Targeted next-generation sequencing of genes involved in Warfarin Pharmacodynamics and pharmacokinetics pathways using the Saudi Warfarin Pharmacogenetic study (SWAP).

BACKGROUND: Warfarin is an oral anticoagulant commonly used for treatment and prophylaxis against thromboembolic events. Warfarins's narrow therapeutic index window is one of the main challenges in clinical practice; thus, it requires frequent monitoring and dose adjustment to maintain patients' therapeutic range. Warfarin dose variation and response are attributed to several inter-and intra-individuals factors, including genetic variants in enzymes involved in warfarin pharmacokinetics (PK) and pharmacodynamics (PD) pathways. Thus, we aim to utilize the next-generation sequencing (NGS) approach to identify rare and common genetic variants that might be associated with warfarin responsiveness. METHOD AND RESULTS: A predesigned NGS panel that included 16 genes involved in Warfarin PK/PD pathways was used to sequence 786 patients from the Saudi Warfarin Pharmacogenetic Cohort (SWAP). Identified variants were annotated using several annotation tools to identify the pathogenicity and allele frequencies of these variants. We conducted variants-level association tests with warfarin dose. We identified 710 variants within the sequenced genes; 19% were novel variants, with the vast majority being scarce variants. The genetic association tests showed that VKORC1 (rs9923231, and rs61742245), CYP2C9 (rs98332238, rs9332172, rs1057910, rs9332230, rs1799853, rs1057911, and rs9332119), CYP2C19 (rs28399511, and rs3758581), and CYP2C8 (rs11572080 and rs10509681) were significantly associated with warfarin weekly dose. Our model included genetics, and non-genetic factors explained 40.1% of warfarin dose variation. CONCLUSION: The study identifies novel variants associated with warfarin dose in the Saudi population. These variants are more likely to be population-specific variants, suggesting that population-specific studies should be conducted before adopting a universal warfarin genotype-guided dosing algorithm.

Attitude of pediatricians toward suspected cases of child sexual abuse (CSA) in Saudi Arabia.

Objective: To assess the attitudes of pediatricians working at the Ministry of National Guard-Health Affairs (MNGHA) to report cases of child sexual abuse (CSA) and to determine the association between the demographic, cultural characteristics, and the attitude toward reporting. Participants and Settings: The participants included all pediatricians, from consultants to residents, employed at the Pediatric Department of the King Abdulaziz Medical City and King Abdullah Specialist Children's Hospital, Riyadh. Additional inclusion criteria were females and males, Saudis and non-Saudis, and age 20-60 years. Methods: A self-administered, hard copy questionnaire was distributed to 277 pediatricians, and the response rate was 58.48%. The sensitivity/specificity emphasis mean score was calculated. Categorical variables were tested against the sensitivity/specificity emphasis mean score using an ANOVA and an independent sample t-test. The reliability of the questionnaire was measured with Cronbach's alpha. Results: In total, 153 completed questionnaires were analyzed. The responses were inclined toward balanced (indecisive toward reporting) and high specificity (favors the decision not to report suspected CSA). No significant difference was found in the sensitivity/specificity mean score between the different levels of professionals, experience, age, gender, and number of prior child abuse-related courses. The skepticism scale showed, for the different professional levels, that the staff physician/resident believed the 3- to 5-year-old girls and boys to be genuine. The consultants/associate consultants believed 6- to 12-year and 13- to 17-year-old girls and boys to be true most of the time. Nearly half of the participants indicated that their reporting decision was affected by the possible consequences of reporting suspected CSA for the children's families and the social perceptions of sexually abused children as adults. Conclusion: The results highlight the low reporting rates of CSA cases. The findings suggest a lack of training and experience of the professionals in this area of assessing, detecting, and reporting CSA cases.

Efficacy of favipiravir in adults with mild COVID-19: a randomized, double-blind, multicentre, placebo-controlled clinical trial.

