Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Paclitaxel-Coated Balloon for Femoropopliteal Artery Disease.

PURPOSE OF THE REVIEW: Percutaneous transluminal angioplasty is an established form of therapy for femoropopliteal artery disease. Currently, percutaneous transluminal angioplasty (PTA) is carried out using standard balloon with or without deployment of a stent but is associated with a high rate of restenosis and stent-related complications. Treatment options for restenosis, especially in-stent restenosis, are limited. Drug-coated balloons promise to reduce the rates of restenosis by effective delivery of antiproliferative agent (paclitaxel) directly to vessel wall without the need for a permanent implant. In this review, we look at the technology and rationale behind drug-coated balloons and examine the evidence available so far. RECENT FINDINGS: Recently, several studies tested the effectiveness of paclitaxel-coated balloon angioplasty compared to that of standard PTA in both de novo lesions and in-stent restenosis of femoropopliteal artery. Paclitaxel-coated balloon use resulted in reduced rates of restenosis and favourable clinical outcomes in both these lesion groups. However, in complex lesions, there is still lack of data to support the use of these balloons. Paclitaxel-coated balloon is a safe and effective therapeutic option in patients with both de novo lesions and in-stent restenosis involving femoropopliteal artery. In light of the new evidence, it is time to consider incorporation of this effective therapeutic option into clinical practice. However, further research is needed for the use of paclitaxel-coated balloons in complex femoropopliteal lesions like calcified lesions especially as adjuncts to cutting balloons and debulking strategies.

Implantable cardioverter defibrillators for primary prevention in cardiomyopathies.

BACKGROUND: Implantable cardioverter defibrillators (ICD) are often used as primary prevention strategy for sudden cardiac death (SCD) in young individuals. This study analyzed appropriate therapies, complications and inappropriate shocks in the real-world Indian population. METHODS: All patients in the cardiomyopathy cohort under follow up who had ICD implanted as a primary prevention strategy were studied. The objective was to assess the incidence of appropriate ICD therapies, inappropriate therapies and complications. ICD was interrogated and stored electrograms analyzed. Underlying arrhythmia or conditions resulting in appropriate or inappropriate ICD therapy were studied. Correlation and regression studies was done to assess for the predictors of appropriate therapy. RESULTS: Fifty patients were followed up for a mean follow-up duration of 4.4 ± 3.1 years with total follow up of 220.2 patient years. Appropriate ICD therapy was delivered in 16 out of 50 (32%) patients, with 65 appropriate therapies (median 2 per patient, range: 0-20). Inappropriate therapy delivered in 7 of the 50 (14%) patients, with 44 inappropriate therapies (median 5 per patient, range: 0-20). Complications occurred in 8 of the 50 (16%) patients. Overall, the rate of appropriate therapy was 29.5 per 100 patient years, that of inappropriate therapy was 19.9 per 100 patient years and the rate of complications was 3.6 per 100 patient years. CONCLUSIONS: When implanted for primary prevention in patients with cardiomyopathies over a mean period of 4.4 ± 3.1 years, appropriate ICD therapy was delivered in 32% patients. However, inappropriate therapy (14% patients) and complications (16% patients) were also common.

Myocardial infarction due to septic thromboembolism in chronic rheumatic heart disease.

Chronic rheumatic heart disease (RHD) is the most troublesome complication of rheumatic fever. Extensive valvular scarring and ventricular remodeling due to pressure and volume overload occur in chronic RHD. Deformed valves are at potential risk for developing infective endocarditis (IE) with further systemic embolism. We hereby describe a case of a patient diagnosed with chronic rheumatic heart disease and severe ventricular dysfunction, planned for aortic valve replacement. The patient developed septic shock during a hospital stay. The autopsy revealed infective endocarditis in the aortic valve with septic thromboembolism in the peripheral branches of the coronary artery and early multifocal myocardial infarction changes.

Perioperative Pain Management Simulation Course: Improving Anesthesia Trainees' Confidence in the Management of Perioperative Pain and the Associated Critical Incidents.

