Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations

Aim and background

To assess drug-related problems in patients with liver cirrhosis by investigating the prevalence of inadequately dosed drugs and their association with adverse drug reactions (ADRs) and hospitalizations.

Methods

This was a cross-sectional retrospective study assessing the dose adequacy of drug treatment of 400 cirrhotic patients at hospital admission based on the authors’ own previous studies and standard literature. The prevalence of total and preventable ADRs and of hospitalizations due to preventable ADRs was determined.

Results

Of all 1653 drugs prescribed (median 4 per patient), 336 (20 %) drugs were inadequately dosed in 184 patients. Overall, 210 ADRs (78 % preventable) occurred in 120 patients. Sixty-nine ADRs (33 % of all ADRs) were associated with inadequate drug dosing in 46 patients, of which 68 % were preventable. Nonsteroidal anti-inflammatory drugs and psycholeptics in particular frequently caused preventable ADRs associated with inadequate drug dosing. Inadequate drug dosing was more frequently associated with ADRs than adequate drug dosing, and patients receiving inadequately dosed drugs were more frequently admitted to the hospital due to ADRs. Hospitalization of patients receiving inadequately dosed drugs that caused preventable ADRs resulted in 94 additional hospital days.

Conclusion

In this retrospective study, inadequate drug dosing was associated with an increased frequency of ADRs, hospital admissions and hospital days in cirrhotic patients. We therefore conclude that the careful dosing of critical drugs is important in patients with liver cirrhosis.     

Use of administrative hospital database to identify adverse drug reactions in a Pediatric University Hospital

Purpose

The aim of the study was to detect adverse drug reactions (ADRs) in pediatric inpatients using the medical administrative database “Programme de Médicalisation des Systèmes d′Information” (PMSI) and to compare these cases ADRs with those spontaneously reported to a regional PharmacoVigilance (PV) Centre.

Methods

The study was conducted from January 2008 to December 2011 in the Children University Hospital of Toulouse (Midi-Pyrénées, South-west France). From PMSI database, all discharge summaries including selected ICD-10 codes (10th International Classification of Diseases) were analyzed. All ADRs spontaneously reported by the Children Hospital of Toulouse and registered in the French PV Database (FPVDB) were included. The capture–recapture method was applied to estimate the incidence of ADRs.

Results

During the study period, we identified 60 reports from the PMSI database and 200 from the FPVDB. The rate of “serious” ADRs was higher in PMSI reports (74.6 % vs 38.9 %, p?Conclusions Use of PMSI database improves from around 30 % detection of ADRs in children. In comparison with classical pharmacovigilance database, it also allows to detect different ADRs and drugs, thus enhancing safe medicine use for pediatric patients.     

A qualitative study to explore how patients identify and assess symptoms as adverse drug reactions

Purpose

To explore how Thai patients assess symptoms as adverse drug reactions (ADRs).

Methods

Out-patients at two hospitals in Thailand previously reporting suspected ADRs to statins were purposively selected to cover factors relevant to the accuracy of ADR reports. Semi-structured interviews explored the mechanisms participants used to work out whether their symptoms were related to their statin. All interviews were audio-recorded, transcribed and independently thematically analyzed by two researchers.

Results

One hundred interviews were suitable for analysis; 52 were male, age range was 36 to 77 years (mean?±?S.D.: 59.83?±?9.14) and most (92) were taking other medicines in addition to statins. Patient assessment of symptoms as ADRs fell into two major themes: medicine-related factors and external factors. Timing relationships were mentioned most frequently (74), followed by information received (55), seeing similar symptoms in others (7) and diagnosis through blood tests (4). Use of multiple medicines, consideration of the medicine versus diseases, symptoms occurring with more than one medicine or relieved through treatment reduced confidence in ADR attribution. Many participants proposed alternative explanations for symptoms, including old age. Lack of information and knowledge were obstacles to the assessment process.

