pharmacoepidemiology and drug safety (2014) Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/pds.3682
ABSTRACT
PRESCRIBING AND RESEARCH IN MEDICINES MANAGEMENT (UK & IRELAND) CONFERENCE 2014 IMPERIAL HOTEL LONDON MAY 2nd 2014 “MEDICINES OPTIMISATION - IN THE NEW COMMISSIONING ENVIRONMENT”
EFFECTIVENESS OF PHARMACIST INDEPENDENT PRESCRIBING ON THE CLINICAL OUTCOMES OF TYPE 2 DIABETIC PATIENTS Mohammed Abutaleb, Douglas Steinke and Mary Tully Manchester Pharmacy School, University of Manchester, UK Background Diabetes is one of the leading causes of mortality in the UK with about 2.9 million people currently diagnosed. The incidence is predicted to continue expanding if alternative means of treatments are not augmented. The aim of this study was to evaluate the impact of pharmacist independent prescribing on the clinical outcomes of patients with type 2 diabetes. Methods A retrospectively designed, secondary database analytical study was carried out using data from medical records of outpatients with type 2 diabetes attending Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes Complex Clinics at the University Hospital of South Manchester NHS Foundation Trust’s (UHSM) for a period of 7 years. The patients were allocated into one of two groups, “doctor only” and “doctor or pharmacist” for patients seen by doctors only in all clinics, or a pharmacist in place of a doctor at any point of time during the study period, respectively. Patients who have at anytime seen a nurse, had just one clinic visit and/or had only one laboratory visit throughout the study period were excluded. Endpoints observed for each patient based on the laboratory and clinic outcomes. The laboratory outcomes were the HbA1C as a primary outcome; total cholesterol, triglycerides, LDL, HDL, and serum creatinine levels were secondary outcomes. Other secondary outcomes included clinic measures such as BMI, body weight, systolic and diastolic blood pressures. All outcomes were measured at baseline prior to the pharmacist’s interventions. Endpoints were recorded as difference between the last available follow up and the baseline.
abstract
Result A total of 1,305 patients were used for the study, 975 (74.7%) and 330 (24.3%) for “doctor only” and “pharmacist” groups, respectively. All clinical outcomes were comparable in both doctor only and pharmacist groups at baseline although other demographic features like ethnicity, and types of some medicines used differ for some patients. Patient in the pharmacist group showed improved clinical and laboratory outcomes which are comparable to the doctor group. For clinical outcomes, there was reduced BMI, weight, systolic and diastolic blood pressures which were comparable to the doctor group although all changes were not statistically significant. For laboratory outcomes, there was decrease in TC and TG with highest decrease in the doctor group. The pharmacist group showed greater reduction in HbA1C where there was an increase in doctor group while HDL levels remained at the same level for both groups. All changes were not statistically significant. A subgroup analysis to show the impact of the pharmacist within a group seeing a collaborator was also carried out. Patients were assigned to the two groups to be as homogenous as possible. The clinical and laboratory outcomes were comparable although there was reduction in mean HbA1C level in the pharmacist group. Conclusion Pharmacist independent prescribing in the management of diabetes did not only show beneficial overall effects but also positively impacted HbA1C levels. Thus, the inclusion of pharmacist as part of diabetes management team may be advantageous to patients with type 2 diabetes mellitus. Keywords Non-Medical Prescribing, Pharmacist Independent Prescribing, Clinical Outcomes, Type 2 Diabetes, Comparative Effectiveness Research, Retrospective Secondary Database Analysis ANTIMICROBIAL PRESCRIBING IN THE MANAGEMENT OF LOWER RESPIRATORY TRACT INFECTIONS (LRTI) IN THE ELDERLY POPULATION (>65YEARS): THE USE OF INFORMATION TECHNOLOGY TO IMPROVE PATIENT CARE Appleton Sarah, Puntan Hannah and Curtis Sally St Mary’s Hospital, Imperial College Healthcare NHS Trust Copyright © 2014 John Wiley & Sons, Ltd.
