ISPE August 2015 Boston2018-08-16T12:11:18+00:00

Project Description

31st International Conference on Pharmacoepidemiology & Therapeutic Risk Management (ICPE), Boston, August 2015

Abstract 133

Abstract 133: Utilisation and safety of deferasirox (Exjade®): Results from an observational cohort study in England

V Osborne, M Davies, D Layton, SAW Shakir

Background: Deferasirox is an oral iron chelating agent (ICA) primarily used to reduce chronic iron overload in patients (pts) receiving blood transfusions for various chronic anaemias and some non-transfusion dependant anaemias. Use in patients 2yrs+ is licensed for certain indications. An identified safety concern is increased serum creatinine (Cr) during treatment (Rx); monitoring is therefore recommended prior to and during Rx.

Objectives

To examine the utilisation and safety of deferasirox used in general practice in England.

Methods

Single exposure observational cohort study. Pts identified from dispensed prescriptions for deferasirox. Prescriptions collected Sep06-Sep14. Outcome data collected via postal questionnaires sent to prescribers ≥6mths after 1st dispensed prescription, including information on prior Cr measurements and prior use of alternative ICAs. Summary descriptive statistics calculated.

Results

Evaluable cohort=122 pts (2-17yrs=51, 41.8%); Median age=23yrs (IQR11-61); 58.2% male. Frequent reasons for prescribing (underlying conditions leading to iron overload): sickle cell anaemia (27/103 where specified,26.2%) and beta thalassaemia (BT) (26,25.2%); 53.8% BT pts had frequent blood transfusions (≥7ml/kg/mth packed red blood cells). Most pts (43/51,84.3%) were prescribed licensed doses of 10 or 20mg/kg/day at start. Rx initiated by a specialist for 100 pts (100/103,97.1%). 18 serum Cr values reported prior to Rx; 4 in excess of reference range [median value of all prior serum Cr 69μmol/L (IQR51-95)]. Events reported in these 4 pts included raised ferritin and renal function decline. In total, 91 incident events were reported, including 2 raised serum Cr after starting Rx. 45.6% pts (26/57) used an alternative ICA in the 12 months prior to Rx; 80.8% desferrioxamine.

Conclusion

These results show that deferasirox is largely being prescribed for its licensed indications in general practice in England and events reported were consistent with the known safety profile. These results contribute to post-marketing information. However, considering the small cohort size, any conclusions from this study should be put into context with results from other studies.

Abstract 138

Abstract 138: Evaluating Prescriber Concordance With Prescribing: Results from a Post-Marketing Study

Deborah Layton, Naseer Qayum, Claire Doe, Shayne Freemantle, Saad AW Shakir

Background: At launch (2005), ivabradine (Procoralan©) was indicated for treatment of chronic stable angina pectoris in patients (pts) with normal sinus rhythm, with a contraindication (CaI)/ intolerance for beta-blockers. A drug utilisation study was conducted to support risk management of the drug. Study objectives incl examining CaI, warnings for use (WFU) and incidence of 2 adverse events: visual phosphenes (phos) and bradycardia (brad) (persistent hr<50bpm).

Objectives

To develop a tool to support assessment of prescribing discordance with recommendations and explore impact on phos and brad incidence.

Methods

An observational single exposure cohort study. Exposure data were collected from dispensed prescriptions (Rx) Nov 2005- May 2009; outcome data (inc. pre-existing pt medical conditions/drugs whichcarried CaI/WFU) from forms sent to physicians (GPs) ≥ 6 months after each pt’s 1st Rx. An algorithm based prescribing framework was developed and assisted with the assessment of available information according to CaI/ WFU in SPC. To explore impact of prescriber discordance, phos and brad risk (%) and 95% CI were calculated by group (≥ 1 CaI; ≥ 1 WFU; both CaI/WFU; concordant or unknown). Descriptive statistics were calculated.

Results

Final cohort (4624), median age 68 yrs (IQR 60, 77); 57% (2663) male. CaI/WFU were assessed for 3357 pts: 74% (2491) were concordant, 21% (701) had WFU, 4% (124) had CaI, and 1% (41) had both CaI/WFU. Brad was reported for 96/4624 pts (2.1% (1.6,2.5)); 73 were assessed: 4/124 pts (3.2% (0.9,8.3) were CaI, 17/701 (2.4% (1.4,3.9)) had WFU, 1/41 had both CaI/WFU, and 51/2491 pts (2.0 (1.5,2.7)) were concordant. Phos was reported for 140/4624 pts (3.0% (2.5,3.6)); 104 were assessed:2/124 pts (1.6% (0.2,5.8)) were CaI, 23/701 had WFU (3.3% (2.1,4.9)), 1/41 had both CaI/WFU, and 78/2491 (3.1% (2.5,3.9)) were concordant.