Introduction Pain management is a crucial aspect of patients' perioperative journey and a fundamental duty of every anesthetist. Throughout anesthesia training, there is an emphasis on the management of critical incidents, several of which surround pain management. With changes to the anesthesia curriculum over recent years, variable exposure to training opportunities, and a reduction in clinical hours during training, many trainees report feeling underprepared for their future roles as consultants. However, pain management remains a small fragment of the core anesthesia curriculum with no pain-focused simulation courses currently available across the UK. Simulation has proven to aid learning transfer in complicated and stressful scenarios with a substantial improvement in knowledge retention and prevention of skill loss while eliminating the risk of harm to patients. Aim A novel perioperative pain management simulation course was designed and implemented in the East of England to equip junior anesthesia trainees with the knowledge, skills, and confidence to manage perioperative pain and the associated critical incidents. Methods A multidisciplinary team (MDT) was involved in the course design. The faculty consisted of anesthesia consultants, trainees, pain nurses, and simulation technicians. The course ran twice over a six-month period both locally and regionally. A blended learning approach was adopted where 17 trainees attended PowerPoint presentations providing an overview of basic pain theories, perioperative pain management, regional anesthesia, and labor analgesia. Trainees then underwent telecasted simulation training using replicated patient notes, imaging, blood gas analysis, and a high-fidelity SimMan®. A debriefing period followed each scenario using Pendleton's model. An anonymized questionnaire was completed by all trainees before and after the course to assess improvement in their knowledge and confidence levels across four domains covering the management of perioperative pain. Results All 17 trainees completed the questionnaire; therefore, the entire dataset was analyzed. The pre-course questionnaire showed that using a scale of zero to 10, the vast majority of trainees reported low levels of confidence (<6/10) in the management of chronic pain during the perioperative period (82%), intraoperative pain management (76%), regional anesthesia (88%), and labor analgesia (65%). Following the simulation training, the results showed an overwhelmingly positive improvement in all 17 trainees' knowledge and confidence across all four tested domains. All 17 trainees (100%) also showed an improvement in their understanding of local pain protocols. The subjective feedback was positive, highlighting the overall usefulness of the course and that the tailored complexity of each simulation scenario was appropriate to each candidate's prior level of experience. Trainees also reported feeling more confident in starting their anesthesia on-calls. Conclusion This novel simulation course is the first of its kind in pain management. It has shown great improvements in trainee confidence in managing perioperative pain and the associated critical incidents. Subjective feedback has also been positively reassuring. Its inclusion into the East of England anesthesia training program and national training curriculum would greatly enhance trainee's knowledge and experience in pain management in the perioperative setting.

Development and validation wise assessment of genotype guided warfarin dosing algorithm in Indian population.

OBJECTIVES: A study was conducted to develop and validate the warfarin pharmacogenetic dose optimization algorithm considering the clinical pharmacogenetic implementation consortium (CPIC) recommendations for the Asian ethnicity population. METHODS: The present prospective observational study recruited warfarin-receiving patients. We collected a three ml blood sample for VKORC1, CYP2C9*2, CYP2C9*3, and CYP4F2 polymorphism assessment during the follow-up visits. Clinical history, sociodemographic and warfarin dose details were noted. RESULTS: The study recruited 300 patients (250 in derivation and 50 in validation timed cohort) receiving warfarin therapy. The baseline characteristics were similar in both cohorts. BMI, presence of comorbidity, VKORC1, CYP2C9*2, and CYP2C9*3 were identified as covariates significantly affecting the warfarin weekly maintenance dose (p<0.001 for all) and the same were included in warfarin pharmacogenetic dose optimization algorithm building. The algorithm built-in the present study showed a good correlation with Gage (r=0.57, p<0.0001), and IWPC (r=0.51, p<0.0001) algorithms, widely accepted in western side of the globe. The receiver operating characteristic curve analysis showed a sensitivity of 73 %, a positive predictive value of 96 %, and a specificity of 89 %. The algorithm correctly identified the validation cohort's warfarin-sensitive, intermediate reacting, and resistant patient populations. CONCLUSIONS: Validation and comparisons of the warfarin pharmacogenetic dose optimization algorithm have made it ready for the clinical trial assessment.

[Efficacité du tirofiban intracoronaire avant pose d'un stent suivi d'une perfusion dans une charge de thrombus importante prouvée par angiographie : une étude randomisée]. / Efficacy of pre stenting intracoronary tirofiban followed by infusion in angiographically proven large thrombus burden : A randomized controlled study.

