Influence of drug-drug interactions on effectiveness and safety of direct-acting antivirals against hepatitis C virus

Objectives
Direct-acting antivirals are the recommended treatment for hepatitis C-infected patients. Drug–drug interactions with concomitant treatments can cause lack of effectiveness and/or safety. The objective of this study is to characterise drug–drug interactions of direct-acting antivirals and to analyse their influence both on the effectiveness of antiviral treatment and on the overall safety of pharmacological treatment in hepatitis C-infected patients.

Methods
Observational and prospective cohort study for 3 years in the pharmaceutical care outpatient consultation of a general hospital, undertaking detection, evaluation and management of drug–drug interactions by clinical pharmacists and physicians. The main outcome measures were sustained virologic response at week 12 for effectiveness and serious drug-related adverse events for safety. Multivariate statistical analysis applied to: (a) patient basal characteristics related to presence of drug–drug interactions; (b) previous antiviral treatments, viral genotype, cirrhosis, decompensations and presence of drug–drug interactions related to the effectiveness of direct-acting antivirals.

Results
Of a total of 1092 patients, the majority of them were men, around 60 years old and HCV-genotype 1 mono-infected, with a high basal viral load, naive to antiviral treatment, treated with ledipasvir/sofosbuvir and without cirrhosis. 24.5% had drug–drug interactions. Proton pump inhibitors were the concomitant drugs that caused the most drug–drug interactions. Age ≥65 years and direct-acting antivirals based on protease inhibitors were independently related to the presence of drug-drug interactions (p≤0.012). All (100%) of the therapeutic recommendations based on detected drug–drug interactions were implemented; 97.7% of patients with interactions versus 99.0% without them reached sustained virologic failure (p=0.109). The serious adverse events rates were 1.5% and 1.3% in patients with and without drug-drug interactions, respectively (p=0.841).

Conclusions
Drug–drug interactions are frequent among hepatitis C-infected patients receiving treatment with direct-acting antivirals. However, the collaboration between physicians and clinical pharmacists makes it possible to detect, evaluate, avoid or clinically manage these drug–drug interactions, in order to maintain whole treatment therapeutic safety and the effectiveness of direct-acting antivirals.

Current situation of carboplatin desensitisation protocols in the hospitals of Spain

Desensitisation protocols allow the continuation of treatment in patients who have presented hypersensitivity reactions. Carboplatin desensitisation solutions are usually prepared in the chemotherapy centralised units of hospital pharmacies and they are diluted under the established concentration limit to guarantee the stability of the preparation. An online survey was sent to hospital pharmacies, inquiring about local desensitisation protocols: reasons for use of desensitisation protocols, the protocols used and the stability given to carboplatin solutions. An important variability among the hospitals in carboplatin desensitisation practice was detected. Six different carboplatin desensitisation protocols were described and discordance with the storage period of the carboplatin solutions was observed. The lack of consensus on which protocol must be followed and data supporting the stability of the diluted product, contribute to distrust of carboplatin desensitisation protocols. Although the efficacy and safety of carboplatin desensitisation protocols has been widely demonstrated, many professionals still have concerns.

Effectiveness and safety of pirfenidone for idiopathic pulmonary fibrosis

ObjectivesTo assess the long-term effectiveness of pirfenidone in idiopathic pulmonary fibrosis (IPF) treatment and to establish its adverse effects profile.
MethodsRetrospective observational study in patients with IPF who initiated treatment with pirfenidone between 2011 and 2016. We collected demographic variables (age, sex); date of first and last treatment; reason for discontinuation; pulmonary function measures (forced vital capacity (FVC), carbon monoxide diffusion capacity (DLCO), and 6 min walk test (6MWT)) at treatment initiation (baseline) and at 1, 2 and 3 year follow-up; adherence to pirfenidone treatment; recorded adverse effects; and mortality.
ResultsThirty-one patients treated with pirfenidone were included; mean±SD age was 69±8 years, 74% were men, and 59% had a smoking history. Mean baseline values were: FVC 2.43±0.66 L (61.8±12.1%); DLCO 46.1±19.4%; and 6MWT 334±125 m. Median duration of treatment was 14±13 months, and treatment was discontinued in 58% of patients. The most frequently observed adverse effects were gastrointestinal disturbances and photosensitivity. Twenty (65%) patients were evaluated at 1 year, when mean FVC was 2.41±0.86 L (64.7±20.3%); DLCO 50.8±26.8%; and 6MWT 341±139 m. At 2 years’ follow-up, 11 patients (36%) who were still taking pirfenidone were evaluated. Mean FVC was 2.34±0.79 L (66.2±14.7%); DLCO 50.0±28.3%; and 6MWT 265±121 m. At 3 years, five patients were still taking the treatment. Mean FVC was 2.71±0.84 L (71.0±24.7%); DLCO 52.6±26.7%; and 6MWT 286±139 m. Nineteen per cent of patients were non-adherent to treatment.
ConclusionsPirfenidone seems to be effective for long-term control of IPF despite substantial variability in response among individual patients. The most frequent adverse effects were digestive and cutaneous, prompting in some cases a reduction in dose or even discontinuation of the treatment.

