International Normalized Ratio Testing Research Articles

The Historical Origins of Modern INR Targets

Prothrombin Time (PT) and its derivative International Normalized Ratio (INR) are frequently ordered to assess the coagulation system. Plasma transfusion to treat incidentally abnormal PT/INR is a common practice with low biological plausibility and without credible evidence, yet INR targets appear in major clinical guidelines and account for the majority of plasma use at many institutions. In this article, we review the historical origins of INR targets. We recount historical milestones in the development of the PT, discovery of Vitamin K Antagonists (VKA), motivation for INR standardization, and justification for INR targets in patients receiving VKA therapy. Next, we summarize evidence for INR testing to assess bleeding risk in patients not on VKA therapy, and plasma transfusion for treating mildly abnormal INR to prevent bleeding in these patients. We conclude with a discussion of the parallels in misunderstanding of historic PT, and present-day INR testing, with lessons from the past which might help rationalize plasma transfusion in the future.

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

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). 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. 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. 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. 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.

Applying a Computer-based Warfarin Management System at a Large Tertiary Cardiovascular Center in Iran.

Regarding adjustments to warfarin dosage, numerous studies have shown that computerized methods are superior to those based on personal experience. To report the efficacy of a computer-based warfarin management system (WMS) in the Iranian population. By utilizing the existing dosing algorithms and obtaining expert opinions, we developed a computer-based WMS at a large tertiary cardiovascular center. The time in therapeutic range (TTR) and the number of international normalized ratio (INR) tests of clinic patients were compared before and after the implementation of WMS. Overall, 803 patients with 5407 INR tests were included in the before phase and 679 patients with 4189 INR tests in the after phase. The mean TTR was 57.3% before and 59% after WMS implementation (mean difference, 1.64, 95% CI: -1.12 to 4.40). In the before phase, the mean number of INR tests was 6.7, which dropped to 6.1 tests in the after phase (mean difference, -0.61, 95% CI: -0.97 to -0.24). Only 54.5% of the warfarin dosing prescriptions were consistent with the dosing recommendations of the WMS, and adherence to the WMS was poorest in the highest INR target range. For the first time in Iran, we demonstrated that a computerized system was as effective as a traditional experience-based method to monitor INR in VKA-anticoagulated patients. Furthermore, it could reduce both the number of INR tests and that of visits.

Mechanical valve replacement for patients with rheumatic heart disease: the reality of INR control in Africa and beyond.

The majority of patients requiring heart valve replacement in low- to middle-income countries (LMICs) need it for rheumatic heart disease (RHD). While the young age of such patients largely prescribes replacement with mechanical prostheses, reliable anticoagulation management is often unattainable under the prevailing socioeconomic circumstances. Cases of patients with clotted valves presenting for emergency surgery as a consequence of poor adherence to anticoagulation control are frequent. The operative mortality rates of reoperations for thrombosed mechanical valves are several times higher than those for tissue valves, and long-term results are also disappointing. Under-anticoagulation prevails in these regions that has clearly been linked to poor international normalised ratio (INR) monitoring. In industrialised countries, safe anticoagulation is defined as >60%-70% of the time in the therapeutic range (TTR). In LMICs, the TTR has been found to be in the range of twenty to forty percent. In this study, we analysed >20,000 INR test results of 552 consecutive patients receiving a mechanical valve for RHD. Only 27% of these test results were in the therapeutic range, with the vast majority (61%) being sub-therapeutic. Interestingly, the post-operative frequency of INR tests of one every 3-4 weeks in year 1 had dropped to less than 1 per year by year 7. LMICs need to use clinical judgement and assess the probability of insufficient INR monitoring prior to uncritically applying Western guidelines predominantly based on chronological age. The process of identification of high-risk subgroups in terms of non-adherence to anticoagulation control should take into account both the adherence history of >50% of patients with RHD who were in chronic atrial fibrillation prior to surgery as well as geographic and socioeconomic circumstances.

The quality of pharmacist-led community warfarin management across 2 provinces in Canada: A cross-sectional observational study.

