and result in mistakes at any number of steps in medication transcription. The emergence of novel oral anticoagulants that are administered in fixed doses may further reduce dosing and infusion pump errors.
      • Eikelboom J.W.
      • Weitz J.I.
      New anticoagulants.
      Circulation. 2010; 121: 1523-1532
      We observed high 30-day mortality (11%) in patients suffering an anticoagulant-associated ADE during hospitalization. We speculate that this may be related to a combination of high medical acuity of patients suffering anticoagulant-associated ADEs and complications of the ADEs themselves. Patients with anticoagulant-associated ADEs had a high frequency of medical conditions such as heart failure, ischemic heart disease, chronic kidney disease, and stroke, all of which may increase patient vulnerability to the complications of anticoagulant-associated ADEs. Furthermore, anticoagulant-associated ADEs may be a marker for fragile patients with complicated hospital courses and long lengths of stay. The contribution of medical errors, including those associated with ADEs, to deaths occurring during hospitalization, may be overestimated in studies relying on physician review.
      • Hayward R.A.
      • Hofer T.P.
      Estimating hospital deaths due to medical errors: preventability is in the eye of the reviewer.
      JAMA. 2001; 286: 415-420
      Regardless of whether anticoagulant-associated ADEs contribute to increased mortality or are markers for higher medical acuity, patients who suffer these events represent a particularly vulnerable population. Accordingly, Quality Improvement initiatives to reduce anticoagulant-associated ADEs are critical.
      Most hospitalization costs after an anticoagulant-associated ADE were attributable to nursing and pharmacy expenses. ADRs that incurred incremental cost doubled the total hospitalization costs and nearly quadrupled postevent costs compared with ADRs that did not incur any incremental expense. Our findings are similar to other reports that demonstrate the heavy financial burden of ADEs.
      • Bates D.W.
      • Spell N.
      • Cullen D.J.
      • et al.
      The costs of adverse drug events in hospitalized patients Adverse Drug Events Prevention Study Group.
      JAMA. 1997; 277: 307-311
      , 
      • Jennings H.R.
      • Miller E.C.
      • Williams T.S.
      • et al.
      Reducing anticoagulant medication adverse vents and avoidable patient harm.
      Jt Comm J Qual Patient Saf. 2008; 34: 196-200
      , 
      • Eckman M.H.
      • Levine H.J.
      • Pauker S.G.
      Making decisions about antithrombotic therapy in heart disease Decision analytic and cost-effectiveness issues.
      Chest. 1995; 108: 457S-470S
      Based on these data, efforts to reduce anticoagulant-associated ADEs have the potential to reduce hospitalization costs as well as improve patient safety.
      Our data were obtained from a voluntary patient safety reporting system and therefore might be limited by underreporting and selective reporting, in which only the most severe ADEs or those with the greatest consequences are reported. Because we excluded patient care areas in which medication administration records were not consistently computerized, we may have omitted subgroups of patients who had suffered a higher proportion of anticoagulant-associated ADEs. Because anticoagulant medications are given throughout the hospital but not all patient care areas have electronic medication administration records, it is not possible to calculate the denominator of patients exposed to anticoagulants. Therefore, we could not calculate the incidence of anticoagulant-associated ADEs and could not identify an appropriate comparison population of patients exposed to anticoagulant drugs who did not suffer ADEs. In addition, our analysis did not encompass community-acquired ADEs that resulted in hospitalization. While 5 deaths were clearly attributable to ADE-related bleeding (n=1) or thromboembolism (n=4), we were not able to quantify the contribution of ADEs to other deaths in this cohort. Finally, because of limitations in our cost accounting software, we were unable to separate costs incurred after the initial ADR from costs associated with subsequent events in a particular patient during the same hospitalization.
      The methodology utilized in this analysis is consistent with published criteria for evaluating the scientific value of clinical data registries.
      • Alpert J.S.
      Are data from clinical registries of any value?.
      Eur Heart J. 2000; 21: 1399-1401
      We utilized a large database generated from a tertiary care center that is representative of similar acute care facilities. Our study provides real-world insights into anticoagulant-associated ADEs from a medical center that has implemented an electronic health record that integrates computerized provider order entry, an electronic medication administration record, “smart” infusion pumps, and barcode technology. We utilized a multidisciplinary group of physicians, pharmacists, and a patient safety officer to provide the highest accuracy for classifying events and determining root causes of ADEs. Finally, we provided outcomes data for patients who suffered anticoagulant-associated ADEs with 100% follow-up.

      Conclusions

      Most anticoagulant-associated ADEs among inpatients result from medication errors and are therefore potentially preventable. Transcription errors are the most common cause of medication errors which, in turn, are a frequent cause of anticoagulant-associated ADRs. We observed elevated 30-day mortality among patients who suffered an anticoagulant-associated ADE and high hospitalization costs following ADRs. Further efforts to reduce anticoagulant-associated medication errors are warranted to improve patient safety and decrease health care expenditures.

