W arfarin is the most commonly pre- scribed oral anticoagulant world- wide and is likely to remain an important drug into the future, based on its proven efficacy and the lack of cost-effective al- ternatives for indications such as chronic atrial fibrillation. 1 Despite almost 60 years of clinical experience with its use, warfarin is still a major cause of adverse drug events and hospital admissions, 2-5 and optimal management remains a challenge. Warfarin-related hemorrhagic events 6,7 and thromboembolic events re- sulting from therapeutic failures 8,9 result in significant morbidity and mortality in individuals and substantial costs to the health-care system. 4 A number of factors complicate war- farin management in the period following discharge from the hospital. Adverse event rates are intrinsically higher after warfarin initiation, with bleeding and re- current thromboembolic events occurring more frequently. 7,10,11 The requirement for closer international normalized ratio (INR) monitoring early in therapy or be- cause of destabilized postdischarge anti- coagulant control 12 often represents a sig- nificant burden for patients with mobility or transportation problems. 13 Some pa- The Annals of Pharmacotherapy ■ 2011 March, Volume 45 ■ 325 Clinical Outcomes of a Collaborative, Home-Based Postdischarge Warfarin Management Service Leanne Stafford, Gregory M Peterson, Luke RE Bereznicki, Shane L Jackson, Ella C van Tienen, Manya T Angley, Beata V Bajorek, Andrew J McLachlan, Judy R Mullan, Gary MH Misan, and Luigi Gaetani theannals.com Ambulatory Care Author information provided at end of text. BACKGROUND: Warfarin remains a high-risk drug for adverse events, especially following discharge from the hospital. New approaches are needed to minimize the potential for adverse outcomes during this period. OBJECTIVE: To evaluate the clinical outcomes of a collaborative, home-based postdischarge warfarin management service adapted from the Australian Home Medicines Review (HMR) program. METHODS: In a prospective, nonrandomized controlled cohort study, patients discharged from the hospital and newly initiated on or continuing warfarin therapy received either usual care (UC) or a postdischarge service (PDS) of 2 or 3 home visits by a trained, HMR-accredited pharmacist in their first 8 to 10 days postdischarge. The PDS involved point-of-care international normalized ratio (INR) monitoring, warfarin education, and an HMR, in collaboration with the patient’s general practitioner and community pharmacist. The primary outcome measure was the combined incidence of major and minor hemorrhagic events in the 90 days postdischarge. Secondary outcome measures included the incidences of thrombotic events, combined hemorrhagic and thombotic events, unplanned and warfarin-related hospital readmissions, death, INR control, and persistence with therapy at 8 and 90 days postdischarge. RESULTS: The PDS (n = 129) was associated with statistically significantly decreased rates of combined major and minor hemorrhagic events to day 90 (5.3% vs 14.7%; p = 0.03) and day 8 (0.9% vs 7.2%; p = 0.01) compared with UC (n = 139). The rate of combined hemorrhagic and thrombotic events to day 90 also decreased (6.4% vs 19.0%; p = 0.008) and persistence with warfarin therapy improved (95.4% vs 83.6%; p = 0.004). No significant differences in readmission and death rates or INR control were demonstrated. CONCLUSIONS: This study demonstrated the ability of appropriately trained accredited pharmacists working within the Australian HMR framework to reduce adverse events and improve persistence in patients taking warfarin following hospital discharge. Widespread implementation of such a service has the potential to enhance medication safety along the continuum of care. KEY WORDS: adverse drug events, community pharmacy services, international normalized ratio, patient discharge, warfarin. Ann Pharmacother 2011;45:325-34. Published Online, 8 Mar 2011, theannals.com, DOI 10.1345/aph.1P617 by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from by guest on October 11, 2013 aop.sagepub.com Downloaded from
Transcript
Warfarin is the most commonly pre-scribed oral anticoagulant world-
wide and is likely to remain an importantdrug into the future, based on its provenefficacy and the lack of cost-effective al-ternatives for indications such as chronicatrial fibrillation.1 Despite almost 60years of clinical experience with its use,warfarin is still a major cause of adversedrug events and hospital admissions,2-5
and optimal management remains achallenge. Warfarin-related hemorrhagicevents6,7 and thromboembolic events re-sulting from therapeutic failures8,9 resultin significant morbidity and mortality inindividuals and substantial costs to thehealth-care system.4
A number of factors complicate war-farin management in the period followingdischarge from the hospital. Adverseevent rates are intrinsically higher afterwarfarin initiation, with bleeding and re-current thromboembolic events occurringmore frequently.7,10,11 The requirement forcloser international normalized ratio(INR) monitoring early in therapy or be-cause of destabilized postdischarge anti-coagulant control12 often represents a sig-nificant burden for patients with mobilityor transportation problems.13 Some pa-
The Annals of Pharmacotherapy n 2011 March, Volume 45 n 325
Clinical Outcomes of a Collaborative, Home-Based Postdischarge
Warfarin Management Service
Leanne Stafford, Gregory M Peterson, Luke RE Bereznicki, Shane L Jackson, Ella C van Tienen,
Manya T Angley, Beata V Bajorek, Andrew J McLachlan, Judy R Mullan, Gary MH Misan, and Luigi Gaetani
theannals.com
Ambulatory Care
Author information provided at end of text.