Background At any one time 41% of inpatients at Imperial College Healthcare NHS1 Trust (ICHNT) are receiving antimicrobial therapy. Lower respiratory tract infections (LRTI’s) are the leading cause for antimicrobial prescribing within secondary care,2,3 with more than 70% of hospital admissions for Community Acquired Pneumonia (CAP) occurring in the over 65’s.4 ICHNT currently use antimicrobial guidelines developed specifically for use in patients over the age of 65, frail or otherwise at risk of Clostridium difficile associated diarrhoea.5 Aim To assess whether patients above 65 years of age with a confirmed diagnosis of LRTI received antimicrobial therapy in accordance with the trust antimicrobial guidelines. Method Data collection took place over a 4 week period. Patients were identified using the post take handover list. All patients over the age of 65 years admitted to St Mary’s hospital via A + E under the care of the acute medical team with a confirmed diagnosis of an LRTI Results Intravenous (IV) antibiotic therapy was initiated in 73% of patients. 12 patients (29%) received Piperacillin/tazobactam (Tazocin®) and 15 (37%) were prescribed Co-amoxiclav (IV). Of those patients receiving IV therapy only 31% (13) of prescriptions were compliant with current trust guidelines. Discussion The number of patients initiated on IV antibiotics was higher than expected. Co-amoxiclav was initiated in a high proportion of patients despite Trust guidelines advising against the use of this agent in the elderly due to the risk of C.diff. Findings were presented to relevant medical teams and relevant education and training was given to junior prescribers. Post audit the ICHNT antimicrobial app for smart phones was
Trust point prevalence study in anti-infective use – October 2013 Woodhead MA, Macfarlane JT, McCracken JS et al. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987; i: 671–4. 3 Garibaldi RA. Epidemiology of community-acquired respiratory tract infections in adults: incidence, etiology, and impact. Am J Med 1985; 78: 32S–7S. 4 British Thoracic Society Adult Community Acquired Pneumonia Audit 4 (national audit period 1 December 2011 – 31 January 2012) Dr Wei Shen Lim, Dr Chamira Rodrigo 1 2
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
abstract
updated to include a step whereby the patient’s age had to be entered prior to the appropriate guideline appearing. A re-audit was conducted post implementation. Conclusion The new improved app along with education and training showed a significant improvement in the prescribing of antimicrobials in the elderly. Rate of compliance with trust guidelines increased to 76%. The percentage of IV antibiotics used decreased from 73% to 44% and the use of Co-amoxiclav decreased to 8%. Results show that simple IT changes can have a very positive and powerful effect on optimising medicines. MEDICINE USE REVIEWS (MURS) AT DISCHARGE: STILL THE CINDERELLA SERVICE Corlett SA1, Goel P1, Kothari S1 and Dodds L1,2 Medway School of Pharmacy, Universities of Kent and Greenwich at Medway 2 East and South East England Specialist Pharmacy Services, West Kent PCT
1
Background Many errors occur with patients’ medication as a consequence of transferring care. Pharmacist input has been shown to reduce such errors.1 Introduced in 2011, discharge MURs (dMURs) provide community pharmacists with the opportunity to support patients post-discharge. Patients can be advised when and how to take their medicines and be provided with information on side effects and changes to treatment.2 This study aimed to survey community pharmacists in Kent and Medway to explore their views and experiences with dMURs. Method All community pharmacies (340) were sent a letter informing them of the purpose of the study. An interview schedule to explore the provision of, barriers to, and facilitators of the dMUR service was developed and piloted. Telephone interviews followed a pre-agreed script and included both open and closed questions. All respondents were accredited to provide MURs. Data were analysed using descriptive statistics. Ethical approval for the study was obtained from Medway School of Pharmacy’s Research Ethics Committee.
