Adverse drug reaction-related hospitalisation in Ethiopia

Adverse drug reactions (ADRs) are an important healthcare problem frequently associated with significant morbidity, hospitalisation and mortality. Globally, the prevalence of ADR-related hospitalisation and mortality vary from 0.2% to 54.5% and 0.1% to 10.0%, respectively. Severe ADRs are important reason for admission to intensive care unit and extensions of hospital stay in approximately one-fifth of overall ADR-related admissions. Overall, the rates of ADRrelated hospital admissions and mortality are comparable between developed and developing countries. However, there are marked differences between developed and developing countries with regard to the nature of the ADRs implicated in hospital admissions and the mortality rate. In addition, there are some important differences in risk factors contributing to ADR-related hospital admissions and mortality due to the differences in population socio-demographics, disease characteristics, drug therapy used, healthcare systems and ethnic origins. In Ethiopia, a developing country, there are number of factors thought to increase the risk of ADR-related hospital admission. These include, but are not limited to, a greater proportion of patients who take anti-tubercular (anti-TB) drugs and antiretroviral therapy (ART), a high prevalence of malnutrition and anaemia, a higher prevalence of concomitant anti-TB drugs and ART use, and widespread use of traditional remedies. In addition, there is a higher proportion of the slow acetylator phenotype among patients on ART and anti-TB drugs that increases susceptibility to ADRs. There is growing attention to chronic disease management with new and complex therapies in ambulatory care clinics, where there are higher rates of drug-related problems and irrational use of medicines that could lead to drug-related harm. Unlike developed countries, there is substantial all-cause mortality rate among patients presenting to emergency departments, a high rate of mortality among HIV/TB co-infected patients on drug therapy, a less health-literate population and a lesser ability to provide healthcare. Moreover, there are increasing rates of concurrent infectious and non-communicable diseases demanding multiple medications with potential drug interactions. The majority of studies focussing on risk factors for ADR-related hospitalisation and mortality have been conducted in developed countries. In Ethiopia, to our knowledge, there are no studies reporting on the prevalence and risk factors associated with ADR-related hospitalisation, or the mortality rate attributable to ADRs in patients presenting to hospital. The limited information available in the Ethiopian setting, the presence of multiple factors suspected to increase the risk of ADR-related admissions and evidence of a substantial burden of ADR-related admissions and mortality in other settings provided the impetus for this study. Determining the magnitude of ADR-related hospitalisation and mortality and identifying factors contributing to ADRs for community-based patients are crucial in understanding the extent of the problem and developing preventive strategies to decrease the clinical and economic burden. Therefore, the main aims of the body of work presented in this thesis were to identify ADRs responsible for ADR-related hospital admissions; investigate the medications and other risk factors associated with the ADRs; and to determine their severity, preventability, clinical presentation and outcomes. Due to the absence of similar studies in Ethiopian patients, we began by reviewing the existing literature on the prevalence and contributing factors of ADR-related hospitalisations in developed and developing countries. From 43 relevant publications identified through systematic review, the median (with interquartile range (IQR)) prevalence of ADR-related hospitalisations in developed and developing countries were 6.3% (3.3-11.0%) and 5.5% (1.1-16.9%), respectively. Similarly, the median proportions of ADR-related mortality in developed and developing countries were 1.7% (0.7-4.8%) and 1.8% (0.8-8.0%), respectively. Older age, female gender, number of medications, renal impairment and heart failure were reported to be associated with an increased risk for ADR-related hospitalisation in both settings, while HIV/AIDS was implicated in developing countries only. The majority of ADRs were preventable in both settings, highlighting the importance of improving medication use, particularly in vulnerable patient groups such as the elderly, patients with multiple comorbidities and, in developing countries, with HIV/AIDS. Following review of existing literature, a prospective observational study determined the prevalence of ADR-related hospitalisation, characterised the ADR types and their preventability, characterised the implicated medications and identified predictors of ADR related hospitalisation. This was determined through detailed review of medical