Cost-Benefit Analysis of Genotype-Guided Interruption Days in Warfarin Pre-Procedural Management

Warfarin is commonly used in thromboembolic conditions. Warfarin interruption represents a significant challenge in pre-operative warfarin management as it is associated with major consequences. Genetics polymorphism demonstrated to be a significant predictor of the required days of warfarin interruption. This study sought to assess the economic benefit of implementing a pharmacogenetic-guided approach in the preprocedural warfarin management. From the hospital's perspective, a cost-benefit analysis was conducted based on a 1-year decision-analytic follow-up model of the economic implications of using a pharmacogenetic algorithm vs standard of care in pre-operative warfarin management in the Hamad Medical Corporation, Qatar. The benefit of the interventional algorithm was based on estimated reduction in the probabilities of clinical events and their cost, added to the avoided cost because of canceled procedures. The cost of the algorithm was the cost of the genotyping assay. The model event probability inputs were extracted from major literature clinical trials, and the setting-specifc and cost inputs were locally obtained. The model was based on a multivariate analysis at its base case. As per 10.3% prevalence of genetic variants, 82% bridging, and a calculated 20% optimization in the preparative period of warfarin management, the benefit to cost ratio was 4.0 in favor genotype-guided approach. This positive benefit to cost ratio was maintained in 100% of the simulated study cases. Sensitivity analyses confirmed the robustness and generalizability of the study conclusion. A pharmacogenetic- guided pre-operative warfarin interruption management is a cost-beneficial approach in the Qatari practice.This work was supported by Hamad Medical Corporation MRC [grant number 1698/2017 ]

Assessment of the attitude, awareness and practice of periprocedural warfarin management among health care professional in Qatar. A cross sectional survey

It is estimated that 10–15% of oral anticoagulant (OAC) patients, would need to hold their OAC for scheduled surgery. Especially for warfarin, this process is complex and requires multi-layer risk assessment and decisions across different specialties. Clinical guidelines deliver broad recommendations in the area of warfarin management before surgery which can lead to different trends and practices among practitioners. To evaluate the current attitude, awareness, and practice among health care providers (HCPs) on warfarin periprocedural management. A multiple-choice questionnaire was developed, containing questions on demographics and professional information and was completed by187 HCPs involved in warfarin periprocedural management. The awareness median (IQR) score was moderate [64.28% (21.43)]. The level of awareness was associated with the practitioner’s specialty and degree of education (P = 0.009, 0.011 respectively). Practice leans to overestimate the need for warfarin discontinuation as well as the need for bridging. Participants expressed interest in using genetic tests to guide periprocedural warfarin management [median (IQR) score (out of 10) = 7 (5)]. In conclusion, the survey presented a wide variation in the clinical practice of warfarin periprocedural management. This study highlights that HCPs in Qatar have moderate awareness. We suggest tailoring an educational campaign or courses towards the identified gaps.This research was supported by financial support from Qatar university student Grant No. QUST-2-CPH-2019-22

Bridging vs Non-Bridging with Warfarin Peri-Procedural Management: Cost and Cost-Effectiveness Analyses

The warfarin peri-procedural management in Qatar is predominantly based on bridging (63%), compared to non-bridging. This study sought to perform a first-time cost analysis of current warfarin peri-procedural management practices, including a cost-effectiveness analysis (CEA) of predominant bridging vs predominant non-bridging practices. From the hospital perspective, a one-year decision-analytic model followed the cost and success consequences of the peri-procedural warfarin in a hypothetical cohort of 10,000 atrial fibrillation patients. Success was defined as survival with no adverse events. Outcome measures were the cost and success consequences of the 63% bridging (vs not-bridging) practice in the study setting, ie, Hamad Medical Corporation, Qatar, and the incremental cost-effectiveness ratio (ICER, cost/success) of the warfarin therapy when predominantly bridging based vs when predominantly non-bridging based. The model was based on Monte Carlo simulation, and sensitivity analyses were performed to confirm the robustness of the study conclusions. As per 63% bridging practices, the mean overall cost of peri-procedural warfarin management per patient was USD 3,260 (QAR 11,900), associated with an overall success rate of 0.752. Based on the CEA, predominant bridging was dominant (lower cost, higher effect) over the predominant non-bridging practice in 62.2% of simulated cases, with a cost-saving of up to USD 2,001 (QAR 7,303) at an average of USD 272 (QAR 993) and was cost-effective in 36.9% of cases. Being between cost-saving and cost-effective, compared to predominant non-bridging practices, the predominant use of bridging with warfarin seems to be a favorable strategy in atrial fibrillation patients

CLINICAL AND ECONOMIC IMPACT OF GENETIC AND NON-GENETIC FACTORS ON INR NORMALIZATION IN PRE-OPERATIVE MANAGEMENT OF WARFARIN PATIENTS