Guidelines for anticoagulation management services recommend personnel be specially trained in warfarin management and suggest using tools such as decision-support software. To date, there have been no Canadian studies documenting the quality of warfarin management using a similar guideline recommended approach. A cross-sectional, retrospective observational study was conducted to measure the quality of pharmacist-led warfarin management using point-of-care international normalized ratio (INR) testing and decision-support software in various ambulatory settings in Canada. Settings included 4 family health teams in Ontario and 40 community pharmacies across Nova Scotia. Quality was measured using time in therapeutic range (TTR) and was reported in 3 manners: mean TTR, median TTR and time-weighted mean TTR. The primary outcome included 963 patients. The combined mean and median TTR for the 2019 Ontario family health teams and Nova Scotia pharmacies was 74.2% and 77.3% (interquartile range 64%-87.9%), respectively. The time-weighted mean TTR was 76.3%. To the best of our knowledge, the TTR achieved by this model of care is the highest reported in Canadian general practice. Since Thrombosis Canada defines good-quality warfarin management as a TTR of 60% or greater, and many studies have reported an association between higher TTR values and lower rates of thrombosis and hemorrhage, this model of care may have significant benefits for patients. This study demonstrates the high quality of anticoagulation management provided by specially trained pharmacists using point-of-care INR testing and decision-support software. These results support expanded access to this service for all Canadians. Can Pharm J (Ott) 2024;157:xx-xx.

Antiphospholipid Antibody Syndrome (APS) Pediatric Patient Outcomes on Warfarin

Background: Antiphospholipid antibody syndrome (APS) is an acquired thromboembolism (TE) risk factor and places patients at very high risk of recurrent TE. APS diagnosis requires venous (deep vein thrombosis (DVT) or pulmonary embolism (PE)) or arterial thromboembolism and laboratory diagnosis including persistently positive lupus anticoagulant (LA) or elevated anticardiolipin (aCL) and/or beta 2 glycoprotein I (B2GPI) antibodies tested 12 weeks apart. Vitamin K antagonist (warfarin) is the standard of care anticoagulant to reduce risk of TE recurrence in APS patients. Warfarin is dosed based on the International Normalized Ratio (INR) with established therapeutic ranges for optimal efficacy and safety. The reported time in therapeutic range (TTR) varies greatly across specialties with an average TTR of 50-55%. However, it is often difficult to maintain target INR in APS. Furthermore, there is limited data evaluating pediatric patients with APS and their TTR on warfarin and outcomes. Aim: To evaluate the relationship of APS status to TTR and outcomes of patients &amp;lt; 21 years of age with APS who are on warfarin anticoagulation. Methods: This was a single center analysis of APS patients between July 2019 and May 2022 who were enrolled in a multi-center prospective study of pediatric patients on warfarin therapy, eKITE (electronic KidClot Thrombophilia Education). The study included an online learning series regarding warfarin management. Home INR meters and test strips were provided to all patients to perform INR testing. INR values were reported by patients and recorded. Demographic and clinical data was extracted from the electronic medical record, target INR was set by the treating provider, and TTR was calculated as a surrogate for safe, effective warfarin management. Results: Nine patients (n=9) with APS were identified for this analysis, mean age 16.7 years (range 12-19 years). Demographic and laboratory findings are summarized in Table 1. Most patients had secondary APS due to systemic lupus erythematous (SLE) 78% (n=7) and 22% (n=2) had other primary diagnoses. APS antibody status included single positive in 67% (n=6), double positive in 22% (n=2), and triple positive in 11% (n=1). More specifically, APS criteria were met by persistently elevated LA in 78% (n=7), aCL IgM in 22% (n=2) with overall mean aCL IgM of 34.4 MPL^ (range 9.9-127.9), B2GPI IgG in 11% (n=1) with overall mean B2GPI IgG SGU* of 13.1 (range 0.9-63.3), and B2GPI IgM in 22% (n=2) with overall B2GPI IgM mean of 32.5 SGU (range 3.3-190.9). At time of presentation 67% (n=6) of patients had DVT, 44% (n=4) had PE, 11% (n=1) had arterial TE, and 22% (n=2) presented with DVT &amp; PE. Mean TTR for all patients was 56%. TTR for single positive APS was 66%, double positive APS 39%, and triple positive APS 33%. TTR for secondary APS (SLE) and non-SLE diagnoses was 53% and 68% respectively. Mean dose changes were 11 (range 0-48) with one single positive LA patient requiring 48 dose changes, and two patients with single positive LA not requiring any dose changes. Two patients (22%) developed recurrent clot. One triple positive APS patient developed two DVTs and one non-SLE patient developed recurrent arterial TE. Three patients (33%) had minor bleeding events including mild epistaxis and hematemesis not requiring intervention. One patient (11%) had a major bleeding event, hemoperitoneum from pseudoaneurysm extravasation, while resuming warfarin during post-operative period, and required takeback surgery with sub-therapeutic INR 1.5 at the time of event. Conclusion: The mean TTR for pediatric patients with APS is similar to what is reported in other populations despite the challenge of managing warfarin in this group where the INR may be affected by primary disease modifying medications or disease flares. The risk of recurrent TE remains high in APS patients. Home INR monitors are a safe and effective strategy in managing warfarin anticoagulation in APS patients, reducing time and laboratory monitoring burden for frequent dose changes, which ultimately improves quality of life.Optimizing TTR is important to decrease risk of recurrent TE or bleeding in these high risk APS patients.