records, laboratory tests and patient interviews followed by causality assessment by the Naranjo algorithm and expert consensus. Of 1,001 patients included, 103 (10.3%) were deemed to have experienced an ADR-related admission. Common ADRs responsible for hospitalisation were hepatotoxicity (35, 29.4%) followed by acute kidney injury (27, 22.7%) and electrolyte disturbances (hypokalaemia and hypocalcaemia) (13, 10.9%). The drug classes most frequently involved in ADRs were anti-TB drugs (36 patients, 35.0%), followed by ART (22 patients, 21.4%) and diuretics (19 patients, 18.4%). Body mass index (BMI) <18.5 kg/m2 (adjusted odd ratio [AOR]=1.69; 95% confidence interval [CI]=1.10-2.62), pre-existing renal disease (AOR=2.84; 95% CI=1.38-5.85), pre-existing liver disease (AOR=2.61; 95% CI=1.38-4.96), number of comorbidities ‚Äöv¢‚Ä¢4 (AOR=2.09; 95% CI=1.27-3.44), number of drugs ‚Äöv¢‚Ä¢6 (AOR=2.02; 95% CI=1.26-3.25) and history of previous ADRs (AOR=24.27; 95% CI=11.29-52.17) were found to be independent predictors of ADR-related hospitalisation in an ADR risk prediction model with an area under the receiver operator curve of 79.0% (95% CI 73.9%-84.1%). Most ADRs (106, 89.1%) were considered preventable. Another component of a prospective observational study determined the prevalence of mortality attributable to ADRs in patients presenting to hospital, and identified drugs and factors associated with ADR-related mortality. Of 1,001 patients, 15 (1.5%, 95% CI=0.80-2.30%) died. Deaths were primarily due to suspected drug-induced hepatotoxicity (7 patients, 43.8%) followed by acute kidney injury (4 patients, 25.0%). Anti-TB drugs and ART together were implicated in 60% of the deaths. A bivariate comparison showed patients who died with ADRs were more likely to have pre-existing liver disease (40.0% vs. 7.0%; 95% CI=8.1- 57.8%), a history of ADRs (40% vs. 1.4%; 95% CI=13.8-63.4%), a low BMI (17.6 ¬¨¬± 2.1 vs. 20.0 ¬¨¬± 2.9; 95% CI=0.9-3.9), exposure to anti-TB drugs (46.7% vs. 18.9%; 95% CI=2.3-53.1%) and ART (40.0 % vs. 7.7%; 95% CI=7.5-57.2%), a higher mean (¬¨¬±SD) number of medications (7.1 ¬¨¬± 3.3 vs. 3.8 ¬¨¬± 2.1; 95% CI=2.2-4.4), and Charlson Comorbidity Index (3.9 ¬¨¬± 2.9 vs. 1.6 ¬¨¬± 1.8; 95% CI=1.4-3.2) than surviving patients without ADRs. Findings from a series of analyses in a prospective observational study led us to further characterise the clinical patterns and severity of drug-induced hepatotoxicity (DIH), which was the commonest ADR implicated in hospitalisation and mortality. In this sub-study, 674 patients with documented previous medical history and regular medication prior to hospital admission and at least one set of liver function tests were included. Of 674 patients, 35 (5.2%) were deemed to have been hospitalised due to DIH, of whom, 22 (62.9%) exhibited a cholestatic pattern, 8 (22.9%) a hepatocellular pattern and 5 (14.3%) a mixed pattern. The most frequent drug classes implicated were anti-TB drugs (21 patients, 60.0%) followed by ART (12 patients, 34.3%). More than two-thirds of the DIH cases (24, 68.6%) were severe or fatal, were mainly caused by anti-TB drugs (15, 42.9%), ART (4, 11.4%) or concomitant anti-TB/ART (6, 17.1%). Our studies provided several novel findings regarding hospitalisation and mortality related to ADRs in Ethiopian patients. Our work revealed that the extent of ADR-related hospitalisation in adults is an important public health problem, with a significant number of fatal ADRs in patients presenting to hospital. Commonly used drugs, such as anti-TB drugs, ART and cardiovascular agents, causing well-known reactions are the most frequently occurring ADRs in patients presenting to hospital, suggesting that strategies for their prevention should be identifiable. Conversely, the ADR-related hospitalisation risk prediction model demonstrated some ability to identify patients at higher risk for ADRs, such as patients with lower BMI, previous ADR history, renal and liver diseases, multiple comorbidities and medications. This was further augmented by an ADR preventability assessment using Schumock and Thornton‚ÄövÑv¥s criteria, in which the majority of the ADRs were preventable provided these risk factors were reviewed and monitored closely. Therefore, consideration of the independent risk factors for ADRs identified in this study, by medical practitioners during assessment of patients at emergency and chronic care centres, might help distinguish patients who are at higher risk of ADR-related hospitalisation. More research is needed into intervention strategies to help reduce ADR-related hospitalisation and mortality. However, key areas that demand urgent interventions based on our study findings include patients taking anti-TB drugs (isoniazid and pyrazinamide) and ART (tenofovir, efavirenz and nevirapine), with a special focus on patients with malnutrition, previous ADR history, and pre-existing renal and liver diseases. Patients with cardiovascular disorders taking furosemide, enalapril, atorvas..