BACKGROUND: Warfarin remains a high-risk drug for adverse events, especiallyfollowing discharge from the hospital. New approaches are needed to minimizethe potential for adverse outcomes during this period.
OBJECTIVE: To evaluate the clinical outcomes of a collaborative, home-basedpostdischarge warfarin management service adapted from the Australian HomeMedicines Review (HMR) program.
METHODS: In a prospective, nonrandomized controlled cohort study, patientsdischarged from the hospital and newly initiated on or continuing warfarin therapyreceived either usual care (UC) or a postdischarge service (PDS) of 2 or 3 homevisits by a trained, HMR-accredited pharmacist in their first 8 to 10 dayspostdischarge. The PDS involved point-of-care international normalized ratio(INR) monitoring, warfarin education, and an HMR, in collaboration with the patient’sgeneral practitioner and community pharmacist. The primary outcome measurewas the combined incidence of major and minor hemorrhagic events in the 90days postdischarge. Secondary outcome measures included the incidences ofthrombotic events, combined hemorrhagic and thombotic events, unplanned andwarfarin-related hospital readmissions, death, INR control, and persistence withtherapy at 8 and 90 days postdischarge.
RESULTS: The PDS (n = 129) was associated with statistically significantlydecreased rates of combined major and minor hemorrhagic events to day 90(5.3% vs 14.7%; p = 0.03) and day 8 (0.9% vs 7.2%; p = 0.01) compared withUC (n = 139). The rate of combined hemorrhagic and thrombotic events to day90 also decreased (6.4% vs 19.0%; p = 0.008) and persistence with warfarintherapy improved (95.4% vs 83.6%; p = 0.004). No significant differences inreadmission and death rates or INR control were demonstrated.
CONCLUSIONS: This study demonstrated the ability of appropriately trainedaccredited pharmacists working within the Australian HMR framework to reduceadverse events and improve persistence in patients taking warfarin followinghospital discharge. Widespread implementation of such a service has thepotential to enhance medication safety along the continuum of care.
KEY WORDS: adverse drug events, community pharmacy services, internationalnormalized ratio, patient discharge, warfarin.
Ann Pharmacother 2011;45:325-34.
Published Online, 8 Mar 2011, theannals.com, DOI 10.1345/aph.1P617
by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from by guest on October 11, 2013aop.sagepub.comDownloaded from
tients leave the hospital with inadequate knowledge abouttheir therapy,14,15 which further increases their risk of sub-optimal anticoagulant control,16,17 poor adherence to thera-py,18,19 and warfarin-related complications.20 Trends towardincreased warfarin use and shorter periods of hospitaliza-tion are apparent, coupled with problems with poor dis-charge planning21 and insufficient communication alongthe continuum of care.21,22 As a result, community-basedhealth services, usually general practitioners (GPs) andpathology providers, may struggle to care for patients tak-ing warfarin after discharge from the hospital.23
Improving the quality use of warfarin in patients transi-tioning from the hospital to the community is of vital im-portance in reducing the risk of medication misadventure.A previous Australian randomized controlled trial demon-strated the benefits of having a trained pharmacist providehome-delivered postdischarge care to patients initiated onwarfarin in the hospital.24 During this trial, patients re-ceived 4 home visits and point-of-care (POC) INR moni-toring on alternate days commencing 2 days postdischarge.Compared with usual care, the service resulted in im-proved attainment of therapeutic INRs, a reduced rate ofsupratherapeutic INRs at 8 days postdischarge, and re-duced rates of hemorrhagic complications to 90 days post-discharge.24
It was identified that an opportunity existed for a post-discharge warfarin management service to be extended topatients Australia-wide, within the framework of the cur-rent Home Medicines Review (HMR) program, funded bythe federal government’s Department of Health and Age-ing.25 An HMR involves a patient being referred by his orher GP and community pharmacy for a home visit by anaccredited pharmacist, who reviews the patient’s medica-tion regimen, offers appropriate education and medicationmanagement support, and provides the GP with a report ofsuggestions to optimize medication-related outcomes.25 Anaccredited pharmacist is an experienced pharmacist whohas undertaken education programs or examinations ap-proved by the relevant professional organizations and hascompleted specified continuing professional education andregular reaccreditation requirements.25 We hypothesizedthat utilizing the existing HMR referral pathway and remu-neration structure would facilitate provision of a morecomprehensive service to patients discharged from the hos-pital taking warfarin. It was acknowledged, however, thatthe intensity of Jackson et al.’s24 4-visit model may notprove sustainable in a real-world setting. A trial was thusconceived to implement and evaluate a more sustainableservice, using the HMR framework.