Assessing Pre-Operative Bleeding Risk Using INR/aPTT: A Systematic Review

Background: The prothrombin time (PT) and activated partial thromboplastin time (aPTT) are often considered “routine” tests to assess perioperative bleeding risk. The PT and its mathematical derivative, the international normalized ratio (INR), allows for monitoring of vitamin K antagonist therapy. The aPTT was developed to screen for hemophilia A and B in family members of affected individuals. Both tests perform extremely poorly as screening tests for inherited bleeding disorders. Therefore, their utility in predicting peri-operative bleeding has been questioned. Objective: The primary objective was to examine the relationship between pre-operative coagulation results and peri-operative bleeding in pediatric and adult patients undergoing elective surgery in the published literature. Methods: A systematic review was conducted using a comprehensive search of MEDLINE, EMBASE, and grey literature between 1970 to July 2022. Randomized trials and observational studies that assessed the predictive accuracy of pre-procedural INR and aPTT test results for perioperative bleeding we deemed eligible for inclusion. Two reviewers independently screened and performed data extraction. A third reviewer adjudicated decisions when consensus could not be reached. Outcomes included any bleeding events in the postoperative period. The study protocol was registered online on PROSPERO (CRD42023385588). Results: 5700 articles were screened, and 79 studies were included in the systematic review. Major surgery (N=53) types included cardiac (n=14), neurosurgery (n=11), liver transplantation or resection (n=16) and general surgery (n=12). Minor surgeries included otolaryngology procedures (n=14) and other minor surgeries/procedures (e.g. pediatric spinal anesthesia, gastrointestinal endoscopy and related procedures, thoracocentesis, hernia repair, circumcision) (n=12). Bleeding complications were rare for minor surgeries and only one out of 26 studies found an association between coagulation test results and bleeding. Thirty-two out of 37 (86.5%) papers exploring other major surgeries found no association or reported a sensitivity under 50% between coagulation test results and bleeding (see Figure 1). Seven out of 16 studies (43.8%) on liver transplantation or resection found an association between the INR and bleeding (see Figure 2). None of the studies evaluated were randomized and none of the observational studies had outcomes adjudicated in blinded fashion. Conclusion: Our findings confirm that bleeding events are rare in minor surgeries, and that coagulation testing is of limited utility in this setting. Similar conclusions can be drawn for patients undergoing major surgeries, with one exception - in patients with liver disease or liver cancer - as there may be an association between bleeding and the pre-operative INR with further studies required. Despite the absence of evidence supporting the practice, routine pre-operative coagulation testing remains prevalent, highlighting the need for targeted knowledge translation.

Position Statement on In-hospital/Clinic Point-of-care Coagulation Testing for Anticoagulation Monitoring in Saudi Arabia.

Hospital overload is a persistent occurrence in daily practice. Interventions such as point-of-care testing (POCT) are needed to alleviate the pressure faced by healthcare providers and administrators. An invited panel of experts from Saudi Arabia was formed under the auspices of the Saudi Heart Association in order to discuss local treatment gaps in the management of patients receiving anticoagulation therapy. This was done in a series of meetings, which resulted in the development of official recommendations for the implementation of POCT for anticoagulation monitoring in the country. Recommendations were based on a comprehensive literature review and international guidelines taking into consideration local clinical practice, clinical gaps, and treatment/testing availabilities. Vitamin K antagonist (VKA)-based anticoagulation therapy requires routine monitoring. POCT is a promising model of care for the monitoring of International Normalized Ratio (INR) in patients receiving oral anticoagulation in terms efficacy, safety and convenience. The availability of POC INR testing should not replace the use of standard laboratory anticoagulation monitoring. However, there are several indications for implementing POCTINR monitoring that was agreed upon by the expert panel. POCT for anticoagulation monitoring should primarily be used in the warfarin (or other VKA) monitoring clinic in order to ensure treatment efficiency, cost-effectiveness of care, patient satisfaction, and quality of life improvement. The expert panel detailed the requirements for the establishment of a warfarin (or other VKA) monitoring clinic in terms of organization, safety, quality control, and other logistic and technical considerations. The limitations of POCT should be recognized and recommendations on best practices should be strictly followed. Core laboratory confirmation should be sought for patients with higher INR results (>4.7) on POCT. Proper training, quality control, and regulatory oversight are also critical for preserving the accuracy and reliability of POCT results. POCT enables more rapid clinical decision-making in the process of diagnosis (rule-in or rule-out), treatment choice and monitoring, and prognosis, as well as operational decision-making and resource utilization. POCT thus can fulfill an important role in clinical practice, particularly for patients receiving VKAs.