Conclusion

In this study, the incidence of brad and phos was common in all concordance groups, although estimates lacked precision. This study demonstrates the feasibility of using a framework to assess prescribing discordance as reported in drug utilisation studies to identify at-risk populations, which may help support post-marketing risk:benefit evaluations.

Abstract 144

Abstract 144: Potential for Underdosing of Antipsychotics (AP) in Primary and Mental Health Care: Findings from Post-Authorisation Safety Studies Conducted on Seroquel XL

Deborah Layton, Vicki Osborne, Miranda Davies, Ian Ratcliffe, Sarah Clarke, Saad AW Shakir, Joe Reilly, Tony Hale.

Background: UK guidelines state that the lowest possible dose of APs should be used and titrated to the lowest effective dose. The Risk Management Plan for quetiapine extended release (Seroquel XL©) had a need to describe utilisation in primary care in all indications (via Modified Prescription-Event Monitoring (MPEM)-12 mths observation (obs)) and in the mental health setting in patients (pts) with schizophrenia (Schiz) or bipolar disorder (BD) (via Specialist Cohort Event Monitoring (SCEM)-12 weeks obs; ENCePP Study reg. 5412). Study objectives included exploring posology.

Objectives

To describe dosing of Seroquel XL©, with a focus on potential for underdosing.

Methods

Exposure, selected prior medical history (pmh) and medications use data were collected for each study from forms sent to hospital specialists for SCEM Dec 2009 – Dec 2012 and to primary care physicians (GPs) for MPEM Sep 2008-Feb 2013, respectively. Descriptive statistics were calculated; doses were converted to % of relevant max dose by indication and titration stage in SPC– underdosing defined as <100%.

Results

In the M-PEM (13276), potential underdosing was very common; start:Schiz:37%(785/2136); BD:3%(98/3500); Major Depressive Disorder (MDD):6%(147/2646); maint: Schiz: 38%(509/1339); BD:33%(721/2165); MDD: 32%(531/1648). In the SCEM (869) potential underdosing was also very common at start: Schiz:56%(144/258); BD:59%(204/305) and at maint (86% (223), and 91% (315) respectively).

Conclusion

Both studies found that potential underdosing occurred for all indications. Start dose data correlated poorly with SPC and expert guidelines to use lowest effective dose, but corresponded to UK prescribing guidelines which do not recommend excessive doses, unless other evidence–based strategies have failed. Possible explanations for more common potential underdosing in SCEM vs MPEM is that pts treated by specialists may require more individualised therapy (incl use of immediate release quetiapine) to initially stabilise their condition, whilst GPs tend to manage pts at later stages. Further work will explore impact of age and prior/concurrent psychotropic use on underdosing.

Abstract 147

Abstract 147: Utilisation of a New Once Weekly Injection for Type 2 Diabetes Mellitus (T2DM): Interim Results from an Observational Cohort Study of Exenatide (Bydureon®) in England

V Osborne, N Qayum, AL Coughtrie, D Layton, SAW Shakir

Background: Bydureon® is indicated for the treatment (Rx) of T2DM in combination with metformin, sulphonylurea (SU), thiazolidindione (TZD) alone, metformin & SU or metformin & TZD for patients (pts) who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies alone. A post-marketing observational cohort study of Bydureon® was requested as part of the EU Risk Management Plan. The final target cohort size is 5000 pts. This study is ongoing.

Objectives

To describe the utilisation characteristics of pts prescribed Bydureon® at interim.

Methods

An observational, population-based cohort design in primary care. Pts in the interim cohort were identified from all dispensed prescriptions for Bydureon® in England Sept11-Jan14 (interim data lock). Data were collected from prescribers via postal questionnaires sent ≥12mths after the 1st prescription was dispensed. Summary descriptive statistics were calculated.