OBJECTIVE: To evaluate whether favipiravir reduces the time to viral clearance as documented by negative RT-PCR results for severe acute respiratory syndrome coronavirus 2 in mild cases of coronavirus disease 2019 (COVID-19) compared to placebo. METHODS: In this randomized, double-blinded, multicentre, and placebo-controlled trial, adults with PCR-confirmed mild COVID-19 were recruited in an outpatient setting at seven medical facilities across Saudi Arabia. Participants were randomized in a 1:1 ratio to receive either favipiravir 1800 mg by mouth twice daily on day 1 followed by 800 mg twice daily (n = 112) or a matching placebo (n = 119) for a total of 5 to 7 days. The primary outcome was the effect of favipiravir on reducing the time to viral clearance (by PCR test) within 15 days of starting the treatment compared to the placebo group. The trial included the following secondary outcomes: symptom resolution, hospitalization, intensive care unit admissions, adverse events, and 28-day mortality. RESULTS: Two hundred thirty-one patients were randomized and began the study (median age, 37 years; interquartile range (IQR): 32-44 years; 155 [67%] male), and 112 (48.5%) were assigned to the treatment group and 119 (51.5%) into the placebo group. The data and safety monitoring board recommended stopping enrolment because of futility at the interim analysis. The median time to viral clearance was 10 days (IQR: 6-12 days) in the favipiravir group and 8 days (IQR: 6-12 days) in the placebo group, with a hazard ratio of 0.87 for the favipiravir group (95% CI 0.571-1.326; p = 0.51). The median time to clinical recovery was 7 days (IQR: 4-11 days) in the favipiravir group and 7 days (IQR: 5-10 days) in the placebo group. There was no difference between the two groups in the secondary outcome of hospital admission. There were no drug-related severe adverse events. CONCLUSION: In this clinical trial, favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment.

Tele-pharmacy Anticoagulation Clinic During COVID-19 Pandemic: Patient Outcomes.

Introduction: It is well-established that clinical pharmacist-managed anticoagulation services achieve superior anticoagulation control, with a positive impact. At King Abdulaziz Medical City (KAMC), Riyadh, Saudi Arabia, the structure of anticoagulation management is a pharmacist-managed specialty service. With the current COVID-19 situation, measures were taken to assure the continuity of patient care by establishing tele-pharmacy anticoagulation clinics. Materials and Methods: This was a prospective study with patients prescribed anticoagulation and followed up for 3 months. Since establishing the anticoagulation virtual clinic in March 2020, 270 patients were recruited in the study. The data collected included age, gender, comorbidities, indication for anticoagulation, intended duration of treatment, warfarin dose, testing of International Normalized Ratio (INR), INR target, range of INR values, time INR that was within the therapeutic range (TTR), and complications of therapy (bleeding and/or bruises). The patients were asked to complete the pharmacist satisfaction survey (PSS) after their consultation to assess patient satisfaction with the new virtual consultation system. Linguistic and cultural validation was conducted for the questionnaire. Results: A total of 270 patients were included in the study. The mean percentage of overall INR values in the range was 59.39% ± 32.84, and the mean time with the overall INR was within the therapeutic range 57.81% ± 32.08. Thirty-one percent of the sample had good anticoagulation control (time in therapeutic range >70%). The median satisfaction score was 32 (IQR 28-36) with a maximum score of 40. Conclusion: This is the first study to assess the tele-pharmacy anticoagulation clinic's efficiency and patient satisfaction in Saudi Arabia during the COVID-19 pandemic. This type of consultation was as effective as face-to-face consultations. The study also highlighted that though the reduction in the cost of care was not substantial, there was a significant increase in resource (clinical pharmacist) utilization as a result of this model. The adoption of tele-pharmacy resulted in time savings for the clinical pharmacists who can be utilized in many other improvement projects in adult ambulatory clinics to ensure the delivery of better quality and safe patient care.

The development and validation of a multivariable model to predict the bleeding risk score for patients with non-valvular atrial fibrillation using direct oral anticoagulants in the Arab population.