Efficacy and safety of remdesivir in hospitalised COVID-19 patients: a systematic review and meta-analysis

Purpose: This review was aimed to synthesise the best available evidence on the effectiveness and safety of remdesivir in the treatment of moderate to severe COVID-19. Method: Randomised controlled trials (RCTs) and observational studies reporting the effectiveness and safety of remdesivir were searched via databases and other sources from December 2019 to December 2020. Two independent reviewers performed literature screening, data extraction and assessment of risk bias. Seven studies involving 3686 patients were included. Results: Treatment with remdesivir was associated with an increase in clinical recovery rate by 21% (RR 1.21; 95% CI 1.08-1.35) on day 7 and 29% (RR 1.29; 95% CI 1.22-1.37) on day 14. The likelihoods of requiring high-flow supplemental oxygen and invasive mechanical ventilation in the remdesivir group were lower than in the placebo group by 27% (RR 0.73; 95% CI 0.54-0.99) and 47% (RR 0.53; 95% CI 0.39-0.72), respectively. Remdesivir-treated patients showed a 39% (RR 0.61; 95% CI 0.46-0.79) reduction in the risk of mortality on day 14 compared to the control group; however, there was no significant difference on day 28. Serious adverse effects (SAEs) were significantly less common in patients treated with remdesivir, with an absolute risk difference of 6% (RD -0.06; 95% CI -0.09 to -0.03). Conclusion: Despite conditional recommendation against its use, remdesivir could still be effective in early clinical improvement; reduction of early mortality and avoiding high-flow supplemental oxygen and invasive mechanical ventilation among hospitalised COVID-19 patients. Remdesivir was also well tolerated without significant SAEs compared to placebo, yet available evidence from clinical studies support the need to conduct close monitoring.</p

Adherence to medication for the treatment of psychosis: rates and risk factors in an Ethiopian population

Background: Medication-taking behavior, specifically non-adherence, is significantly associated with treatment outcome and is a major cause of relapse in the treatment of psychotic disorders. Non-adherence can be multifactorial; however, the rates and associated risk factors in an Ethiopian population have not yet been elucidated. The principal aim of this study was to evaluate adherence rates to antipsychotic medications, and secondarily to identify potential factors associated with non-adherence, among psychotic patients at tertiary care teaching hospital in Southwest Ethiopia.Methods: A cross-sectional study was conducted over a 2-month period in 2009 (January 15th to March 20th) at the Jimma University Specialized Hospital. Adherence was computed using both a compliant fill rate method and self-reporting via a structured patient interview (focusing on how often regular medication doses were missed altogether, and whether they missed taking their doses on time). Data were analyzed using SPSS for windows version 16.0, and chi-square and Pearsons r tests were used to determine the statistical significance of the association of variables with adherence.Result: Three hundred thirty six patients were included in the study. A total of 75.6% were diagnosed with schizophrenia, while the others were diagnosed with other psychotic disorders. Most (88.1%) patients were taking only antipsychotics, while the remainder took more than one medication. Based upon the compliant fill rate, 57.5% of prescription fills were considered compliant, but only 19.6% of participants had compliant fills for all of their prescriptions. In contrast, on the basis of patients self-report, 52.1% of patients reported that they had never missed a medication dose, 32.0% sometimes missed their daily doses, 22.0% only missed taking their dose at the specific scheduled time, and 5.9% missed both taking their dose at the specific scheduled time and sometimes missed their daily doses. The most common reasons provided for missing medication doses were: forgetfulness (36.2%); being busy (21.0%); and a lack of sufficient information about the medication (10.0%). Pill burden, medication side-effects, social drug use, and duration of maintenance therapy each had a statistically significant association with medication adherence (P ≤ 0.05).Conclusion: The observed rate of antipsychotic medication adherence in this study was low, and depending upon the definition used to determine adherence, it is either consistent or low compared to previous reports, which highlights its pervasive and problematic nature. Adherence must therefore be considered when planning treatment strategies with antipsychotic medications, particularly in countries such as Ethiopia. © 2012 Alene et al.; licensee BioMed Central Ltd