The aim of this Ph.D. was to evaluate the periprocedural anticoagulation management of patients receiving warfarin in Qatar clinically and economically. In addition, exploring the clinical and economic impact of genetic and non-genetic factors on INR normalization in pre-operative management of warfarin patients in Arab population. our review concluded that the clinical decision regarding perioperative warfarin management is a complex aspect of care. Indeed, such an issue would ultimately lead to undesirable variation in care. This would be complicated by the lack of institutional standardized protocols and hence differences in practices, attitudes and periprocedural outcomes. A local cross-sectional survey on the periprocedural management of warfarin was developed for a better understanding of the current practice, the gap in knowledge and attitude among health care providers in Qatar. It has found that the awareness median (IQR) score was moderate [64.28% (21.43)]. The level of awareness was associated with the practitioner's specialty and degree of education (P= 0.009, 0.011 respectively). Practice leans to overestimate the need for warfarin discontinuation as well as the need for bridging. Participants expressed interest in using genetic tests to guide periprocedural warfarin management [median (IQR) score (out of 10) = 7 (5)]. The results of the mentioned survey were influencer to evaluate the real-world clinical practice of warfarin periprocedural management and investigate the clinical outcomes associated with warfarin bridging versus non-bridging. This prospective cohort study demonstrated that warfarin was interrupted in 90% of patients, out of them 82% received anticoagulant bridging medication. Minor or low-bleeding risk procedures represented 75% of the performed procedures. The median (IQR) of preoperative warfarin interruption days was 3 (2). No thromboembolic events were observed, while 39.1% of patients experienced bleeding events during the study period. The incidence of overall bleeding and major bleeding were numerically higher for bridging group compared to non-bridging but did not reach statistical significance [(30.6% Vs 22.2%, p= 0.478) and (12.9% Vs 5.6%, p=0.375), respectively]. The results of the above study showed significant limitations that undermine the benefit of bridging and showed that this benefit may not worth the monetary spending and may not achieve cost-effectiveness. To our knowledge, there are no evaluations of the economic value of bridging in the literature. Consequently, a study was conducted to assess the economic consequences of peri-procedural warfarin management of AF patients in Qatar. The economic evaluation of the above practice demonstrated that the mean overall cost of peri-procedural warfarin management per patient was USD 3,260 (QAR 11,900), associated with an overall success rate of 0.752. Based on the cost-effective analysis (CEA), predominant bridging was dominant (lower cost, higher effect) over the predominant non-bridging practice in 62.2% of simulated cases, with a cost-saving of up to USD 2,001 (QAR 7,303) at an average of USD 272 (QAR 993) and was cost-effective in 36.9% of cases. To optimize the period of preprocedural warfarin interruption to decrease the incidence of bleeding in case of bridging and the incidence of thromboembolism in case of non-bridging, a study was conducted to determine the influence of CYP2C9, VKORC1, CYP4F2, FII, and FVII genetic polymorphisms and non-genetic factors on INR decline in a cohort of Arabs undergoing a procedure that requires warfarin interruption and developing an algorithm to tailor the duration of warfarin interruption before the procedure. The study revealed that bridging, INR index and being Sudanese are significant predictors of INR normalization. Moreover, CYP2C9 and VKORC1 genetic polymorphisms are influencers to warfarin maintenance weekly dose but none of the genetic factors were associated with the INR decline rate. A more extensive study may be warranted to confirm such findings. Equally important, cost-effective analysis of implementing pharmacogenetics-based algorithm will guide decision-makers to which approach must be subsidized. To the best of our knowledge, no economic evaluation study investigated the use of pharmacogenetics information in pre-operative warfarin interruption to direct decision-makers. Therefore, a cost-benefit analysis was conducted to examine if the benefits of implementing a genetic-testing in periprocedural warfarin management outweigh the cost. The study showed that the average cost per patient was USD 573.72 (QAR 2,094.07) less with the genetic-guided approach of management compared to the standard of care. This led to an average benefit to cost ratio of 4; whereby, for each USD 1 spent on genetic testing, USD 4 is generated in benefit. This was maintained in 100% of simulated cases

Genetic polymorphism effect on warfarin–rifampin interaction: A case report and review of literature

Warfarin–rifampin interaction has been reported since the 1970s. Due to rifampin’s strong induction of CYP2C9, most cases could not attain the target international normalized ratio (INR) despite warfarin dose escalation. Genetic polymorphisms determine up to 50% of warfarin dose variability. A 38-year-old woman was started on warfarin and rifampin for cerebral venous sinus thrombosis and pulmonary tuberculosis. Over six weeks, the daily warfarin dose was increased from 3 to 10 mg to attain three consecutive in-clinic therapeutic INRs. She completed three complications-free months of warfarin treatment with time in therapeutic range (TTR) of 46%. We performed retrospective genetic testing to determine the patient’s CYP2C9, CYP4F2, and VKORC1 genotypes and whether they had affected the interaction outcome. The analysis revealed that the subject carries CYP2C9*3*3 and VKORC1-1639 (GA) mutations, classifying her as a slow metabolizer and, hence, highly warfarin-sensitive. This was reflected on how the case responded to a relatively lower dose than previously reported cases that did not achieve the target on warfarin daily doses up to 35 mg. This is the first report addressing the genotype effect on this interaction. Patients with genetic variants requiring low warfarin doses are more likely to respond at a feasible dose while on rifampin. Future studies to evaluate warfarin–rifampin-gene interaction are warranted.The publication of this article was funded by Qatar National Library (QNL)