Identifying and understanding the care pathway of patients with atrial fibrillation in Brazil and the impact of the COVID-19 pandemic: A mixed-methods study.

Atrial fibrillation (AF) is a major risk factor for stroke. To enable improvements to AF diagnosis and follow-up care, understanding current patient pathways and barriers to optimal care are essential. We investigated the patient care pathways and their drivers, and the impact of the COVID-19 pandemic on patient pathways in a middle-income country setting, Brazil. This mixed-methods study in São Paulo, included adults (≥18y) with AF from 13 primary/secondary healthcare facilities. Surveys using baseline, follow-up (administered ≥two months after baseline) and COVID-19 questionnaires (quantitative), and three focus group discussions (FGDs) were conducted. Minimum sample size for the quantitative component was 236 and we aimed to reach saturation with at least three FGDs for the qualitative component. Descriptive statistics were used for quantitative data and a content analysis was used for qualitative data to identify themes related to AF diagnosis and follow-up care. 267 participants completed the baseline questionnaire: 25% were diagnosed in primary care, 65% in an emergency or inpatient department. At follow-up (n = 259), 31% visited more than one facility for AF care, and 7% had no follow-up. Intervals between international normalised ratio (INR) tests were increased during the pandemic, and the number of healthcare visits and availability of medication were reduced. Seventeen patients participated in three FGDs and revealed that AF diagnosis often occurred following a medical emergency and patients often delay care-seeking due to misconceptions about AF symptoms. Long waiting times, doctor/patient interactions and health system factors, such as doctor availability and the referral system, influence where participants visited for follow-up care. Lack of public awareness and underdeveloped primary healthcare lead to delayed diagnosis, which impacts clinical outcomes and excess patient and healthcare system costs. Health system, care-provider, and pandemic factors disrupt timely and effective continuity of care.

Awareness and Perception of Dentists in Kuwait Regarding the Dental Management of Patients on Oral Antithrombotic Medications

Abstract Objective It is crucial that dentists are up to date on the most recent recommendations for managing patients on oral antithrombotic medications (OAMs). The current study aims to analyze dental practitioners' knowledge and practice of perioperative treatment of patients on OAM in Kuwait. Materials and Methods The study was performed among dentists in Kuwait utilizing a structured questionnaire. The questionnaire tested their knowledge about common OAMs and their indications, the bleeding risk of specific dental procedures, as well as the dangers of stopping antithrombotic therapy. Questions regarding the practice of obtaining relevant blood investigations as well as consultations with health professionals and their current course of management pertaining to specific dental procedures were included. Statistical Analysis The collected data were analyzed by SPSS statistical software for Windows, version 28.0 (Chicago, Illinois, United States). The Student's t-test was used to compare mean percentage knowledge scores. Association between independent variables (predictors) and knowledge was assessed by employing univariate and multivariate logistic regression. A p-value of ≤ 0.05 was considered statistically significant. Results A majority of the dentists (60.9%) demonstrated fair knowledge. Gender, practice type, and years of experience were significantly associated with knowledge. Very few dentists knew about direct oral anticoagulants. Eighty-two (33.1%) would rely on international normalized ratio tests done within 72 hours. Sixty-six (26.6%) dentists would interrupt aspirin therapy before extensive dental scaling without a medical consult and 45 (18.1%) would ask the patient to stop warfarin 3 days before extraction of one to three teeth. For patients on aspirin or warfarin, 35.1 and 47.2% of the dentists perceived the postoperative bleeding risk after a simple extraction to be high, and 14.4 and 11.2% of the dentists considered the rethrombosis risk to be low if aspirin and warfarin were interrupted. Conclusion In this study, the dentists demonstrate a lack of knowledge and are not clear regarding practice recommendations. Every dental care provider therefore needs to update their knowledge with the latest antithrombotic medications and their indications, when to order blood investigations and medical consult, bleeding risk associated with each dental procedure, interruption of therapy, and risk of bleeding versus rethrombosis risk.

A "Bundle of Care" to Improve Anticoagulation Control in Patients Receiving Warfarin in Uganda and South Africa: Protocol for an Implementation Study.