Results

Evaluable cohort at interim=520 pts; median age 58yrs (IQR 51-65); 58.1% male. T2DM and time since diagnosis was specified for 493 pts; the majority were diagnosed >10yrs prior to starting Rx (210, 42.6%). Where specified (n=441), 91.1% pts were classed as obese (BMI >30.0 kg/m2) immediately prior to Rx. On starting, 48.4% (134/277) had a HbA1c >9%, representing very poor diabetes control. Most pts had HbA1c ≥7.5% (223, 80.5%). The majority of pts used 2mg once weekly (489/492, 99.4%) and most pts were prescribed Bydureon® as either second line (158/477, 33.1%) or third line co-therapy (307, 64.4%). The majority of pts were prescribed Bydureon® with metformin (417/520, 80.2%). Co-prescribing of insulin was also reported (117, 22.5%).

Conclusion

These interim results characterise the utilisation of Bydureon® in primary care in England. The majority of pts had T2DM, used 2mg once weekly and were co-prescribed metformin. Most pts were obese which raises the possibility of channelling by prescribers due to the purported benefits of Bydureon® in weight loss. This interim analysis will be superseded when validation and follow-up are complete for the final analysis.

Abstract 151

Abstract 151: Utilisation of Asenapine in the Mental Health Care Setting in England and Wales: First Results from a Specialist Cohort Event Monitoring (SCEM) Study

V Osborne, J Slade, D Layton, SAW Shakir, Joe Reilly

Background: OBSERVA is a SCEM study being conducted as part of the EU Risk Management Plan to monitor the short-term safety and utilisation of asenapine prescribed to new user patients (pts) by psychiatrists in the mental health care setting in England and Wales.

Objectives

To describe utilisation characteristics of pts prescribed asenapine at interim and assess use in relation to the license.

Methods

Single exposure observational cohort of pts prescribed asenapine over 3yrs. Pts identified via network of psychiatrists in collaboration with Mental Health Research Network. Data are abstracted from medical records. After pt consent, questionnaires completed by study investigators collect: baseline data incl.exposure and 12wks post index date outcomes. At interim, pts were recruited from 14 NHS trusts Feb13-Feb14 (interim data lock). Descriptive statistics calculated (% specified, excl.missing).

Results

Interim cohort=57 consented pts; of which 46 pts evaluable with baseline data. Most frequent indication was bipolar disorder (36,78.3%) though 10 non-licensed indications were reported (21.7%). Most frequent dose at index date was 5mg 2x daily in 16 pts (16/46,34.8%), whilst at maintenance it was 10mg 2x daily (9/42,21.4%). Doses other than 5 or 10mg 1x or 2x daily were reported for 3pts at index (6.5%) and 5pts at maintenance (11.9%). Past history (>28days prior) of psychiatric conditions (suicide/self-injury & depression) was common (19/46;41.3% & 25/46;54.4%, respectively). Past history of diabetes mellitus was also common (5/46;10.9%). Of risk factors for potential misuse at baseline, majority of pts had no prior or current history of alcohol misuse (25/45,55.6%) or substance abuse (29/43,67.4%).

Conclusion

The majority of new user pts at interim were treated with asenapine for licensed indications. Prior history of psychiatric conditions is as expected for populations treated for mental health conditions. Prevalence of off-label indications was common, as were risk factors for potential misuse. These interim data demonstrate the importance of SCEM to gather real-world data to support post-marketing risk:benefit management.

Abstract 217

Abstract 217: Use of Antipsychotics (AP) in Mental Health Secondary Care Setting Vs Primary Care

Deborah Layton, Vicki Osborne, Miranda Davies, Ian Ratcliffe, Sarah Clarke, Saad AW Shakir, Joe Reilly, Tony Hale

Background: Safety studies conducted exclusively in the primary care setting may be subject to bias because of exclusion of patients (pts) who are managed predominantly within secondary care. These pts may have different characteristics and health events to those treated in primary care for similar indications. The Risk Management Plan for quetiapine extended release (Seroquel XL©) had a need to describe utilisation and monitor safety as prescribed in primary care (in a Modified Prescription-Event Monitoring (MPEM) – all indications) and in mental health secondary care (in a Specialist Cohort Event Monitoring (SCEM)-ENCePP Study reg.5412 – Schizophrenia (Schiz) and Bipolar disorder (BD) indications only).