Fingolimod in multiple sclerosis: profile of use in habitual practice

ObjectivesFingolimod is the first oral drug indicated in monotherapy as a modifier of the course of very active relapsing-remitting multiple sclerosis (RRMS). The safety profile of fingolimod is well established in clinical trials and post-marketing studies. Our objective was to study the profile of fingolimod use in our health area.
MethodsA retrospective, observational, descriptive study was performed on the use of fingolimod in adult patients diagnosed with RRMS between January 2015 and February 2017 or until suspension of treatment in a reference hospital in north-western Spain.
ResultsA total of 55 patients were included with a mean±SD time of treatment with fingolimod of 26±14.6 months (range 2–53). Thirteen patients permanently discontinued the treatment (10 due to outbreaks/disease progression and 3 due to adverse effects). No statistically significant differences were found between the percentage of patients who discontinued fingolimod and who had received only one previous treatment and those who had received two or more treatments. No cases of symptomatic bradycardia were reported.
ConclusionsFingolimod is a safe treatment for patients with multiple sclerosis.

A systematic review examining the characteristics of users of NHS patient medicines helpline services, and the types of enquiries they make

Background and objectivePatient medicines helpline services (PMHS) are available from some National Health Service Trusts in the UK to support patients following their discharge from hospital. The aim of this systematic review was to examine the available evidence regarding the characteristics of enquirers and enquiries to PMHS, in order to develop recommendations for service improvement.
MethodsSearches were conducted using Medline, Embase, Cumulative Index of Nursing and Allied Health Literature, Scopus, and Web of Science, on 4 June 2019. Forward and backward citation searches were conducted, and grey literature was searched. Studies were included if they reported any characteristics of enquirers who use PMHS, and/or enquiries received. Study quality was assessed using the Axis tool. A narrative synthesis was conducted, and where appropriate, weighted means (WMs) were calculated. Where possible, outcomes were compared with Hospital Episode Statistics (HES) data for England, to establish whether the profile of helpline users may differ to that of hospital patients.
ResultsNineteen studies were included (~4362 enquiries). Risk of bias from assessed studies was 71%. Enquirers were predominantly female (WM=53%; HES mean=57%), elderly (WM=69 years; HES mean=53 years) and enquired regarding themselves (WM=72%). Out of inpatient and outpatient enquirers, 50% were inpatients and 50% were outpatients (WM). Six of 15 studies reported adverse effects as the main enquiry reason. Two of four studies reported antimicrobial drugs as the main enquiry drug class. From two studies, the main clinical origin of enquiries were general surgery and cardiology. Across six studies, 27% (WM) of enquiries concerned medicines-related errors.
ConclusionsOur findings show that PMHS are often used by elderly patients, which is important since this group may be particularly vulnerable to experiencing medicines-related issues following hospital discharge. Over a quarter of enquiries to PMHS may concern medicines-related errors, suggesting that addressing such errors is an important function of this service. However, our study findings may be limited by a high risk of bias within included studies. Further research could provide a more detailed profile of helpline users (eg, ethnicity, average number of medicines consumed), and we encourage helpline providers to use their enquiry data to conduct local projects to improve hospital services (eg, reducing errors).
PROSPERO registration numberCRD42018116276.

Application of vancomycin in patients with augmented renal clearance

Objective

To analyse the influence of factors on the steady-state trough concentration (Ctrough) of vancomycin, especially in patients with augmented renal clearance, and to provide a reference for clinical application.


Methods

Data on patient demographics, routine blood examination, hepatic function and kidney function were collected from May 2013 to October 2016. A total of 292 patients were enrolled and correlations between Ctroughof vancomycin and other test indices were analysed by SPSS software.


Results

The patients with augmented renal clearance were significantly younger with relatively lower Ctrough values and higher weight, ALB and PLT compared to others. And age was the most important factor of Ctroughamong subgroups of ARC.


Conclusions

Inpatients with augmented renal clearance,vancomycin Ctrough was mainly affected by age. Clinicians and pharmacists should adjust the dosage regimen in a timely manner based on therapeutic drug monitoring and these influencing factors.