The objective of this study was to compare the clinicaloutcomes of postdischarge usual care (UC) with those of acollaborative, home-based postdischarge service (PDS) forwarfarin management. The PDS comprised 2 or 3 home
visits by a trained HMR-accredited pharmacist to patientstaking warfarin in their first 8 to 10 days after dischargefrom the hospital.
Methods
STUDY POPULATION
This prospective, nonrandomized controlled cohortstudy involved patients discharged from 8 hospitals across5 metropolitan, rural, and remote regions of Australia. Eli-gible patients were recruited into the UC group betweenNovember 2008 and August 2009 and into the PDS groupbetween May and December 2009. Inclusion criteria were:patients over the age of 18 years discharged from the hos-pital, either newly initiated on warfarin or continuingpreadmission therapy, with an indication necessitating atleast 3 months of therapy. Both patients and their GPs hadto provide informed consent prior to involvement in thestudy. Exclusion criteria were: patients with lupus antico-agulant or antiphospholipid syndrome, residents of aged-care facilities and others not eligible for an HMR under theAustralian government program,25 patients with a docu-mented history of dementia or a mini-mental state exami-nation (MMSE) score less than 24, and patients enteringother preexisting postdischarge outreach programs.
The calculated sample size required to detect a differ-ence between 2 proportions, using the normal approxima-tion to the binomial distribution and incorporating a conti-nuity correction, was 142 patients (71 in each group) at apower of 80% and an α of 0.05, based on the aim of reduc-ing the rate of bleeding complications within 3 months ofhospital discharge from 30%7,24,26,27 to 10%.
USUAL CARE
Baseline demographic and warfarin-specific data werecollected prior to hospital discharge from patient inter-views and medical records. Postdischarge, UC patientswere managed according to their community health-careproviders’ usual warfarin management practices. No re-strictions were placed on what this comprised, except thatit could not involve a formal postdischarge outreach pro-gram as described above. UC typically involved patientsundergoing venous blood sampling for INR testing at theirGP surgeries or pathology specimen collection centers andthe results being reported to the GPs, who then communi-cated the need for dosage adjustments to the patients ortheir caregivers.
UC patients received a single home visit by a project of-ficer for data collection purposes approximately 8 dayspostdischarge, at which time a POC INR test (CoaguChekXS, Roche Diagnostics) was performed and data were col-lected regarding warfarin therapy, INR results, and any ad-
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verse events experienced since discharge. A final follow-up was conducted via both telephone and postal question-naires approximately 90 days postdischarge. Corroborationof INR and adverse event data was requested from the pa-tient’s GP via a postal form. For patients experiencing hos-pital readmission during their 90 days postdischarge, Aus-tralian Refined Diagnosis Related Group (AR-DRG) codesand other details were obtained from the relevant hospital’smedical records department.
POSTDISCHARGE SERVICE
PDS baseline data collection occurred as described forUC patients. Prior to hospital discharge, the HMR referralprocess was initiated such that patients received their firstfollow-up home visit approximately 2 to 3 days postdis-charge. The PDS was provided by 1 of the 62 accreditedpharmacists who had successfully completed the trainingprogram described elsewhere.28 The decision regarding thesubsequent number of home visits received by an individu-al patient, either 1 (Level 1 Service) or 2 (Level 2 Service),was based on a collaborative risk assessment by the ac-credited pharmacist and the patient’s GP, including consid-eration of the patient’s Outpatient Bleeding Risk Index,29
INR stability,30 and drug interaction potential. Level 1 Ser-vice involved Visit 1, which was scheduled for 2 to 3 dayspostdischarge, and Visit 3 at 7 to 8 days postdischarge. Vis-it 2 was an optional additional visit based on the risk as-sessment. Recipients of Level 2 Service were thereforescheduled to receive visits at 2 to 3 days (Visit 1), 4 to 6days (Visit 2), and 8 to 10 days postdischarge (Visit 3). Atdischarge, all community-based health-care providers re-ceived a summary of the patient’s inpatient warfarin thera-py in addition to the usual discharge summary. This wasdesigned to include the information necessary to support asmooth transition of the patient’s warfarin management.31
Visit 1 involved 4 elements: an HMR; POC INR moni-toring, the results of which were communicated to the pa-tient’s GP for dose adjustment, if necessary, and the dosechange was then communicated to the patient; comprehen-sive warfarin education or reinforcement of previous edu-cation as required; and data collection.
Visits 2 and 3 provided an opportunity for POC INRmonitoring, further warfarin education, and resolution ofany drug-related problems identified. At Visit 3 (approxi-mately equivalent to day 8 for the UC patients), additionalwarfarin therapy, INR, and adverse event data were col-lected. Standard documents transferring full care back tothe GP ensured appropriate patient follow-up on comple-tion of the PDS. Day 90 follow-up was conducted as de-scribed under UC.
Ethics approval was obtained from the relevant humanresearch ethics committees and the study was registered on
the Australian New Zealand Clinical Trials Registry (AC-TRN: 12608000334303).