Objectives

An ad-hoc analysis to describe the characteristics of two study cohorts prescribed Seroquel XL© for similar indications under normal conditions of use in each setting

Methods

Exposure, selected past medical history (pmh) and prior medications use (incl. quetiapine immediate release (IR)) data were collected from forms sent to specialists Dec2009-Dec2012 and to General Practitioners (GPs) Sep2008-Feb 2013. Descriptive statistics and univariate analyses were performed (% denominator assumes no missing data).

Results

The SCEM cohort (869) inc. 258 pts (40%) with Schiz, 345 pts (53%) with BD. The MPEM cohort (13276) inc 2373 pts (18%) with Schiz, 3820 pts (30%) with BD. In those with Schiz, SCEM pts were more likely than MPEM pts to be < 30 yrs old, have a pmh of: depression, extrapyramidal symptoms (EPS) and prior antipsychotic (AP) use, but prior IR use was less likely. In those with BD, SCEM pts were more likely than MPEM pts to have a pmh of: depression, EPS, diabetes and AP use, and prior IR use was less likely.

Conclusion

In this ad-hoc analysis, SCEM pts appeared overall to have a higher burden of some pre-existing conditions (depression, EPS and diabetes) than MPEM pts, highlighting important differences in pt risk profiles. Considerations include differences in the recording of data in medical records held by specialists vs GPs. Nevertheless, these findings support the need for systematic surveillance across both primary and secondary care settings to avoid exclusion of high risk pts.

Abstract 266

Abstract 266: Antipsychotic (AP) Use in Older Adults With Dementia: Results from a Post-Authorisation Safety Study (PASS)

D Layton, M Davies, V Osborne, SAW Shakir

Background:The UK National Institute for Health and Care Excellence recommends that APs can be used in elderly patients (pts) under strict guidelines, however use is associated with serious safety concerns (incl cerebrovascular accidents (CVA)). Modified Prescription-Event Monitoring (M-PEM) study was conducted as part of the Risk Management Plan for Seroquel XL© to examine safety and use as prescribed in primary care in England.

Objectives

A post hoc analysis to examine the risk of CVA in the elderly

Methods

M-PEM uses an observational cohort design; data on exposure were derived from dispensed prescriptions Sep2008-Feb2013; data on events from forms completed by physicians 12+ months(m) post each pt’s start date. Age & sex adjusted (adj) Mantel-Haenszel Odds Ratios (ORs) and 95%CI were calculated for all cause deaths and CVA (MedDRA PT: CVA, Cerebellar infarction, Cerebral haemorrhage, Haemorrhagic stroke) in elderly pts with/without dementia, and with/without psychosis.

Results

Final elderly cohort= 3127; median age 77 yrs (IQR 69,84); 62% (1940) female; 892 (29%) had indications associated with dementia, of which 148 (17%) had concomitant psychosis. Within 12m of starting Seroquel XL© 10% (301) died; commonly from bronchopneumonia (44). Deaths were more likely in elderly with dementia than without [15% (136/892) vs 8% (165/2070); adjOR 1.5(1.2, 1.9)] but not for dementia pts with psychosis vs those without [14% (21/148) vs 15% (115/744); adjOR 1.0 (0.6,1.6)]. 23 (1%) had at least 1 report of CVA; 17 fatal. CVA events were twice as likely in pts with dementia than without [48% (11/23) vs 28% (881/3104); adjOR 2.8 (1.3, 6.2).

Conclusion

Approximately one-third (29%) of this elderly cohort had dementia +/- psychosis. A higher rate of death was observed in elderly pts with dementia than without, but concomitant psychosis with dementia did not appear to be a risk factor. CVA was uncommon (<1%), but more likely in elderly with dementia than those without. Study limitations include low CVA counts, possible misclassification of depression and delirium as dementia and limited information on other possible factors (other modifiable medical and environmental factors).

Abstract 295

Abstract 295: Applying the Ready Reckoner (RRec) Tool for Assessing Antipsychotic (AP) Prescribing Within Post-Authorisation Safety Studies (PASS)

Deborah Layton

Background: In the UK, the RRec monitors AP dosing in patients (pts) with complex AP regimens – each AP dose is converted to % of relevant max dose by indication and titration stage in SPC. Total dose% >100% identifies pts at risk. A nested case control (NCC) study was undertaken as part of a PASS to explore possible dose-event response for somnolence/ sedation (SS) after starting a new AP formulation. The primary objective evaluated total daily dose (TDDmg)> 600.

Objectives

An exploratory objective evaluated use of the RRec as an alternative indication-adjusted dose metric to model AP treatment effects.