Conclusions

Patients assessed possible ADRs most often by considering timing relationships. While they also used medicine information, Thai patients received inadequate information to help them assess their symptoms. Patients expressed uncertainty and difficulties in deciding attribution when concomitant medicines and diseases were involved. The findings could support the development of a patient-friendly systematic tool for identifying and assessing possible ADRs.     

Association of long-term adherence to evidence-based combination drug therapy after acute myocardial infarction with all-cause mortality. A prospective cohort study based on claims data

Purpose

To determine long-term adherence to evidence-based secondary preventive combination pharmacotherapy in survivors of acute myocardial infarction (AMI) and to investigate the association between adherence to recommended therapy and all-cause mortality in claims data.

Methods

Prospective cohort study based on claims data of an 18.75?% random sample of all persons insured with the local statutory health insurance fund AOK Hesse. Study population included patients with hospital discharge diagnoses of AMI between 2001 and 2005 excluding those who died within the first 30?days after AMI or who had been hospitalised with an AMI in the previous 2?years. A total of 3,008 patients were followed up until death, cancellation of insurance, or the end of the study period on 31 December 2007, whichever came first (median follow-up: 4.2?years).

Results

Drug adherence to single drug groups as determined by proportion of days covered ≥80?% was 21.8?% for antiplatelet drugs, 9.4?% for beta-blockers, 45.6?% for ACE inhibitors or angiotensin II receptor blockers and 45.1?% for lipid-lowering drugs. A total of 924 (39.7?%) patients met our definition of guideline adherence: Drugs available from three of four relevant drug groups on the same day for at least 50?% of the observation time. Of the patients adhering to the guidelines, 17.3?% died and of the non-adherents, 32.4?% died. All-cause mortality was 28?% lower for guideline-adherent patients than for the non-adherent group (adjusted HR 0.72, 95?% CI 0.60–0.86).

Conclusions

In everyday practice, post AMI patients benefit from guideline-oriented treatment, but the percentage of adherent patients should be improved.     

Pharmacovigilance in children in Camagüey Province, Cuba

Purpose

Our aim was to describe the adverse drug reactions (ADRs) detected following increased education about pharmacovigilance and drug toxicity in children in Camagüey Province, Cuba.

Methods

Over a period of 24?months (January 2009 to December 2010), all reports of suspected ADRs in children to the Provincial Pharmacovigilance Centre in Camagüey Province were analysed. ADRs were classified in relation to causality and severity.

Results

There were 533 reports involving suspected ADRs in children in the period. Almost one third of the reports received were classified as moderate (155, 29%) or severe (10, 2%). There was one fatality in association with the use of ceftriaxone. Vaccines and antibiotics were responsible for most of the ADR reports (392, 74%) and for all ten severe ADRs. After an intensive educational package, both within the community and the Children’s Hospital, the number of reports increased from 124 in 2008 to 161 in 2009 and 372 in 2010. This was equivalent to a reporting rate of 879 and 2,031 reports per million children per year for 2009 and 2010, respectively.

Conclusions

The incidence of ADRs in children Camagüey Province, Cuba, is greater than previously reported. An educational intervention about pharmacovigilance and drug toxicity in children can improve the reporting of ADRs.     

Meta-Analysis of Oral Anticoagulants with Dual versus Single Antiplatelet Therapy in Patients after Percutaneous Coronary Intervention

Background

The combined use of dual antiplatelet therapy with oral anticoagulation (OAC) is required after coronary artery stenting or acute coronary syndromes (ACS).

Methods and Results

We performed a meta-analysis (Embase and MEDLINE search) of the comparative effects of triple antithrombotic therapy (TT) versus OAC with single antiplatelet therapy (dual therapy [DT]) on all-cause mortality, stroke, cardiovascular death, myocardial infarction (MI), target vessel revascularization, and major bleeding. Three prospective controlled studies and five cohort studies compared TT versus DT. We identified three prospective controlled and five cohort studies with 4564 patients on TT and 1848 on DT with an average follow-up duration of 10.1 months. TT is associated with similar rates of all-cause mortality, stroke, and major bleeding but significantly lower rates of MI compared with DT.