      References

        • Zaidenstein R.
        • Eyal S.
        • Efrati S.
        • et al.
        Adverse drug events in hospitalized patients treated with cardiovascular drugs and anticoagulants.
        Pharmacoepidemiol Drug Saf. 2002; 11: 235-238
        View in Article
        • Silverman J.B.
        • Stapinski C.D.
        • Churchill W.W.
        • et al.
        Multifaceted approach to reducing preventable adverse drug events.
        Am J Health Syst Pharm. 2003; 60: 582-586
        View in Article
        • Piazza G.
        • Goldhaber S.Z.
        Computerized decision support for the cardiovascular clinician: applications for venous thromboembolism prevention and beyond.
        Circulation. 2009; 120: 1133-1137
        View in Article
        • Morimoto T.
        • Sakuma M.
        • Matsui K.
        • et al.
        Incidence of adverse drug events and medication errors in Japan: the JADE Study.
        J Gen Intern Med. 2010; 26: 148-153
        View in Article
        • Hug B.L.
        • Witkowski D.J.
        • Sox C.M.
        • et al.
        Adverse drug event rates in six community hospitals and the potential impact of computerized physician order entry for prevention.
        J Gen Intern Med. 2009; 25: 31-38
        View in Article
        • Classen D.C.
        • Jaser L.
        • Budnitz D.S.
        Adverse drug events among hospitalized Medicare patients: epidemiology and national estimates from a new approach to surveillance.
        Jt Comm J Qual Patient Saf. 2010; 36: 12-21
        View in Article
        • Bates D.W.
        • Cullen D.J.
        • Laird N.
        • et al.
        Incidence of adverse drug events and potential adverse drug events.
        JAMA. 1995; 274: 29-34
        View in Article
        • Poon E.G.
        • Keohane C.A.
        • Yoon C.S.
        • et al.
        Effect of bar-code technology on the safety of medication administration.
        N Engl J Med. 2010; 362: 1698-1707
        View in Article
        • Poon E.G.
        • Cina J.L.
        • Churchill W.
        • et al.
        Medication dispensing errors and potential adverse drug events before and after implementing bar code technology in the pharmacy.
        Ann Intern Med. 2006; 145: 426-434
        View in Article
        • Leape L.L.
        • Bates D.W.
        • Cullen D.J.
        • et al.
        Systems analysis of adverse drug events.
        JAMA. 1995; 274: 35-43
        View in Article
        • Grissinger M.C.
        • Hicks R.W.
        • Keroack M.A.
        • et al.
        Harmful medication errors involving unfractionated and low-molecular-weight heparin in three patient safety reporting programs.
        Jt Comm J Qual Patient Saf. 2010; 36: 195-202
        View in Article
        • Fanikos J.
        • Stapinski C.
        • Koo S.
        • et al.
        Medication errors associated with anticoagulant therapy in the hospital.
        Am J Cardiol. 2004; 94: 532-535
        View in Article
        • Bates D.W.
        • Spell N.
        • Cullen D.J.
        • et al.
        The costs of adverse drug events in hospitalized patients.
        JAMA. 1997; 277: 307-311
        View in Article
        • Fanikos J.
        • Cina J.L.
        • Baroletti S.
        • et al.
        Adverse drug events in hospitalized cardiac patients.
        Am J Cardiol. 2007; 100: 1465-1469
        View in Article
        • Hanlon J.T.
        • Pieper C.F.
        • Hajjar E.R.
        • et al.
        Incidence and predictors of all and preventable adverse drug reactions in frail elderly persons after hospital stay.
        J Gerontol A Biol Sci Med Sci. 2006; 61: 511-515
        View in Article
        • Hajjar E.R.
        • Hanlon J.T.
        • Artz M.B.
        • et al.
        Adverse drug reaction risk factors in older outpatients.
        Am J Geriatr Pharmacother. 2003; 1: 82-89
        View in Article
        • Nebeker J.R.
        • Barach P.
        • Samore M.H.
        Clarifying adverse drug events: a clinician's guide to terminology, documentation, and reporting.
        Ann Intern Med. 2004; 140: 795-801
        View in Article
      18. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction.
        N Engl J Med. 1993; 329: 673-682
        View in Article
        • Eikelboom J.W.
        • Weitz J.I.
        New anticoagulants.
        Circulation. 2010; 121: 1523-1532
        View in Article
        • Hayward R.A.
        • Hofer T.P.
        Estimating hospital deaths due to medical errors: preventability is in the eye of the reviewer.
        JAMA. 2001; 286: 415-420
        View in Article
        • Jennings H.R.
        • Miller E.C.
        • Williams T.S.
        • et al.
        Reducing anticoagulant medication adverse vents and avoidable patient harm.
        Jt Comm J Qual Patient Saf. 2008; 34: 196-200
        View in Article
        • Eckman M.H.
        • Levine H.J.
        • Pauker S.G.
        Making decisions about antithrombotic therapy in heart disease.
        Chest. 1995; 108: 457S-470S
        View in Article
        • Alpert J.S.
        Are data from clinical registries of any value?.
        Eur Heart J. 2000; 21: 1399-1401
        View in Article

      Article info

      Footnotes

      Funding: Dr Piazza is supported by a Research Career Development Award (K12 HL083786) from the National Heart, Lung, and Blood Institute (NHLBI). This study was funded, in part, by a clinical research grant from Johnson & Johnson (New Brunswick, NJ).

      Conflict of Interest: None.

      Authorship: All authors had access to the data and played a role in writing this manuscript.

      Identification

      DOI: https://doi.org/10.1016/j.amjmed.2011.06.009

      Copyright

      © 2011 Elsevier Inc. Published by Elsevier Inc. All rights reserved.

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