DATA ANALYSIS
The primary outcome measure was the incidence ofcombined major and minor hemorrhagic events to day 90postdischarge. Major hemorrhage was defined as fatalbleeding, and/or symptomatic bleeding in a critical area ororgan (especially intracranial or retroperitoneal bleeding),and/or bleeding causing a fall in hemoglobin level of 2g/dL or more, or requiring transfusion of 2 or more units ofwhole blood or red cells.32 Minor hemorrhage was definedas bleeding requiring health professional consultation butnot hospitalization.33
Secondary outcome measures, assessed at 8 and 90 dayspostdischarge, included the incidence of thrombotic events(defined as cerebrovascular accident, transient ischemic at-tack, myocardial infarction, deep vein thrombosis complica-tion, other thromboembolic event, fatal thromboembolicevent, and hospital readmission due to a thromboembolicevent), combined hemorrhagic and thrombotic events, un-planned hospital readmissions, warfarin-related hospitalreadmissions, and death from any cause; INR control, basedon the percentage of INR results that were subtherapeutic,therapeutic, and supratherapeutic at day 8 (subtherapeutic,therapeutic, and supratherapeutic INR results were definedfor each patient as below, within, or above the individual’starget INR range), and time in therapeutic range (TTR) cal-culated using Rosendaal’s linear interpolation method at day9034; and persistence with warfarin therapy (defined as thepercentage of patients continuing therapy at day 90).
Other variables, including warfarin knowledge, medica-tion adherence, quality of life, and participant satisfaction,were assessed but only clinical outcomes are described inthis paper.
STATISTICAL ANALYSIS
Data were analyzed using SPSS for Windows 16.0(SAS Institute, Cary, NC). Independent samples t-testingwas utilized for continuous variables and χ2 analyses fordiscrete variables. To confirm the outcomes of the PDS,the influence of patient characteristics on adverse eventrates was investigated using binary univariate and multi-variate logistic regression analyses. A p value of <0.05 wasspecified as statistically significant for all analyses.
Results
PATIENT CHARACTERISTICS
Between November 2008 and December 2009, 139 UCpatients and 129 PDS patients across the 8 hospital sites were
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recruited and completed the postdischarge phase of the study.Patient recruitment and follow-up is illustrated in Figure 1.
Excluding those patients who were ineligible for in-volvement in the study or were living out of the study re-cruitment area, recruitment rates of 37.4% (139/372 pa-tients) in the UC phase and 27.8% (129/464) in the PDSphase were achieved.
Based on the characteristics of the UC and PDS patients(summarized in Table 1), it is evident that the 2 groups werewell matched in relation to most variables. There were no sta-tistically significant differences between groups with respectto the proportions of patients taking medications with severeand moderate potential for interaction with warfarin (basedon the classification of the eMIMS database),35 or their meannumber of comorbidities. Differences only arose in relationto higher self-reported or documented rates of previousbleeding history and previous myocardial infarction in theUC group. A baseline estimation of bleeding risk, using the
Outpatient Bleeding Risk Index,29 however, failed to demon-strate a difference between groups.
The details of the patients’ warfarin therapy were alsosimilar between groups, as displayed in Table 2. PDS pa-tients were more likely than UC patients to be taking war-farin after a mechanical heart valve replacement. In themajority of these cases, however, patients were continuingtherapy rather than newly commenced on warfarin postop-eratively, so this was unlikely to have influenced their war-farin sensitivity.36
Level 1 Service was received by 64.8% of PDS patientsand Level 2 Service by 35.2%. Visits 1, 2, and 3 were con-ducted a mean of 2.9 days, 6.1 days, and 9.5 days postdis-charge, respectively, and lasted a mean of 68.1 minutes,22.5 minutes, and 34.9 minutes, respectively. Day 8 visitsfor the patients receiving UC were conducted on average9.2 days postdischarge, comparable with Visit 3 for thePDS group (p = 0.34). Day 90 follow-ups were completed
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Figure 1. Consort diagram of patient recruitment and follow-up. GP = general practitioner.
for 128 UC and 108 PDS patients at means of 95.9 and95.0 days postdischarge, respectively (p = 0.58).
ADVERSE EVENTS
As detailed in Table 3, the PDS was associated with astatistically significant reduction in the primary outcomemeasure, combined major and minor hemorrhagic eventsto day 90 postdischarge. Statistically significant reductionswere also demonstrated in the rates of combined hemor-rhagic events to day 8 and combined hemorrhagic andthrombotic events to day 8 and day 90. These findingswere largely related to reductions in the rates of minorhemorrhagic events. A nonsignificant trend toward a re-duction in thrombotic events was also demonstrated. Uni-variate analyses (Table 4) demonstrated that the differencesin the indication for warfarin and comorbidities betweenthe 2 groups did not contribute significantly to the ob-served differences in combined hemorrhagic events orcombined hemorrhagic and thrombotic events. Studygroup (ie, UC vs PDS) was the only variable demonstratedto significantly influence patient outcome, with patients re-ceiving UC more than 3 times more likely to experience
either a combined hemorrhagic event or combined hemor-rhagic and thrombotic event than were those receiving thePDS. These findings were confirmed by multivariate logis-tic regression analyses. There were no significant differ-ences in unplanned hospital readmissions, warfarin-relatedreadmission, or death rates. None of the deaths recordedwere deemed to have been warfarin related.