Conclusions

Triple antithrombotic therapy is associated with similar mortality and bleeding rates but fewer MIs compared with OAC and single antiplatelet therapy.

     

Behavioural and neuroinflammatory effects of the combination of binge ethanol and MDMA in mice

Rationale

Binge drinking is a common pattern of alcohol consumption among young people. Binge drinkers are especially susceptible to brain damage when other substances are co-administered, in particular, 3,4-methylendioxymethamphetamine (MDMA).

Objective

To evaluate the behavioural consequences of voluntary binge ethanol consumption, alone and in combination to MDMA. Also, to elucidate the effects of the combined consumption of these two drugs on neuroinflammation.

Materials and methods

Adolescent mice received MDMA (MDMA-treated mice), ethanol (ethanol-treated mice group) or both (ethanol plus MDMA-treated mice). Drinking in the dark (DID) procedure was used as a model of binge. Body temperature, locomotor activity, motor coordination, anxiety-like and despair behaviour in adolescent mice were evaluated 48?h, 72?h, and 7?days after the treatments. Also, neuroinflammatory response to these treatments was measured in the striatum.

Results

The hyperthermia observed in MDMA-treated mice was abolished by pre-exposition to ethanol. Ethanol plus MDMA-treated mice showed lower locomotor activity. Ethanol-treated mice showed motor coordination impairment and increased despair behaviour. Anxiety-like behaviour was only seen in animals that were treated with both drugs. Contrarily, neuroinflammation was mostly seen in animals treated only with MDMA.

Conclusions

Ethanol and MDMA co-administration increases the neurobehavioural changes induced by the consumption of each one of these drugs. However, as ethanol consumption did not increase neuroinflammatory responses induced by MDMA, other mechanisms, mediated by ethanol, are likely to account for this effect and need to be evaluated.     

Paediatric adverse drug reactions reported to the Spanish Pharmacovigilance System from 2004 to 2009

Purpose

This study was conducted to evaluate relevant new information about ADRs reported in the Spanish paediatric population over a 6-year period.

Methods

Adverse drug reactions (ADRs) for individuals aged 0–17?years reported to the Spanish Pharmacovigilance System from 2004 to 2009 were analysed with respect to time, age and sex, category of ADR [System Organ Class (SOC)], seriousness, suspected medicines [level 2 of the Anatomical Therapeutic Chemical (ATC) Classification System] and type of reporter.

Results

In total, 4,279 ADR reports corresponding to 8,196 ADRs were analysed, approximately two ADRs per report. The rate of paediatric ADR reports in 2009 was 165 per million, of which nearly half (46?%) were for children (age group 2–11?years). Similar total numbers of ADRs were reported for boys and girls. The most frequent ADRs reported were from the following SOCs: general disorders and administration site conditions (34?%); skin and subcutaneous tissue disorders (15?%); nervous system disorders (14?%). Reports encompassed medicines from various ATC groups: vaccines and anti-infectives for systemic use (67?%); nervous system (9?%); respiratory system (9?%). On average, 37?% of ADRs were classified as serious. There were 33 fatal ADRs, and 35?% of the paediatric population associated with the ADR notifications required hospitalization or extended hospital stay.

Conclusions

In Spain, ADR reporting rate in the paediatric population has increased since 2004. The proportion of suspected ADR reports related to vaccines was predominant, which highlights the important role played by nurses. ADR notification of congenital malformations in newborn infants highlights the need for joint action between the Spanish System of Pharmacovigilance of Medicines for Human Use (SEFV-H) and paediatricians, obstetricians and gynaecologists. The publication of safety reports by regulatory agencies is determinant for the increased number of ADR notifications.     

Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors or chemotherapy alone in advanced NSCLC: a meta-analysis of randomized controlled trials

Background

Most patients with advanced non-small-cell lung cancer (NSCLC) require systemic chemotherapy. Chemotherapy plus multitargeted antiangiogenic tyrosine kinase inhibitors (TKI; e.g., sorafenib, sunitinib, cediranib, vandetanib, BIBF 1120, pazopanib, axitinib) has recently been evaluated in patients with NSCLC. However, the advantage of this therapy over chemotherapy alone in patients with advanced NSCLC remains largely unknown.

Methods

A meta-analysis of randomized controlled trials (RCTs) was performed to compare the efficacy and toxicity of chemotherapy plus multitargeted antiangiogenic TKI with chemotherapy alone in patients with advanced NSCLC. PubMed, the ASCO and ESMO databases, and the Cochrane Library were searched for references to published articles. Two reviewers independently assessed the quality of the trials. Data were extracted, and overall response rate (ORR), pooled progression-free survival (PFS), overall survival (OS) with 95 % confidence intervals (CI), and major toxicities/adverse effects were analyzed.

Results

Six RCTs involving 3,337 patients with advanced NSCLC were ultimately analyzed. Compared to chemotherapy alone, chemotherapy plus multitargeted antiangiogenic TKI significantly increased the ORR [relative risk (RR)?1.71, 95 % CI??1.43–2.05] and PFS [hazard ratio (HR) ?0.83, 95 % CI?0.76–0.90], but not OS (HR 0.93, 95 % CI?0.83–1.03). Patients who received chemotherapy plus multitargeted antiangiogenic TKI exhibited more rash, diarrhea and hypertension (OR?2.78, 95 % CI? 2.37–3.26; OR?1.92, 95 % CI?1.65–2.24; OR ?2.90, 95 % CI?2.19–3.84, respectively) and less nausea and vomiting (OR?0.71, 95 % CI?0.60–0.83; OR?0.75, 95 % CI?0.61–0.92, respectively). The incidence of hemorrhage, fatigue, cough, constipation, anorexia, and alopecia were comparable between the two groups.

Conclusions

Therapy consisting of chemotherapy plus multitargeted antiangiogenic TKI was found to have specific advantages over chemotherapy alone in terms of PFS and ORR. The toxicity was comparable between the two therapies. Therefore, chemotherapy plus multitargeted antiangiogenic TKI may be a safe and valid therapeutic option for patients with advanced NSCLC.     

Comparative epidemiology of hospital-acquired adverse drug reactions in adults and children and their impact on cost and hospital stay – a systematic review

Purpose

To study and analyze the comparative impact of hospital-acquired adverse drug reactions (ADRs) in adult and pediatric patients in terms of the economic implications, (length of) hospital stay, and salient features in relation to the incidence rate, severity, morbidity, mortality, and preventability of the ADRs.

Methods

A systematic search to identify and retrieve relevant articles/studies in the PubMed, Medline, Scopus, MEDPAR, and Cochrane databases and by the Google search engine was performed for the study period 2000 to April 2013. In total, 51 studies were identified on patients hospitalized for ADRs, and these were included in the study. The incidence rate of ADRs, their severity, mortality, morbidity, preventability, cost, and association with extended hospital stay due to ADRs were extracted and scrutinized.

Results

Hospital-acquired ADRs are more widely studied in adults than in children, and the incidence rate is higher in the former. However, a wide variation in the incidence rate worldwide is observed in both groups. Irrespective of the ages of patients, ADRs are among the most frequent causes of morbidity and mortality. Interestingly, preventable ADRs are more frequently observed in patients at the younger and older ends of the age spectrum. Hospital-acquired ADRs place an immense economic burden on healthcare systems, with the overall cost for a hospitalized patient with an ADR reported to be $2,401 per patient, which is equivalent to a 19.86 % additional increase in the total cost of care and an increase in average length of hospital stay of 8.25 %.

Conclusion

Based on the findings of this review, we suggest that excellent assertive measures of pharmacovigilance with the aim to diminish the incidence rate of hospital-acquired ADRs and support the development of interventions are needed to promote vital facets of drug safety with an overall objective to avert potential ADRs.     