BACKGROUND: Frequently used models, such as the HAS-BLED, ATRIA, ORBIT, and GARFIELD-AF evaluate the risk of bleeding when using an anticoagulant, for example warfarin, in patients with non-valvular atrial fibrillation. Limited studies are available reporting a model with a good discriminative ability to predict the bleeding risk score when using direct oral anticoagulants. METHODS: Patient data were collected from King Abdulaziz Medical City, King Fahad Cardiac Center, and Prince Sultan Cardiac Center in Riyadh, from outpatients, inpatients, or primary care clinics. In total, 1722 patients with a prescription for a new oral anticoagulant, Dabigatran, Rivaroxaban, or Apixaban, were enrolled. A resampling approach for variable selection was used and a five-fold cross-validation to assess the model fit and misclassification probabilities. The analysis used the receiver operating characteristics curve (ROC) and the concordance (c) statistic to assess the validation models' discriminative power. The final penalized likelihood parameters were used for the development of the risk prediction tool. The accuracy of a classification and the prediction are reported with the sensitivity, specificity, and Brier score. RESULTS: Bleeding occurred in 11.15% of cases, of which 23.08% required a blood transfusion and 51.65% had a reduction in haemoglobin of more than 2 gm. The variable selection model identified 15 predictors associated with major bleeding. The discriminative ability of the model was good (c-statistic 0.75, p = 0.035). The Brier score of the model was 0.095. With a fixed cut-off probability value of 0.12 for the logistic regression equation, the sensitivity was 72.7%, and the specificity 66.3%. CONCLUSION: This model demonstrated a good performance in predicting the bleeding risk in Arab patients treated with novel oral anticoagulants. This easy to use bleeding risk score will allow the clinician to quickly classify patients according to their risk category, supporting close monitoring and follow-up for high-risk patients, without laboratory and radiological monitoring.

Multicentre randomised double-blinded placebo-controlled trial of favipiravir in adults with mild COVID-19.

INTRODUCTION: A novel coronavirus, designated SARS-CoV-2, caused an international outbreak of a respiratory illness, termed COVID-19 in December 2019. There is a lack of specific therapeutic agents based on evidence for this novel coronavirus infection; however, several medications have been evaluated as a potential therapy. Therapy is required to treat symptomatic patients and decrease the virus carriage duration to limit the communitytransmission. METHODS AND ANALYSIS: We hypothesise that patients with mild COVID-19 treated with favipiravir will have a shorter duration of time to virus clearance than the control group. The primary outcome is to evaluate the effect of favipiravir on the timing of the PCR test conversion from positive to negative within 15 days after starting the medicine.Adults (>18 years, men or nonpregnant women, diagnosed with mild COVID-19 within 5 days of disease onset) are being recruited by physicians participating from the Ministry of National Guard Health Affairs and the Ministry of Health ethics committee approved primary healthcare centres. This double-blind, randomised trial comprises three significant parts: screening, treatment and a follow-up period. The treating physician and patients are blinded. Eligible participants are randomised in a 1:1 ratio to either the therapy group (favipiravir) or a control group (placebo) with 1800 mg by mouth two times per day for the first day, followed by 800 mg two times per day for 4-7 days. Serial nasopharyngeal/oropharyngeal swab samples are obtained on day 1 (5 days before therapy). On day5±1 day, 10±1 day, 15±2 days, extra nasopharyngeal/oropharyngeal PCR COVID-19 samples are requested.The primary analysis population for evaluating both the efficacy and safety outcomes will be a modified intention to treat population. Anticipating a 10% dropout rate, we expect to recruit 288 subjects per arm. The results assume that the hazard ratio is constant throughout the study and that the Cox proportional hazard regression is used to analyse the data. ETHICS AND DISSEMINATION: The study was approved by the King Abdullah International Medical Research Centre Institutional Review Board (28 April 2020) and the Ministry of Health Institutional Review Board (1 July 2020). Protocol details and any amendments will be reported to https://clinicaltrials.gov/ct2/show/NCT04464408. The results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: National Clinical Trial Registry (NCT04464408).

The effect of the VKORC1 promoter variant on warfarin responsiveness in the Saudi WArfarin Pharmacogenetic (SWAP) cohort.