INR CONTROL
Figure 2 displays the results of POC INR monitoring atday 8. While there was a trend toward improvement in thepercentage of PDS patients with a therapeutic INR at day8, with an associated reduction in subtherapeutic INRs, thiswas not statistically significant (p = 0.54). This finding wasunaffected by whether patients had been within their thera-peutic INR ranges at discharge and whether they werenewly initiated on warfarin or continuing with therapy.
INR results from day 8 to day 90 were available for 100UC patients and 86 PDS patients. During this follow-up peri-od, UC and PDS patients underwent a mean of 7.7 (95% CI6.8 to 8.5) and 7.8 (95% CI 6.8 to 8.7) INR tests per patient,respectively, with no statistically significant difference be-
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Table 1. Patient Characteristics
Pts., n (%)a
UC PDSCharacteristic (n = 139) (n = 129) p Value
Mean age, y (95% CI) 66.2 (63.6 to 68.8) 67.7 (65.1 to 70.3) 0.42
Male 83 (59.7) 80 (62.0) 0.70
Managed medication alone 93 (75.0) 75 (81.5) 0.24
Mean length of hospital admission, days (95% CI) 9.7 (7.9 to 11.6) 11.6 (9.6 to 13.6) 0.18
Mean number of comorbidities (95% CI) 6.2 (5.6 to 6.7) 6.7 (6.1 to 7.2) 0.23
Mean number of drugs at discharge (95% CI) 8.0 (7.4 to 8.6) 8.2 (7.6 to 8.8) 0.54
PDS = postdischarge service; UC = usual care.aUnless otherwise stated. bp < 0.05. cAspirin, nonsteroidal antiinflammatory drugs, clopidogrel, heparin, and enoxaparin. dAmoxicillin, ciprofloxacin, doxycycline, metronidazole, roxithromycin, and trimethoprim/sulfamethoxazole.
tween groups (p = 0.85). There was also no difference inmean TTR between groups (55.2% vs 55.6%; p = 0.92).
PERSISTENCE WITH WARFARIN THERAPY
A statistically significantly greater proportion of PDSpatients (103, 95.4%) than UC patients (107, 83.6%) werecontinuing warfarin at day 90 (p = 0.004). Importantly, 7
patients in the UC group (5.5%) were reported to have dis-continued warfarin due to warfarin-related adverse eventsor difficulties with ongoing warfarin management; this wasnot the reason for discontinuation for any patients in thePDS group (p = 0.015). Other reasons for discontinuationincluded warfarin no longer being indicated (6 UC and 2PDS patients), death of the patient from non–warfarin-re-lated causes (2 UC and 3 PDS patients), and the patient’s
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Table 3. Comparison of Adverse Event Rates Between Groups
Discharge to Discharge toDay 8, n (%) Day 90, n (%)
PDS = postdischarge service; UC = usual care.aχ2 analysis. bp < 0.05.cUC: hemorrhagic pancreatitis, active bleeding and a large hematoma; collapsed with melena, hemoglobin level 5.0 g/dL and INR 4.2, 3 units ofpacked red blood cells and vitamin K administered; hemoglobin dropped from 10.3 g/dL to 8.9 g/dL, cause unknown; patient collapsed at home, un-derwent endoscopy to determine source of bleeding; no details. PDS: admitted to hospital with superficial hematoma, INR 8.7; epistaxis requiringhospital admission.
dUC: bleeding arm and leg injuries; bleeding at injection sites (n = 2); bleeding from surgical wounds (n = 2); heavy period; epistaxis (5); positive fecal oc-cult blood test, referred for colonoscopy; no details (n = 2). PDS: hematoma following skin cancer excision; subconjunctival hemorrhage; epistaxis.
eData available for 124 UC and 107 PDS patients.fUC: cerebrovascular accident; myocardial infarction with ventricular fibrillation arrest and extended period of rehabilitation; deep vein thrombosis (n = 2);exacerbation of symptoms associated with pulmonary embolism; transient ischemic attack (n = 2). PDS: cerebrovascular accident.
INR = international normalized ratio; PDS = postdischarge service; UC = usual care.aPercentages exceed 100% because some patients had more than 1 indication for warfarin.bp < 0.05. cDischarge INR results available for 124 UC and 113 PDS patients.
clinical instability (1 UC patient). In 5 UC patients, no rea-son for warfarin cessation was available.