The antidepressant-like effects of topiramate alone or combined with 17β-estradiol in ovariectomized Wistar rats submitted to the forced swimming test

Rationale

There is a significant delay in the clinical response of antidepressant drugs, and antidepressant treatments produce side effects.

Objective

We examined the relationship between 17β-estradiol and topiramate in ovariectomized Wistar rats submitted to the forced swimming test (FST).

Methods

Topiramate was administered alone or combined with 17β-estradiol to ovariectomized rats submitted to the FST.

Results

Topiramate (20 mg/kg, P?P?P?P?P?Conclusions Topiramate alone or combined with 17β-estradiol produced antidepressant-like actions; and 17β-estradiol shortened the onset of the antidepressant-like effects of topiramate.     

Bevacizumab-induced serious side-effects: a review of the French pharmacovigilance database

Purpose

Bevacizumab, a recombinant humanized monoclonal antibody to vascular endothelial growth factor, is widely used in association with standard chemotherapy in metastatic cancer. Well tolerated, bevacizumab is sometimes associated with serious adverse drug reactions (ADRs). The objective of this study is to describe the profile of ADRs related to bevacizumab and reported to the French Pharmacovigilance system.

Method

All serious cases of ADRs associated with bevacizumab recorded in the French Pharmacovigilance database up to November 31, 2010 were identified and analyzed, focusing on patient information, drug exposure, and characteristics of the ADRs. Categorical variables were compared using the chi-square test when appropriate.

Results

A total of 351 serious cases involving 626 ADRs were recorded in the database during the study interval. The most frequent ADRs reported involved the gastrointestinal system (21.9%). The most frequent ADRs included gastrointestinal perforation (4.8%), thromboembolic events (4.0%), pulmonary embolism (3.2%), hypertension (2.7%), gastrointestinal hemorrhage (2.7%), and cerebral hemorrhage or vascular accident (2.6%). The median duration of bevacizumab exposure was four cycles (range 1–30) when ADRs occurred. In 18 cases of death directly caused by ADRs, 50% occurred after only one cycle. In cases of disability, 40% of ADRs were neurologic: neuropathy, paralysis, and paresis.

Conclusion

To the best of our knowledge, this is the first analysis of bevacizumab safety profile using data collected in a national pharmacovigilance database. Our study confirms the frequency and seriousness of gastrointestinal, thromboembolic, and hemorrhage events with bevacizumab use and provides a picture of the bevacizumab safety profile in daily medical practice, despite intrinsic limitations.     

Healthcare providers’ experiences with adverse drug reactions and adherence challenges in antiretroviral therapy of HIV patients in the Eastern Cape Province, South Africa

Purpose

To gain insight into the experiences and handling of adverse drug reactions (ADRs) by the staffs of public primary healthcare (PHC) clinics in Eastern Cape Province, South Africa, as well as their perceptions of related adherence challenges in the treatment and follow-up of human immunodeficiency virus (HIV)-positive patients.

Methods

Healthcare providers working at the PHC level in the public sector in the study area were approached and asked to participate in focus group discussions (FGDs). Seven FGDs were conducted with 32 healthcare providers (9 nurses, 23 auxiliary staff). Questions introduced by the moderator of each FGD were freely discussed by the participants. Discussions were audio-recorded and subjected to thematic content analysis.

Results

Several challenges in the treatment and follow-up of patients on ART were identified. These include: (1) lack of training of healthcare providers in PHC clinics to confidently identify, manage and treat the ADRs HIV-positive patients receiving ART; (2) patients’ difficulty in communicating information on ADRS; (3) insufficient pharmacovigilance; (4) role of poverty.

Conclusion

Both nurses and auxiliary staff expressed lack of knowledge and confidence regarding ADRs in HIV patients and management of this. More emphasis is warranted on training the healthcare providers to identify ADRs and provide adequate advice for continued treatment of patients experiencing potential drug related problems.