Analgesic consumption evolution at the emergency department of a university hospital (2006-2017): a defined daily doses based analysis

Objective

Pain management in the emergency department (ED) is a key issue that must be regularly evaluated. Practice evaluation gold standard remains patient file analysis, but is highly time consuming. The aim of this study is to evaluate the interest of a defined daily dose (DDD) based analysis in the evaluation of pain management in the ED.


Methods

A local indicator was elaborated based on the DDD concept: the defined dose per admission (DDA). Unlike the DDD that corresponds to a standardised total dose administered over a day, the DDA represents the average total dose administrated to a patient throughout the stay in the ED. A DDA was assigned to every analgesic, from step 1 to step 3. Oral and injectable forms were studied, but transdermal forms were not considered. DDA values were assimilated to the existing DDDs when these were officially established by the WHO. When values were not defined by the WHO, mean values observed in local practice were selected. Annual numbers of patients admitted to the ED and quantities of each analgesic supplied by the pharmacy ward were annually extracted from respective data files. Paediatric patients being treated at a specific separate ED, only adults were considered throughout the study. Raw quantities of analgesics used each year were converted to their equivalent amounts in DDA, and then expressed in numbers of DDA per 100 admissions (DDA/100A). This indicator allowed us to describe relative evolutions of analgesics prescriptions from 2006 to 2017.


Results

Analgesic overall use rose from 18.4 to 30.2 DDA/100A between 2006 and 2017, representing a prescription increase of 64%. Throughout the study, step 1 analgesics rose from 10.8 to 19.3 DDA/100A (+79%), step 3 from 1.8 to 5.4 (+200%) and step 2 remained stable around 5.6 DDA/100A. The integration of orodispersible paracetamol tablets in 2013 allowed us to halve the consumption of injectable paracetamol in the long term and had no effect on classic paracetamol oral forms such as tablets or capsules. Tramadol increased from 41% to 78% among step 2 analgesics after the withdrawal of dextropropoxyphene in 2011. Codeine use shows a steady decline from 1.9 DDA/100A in 2011 to 0.72 in 2017.


Discussion/conclusion

The DDA concept appears to be an effective tool for assessing long-term analgesic-use trends at hospital EDs. This tool can also mitigate one major bias at EDs, that is the lack of traceability of analgesic administration in emergency contexts. This tool could be adjusted by integrating the average length of stay in the ED.

Guide to undertaking person-centred inpatient (ward) outpatient (clinic) and dispensary-based pharmacy consultations

WHO uses the internationally accepted term ‘person-centred care’, also usedby the Royal Pharmaceutical Society in the UK, to highlight the importance of considering that patients are people first; they have families, communities and are living with conditions for which they receive healthcare. The challenge that faces pharmacy professionals is embedding a person-centred approach to pharmacy practice. In a hospital setting, there are specific processes that must be completed to optimise safe, efficient and effective practice, however thesetend to be professionally focused. The coaching model, GROW, supports more person-centred conversations and has been used successfully in health in the National Health Service (NHS) in the UK . Inin pharmacy, practitioners were challenged with the task of integratingperson-centred consultation techniques as part of the pharmacy processes they were required to complete within their everyday activities. Therefore, a set of person-centred questions were developed, using concepts from GROW and the Four E’s, to create guides for practitioners to use within each of the pharmacy processes they commonly undertook. The guides were piloted with three pre-registration pharmacists and, following modification, were included in the skill development sessions described in a related publication in this issue ’A pilot study to evaluate knowledge of person-centred care (PCC), before and after a skill development programme, in a cohort of pre-registration pharmacists (PRPs) within a large London Hospital’. These guides are used by pharmacy staff in the author’s organisation to support a person-centred approach to pharmacy practice.

Evaluation of the use, effectiveness and safety of tyrosine kinase inhibitors in chronic myelogenous leukaemia in a general university hospital

Objectives

To evaluate the use, effectiveness and safety of tyrosine kinase inhibitors (TKIs) for chronic myelogenous leukaemia (CML) in clinical practice.


Methods

A retrospective longitudinal study of patients with CML who received TKIs for at least 6 months was performed. Endpoints to evaluate effectiveness were haematological, cytogenetic and molecular responses. Safety was assessed according to the occurrence of adverse events.


Results

Sixty-two patients were included. All received imatinib as the initial TKI; 8% switched to nilotinib due to lack of major molecular response (MMR) to imatinib and 3% switched to dasatinib because of progression to blast crisis or lack of MMR. At the end of the study all patients had achieved at least a complete cytogenetic response. With regard to safety, in 11 patients the dose of imatinib was decreased and four patients switched to a second-generation TKI due to imatinib toxicity.


Conclusions

Considering the good responses of most patients and its better known safety profile, imatinib should remain a good option for first-line treatment of CML.