Discussion
This prospective, nonrandomized controlled cohort studydemonstrated the successful extension into wider clinicalpractice of a previous research project.24 The PDS was asso-ciated with similar statistically significant reductions in totaland minor hemorrhagic events, compared with UC, to thoseobserved with the intervention in the previous study. A reduc-tion was also demonstrated in combined hemorrhagic andthrombotic events, and a higher proportion of patients in thePDS group were persisting with warfarin therapy at 90 dayspostdischarge. This resulted in an additional 5.5% of patientscontinuing therapy, whereas it may otherwise have beenceased due to adverse events or management issues. Notably,there were fewer warfarin cessations in the PDS group to day8 (none compared with 3 in the UC group). Improved patientempowerment related to the additional warfarin educationmay have contributed to the observed improvement in persis-tence with therapy.
Improvements in the patients’ clinical outcomes mayhave also been attributable to the provision of additionaleducation, or reinforcement of previous education, espe-cially as the benefits occurred in the absence of any objec-tive improvements in INR control at day 8 or TTR to day90. For example, the PDS may have empowered patientsto have greater involvement in their own care and thusself-manage minor hemorrhagic events, resulting in theirfailing to be classified as events by our definition.
In contrast to the previous trial, the PDS in the currentstudy was not associated with a statistically significant re-duction in the rate of major hemorrhagic events.24 Thereare several potential reasons for this finding. The majorhemorrhage rate in our UC group proved to be lower thanpreviously described. This may have been because our pa-tients were both newly initiated on warfarin and continuingon therapy, while the previous study included only newlyinitiated patients. In addition, there was a potential con-
founding effect associated with GP contact in our UCgroup. At the day 8 visit, if the project officers felt thattheir duty of care to a patient required them to contact thepatient’s GP to inform him or her of any findings, includ-ing out-of-range INR results, they were permitted to do so.This occurred for 39.2% of patients receiving UC in thecurrent study, but only in 24% in the previous study.24 Thismay have resulted in a reduction in subsequent event ratesin the UC group, underestimating the true clinical benefitsof the PDS. Although major hemorrhagic events could beconsidered a more robust and thus preferable primary out-come measure compared with combined major and minorhemorrhagic events, all warfarin-related adverse events re-ported in this study, by definition, necessitated medicalcare and were thus not inconsequential. In this respect, thedefinition of minor bleeding used in this study differs fromthat in some previous studies,24,37 so the results cannot bedirectly compared.
Future directions for the PDS may be influenced by pro-posed changes within the HMR program and Australianpublic hospital system. A direct HMR referral system hasbeen proposed, which should improve timely initiation ofthe PDS and its tailoring to patients’ individual needs. De-velopment of key performance indicators based on the2005 Australian Pharmaceutical Advisory Council’s(APAC) Guiding Principles to Achieve Continuity in Med-ication Management38 recognizes the value of postdis-charge HMRs and encourages a greater role for pharma-cists in their facilitation.39
LIMITATIONS
Several factors may influence the generalizability of theresults of this study. Patients were recruited from 8 hospi-tals across 3 Australian states, with the majority recruitedfrom 3 metropolitan sites. Significant dementia, residencein an aged care facility, and an inability to speak Englishwere exclusion criteria. A number of high-risk patientswere thus ineligible to receive the PDS, although it is rec-ognized that they may have benefitted most, especially
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Table 4. Odds Ratios for Adverse Events, Based on Patient Characteristics, Using Binary Logistic Regression Analysis
Combined Major and Combined Hemorrhagic andMinor Hemorrhagic Events, Thrombotic Events,
UC pt. 3.06 (1.08 to 8.63)a 3.02 (1.04 to 8.77)a 3.43 (1.33 to 8.86)a 3.38 (1.28 to 8.94)a
Mechanical heart valve recipient 0.62 (0.14 to 2.82) 0.46 (0.10 to 2.06)
Previous bleeding history 0.94 (0.11 to 7.77) 0.70 (0.09 to 5.78)
Previous myocardial infarction 1.58 (0.49 to 5.06) 1.56 (0.54 to 4.53)
UC = usual care.ap < 0.05.
given that advanced age is a risk factor for warfarin-relatedbleeding.7 The definition of UC utilized in the study specif-ically excluded patients enrolled in hospital-based postdis-charge outreach programs, although it is recognized thatsuch services actually constitute standard or usual care insome regions. The extent of such programs Australia-wideis unknown. The PDS was also not tested in any regionswhere warfarin therapy for community-based patients isprimarily managed by pathology providers rather thanGPs.
Statistically significant differences were evident be-tween the UC and PDS groups, based on the proportion ofpatients taking warfarin after a mechanical heart valve re-placement and rates of previous bleeding history and previ-ous myocardial infarction, although the reductions in ad-verse event rates associated with the PDS were demon-strated to be independent of these differences. Follow-updata collection relied on patient and GP reports. Any re-sulting uncertainty was ameliorated by accessing AR-DRGcodes for hospital readmissions, ensuring capture of themajority of significant adverse events.