Methods

An incidence density matched NCC study using a primary care cohort (13276) identified Sep2008-Feb2013. Of 756 cases, 212(28%) were randomly selected and 170 risk sets created. For all subjects, the reported TDDmg (start, maintenance and event) were converted to dose% (Non-licensed indications used SPC dose range for major depression). Fractional polynomial (FP) logistic models explored functional form; empirical and fitted within-person OLS dose trajectories described patterns over time.

Results

SS cases tended have higher reported TDDmg vs controls at start [median 300 (IQR 200,600) vs 200mg (IQR 100,300), p<0.01] but the inverse was seen when the dose % metric was applied (median 50% (IQR 16,100) vs 75% (33,100), p=0.02). At maintenance and event, similar relationships were observed for reported TDDmg and dose % variables. SS risk was a negative function of TDDmg and dose%. No deviation from linear assumption was apparent for start and maintenance doses (FP2 vs linear, P>0.05), but was non-linear for dose% at event (p=0.04). In exploring pattern over time, the general trend was decreasing for both cases and controls, although slower for controls.

Conclusion

This exploratory analysis demonstrates the feasibility of the RRec as an alternative indication-adjusted variable for analysing dose, particularly where multiple indications may exist that use various dose ranges. Analytical advantages include avoiding creation of strata of small sample sizes. Limitations include possible metric under-estimation from missing data for other concomitant APs.

Abstract 308

Abstract 308: New Methodology for Enhanced Safety Surveillance of Nasal Quadrivalent Live Attenuated Influenza Vaccine (QLAIV) Using Participant Questionnaire Feedback: Interim Results

Rhian McNaughton, Elizabeth Lynn, Vicki Osborne, Saad Shakir

Background:An active surveillance study was performed at the start of the 2014/2015 influenza season following publication of EMA guidance for enhanced safety surveillance of influenza vaccines.

Objectives

To rapidly detect a clinically significant change in the frequency and/or severity of expected “reactogenicity” and other adverse events of interest (AEIs) during the first 14 days post vaccination with intranasal QLAIV (Fluenz Tetra®).

Methods

Children and adolescents vaccinated with QLAIV were recruited to this prospective observational cohort study through GPs or schools in pilot areas in England during a mass influenza vaccination programme. Three age groups with 100 vaccinees in each were planned: Group 1: 2-4 years, Group 2: 5-10 years, Group 3: 11-17 years. Participants completed simple online or postal questionnaires detailing exposure, covariates (e.g. medical conditions) and targeted outcome information about AEIs (primary outcome). AEI summary descriptive statistics, crude incidence risks and incidence rates (IR) per 1,000 patient-weeks (95%CI) were calculated.

Results

With data collected from September to November 2014, the cohort comprised 282 participants (Group 1: n=143; Group 2: n=103; Group 3: n=36). The most frequently reported AEI was nasal congestion in all age groups (Group 1: n = 67 (46.9%), IR: 317.3 (244.2, 412.3); Group 2: n = 46 (44.7%), IR: 264.6 (189.1, 370.3); Group 3: n = 15 (41.7%), IR: 295.2 (174.8, 298.4). Although four hypersensitivity type reactions were reported (Group 1: n = 1; Group 2: n = 2; Group 3: n = 1), on follow-up none was a true allergic reaction, serious or required hospitalisation.

Conclusion

No apparent safety signal was detected from the small amount of data collected. This study demonstrates that the methodology applied is well suited to rapidly monitor the incidence of AEIs with QLAIV, minimising any additional workload for healthcare professionals.

Abstract 582

Abstract 582: Observational Assessment of Safety in Seroquel (OASIS) Rates & Patterns of Common Events Observed in Users of Quetiapine Extended-Release (Seroquel XL) and Immediate Release (IR)

Deborah Layton, Sarah Clarke, Ian Ratcliffe, Saad AW Shakir, Tony Hale

Background:The aim of OASIS (ENCePP Study reg.5412) was to extend the post-authorisation safety knowledge of quetiapine XL, with a focus on short-term (12-week (w)) safety and high dose (>600mg/day) use, as prescribed by psychiatrists in patients (pts) with Schizophrenia (Schiz) or Bipolar Disorder (BD), vs quetiapine IR. Study objectives incl. quantifying event incidence and pattern.

Objectives

To compare common event rates between users defined by dose and formulation.