Warfarin is a frequently prescribed oral anticoagulant with a narrow therapeutic index, requiring careful dosing and monitoring. However, patients respond with significant inter-individual variability in terms of the dose and responsiveness of warfarin, attributed to genetic polymorphisms within the genes responsible for the pharmacokinetics and pharmacodynamics of warfarin. Extensive warfarin pharmacogenetic studies have been conducted, including studies resulting in genotype-guided dosing guidelines, but few large scale studies have been conducted with the Saudi population. In this study, we report the study design and baseline characteristics of the Saudi WArfarin Pharmacogenomics (SWAP) cohort, as well as the association of the VKORC1 promoter variants with the warfarin dose and the time to a stable INR. In the 936 Saudi patients recruited in the SWAP study, the minor allele C of rs9923231 was significantly associated with a 8.45 mg higher weekly warfarin dose (p value = 4.0 × 10-46), as well as with a significant delay in achieving a stable INR level. The addition of the rs9923231 status to the model, containing all the significant clinical variables, doubled the warfarin dose explained variance to 31%. The SWAP cohort represents a valuable resource for future research with the objective of identifying rare and prevalent genetic variants, which can be incorporated in personalized anticoagulation therapy for the Saudi population.

A comparison between warfarin and apixaban: A patient's perspective.

BACKGROUND: Novel oral anticoagulants (NOACs) were developed as alternatives to warfarin. However, the patients' preference regarding warfarin or the NOACs has not been established. Quality-of-life (QOL) surveys are a well-established method for determining the patients' preference for a treatment route. AIMS: This study compared the patients' perspectives on treatment with warfarin versus apixaban using the QOL measures. SETTINGS AND DESIGN: This cross-sectional study was conducted in 2019 for patients treated with either warfarin or apixaban at King Abdulaziz Medical City, Riyadh, Kingdom of Saudi Arabia. METHODS: We used a series of descriptive statistics to examine the differences in sociodemographic characteristics among patients. A propensity score-matching approach was employed to reduce the effect of confounding variables that often influence treatment selection. Greedy matching approach was used to analyze the QOL. RESULTS: A total of 388 patients were identified, of which 124 were matched between the two groups (62 patients in each group). Most of the patients were female, married, below the sufficiency level, educated, and nonsmokers. The patients using warfarin had a significantly better health state (M = 69.64, standard deviation [SD] = 16.52) than those using apixaban (M = 66.33, SD = 23.17), P = 0.011. CONCLUSIONS: Future studies should explore why patients using apixaban showed lower QOL scores and improve health-care providers' awareness of these issues.

Mental Health Outcomes Amongst Health Care Workers During COVID 19 Pandemic in Saudi Arabia.

Objectives: The study aimed to assess the mental health outcomes and associated factors among health care workers during COVID 19 in Saudi Arabia. Design, Setting, and Participants: We conducted a cross-sectional survey of health care workers from tertiary care and ministry of health Centers across the Central, Eastern, and Western regions of Saudi Arabia. There were 1,130 participants in the survey, and we collected demographic and mental health measurements from the participants. Primary Outcomes and Measures: The magnitude of symptoms of depression, anxiety, and insomnia was measured using the original version of 9-item patient health questionnaire (PHQ-9), the 7-item generalized anxiety disorder scale (GAD-7), and 7-item insomnia severity index (ISI). We use the multiple logistic regression analysis to identify the associated risk factors of individual outcomes. Results: The scores on the PHQ-9 showed that the largest proportion of health care workers (76.93%) experienced only normal to mild depression (50.83 and 26.1%, respectively). The scores on the GAD-7 showed that the largest proportion of health care workers (78.88%) experienced minimal to mild anxiety (50.41 and 28.47%, respectively). The scores on the ISI showed that the largest proportion of health care workers (85.83%) experienced absence to subthreshold insomnia (57.08 and 28.75%, respectively). The risk factors for depression in health care workers were Saudi, living with family, working from an isolated room at home and frontline worker. For anxiety, being female was risk factor and for insomnia, being frontline worker was risk factor. Conclusion: It was observed that the symptoms of depression, anxiety, and insomnia were reported in a lower proportion of health care workers in our study. The participants who were female, frontline workers, Saudi, living with family, and working from home in isolated rooms were predisposed to developing psychological disorders.

Validation and Psychometric Properties of the Arabic Version of the Duke Anticoagulation Satisfaction Scale (DASS).