pharmacist. Over half (56%, n = 95) had never conducted a dMUR. Of those that had, 47 (63%) pharmacists thought that they were more challenging than a standard medicine use review. The majority (88%, n = 150) of all respondents thought that dMURs were useful to patients because they enabled pharmacists to increase a patient’s knowledge about their new medicines, explain any medicine changes, improve adherence and decrease the number of medicine errors. A minority (6%, n = 11) thought that dMURs were of limited value to patients because they repeated information already provided in hospital. Seventy nine percent (n = 135) of respondents felt that they had appropriate support and resources to undertake a dMUR The main barrier to providing the service was indentifying patients who were eligible to receive it. Some respondents (14%, n = 24) would have liked a fax, e-mail or phone call from the discharging hospital and the majority (67%, n = 113) of pharmacists expressed a desire to see the discharge summary. Eleven percent (n = 18) stated that patients could share the discharge summaries with them. Conclusion The majority of community pharmacists believe that dMURs are beneficial to patients. However, despite this the uptake of dMURs is still low and over half of the pharmacists in this study had not conducted a dMUR more than two years after their introduction. The key barrier to improving the provision of dMURs remains communication between primary and secondary care pharmacy services. References 1. Barber N, Rawlins M, Franklin BD. Reducing prescribing error: competence, control and culture. Qual Saf Health Care 2003; 12(1):23–32. 2. Pharmaceutical Services Negotiating Committee. 2013. Pharmaceutical Services Negotiating Committee. Available at: http://psnc.org.uk/services-commissioning/advanced-services/murs/ [17 October 2013]. MEDICINES OPTIMISATION POST-STROKE & TIA: ARE WE DOING ENOUGH? Dodds LJ1,2, Mok E1, Patel K1 and Corlett SA1 Medway School of Pharmacy, Universities of Kent and Greenwich at Medway 2 East and South East England Specialist Pharmacy Services, West Kent PCT
1
Results Fifty percent (n = 170) of pharmacists completed the interview. Of these, 139 (82%) were the regular Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
abstract Table 1. Proportion of stroke/ TIA patients achieving targets for cholesterol and BP Antihypertensives BP % (no.) of patients Achieving RCP targets Achieving QOF targets Not achieving QOF target
Lipid regulating drugs - Cholesterol
TIA
Stroke
TIA
Stroke*
40 (44) 96 (106) 4 (4)
39 (60) 85 (131) 15 (23)
73 (80) 90 (99) 10 (11)
68 (105) 84 (130) 13 (20)
*Cholesterol not recorded for 4 patients No statistical differences were observed between the blood pressure or cholesterol level measurements of stroke and TIA survivors (p > 0.05; t-test). Over 90% of TIA and 80% of stroke survivors achieved the QOF targets for BP and total cholesterol respectively, but only 40% achieved an optimal BP of 130/80 mmHg and 70% a total cholesterol of 35 days. For both drugs, over 60% of patients were in the 75+ age-group. ‘Caution’ drugs were dispensed alongside a NOAC in 36% of dabigatran patients and 26% of rivaroxaban patients. These predominantly included antiplatelet drugs (17% of dabigatran patients, 18% of rivaroxaban patients) and SSRI/SNRI drugs (13% of dabigatran patients). Both GMS data and prescriber-completed reimbursement authorisation forms contained frequent incidences of rivaroxaban prescribed at a daily dose of 10 mg, indicating potential underdosing in atrial fibrillation. Conclusions High uptake of dabigatran and rivaroxaban for long-term anti-coagulation therapy was observed. Co-prescribing of interacting drugs was frequent. The combination of suboptimal dosages and potential drug interactions observed may represent a significant safety concern in clinical practice. Findings led to the issuing by the MMP of a letter to all practicing doctors in Ireland in order to highlight potentially inappropriate prescribing. References 1. Xu Y, Holbrook AM, Simpson CS, Dowlatshahi D, Johnson AP. Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a populationbased descriptive analysis. Can Med Assoc Open Access J 2013; 1(3): E115–E9. 2. Carley B, Griesbach S, Larson T, Krueger K. Assessment of dabigatran utilization and prescribing patterns for atrial fibrillation in a physician group practice setting. Am J Cardiol 2014; 113(4): 650–4.
AUTHOR INDEX Abutaleb, M Appleton, S Corlett, S A Dodds, L J Gill, T S Godman, B Copyright © 2014 John Wiley & Sons, Ltd.