Methods

An observational cohort design. Questionnaires completed by specialists collected data on pt characteristics, exposure and events Dec2009-Dec2012. Exposure (pt-w) was calculated for: total cohort and stratified by formulation. Stratum specific exposure was calculated for three 4-w periods for total cohort, formulation and high dose use (where >600mg/day for >50% of each 4-w period). Crude event Incidence Densities (ID) per 1000 pt-w and ID differences (IDD+95%CI) were calculated within/between groups; IDD 95%CI excluding the null (0) were signals of events associated with starting treatment and/or high dose.

Results

Cohort = 845: Schiz: 338(40%), BD: 442(52%), Other: 65 (8%); 471 (59%) female; median age 39 (IQR 29,49). High dose use was reported for 28/631 (4%) in XL group and 3/214 (1%) IR group. The most frequently reported events (not associated with indication) were: sedation:ID 24, somnolence:ID 20, akasthesia: ID 3, and parkinsonism: ID 2. In the XL group, the IDDs for these 4 events were non-significantly lower for high vs standard dose for total study period and weeks 1-4. Within XL high dose group, sedation and somnolence were associated with starting treatment (IDD w 1-4 – w 5-8 : 25 (7, 42) and 14 (14, 15) respectively); this pattern was also observed within XL and IR standard dose groups. Low counts in high dose group and IR cohort precluded reliable comparisons.

Conclusion

This study found that sedation and somnolence were common events associated with starting treatment, but not with high dose. Although the frequency of high dose use was low, OASIS provides important information on the safety and utilisation of quetiapine XL.

Abstract 814

Abstract 814: Defining Risk Profiles in Special Populations -Results from a Post Authorisation Safety Study (PASS) of Seroquel XL Conducted in Primary Care in England

Deborah Layton, Vicki Osborne, Miranda Davies, Saad Shakir

Background: A Risk Management Plan developed for quetiapine extended release (Seroquel XL©), included a PASS to examine its safety and use as prescribed in primary care. Objectives incl. exploring risks in special populations (SP).

Objectives

To describe risk profiles by SP groups (indication, past medical (pmh) history, prior psychoactive drugs, and age >65,<64).

Methods

An observational, single-exposure cohort design. Data were derived on exposure from dispensed prescriptions; on events from forms completed by physicians 12 months (m) post first exposure. For general surveillance crude incidence densities (ID) per 1000 pt-m were calculated for events in m1, 2-6, 7-12 and 1-12 for cohort, and by SP group. Overdose events were grouped by suicidal ideation (SI), suicidal behaviour (SB), self-injurious behaviour (SIB). Event ID differences (IDD 1- 2-6 ) + 95%CI excluding the null (0) were signals of starting treatment. Survival methods estimated rates of overdose and hyperglycaemic (HG) events (+95%CI) per 1000 pt-m (where n>7 and excl pts if event date missing).

Results

Cohort=13276; 59% female; median age 43 (IQR 33,55). Events with highest ID 1-12 were: Sedation, n=317: ID 40; Somnolence,n=288: ID 47; and Weight increased,n=198: ID 54. Somnolence and Sedation were associated with starting treatment overall (IDD 1-2-6 :3.8(1.5,5.7) and 2.5(0.8,4.2) respectively) and in SP groups: Indication Bipolar Bisorder or Non-licensed indications; age ≤64; and pmh depression. For HG events, the highest rates m 1-12 were: raised random blood sugar (n=122):1.0 (0.8,1.2) and raised fasting plasma glucose (n=104):0.8 (0.7,1.0). SP groups with pmh IGT and diabetes appeared to have highest rates.Of 104 overdose events, pmh mental illness was reported for all pts; event rates m 1-12 were: SB (n=84):101.8 (82.2,126.1), SI (n=1):4.0 (0.6,28.4), and SIB (n=15): 36.6 (22.0,60.1).

Conclusion

For frequently reported central nervous system, psychiatric and HG events, many pts had pre-existing risk factors that are likely to put them at elevated risk. This study demonstrates the ongoing importance of observational studies to support the risk:benefit evaluation of medications.