BACKGROUND: The presence of angiographic thrombus is associated with poor outcomes in contemporary cardiology practice. Percutaneous coronary intervention (PCI) in such lesions is associated with slow flow and no-reflow phenomenon which translate into poor clinical outcomes. METHODS: This was a single-centre, prospective, open-label, randomized controlled study with 50 patients each in intervention group and control group. Patients with angiographically proven large thrombus burden were recruited. In the intervention group, patients were given loading dose of intracoronary tirofiban (25 mcg/kg infused over 5 minutes) followed by prolonged infusion of tirofiban (0.15 mcg/kg/min for 12-18 hours) followed by PCI after 48-72 hours interval. In control group patients were taken up directly for PCI during the index procedure. Outcomes were assessed angiographically and in terms of clinical endpoints. RESULTS: The primary composite-endpoint of recurrent angina, myocardial infarction, cardiovascular death, target lesion revascularization and unscheduled CABG was significantly lower in the intervention arm compared to control arm (4% vs 16%, p = 0.04). Amongst the secondary endpoints, a statistically significant 30-day increase in ejection fraction from baseline was observed in the intervention group compared to the control group (1.6 ± 1.3 vs 0.2 ± 0.4, p = 0.0001). Overall mortality was similar in the two groups (4% vs 8%, p = 0.39). The primary safety endpoint of major bleeding was also similar in the 2 groups (2% vs 0%, p = 0.31). CONCLUSIONS: Tirofiban use prior to PCI in high thrombus burden was associated with improved clinical and angiographic endpoints with similar adverse events compared to controls.

Alleviating Work Exhaustion, Improving Professional Fulfillment, and Influencing Positivity Among Healthcare Professionals During COVID-19: A Study on Sudarshan Kriya Yoga.

Demanding work-life and excessive workload, the conflict between professional and personal lives, problems with patients and those related to the occurrence of death and high risk for their own life are a few factors causing burnout, disengagement, and dissatisfaction in the professional lives of healthcare professionals (HCPs). The situation worsened during the COVID-19 pandemic. It is of utmost importance to find effective solutions to mitigate the stress and anxiety adversely affecting the mental well-being and professional lives of HCPs. This study was designed to examine the efficacy of Sudarshan Kriya Yoga (SKY) for alleviating work exhaustion, improving Professional Fulfillment, and influencing positivity among HCPs during COVID-19. In a comparative observation before the intervention (Pre), after the intervention (Post), and 30 days after the intervention (Day 30) in the Experimental Group (29 physicians) and Control Group (27 physicians), it was found that immediately after SKY, HCPs experienced a significant improvement in Professional Fulfillment (p = 0.009), work exhaustion (0.008), positive affect (p = 0.02), and negative affect (p < 0.001) compared to the Control Group. The effect of SKY continued until Day 30 for Professional Fulfillment and had positive and negative effects. Findings suggest that SKY elevated Professional Fulfillment among HCPs during the COVID-19 pandemic and reduced their work exhaustion and the negative effect on their mental health. SKY can aid HCPs in maintaining their well-being when faced with unprecedented challenges.

Evaluation of Asymptomatic Carotid Artery Stenosis Prior to Coronary Artery Bypass Grafting - A Prospective Observational Study in North Indian Population.

Background: Carotid artery stenosis (CAS) is an established risk factor for peri-operative neurological complications in patients following coronary artery bypass grafting (CABG). However, routine pre-surgical screening for CAS is still a matter of debate. This study was conducted to study the prevalence of asymptomatic carotid artery disease in patients undergoing CABG and to determine the predictors of significant carotid stenosis in them. Methods: In this prospective observational study, 112 patients, who were planned for CABG, were enrolled, and their demographic details, risk factor profile, and coronary angiogram parameters were analyzed. Results: Carotid stenosis was observed in 75.0% of the study population with 11.6% having unilateral and 63.4% having bilateral carotid stenosis. A total of 56.2% of the patients had mild, 14.3% had moderate, and 4.5% had severe carotid stenosis. The presence of significant carotid stenosis showed a correlation with chronic stable angina (P = 0.009), significant left main (LM) disease (P = 0.001), chronic total occlusion (P = 0.043), and coronary vessel calcification (P = 0.004). Multivariate analysis of all the predictor variables in a regression model showed that significant LM disease (Odds ratio (OR):6.5, P = 0.002) and coronary artery calcification (OR: 4.3, P = 0.024) were the only independent predictors of significant CAS in the study population. Conclusion: The presence of significant carotid vessel stenosis in patients undergoing CABG in the Indian population has a stronger association with the chronicity of the coronary artery disease rather than the coronary atheroma load (as determined by the modified Gensini score). The presence of significant LM disease and coronary artery calcification may be useful in detecting high-risk patients for significant CAS during the pre-surgical workup.