Analysis of the impact of antimicrobial management and rational use of antibiotics

Objective

The scientific antimicrobial management strategy (AMS) was used to standardise the clinical use of antibiotics and optimise the anti-infection treatment protocol.


Methods

By formulating antibiotic use indicators and policy interventions, carrying out prescription audits and drug analysis by pharmacists, and establishing an early warning mechanism for bacterial drug resistance, we formed a long-term and scientific antimicrobial management strategy.


Results

From 2012 to 2017, the clinical antibiotics use indicators appeared to trend downward. The rate of antibiotic use in outpatients, the rate of antibiotic use in hospitalised patients, and the antimicrobial use density decreased by 40.36%, 20.93%, and 10.71%, respectively, and the per capita drug cost of antibiotics in outpatients and inpatients decreased. The microbiological susceptibility test rate of antibiotics in hospitalised patients increased each year, and the resistance rate of the main detected bacteria did not significantly increase in the last 6 years. In the evaluation of rational drug use, the use of antibiotics has become more reasonable and standardised, and irrational drug use has been significantly reduced, but we still need to strengthen the optimisation of treatment prescription.


Conclusions

Scientific management can promote the rational use of antibiotics, reduce the expense of drug use and slow the development of drug resistance, but we need to further optimise the prescription of antibiotics to improve the level of drug treatment.

Effects of a multifaceted intervention in psychogeriatric patients: one-year prospective study

Objectives

The aetiology of behavioural and psychological symptoms (BPSD) could be related to inadequate treatment in patients with dementia. The aim of this study was to determine how a multifaceted intervention based on a medication review and multidisciplinary follow-up could improve treatment and minimise risk in these patients.


Methods

A prospective interventional study was undertaken between July 2015 and July 2016 of patients with dementia admitted to control BPSD. Patients with previous psychiatric illness or palliative care were excluded. Prescription information was obtained from Aegerus and the Catalonia clinical record HC3. The intervention was conducted by a multidisciplinary team. The Medication Appropriateness Index (MAI) was used to assess the intervention.


Results

65 patients (60% women, mean age 84.9±6.7 years) with mild-moderate cognitive impairment (mean 4.5±1.8), moderate-severe functional dependence (mean 43.8±23.9) and a high prevalence of geriatric syndromes and comorbidity were included in the study. 87.7% of the patients were taking ≥5 drugs (mean 9.0±3.1) and 38.5% were taking ≥10. Patients presented with BPSD values of 1.9±0.8 at admission. Common symptoms prompting admission were agitation (47.7%) and irritability (43.1%). A total of 175 drug-related problems (DRPs) were detected (2.97 per patient). Significant differences (p<0.001) were found between the MAI score at admission (4±4.6) and post-intervention (0.5±2.6). Most prevalent MAI criteria were related to interactions (40%), dosage (38.5%) and duplication (26.2%). 55 patients (84.6%) were taking anticholinergic drugs at admission (2.6±1.2 anticholinergic drugs per patient), and the post-intervention reduction was significant (p<0.016).


Conclusions

The balance between effective treatment and safety is complex in these patients. Medication review in interdisciplinary teams is an essential component to optimise interventions and assessment of safety.

Overview of treatments used in transthyretin-related hereditary amyloidosis: a systematic review

Objective

To carry out a systematic review of the literature to analyse the efficacy and safety of treatments available or under investigation for amyloidosis due to mutations in the transthyretin gene (ATTR).


Methods

A bibliographic search was carried out in the following electronic databases up to September 2017: PubMed, Cochrane Library and EMBASE. The inclusion criteria were: efficacy and/or safety studies conducted in humans, studies that included treatments, including treatments in the research phase, and studies that included 10 or more patients.


Results

A total of 21 articles were included; 16 were clinical trials, eight of them (50%) phase III trials, and five were observational studies. Of the total number of studies selected, 11 were on tafamidis, four on diflunisal, two on liver transplantation, two on patisiran and two on other therapeutic alternatives. Of the 11 studies related to the drug, the pivotal trial, the results of its two extension studies and an additional post hoc analysis were selected. In addition, two phase III trials were included in specific populations, two phase II studies, one safety study and two observational studies. Regarding the four included studies related to the drug, one was the pivotal trial that gave the indication to diflunisal, another a safety summary of the pivotal trial, and the other two trials were carried out in specific populations, one in a Japanese population and another phase I trial in cardiac amyloidosis in the USA. As far as other alternatives are concerned, of the six studies included in this section, two were related to liver transplantation, two to patisiran and two to different therapeutic alternatives.


Conclusions

Sufficient evidence has not been found that demonstrates superiority among the available oral alternatives, diflunisal or tafamidis, in the treatment of ATTR. Direct comparisons between both drugs and pharmacoeconomic studies would be necessary to select the most efficient treatment.