Utilization and Dose Optimization of Angiotensin-Converting Enzyme Inhibitors among Heart Failure Patients in Southwest Ethiopia

Background: Optimal use of angiotensin-converting enzyme inhibitors (ACEIs) is crucial to improve the treatment outcome in heart failure patients. However, little is known about the optimal use of ACEIs among heart failure patients in our setting. Terefore, our study aimed to investigate the utilization and optimal dosing of ACEIs and associated factors in heart failure patients. Method: A cross-sectional study was conducted on randomly selected patients with heart failure between February 2016 and June 2016 at ambulatory care clinic of Jimma University Medical Center, Ethiopia. Data were collected through patient interview and review of medical records. Binary logistic regression analysis was done to identify factors associated with utilization and optimal dosing of ACEIs. Results: A total of 308 patients were included in the fnal analysis of this study. Te mean (±standard deviation) age of the patients was 52.3 ±15.5 years. Out of the total, 74.7% of the patients were receiving ACEIs. Among the patients who were receiving ACEIs, only 35.7% were taking optimal dose. New York Heart Association (NYHA) class III (Adjusted odds ratio (AOR):0.12, 95% confdence interval (CI):0.02–0.98), valvular heart disease (AOR: 0.27, 95% CI: 0.13-0.56), hypertension (AOR: 5.82, 95% CI: 2.16- 15.71), and diabetes mellitus (AOR: 3.84, 95% CI: 1.07-13.86) were signifcantly associated with the use of ACEIs, whereas age ≥65 (AOR: 2.61, 95%CI: 1.20-5.64), previous hospitalization for heart failure (AOR: 2.08, 95%CI: 1.11-3.92), diuretic use (AOR: 5.60, 95%CI: 2.75-11.40), and dose of furosemide >40mg (AOR: 9.80, 95%CI: 3.00-31.98) were predictors of suboptimal dosing of ACEIs. Conclusion: Although majority of patients were receiving ACEIs, only about one-third were using optimal dosage. Valvular heart disease and NYHA class III were negatively associated with the use of ACEIs while previous hospitalization for heart failure, old age, diuretic use, and diuretic dose were predictors of suboptimal dosing of ACEIs. Terefore, more efort needs to be done to minimize the potentially modifable risk factors of suboptimal use of ACEIs therapy in heart failure patients.</p

Mortality from adverse drug reaction-related hospitalizations in south-west Ethiopia: A cross-sectional study