Abstract 821

Abstract 821: Reasons for and Time To Antipsychotic (AP) Treatment Discontinuation: Results from a Post-Authorisation Safety Study

Deborah Layton, Vicki Osborne, Miranda Davies, Saad Shakir

Background: APs are generally effective but some patients (pts) may stop soon after starting due to poor tolerability. Quetiapine prolonged-release (Seroquel XL©) was developed to improve tolerability and administration via once daily dosing. The Risk Management Plan had a requirement to describe utilisation and monitor safety as prescribed to new XL users in primary care, via Modified Prescription-Event Monitoring (MPEM).

Objectives

A post-hoc analysis to describe common factors associated with stopping XL

Methods

MPEM uses an observational cohort design. Questionnaires completed by physicians (GPs) collected data on pt demographics, prior medical history (pmh), prior/current medication use, XL exposure and events (incl. reasons for stopping (RFS)) Sep2008-Feb2013. Descriptive statistics described the cohort. Kaplan Meier methods analysed time to stopping in first 12 months after starting. Crude Odds Ratios (OR) and 95%CI) were calculated to explore relationships between stopping and pt characteristics.

Results

Cohort = 13276; 59% (7828) female; median age 43 yrs (IQR 33,55); indication: Bipolar Disorder (30%,3820), Major Depressive Disorder (22%,2844), Schizophrenia (18%,2373) and Other non-licensed (29%,3750). 3753 pts (28% cohort) stopped treatment (10% by day 56; 25% by day 220). There was significant variation by indication (Log rank test p<0.001) – pts with Other non-licensed indications were most likely to stop (31%, 1162). The most frequent non-clinical and clinical RFS were the events: ‘drug ineffective’ (19%, 581/3094) and ‘sedation’ (15%, 269/750). Pts with a pmh somnolence/ sedation vs those without were more likely to stop due to Sedation: OR 3.3 (2.1, 4.9). Naive AP use, a pmh of extrapyramidal symptoms, metabolic syndrome, diabetes, and impaired glucose tolerance appeared to be risk factors for stopping for any reason.

Conclusion

In this study, nearly one third of pts stopped Seroquel XL© <12 months and RFS were varied. Certain pt characteristics may also be associated with a higher risk of stopping. Further work will explore the impact of dosing. This data can help support GPs decisions on prescribing and management to prevent premature treatment cessation.

Abstract 1003

Abstract 1003: Application of the International Society on Thrombosis and Haemostasis (ISTH) Definition of Major Bleeds To Bleeding Events Within a Post Authorization Safety Study

Miranda Davies, Vicki Osborne, Deborah Layton, Saad Shakirr

Background: Haemorrhage is a frequent complication of anticoagulant (AC) use. In order to compare incidencesbetween trials a definition of major bleeds (MB) in non surgical studies was developed by the InternationalSociety on Thrombosis and Haemostasis (ISTH) in 2005. In recent years, the Committee for Medicinal Productsfor Human Use (CHMP) has recommended its use in studies for prevention of stroke and systemic embolicevents (SEE) in patients (pts) with non valvular atrial fibrillation (NVAF) and prevention of deep vein thrombosis(DVT) and pulmonary embolus (PE). Bleeds reported in a Specialist Cohort Event Monitoring (SCEM) study onthe oral AC rivaroxaban (conducted as part of Risk Management Plan) will be classified using this definition.

Objectives

To describe the methodological considerations of applying this definition to observational data.

Methods

Aim to collect data on 1700 pts treated for the prevention of SEE [n=561], and the treatment andprevention of recurrent DVT and PE [n=1005]. Recruitment Sep2013-2016. Information (info) was obtained onbleeds that occurred during initial 12 weeks; criteria for MB included: a fall in Hb of ≥ 2 g/dL, a transfusion of ≥2 units, critical organ site, or fatal outcome. Bleeds will be classified as clinically relevant non major (CRNM) ifnone of the MB criteria were met, but if medical attention was required and/or a change in antithrombotic therapyand/or any other bleed with clinical consequences.

Results

To minimise misclassification, supplementary info will be used to validate and confirm the type, obtain missing data and further details of the bleed (site, management, and outcome). All bleeds will be adjudicated by an expert, and interim results will be published.

Conclusion

By systematically applying the ISTH definition, we hope to gain better understanding of the type of bleeds reported in a cohort of AC users, associated risk factors and outcome details. This should enable more meaningful comparisons to be made between major and CRNM bleeding incidences obtained in this setting with those observed during trials.

Contact Info

Drug Safety Research Unit Bursledon Hall, Blundell Lane, Southampton, SO31 1AA, U.K.

Phone: +44 (0)23 80 40 86 00

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