This study demonstrated the viability of a PDS involv-ing trained accredited pharmacists working within the ex-isting Australian HMR framework to improve the clinicaloutcomes of patients taking warfarin after discharge fromthe hospital. The benefits of the PDS, in terms of reducedadverse event rates and improved persistence, were sub-stantial and may have represented an underestimation of itstrue value, given the potential confounding effect of GPcontact in the UC group. The PDS has great potential tocontribute to improved medication safety along the contin-uum of care for this high-risk patient population.
Leanne Stafford BPharm (Hons) (Curtin), PhD Candidate, Unit forMedication Outcomes Research and Education, School of Pharma-cy, University of Tasmania, Hobart, Tasmania, AustraliaGregory M Peterson PhD, Professor of Pharmacy, Head of School,Unit for Medication Outcomes Research and Education, School ofPharmacy, University of TasmaniaLuke RE Bereznicki PhD, Senior Lecturer in Pharmacy Practiceand Senior Research Fellow, Unit for Medication Outcomes Re-search and Education, School of Pharmacy, University of TasmaniaShane L Jackson PhD, Senior Research Fellow, Unit for Medica-tion Outcomes Research and Education, School of Pharmacy, Uni-versity of TasmaniaElla C van Tienen BPharm (Hons), PhD Candidate, Unit for Med-ication Outcomes Research and Education, School of Pharmacy,University of TasmaniaManya T Angley PhD, Senior Research Fellow, Sansom Institutefor Health Research, School of Pharmacy and Medical Sciences,University of South Australia, Adelaide, South AustraliaBeata V Bajorek PhD, Faculty of Pharmacy, University of Sydneyand Department of Pharmacy and Clinical Pharmacology (Pharma-cy Research Unit), Royal North Shore Hospital, Northern SydneyCentral Coast Area Health Service, Sydney, AustraliaAndrew J McLachlan PhD, Faculty of Pharmacy and Centre forEducation and Research in Ageing, University of SydneyJudy R Mullan PhD, Graduate School of Medicine, University ofWollongong, New South Wales, AustraliaGary MH Misan PhD, Spencer Gulf Rural Health School, Universityof South Australia and University of Adelaide, Adelaide, AustraliaLuigi Gaetani MBA, Department of Pharmacy, Wollongong Hos-pital and Graduate School of Medicine, University of WollongongCorrespondence: Ms. Stafford, [email protected]/Online Access: www.theannals.com/cgi/reprint/aph.1P617
Conflict of interest: The Unit for Medication Outcomes Researchand Education has received support from Roche Diagnostics Aus-tralia for previous warfarin-related research, principally in the supply ofpoint-of-care international normalized ratio monitors. Dr. Bereznickihas received educational funding from Roche Diagnostics and Sanofi-Aventis and consultancy funding from Boehringer-Ingelheim.
This study was funded by the Australian Government Departmentof Health and Ageing as part of the Fourth Community PharmacyAgreement through the Fourth Community Pharmacy AgreementGrants Program, managed by the Pharmacy Guild of Australia.
We acknowledge other members of the Project Team, includingProfessor Mark Nelson, Mr. Vaughn Eaton, Dr. Sepehr Shakib, Dr.John Maddison, Associate Professor Chris Doecke, Associate Pro-fessor Arduino Mangoni, Ms. Suzette Seaton, Mr. Peter Gee, andMs. Kimbra Fitzmaurice; the Project Advisory Panel, for its valu-able insights and constructive comments; and all participants inthe study, from patients, general practitioners, community phar-macists, and accredited pharmacists to project officers and hos-pital staff.
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Resultados Clínicos de un Servicio Colaborativo, Basado en elHogar para el Manejo de Warfarina luego de una Hospitalización
L Stafford, GM Peterson, LRE Bereznicki, SL Jackson, EC van Tienen, MTAngley, BV Bajorek, AJ McLachlan, JR Mullan, Gary MH Misan, y L Gaetani
Ann Pharmacother 2011;45:325-34.
EXTRACTO
TRASFONDO: Warfarina continúa siendo un fármaco de alto riesgo paraeventos adversos, especialmente luego de una hospitalización. Serequieren nuevas intervenciones para minimizar el potencial deresultados adversos durante este perìodo.
OBJETIVO: Evaluar los resultados clínicos de un servicio colaborativo,basado en el hogar para el manejo de warfarina luego de unahospitalización adaptado del Programa Australiano de Revisión deMedicamentos en el Hogar (RMH).
MÉTODO: Se realizó un estudio prospectivo, no-aleatorio, controlado concohorte. Los pacientes dados de alta del hospital y comenzados en ocontinuando terapia de warfarina recibieron el cuidado usual (CU) o el
Clinical Outcomes of a Home-Based Warfarin Management Service
The Annals of Pharmacotherapy n 2011 March, Volume 45 n 333theannals.com
servicio post-hospitalización (SPH) de 2 ó 3 visitas al hogar por unfarmacéutico acreditado por el programa de RMH durante los primeros8-10 días luego de la hospitalización. El SPH incluía evaluación de larazón internacional normalizada (INR), educación sobre warfarina y unaRMH, en colaboración con el proveedor de salud y el farmacéutico decomunidad del paciente. La medida de resultados primaria fue laincidencia combinada de eventos hemorrágicos mayores y menores enlos 90 días luego de la hospitalización. Las medidas de resultadossecundarias incluyeron la incidencia de eventos trombóticos, eventoshemorrágicos y trombóticos combinados, re-hospitalizaciones no-planificadas y relacionadas a warfarina, muerte, control de INR ypersistencia con la terapia a los 8 y 90 días después de la admisión.