Background: To assess the health-related quality of life (HRQoL) of oral anticoagulant therapy users, different types of instruments are available, either general or specific tools like Duke Anticoagulation Satisfaction Scale (DASS). These tools allow the clinician to adjust the treatment regimen to focus on increasing anticoagulation adherence and reduce adverse clinical outcomes. This study aims to validate the translated Arabic version of DASS to assess the satisfaction level of patients using oral anticoagulants in the Arab population. Methods: The Duke Anticoagulation satisfaction scale (DASS) was translated into the Arabic language using MAPI group services. DASS was administered to 505 patients receiving anticoagulation with warfarin or apixaban. The generic scale measuring the quality of life EQ-5D-5L was also administered. Psychometric properties were assessed by Confirmatory Factor Analysis, internal consistency (Cronbach's Alpha), exploratory factor analysis, convergent and divergent validity, and the correlation between the DASS and demographic variables, clinical characteristics, and the EQ-5D-5L instrument. Results: 439 subjects answered all the questions. From a total of 25 items, 22 grouped into three factors (limitations, positive impact, and negative impact). Each factor had good internal consistency (Cronbach Alpha 0.78-0.88). All the three factors correlated consistently with EQ-5D-5L measuring generic quality of life. Conclusion: The psychometric properties of the Arabic DASS version were comparable to the original English version. The Arabic version of the DASS showed very good reliability and validity. It can be used by health care professionals in other settings of anticoagulation clinics to assess patient's satisfaction and limitations to anticoagulant treatment.

A cross-sectional observational study to assess inhaler technique in Saudi hospitalized patients with asthma and chronic obstructive pulmonary disease.

OBJECTIVES: To assess the proportion of critical errors committed while demonstrating the inhaler technique in hospitalized patients diagnosed with asthma and chronic obstructive pulmonary disease (COPD).  METHODS: This cross-sectional observational study was conducted in 47 asthmatic and COPD patients using inhaler devices. The study took place at King Abdulaziz Medical City, Riyadh, Saudi Arabia between September and December 2013. Two pharmacists independently assessed inhaler technique with a validated checklist.  RESULTS: Seventy percent of patients made at least one critical error while demonstrating their inhaler technique, and the mean number of critical errors per patient was 1.6. Most patients used metered dose inhaler (MDI), and 73% of MDI users and 92% of dry powder inhaler users committed at least one critical error.   CONCLUSION: Inhaler technique in hospitalized Saudi patients was inadequate. Health care professionals should understand the importance of reassessing and educating patients on a regular basis for inhaler technique, recommend the use of a spacer when needed, and regularly assess and update their own inhaler technique skills.

Attitude, barriers and facilitators to practice-based research: cross-sectional survey of hospital pharmacists in Saudi Arabia.

BACKGROUND: Little is known about the perceived attitude, barriers and facilitators of Saudi Pharmacists about practice based research. We aimed to measure the attitude, barriers, and facilitators of Saudi hospital pharmacists towards pharmacy practice research. METHOD: A cross-sectional survey of hospital pharmacists (n = 216) working in King Abdulaziz Medical Cities in Central, Eastern and Western region hospitals was conducted during first week of September, 2013. The survey instrument comprised of six different sections that explored pharmacists previous participation in research, items regarding attitude, perception and willingness to participate, motivators, barriers, different areas of interest for doing research and patient demographics. Quantitative data collected was initially explored using frequency distribution, and descriptive analysis was carried out. Mann-Whitney U and independent samples t-test were used to explore the differences between the study variables. RESULTS: One hundred and eighty two pharmacists completed the survey yielding a response rate of 84 %. Fifty-nine percent of pharmacists have prior research experience. Pharmacists with research experience were more confident in reading and evaluating research papers (p = 0.01), and designing a research study (p = 0.001). Pharmacists with previous research experience were also more likely to participate in future research opportunities (p = 0.004) and were confident in their research skills (p = 0.003). No differences were observed about the perceived value of research, facilitators and barriers to participate in research, between pharmacists with prior research experience and pharmacists who have no prior experience to do research. CONCLUSION: Pharmacists in this study were unanimous about the importance of research but showed considerable differences in their confidence to carry out research. There is a need to provide additional support to enable Saudi pharmacists in conducting practice based research.