Katusiime, B Keers, R N Kelly, M Kelly, M Latif, A
Poluzzi, E Rodgers, R M Salema, N Salman, D Spillane, S
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
ABSTRACT
PRESCRIBING AND RESEARCH IN MEDICINES MANAGEMENT (UK & IRELAND) CONFERENCE 2014 IMPERIAL HOTEL LONDON MAY 2nd 2014 “MEDICINES OPTIMISATION - IN THE NEW COMMISSIONING ENVIRONMENT”
EFFECTIVENESS OF PHARMACIST INDEPENDENT PRESCRIBING ON THE CLINICAL OUTCOMES OF TYPE 2 DIABETIC PATIENTS Mohammed Abutaleb, Douglas Steinke and Mary Tully Manchester Pharmacy School, University of Manchester, UK Background Diabetes is one of the leading causes of mortality in the UK with about 2.9 million people currently diagnosed. The incidence is predicted to continue expanding if alternative means of treatments are not augmented. The aim of this study was to evaluate the impact of pharmacist independent prescribing on the clinical outcomes of patients with type 2 diabetes. Methods A retrospectively designed, secondary database analytical study was carried out using data from medical records of outpatients with type 2 diabetes attending Copyright © 2014 John Wiley & Sons, Ltd.
Diabetes Complex Clinics at the University Hospital of South Manchester NHS Foundation Trust’s (UHSM) for a period of 7 years. The patients were allocated into one of two groups, “doctor only” and “doctor or pharmacist” for patients seen by doctors only in all clinics, or a pharmacist in place of a doctor at any point of time during the study period, respectively. Patients who have at anytime seen a nurse, had just one clinic visit and/or had only one laboratory visit throughout the study period were excluded. Endpoints observed for each patient based on the laboratory and clinic outcomes. The laboratory outcomes were the HbA1C as a primary outcome; total cholesterol, triglycerides, LDL, HDL, and serum creatinine levels were secondary outcomes. Other secondary outcomes included clinic measures such as BMI, body weight, systolic and diastolic blood pressures. All outcomes were measured at baseline prior to the pharmacist’s interventions. Endpoints were recorded as difference between the last available follow up and the baseline.
abstract
Result A total of 1,305 patients were used for the study, 975 (74.7%) and 330 (24.3%) for “doctor only” and “pharmacist” groups, respectively. All clinical outcomes were comparable in both doctor only and pharmacist groups at baseline although other demographic features like ethnicity, and types of some medicines used differ for some patients. Patient in the pharmacist group showed improved clinical and laboratory outcomes which are comparable to the doctor group. For clinical outcomes, there was reduced BMI, weight, systolic and diastolic blood pressures which were comparable to the doctor group although all changes were not statistically significant. For laboratory outcomes, there was decrease in TC and TG with highest decrease in the doctor group. The pharmacist group showed greater reduction in HbA1C where there was an increase in doctor group while HDL levels remained at the same level for both groups. All changes were not statistically significant. A subgroup analysis to show the impact of the pharmacist within a group seeing a collaborator was also carried out. Patients were assigned to the two groups to be as homogenous as possible. The clinical and laboratory outcomes were comparable although there was reduction in mean HbA1C level in the pharmacist group. Conclusion Pharmacist independent prescribing in the management of diabetes did not only show beneficial overall effects but also positively impacted HbA1C levels. Thus, the inclusion of pharmacist as part of diabetes management team may be advantageous to patients with type 2 diabetes mellitus. Keywords Non-Medical Prescribing, Pharmacist Independent Prescribing, Clinical Outcomes, Type 2 Diabetes, Comparative Effectiveness Research, Retrospective Secondary Database Analysis ANTIMICROBIAL PRESCRIBING IN THE MANAGEMENT OF LOWER RESPIRATORY TRACT INFECTIONS (LRTI) IN THE ELDERLY POPULATION (>65YEARS): THE USE OF INFORMATION TECHNOLOGY TO IMPROVE PATIENT CARE Appleton Sarah, Puntan Hannah and Curtis Sally St Mary’s Hospital, Imperial College Healthcare NHS Trust Copyright © 2014 John Wiley & Sons, Ltd.