RESULTADOS: El SPH (n = 129) se asoció con una reducciónestadísticamente significativa en la incidencia combinada de eventoshemorrágicos mayores y menores al Día 90 (14.7% vs. 5.3%, p = 0.03)y al Día 8 (7.2% vs. 0.9%, p = 0.01) comparado al CU (n = 139). Laincidencia de eventos hemorrágicos y trombóticos combinados al día 90también se redujo (19.0% vs. 6.4%, p = 0.008) y la persistencia con laterapia de warfarina mejoró (83.6% vs. 95.4%, p = 0.004). No sedemostró diferencias significativas en la incidencia de readmisiones omuertes, o en el control de INR.
CONCLUSIONES: Este estudio demuestra la habilidad de farmacéuticosacreditados que trabajan con el Programa Australiano de RMH yadiestrados apropiadamente de reducir los eventos adversos y mejorar lapersistencia en pacientes que toman warfarina luego de unahospitalización. La implementación amplia de este servicio tiene elpotencial de mejorar la seguridad en el uso de medicamentos en elcontinuum del cuidado.
Traducido por Giselle Rivera-Miranda
Les Résultats d’un Service Ambulatoire pour la GestionThérapeutique de la Warfarine
L Stafford, GM Peterson, LRE Bereznicki, SL Jackson, EC van Tienen, MTAngley, BV Bajorek, AJ McLachlan, JR Mullan, Gary MH Misan, et L Gaetani
Ann Pharmacother 2011;45:325-34.
RÉSUMÉ
OBJECTIF: La warfarine demeure un agent à haut risque d’engendrer deseffets indésirables, particulièrement durant la période suivant unehospitalisation. De nouvelles approches sont nécessaires pour minimiserle potentiel d’effets indésirables durant cette période. L’objectif de cetteétude était d’évaluer un service ambulatoire de gestion thérapeutique dela warfarine, service ayant été adapté d’un programme australien derevue médicamenteuse ambulatoire (RMA).
DEVIS EXPÉRIMENTAL: Il s’agit d’une étude de cohorte contrôléeprospective de patients dont le profil pharmacologique incluait lawarfarine lors de leur sortie d’hôpital. Les patients étaient répartis à ungroupe contrôle recevant les soins usuels ou à un groupe recevant 2 ou 3visites à domicile d’un pharmacien accrédité par le programmeaustralien RMA dans les 10 jours suivant leur sortie d’hôpital. Ceservice ambulatoire de gestion de la warfarine comprenait un évaluationdu rapport normalisé international (RNI), une formation sur la warfarineainsi qu’une revue médicamenteuse effectuée en collaboration avec lepharmacien communautaire et le médecin de famille du patient. Leparamètre primaire d’évaluation de l’étude était de documenterl’incidence combinée d’événements hémorragiques mineurs et majeursdans les 90 jours suivant l’hospitalisation. Les paramètres secondairesincluaient la documentation des incidences d’événementsthrombotiques, des incidences combinées d’événements hémorragiqueset thrombotiques, des réadmissions hospitalières dues à l’utilisation de lawarfarine, des décès, de l’utilisation des tests de contrôle du RNI et de lapersistance à poursuivre la thérapie de warfarine aux jours 8 et 90 post-hospitalisation.
SYNTHÈSE DES DONNÉES: Comparativement au groupe contrôle (n = 139),le service ambulatoire de gestion de la warfarine des 129 patientsassignés à ce groupe a été associé à une diminution statistiquementsignificative des événements hémorragiques mineurs et majeurs au jour8 (7.2% versus 0.9%, p = 0.01) et au jour 90 (14.7% versus 5.3%, p =0.03). Le taux combiné des événements hémorragiques et thrombotiquesau jour 90 a aussi diminué (19% versus 6.4%, p = 0.008) et lapersistance à poursuivre la warfarine s’est améliorée (95.4% versus83.6%, p = 0.004). Aucune différence significative quant au taux deréadmission hospitalière, au nombre de décès et à l’utilisation des testsde contrôle du RNI n’a toutefois été documentée.
CONCLUSIONS: Cette étude démontre qu’un service ambulatoire géré pardes pharmaciens accrédités peut réduire les effets indésirables reliés àl’utilisation de la warfarine et améliorer la persistance à la thérapiesuivant une hospitalisation. L’implantation élargie d’un tel service a lepotentiel d’augmenter l’utilisation sécuritaire des médicaments dans uncadre de continuité des soins.
Traduit par Sylvie Robert
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