A Tumor and Immune-Related Micro-RNA Signature Predicts Relapse-Free Survival of Melanoma Patients Treated with Ipilimumab

Despite the unprecedented advances in the treatment of melanoma with immunotherapy, there continues to be a major need for biomarkers of clinical benefits and immune resistance associated with immune checkpoint inhibitors; microRNA could play a vital role in these efforts. This study planned to identify differentially expressed miRNA molecules that may have prognostic value for clinical benefits. Patients with surgically operable regionally advanced melanoma were treated with neoadjuvant ipilimumab (10 mg/kg intravenously every 3 weeks × two doses) bracketing surgery. Tumor biospecimens were obtained at baseline and surgery, and microRNA (miRNA) expression profiling was performed on the tumor biopsies. We found that an expression profile consisting of a 4-miRNA signature was significantly associated with improved relapse-free survival (RFS). The signature consisted of biologically relevant molecules previously reported to have prognostic value in melanoma and other malignancies, including miR-34c, miR-711, miR-641, and miR-22. Functional annotation analysis of target genes for the 4-miRNA signature was significantly enriched for various cancer-related pathways, including cell proliferation regulation, apoptosis, the MAPK signaling pathway, and the positive regulation of T cell activation. Our results presented miRNAs as potential biomarkers that can guide the treatment of melanoma with immune checkpoint inhibitors. These findings warrant further investigation in relation to CTLA4 blockade and other immune checkpoint inhibitors. ClinicalTrials.gov NCT00972933

Genetic and non-genetic factors impact on inr normalization in preprocedural warfarin management

Background: Annually, 10% of warfarin patients will likely need to stop warfarin prior to elective surgery to achieve a baseline international normalization ratio (INR) level (INR ≤ 1.2) at the time of the procedure. This study explores the influence of genetic and nongenetic factors on INR normalization in the Arab (major part of Near Eastern) population in preprocedural warfarin management. Methods: An observational prospective cohort study was designed to recruit Arab patients taking warfarin and scheduled for an elective procedure. Two INR readings were recorded. DNA extraction and genotyping of variants in CYP2C9*2, CYP2C9*3, CYP4F2*3, VKORC1*2, and FII (rs5896) and FVII (rs3093229) genes using real-time polymerase chain reaction were performed. Results: Data from 116 patients were included in the analysis. CYP2C9 and VKORC1 genetic variants carriers required lower maintenance dose compared to non-carriers. The analysis showed that ciprofloxacin, antiplatelet medications, and INR index (INR at visit 1) are the only factors associated with the INR decline rate. Also, the proportion of CYP2C9*3 carriers with normal INR (≤1.2) on the day of surgery was significantly lower than those with wild-type genotype (28% vs 60%, p=0.013). In addition, heparin bridging, INR target, and Sudanese nationality are significant predictors of INR normalization (≤1.2) on the day of the procedure. Conclusion: Despite the confirmed effect of genetic factors on warfarin maintenance dose, the study was not able to find a significant effect of any genetic factor on the rate of INR normalization possibly due to the small sample size. Index INR and interacting medications showed to be significant predictors of INR decline rate.This work was supported by Hamad Medical Corporation MRC [grant number 1698/2017]

Periprocedural Anticoagulation Management of Patients receiving Warfarin in Qatar: A Prospective Cohort Study

Background: The use of anticoagulant bridging remains controversial. This study was conducted to evaluate our warfarin periprocedural management in Qatar and investigate the associated clinical outcomes with such management. Methods: A prospective cohort study was designed to describe the periprocedural clinical practice in warfarin patients in Qatar and to compare clinical safety and efficacy outcomes between anticoagulant bridging and nonbridging. Results: 103 patients were recruited. Bridging occurred in 82% of the participants. No thromboembolic events were observed, while 39.1% of patients experienced bleeding events during the study period. The incidence of overall bleeding and major bleeding were numerically higher for bridging group compared to nonbridging but did not reach statistical significance ([30.6% vs 22.2%, P = 0.478] and [12.9% vs 5.6%, P = 0.375], respectively). Conclusion: Warfarin interruption and bridging are overwhelmingly used in warfarin-treated patients in Qatar. While bridging was numerically associated with increased bleeding events, there is no statistical difference in reported clinical events between bridging and nonbridging strategies