Background At any one time 41% of inpatients at Imperial College Healthcare NHS1 Trust (ICHNT) are receiving antimicrobial therapy. Lower respiratory tract infections (LRTI’s) are the leading cause for antimicrobial prescribing within secondary care,2,3 with more than 70% of hospital admissions for Community Acquired Pneumonia (CAP) occurring in the over 65’s.4 ICHNT currently use antimicrobial guidelines developed specifically for use in patients over the age of 65, frail or otherwise at risk of Clostridium difficile associated diarrhoea.5 Aim To assess whether patients above 65 years of age with a confirmed diagnosis of LRTI received antimicrobial therapy in accordance with the trust antimicrobial guidelines. Method Data collection took place over a 4 week period. Patients were identified using the post take handover list. All patients over the age of 65 years admitted to St Mary’s hospital via A + E under the care of the acute medical team with a confirmed diagnosis of an LRTI Results Intravenous (IV) antibiotic therapy was initiated in 73% of patients. 12 patients (29%) received Piperacillin/tazobactam (Tazocin®) and 15 (37%) were prescribed Co-amoxiclav (IV). Of those patients receiving IV therapy only 31% (13) of prescriptions were compliant with current trust guidelines. Discussion The number of patients initiated on IV antibiotics was higher than expected. Co-amoxiclav was initiated in a high proportion of patients despite Trust guidelines advising against the use of this agent in the elderly due to the risk of C.diff. Findings were presented to relevant medical teams and relevant education and training was given to junior prescribers. Post audit the ICHNT antimicrobial app for smart phones was
Trust point prevalence study in anti-infective use – October 2013 Woodhead MA, Macfarlane JT, McCracken JS et al. Prospective study of the aetiology and outcome of pneumonia in the community. Lancet 1987; i: 671–4. 3 Garibaldi RA. Epidemiology of community-acquired respiratory tract infections in adults: incidence, etiology, and impact. Am J Med 1985; 78: 32S–7S. 4 British Thoracic Society Adult Community Acquired Pneumonia Audit 4 (national audit period 1 December 2011 – 31 January 2012) Dr Wei Shen Lim, Dr Chamira Rodrigo 1 2
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
abstract
updated to include a step whereby the patient’s age had to be entered prior to the appropriate guideline appearing. A re-audit was conducted post implementation. Conclusion The new improved app along with education and training showed a significant improvement in the prescribing of antimicrobials in the elderly. Rate of compliance with trust guidelines increased to 76%. The percentage of IV antibiotics used decreased from 73% to 44% and the use of Co-amoxiclav decreased to 8%. Results show that simple IT changes can have a very positive and powerful effect on optimising medicines. MEDICINE USE REVIEWS (MURS) AT DISCHARGE: STILL THE CINDERELLA SERVICE Corlett SA1, Goel P1, Kothari S1 and Dodds L1,2 Medway School of Pharmacy, Universities of Kent and Greenwich at Medway 2 East and South East England Specialist Pharmacy Services, West Kent PCT
1
Background Many errors occur with patients’ medication as a consequence of transferring care. Pharmacist input has been shown to reduce such errors.1 Introduced in 2011, discharge MURs (dMURs) provide community pharmacists with the opportunity to support patients post-discharge. Patients can be advised when and how to take their medicines and be provided with information on side effects and changes to treatment.2 This study aimed to survey community pharmacists in Kent and Medway to explore their views and experiences with dMURs. Method All community pharmacies (340) were sent a letter informing them of the purpose of the study. An interview schedule to explore the provision of, barriers to, and facilitators of the dMUR service was developed and piloted. Telephone interviews followed a pre-agreed script and included both open and closed questions. All respondents were accredited to provide MURs. Data were analysed using descriptive statistics. Ethical approval for the study was obtained from Medway School of Pharmacy’s Research Ethics Committee.