What is known and objective: Adverse drug reactions (ADRs) are an important cause of mortality during medical care. To our knowledge, no Ethiopian studies have reported on mortality due to ADRs in patients presenting to hospital from the community setting. The aim of this study was to determine the mortality rate attributable to ADRs in patients presenting to hospital, identify drugs implicated in the ADR‐related deaths and identify factors contributing to ADR‐related mortality at Jimma University Specialised Hospital (JUSH), south‐west Ethiopia. Methods: This cross‐sectional study included 1001 patients aged ≥18 years consecutively admitted to medical wards from May 2015 to August 2016. ADR‐related mortality was determined through detailed review of medical records, laboratory tests and patient interviews followed by causality assessment by the Naranjo algorithm and expert consensus. Results: Of 1001 patients, 15, 1.5% (95% confidence interval [CI]: 0.80%‐2.30%) died with an ADR. The primary suspected causes of death were drug‐induced hepatotoxicity (7, 43.8%) followed by acute kidney injury (4, 25.0%). Isoniazid (6, 33.3%), pyrazinamide (3, 16.7%), efavirenz (2, 11.1%) and tenofovir (2, 11.1%) were commonly implicated drugs. The majority of ADRs (14, 93.8%) were preventable. Unadjusted bivariate comparisons suggested patients who died with ADRs were more likely to have pre‐existing liver disease (40.0% vs 7.0%; 95% confidence interval [CI]: 8.1%‐57.8%), a history of ADRs (40% vs 1.4%; 95% CI: 13.8%‐63.4%), a lower mean (±SD) body mass index (BMI, 17.6 ± 2.1 vs 20.0 ± 2.9 kg/m2; 95% CI = 0.9‐3.9), exposure to antitubercular (46.7% vs 18.9%; 95% CI: 2.3%‐53.1%) and antiretroviral (40.0% vs 7.7%; 95% CI: 7.5%‐57.2%) therapies, and a higher mean number of medications (7.1 ± 3.3 vs 3.8 ± 2.1; 95% CI: 2.2‐4.4) and Charlson Comorbidity Index (3.9 ± 2.9 vs 1.6 ± 1.8; 95% CI: 1.4‐3.2) than surviving patients without ADRs. What is new and conclusion: Fatal ADRs were common in patients presenting to hospital. The drugs implicated were mostly antitubercular and antiretroviral therapies, reflecting the high burden of HIV and tuberculosis in the study population. ADR‐related deaths were significantly associated with poor nutritional status. The majority of ADR‐related deaths were preventable, highlighting the need to develop a multidisciplinary approach to closely monitor patients who are prescribed antitubercular and antiretroviral therapies, particularly in patients with hepatic disease, a history of ADRs, who are malnourished and who are exposed to multiple medications.</p

Predictors of adverse drug reaction-related hospitalisation in Southwest Ethiopia: A prospective cross-sectional study

Background: Adverse drug reactions (ADRs) are important causes of morbidity and mortality in the healthcare system; however, there are no studies reporting on the magnitude and risk factors associated with ADR-related hospitalisation in Ethiopia. Objectives: To characterise the reaction types and the drugs implicated in admission to Jimma University Specialized Hospital, Southwest Ethiopia, and to identify risk factors associated with ADR-related hospitalisation. Methods: A prospective cross-sectional study was conducted from May 2015 to August 2016 among consenting patients aged ≥ 18 years consecutively admitted to medical wards taking at least one medication prior to admission. ADR-related hospitalisations were determined through expert review of medical records, laboratory tests, patient interviews and physical observation. ADR causality was assessed by the Naranjo algorithm followed by consensus review with internal medicine specialist. ADR preventability was assessed using Schumock and Thornton’s criteria. Only definite and probable ADRs that provoked hospitalisation were considered. Binary logistic regression was used to identify independent predictors of ADR-related hospitalisation. Results: Of 1,001 patients, 103 (10.3%) had ADR-related admissions. Common ADRs responsible for hospitalisation were hepatotoxicity (35, 29.4%) and acute kidney injury (27, 22.7%). The drug classes most frequently implicated were antitubercular agents (45, 25.0%) followed by antivirals (22, 12.2%) and diuretics (19, 10.6%). Independent predictors of ADR-related hospitalisation were body mass index (BMI) 2 (adjusted odd ratio [AOR] = 1.69; 95% confidence interval [CI] = 1.10–2.62; p = 0.047), pre-existing renal disease (AOR = 2.84; 95%CI = 1.38–5.85, p = 0.004), pre-existing liver disease (AOR = 2.61; 95%CI = 1.38–4.96;  = 0.003), number of comorbidities ≥ 4 (AOR = 2.09; 95%CI = 1.27–3.44; p = 0.004), number of drugs ≥ 6 (AOR = 2.02; 95%CI = 1.26–3.25; p = 0.004) and history of previous ADRs (AOR = 24.27; 95%CI = 11.29–52.17; p  Conclusions: ADRs were a common cause of hospitalisation. The majority of ADRs were preventable, highlighting the need for monitoring and review of patients with lower BMI, ADR history, renal and liver diseases, multiple comorbidities and medications. ADR predictors should be integrated into clinical pathways and pharmacovigilance systems.</p