pharmacist. Over half (56%, n = 95) had never conducted a dMUR. Of those that had, 47 (63%) pharmacists thought that they were more challenging than a standard medicine use review. The majority (88%, n = 150) of all respondents thought that dMURs were useful to patients because they enabled pharmacists to increase a patient’s knowledge about their new medicines, explain any medicine changes, improve adherence and decrease the number of medicine errors. A minority (6%, n = 11) thought that dMURs were of limited value to patients because they repeated information already provided in hospital. Seventy nine percent (n = 135) of respondents felt that they had appropriate support and resources to undertake a dMUR The main barrier to providing the service was indentifying patients who were eligible to receive it. Some respondents (14%, n = 24) would have liked a fax, e-mail or phone call from the discharging hospital and the majority (67%, n = 113) of pharmacists expressed a desire to see the discharge summary. Eleven percent (n = 18) stated that patients could share the discharge summaries with them. Conclusion The majority of community pharmacists believe that dMURs are beneficial to patients. However, despite this the uptake of dMURs is still low and over half of the pharmacists in this study had not conducted a dMUR more than two years after their introduction. The key barrier to improving the provision of dMURs remains communication between primary and secondary care pharmacy services. References 1. Barber N, Rawlins M, Franklin BD. Reducing prescribing error: competence, control and culture. Qual Saf Health Care 2003; 12(1):23–32. 2. Pharmaceutical Services Negotiating Committee. 2013. Pharmaceutical Services Negotiating Committee. Available at: http://psnc.org.uk/services-commissioning/advanced-services/murs/ [17 October 2013]. MEDICINES OPTIMISATION POST-STROKE & TIA: ARE WE DOING ENOUGH? Dodds LJ1,2, Mok E1, Patel K1 and Corlett SA1 Medway School of Pharmacy, Universities of Kent and Greenwich at Medway 2 East and South East England Specialist Pharmacy Services, West Kent PCT
1
Results Fifty percent (n = 170) of pharmacists completed the interview. Of these, 139 (82%) were the regular Copyright © 2014 John Wiley & Sons, Ltd.
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
abstract Table 1. Proportion of stroke/ TIA patients achieving targets for cholesterol and BP Antihypertensives BP % (no.) of patients Achieving RCP targets Achieving QOF targets Not achieving QOF target
Lipid regulating drugs - Cholesterol
TIA
Stroke
TIA
Stroke*
40 (44) 96 (106) 4 (4)
39 (60) 85 (131) 15 (23)
73 (80) 90 (99) 10 (11)
68 (105) 84 (130) 13 (20)
*Cholesterol not recorded for 4 patients No statistical differences were observed between the blood pressure or cholesterol level measurements of stroke and TIA survivors (p > 0.05; t-test). Over 90% of TIA and 80% of stroke survivors achieved the QOF targets for BP and total cholesterol respectively, but only 40% achieved an optimal BP of 130/80 mmHg and 70% a total cholesterol of 35 days. For both drugs, over 60% of patients were in the 75+ age-group. ‘Caution’ drugs were dispensed alongside a NOAC in 36% of dabigatran patients and 26% of rivaroxaban patients. These predominantly included antiplatelet drugs (17% of dabigatran patients, 18% of rivaroxaban patients) and SSRI/SNRI drugs (13% of dabigatran patients). Both GMS data and prescriber-completed reimbursement authorisation forms contained frequent incidences of rivaroxaban prescribed at a daily dose of 10 mg, indicating potential underdosing in atrial fibrillation. Conclusions High uptake of dabigatran and rivaroxaban for long-term anti-coagulation therapy was observed. Co-prescribing of interacting drugs was frequent. The combination of suboptimal dosages and potential drug interactions observed may represent a significant safety concern in clinical practice. Findings led to the issuing by the MMP of a letter to all practicing doctors in Ireland in order to highlight potentially inappropriate prescribing. References 1. Xu Y, Holbrook AM, Simpson CS, Dowlatshahi D, Johnson AP. Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a populationbased descriptive analysis. Can Med Assoc Open Access J 2013; 1(3): E115–E9. 2. Carley B, Griesbach S, Larson T, Krueger K. Assessment of dabigatran utilization and prescribing patterns for atrial fibrillation in a physician group practice setting. Am J Cardiol 2014; 113(4): 650–4.
AUTHOR INDEX Abutaleb, M Appleton, S Corlett, S A Dodds, L J Gill, T S Godman, B Copyright © 2014 John Wiley & Sons, Ltd.
Katusiime, B Keers, R N Kelly, M Kelly, M Latif, A
Poluzzi, E Rodgers, R M Salema, N Salman, D Spillane, S
Pharmacoepidemiology and Drug Safety, (2014) DOI: 10.1002/pds