The quality of warfarin anticoagulation among Sub-Saharan African patients is suboptimal. This is due to several factors, including a lack of standardized dosing algorithms, difficulty in providing timely international normalized ratio (INR) results, a lack of patient feedback on their experiences with treatment, a lack of education on adherence, and inadequate knowledge and training of health care workers. Low quality of warfarin anticoagulation, expressed as time in therapeutic range (TTR), is associated with higher adverse event rates, including bleeding and thrombosis, and ultimately, increased morbidity and mortality. Processes and interventions that improve this situation are urgently needed. This study aims to evaluate the implementation of the "warfarin bundle," a package of interventions to improve the quality of anticoagulation and thereby clinical outcomes. The primary outcome for this study is TTR over the initial 3 months of warfarin therapy. Patients aged 18 years or older who are newly initiated on warfarin for venous thromboembolism, atrial fibrillation, or valvular heart disease will be enrolled and followed up for 3 months at clinics in Cape Town, South Africa, and Kampala, Uganda, where the warfarin bundle is implemented. A retrospective review of the clinical records of patients on warfarin treatment before implementation (controls) will be used for comparison. This study uses a mixed methods approach of the implementation of patient- and process-centered activities to improve the quality of anticoagulation. Patient-centered activities include the use of clinical dosing algorithms, adherence support, and root cause analysis, whereas process-centered activities include point-of-care INR testing, staff training, and patient education and training. We will assess the impact of these interventions by comparing the TTR and safety outcomes across the 2 groups, as well as the cost-effectiveness and acceptability of the package. We started recruitment in June 2021 and stopped in August 2022, having recruited 167 participants. We obtained ethics approval from the University of Cape Town Faculty of Health Sciences Human Research Ethics Committee, the Provincial Health Research Committees in South Africa, the Joint Clinical Research Centre Institutional Review Board, Kampala, and the University of Liverpool Research Ethics Committee. As of February 2023, data cleaning and formal analysis are underway. We expect to publish the full results by December 2023. We anticipate that the "bundle of care," which includes a clinical algorithm to guide individualized dosing of warfarin, will improve INR control and TTR of patients in Uganda and South Africa. We will use these findings to design a larger, multisite clinical trial across several Sub-Saharan African countries. DERR1-10.2196/46710.

Low-Dose vs Standard Warfarin After Mechanical Mitral Valve Replacement: A Randomized Trial

BackgroundCurrent guidelines recommend a target international normalized ratio (INR) range of 2.5 to 3.5 in patients with a mechanical mitral prosthesis. The Prospective Randomized On-X Anticoagulation Clinical Trial (PROACT) Mitral randomized controlled noninferiority trial assessed safety and efficacy of warfarin at doses lower than currently recommended in patients with an On-X (Artivion, Inc) mechanical mitral valve. MethodsAfter On-X mechanical mitral valve replacement, followed by at least 3 months of standard anticoagulation, 401 patients at 44 North American centers were randomized to low-dose warfarin (target INR, 2.0-2.5) or standard-dose warfarin (target INR, 2.5-3.5). All patients were prescribed aspirin, 81 mg daily, and encouraged to use home INR testing. The primary end point was the sum of the linearized rates of thromboembolism, valve thrombosis, and bleeding events. The design was based on an expected 7.3% event rate and 1.5% noninferiority margin. ResultsMean patient follow-up was 4.1 years. Mean INR was 2.47 and 2.92 (P <.001) in the low-dose and standard-dose warfarin groups, respectively. Primary end point rates were 11.9% per patient-year in the low-dose group and 12.0% per patient-year in the standard-dose group (difference, −0.07%; 95% CI, −3.40% to 3.26%). The CI >1.5%, thus noninferiority was not achieved. Rates (percentage per patient-year) of the individual components of the primary end point were 2.3% vs 2.5% for thromboembolism, 0.5% vs 0.5% for valve thrombosis, and 9.13% vs 9.04% for bleeding. ConclusionsCompared with standard-dose warfarin, low-dose warfarin did not achieve noninferiority for the composite primary end point. (PROACT Clinicaltrials.gov number, NCT00291525).

Anesthesia in Low-Resourced Settings. Near Misses and Lessons Learned

Physician training requires the highest intelligence quotient of all professions to assimilate the vast amounts of complex knowledge required. The most critical decision-making medical specialty is anesthesiology, which requires much art of practicing medicine. That art is acquired via experience from years of medical practice.Clinical experience can also be gleaned from studying these 90 case reports in Brock-Utne’s book, Anesthesia in Low-Resourced Settings. These cases are from third-world countries, but any of these situations could also occur in American Ivy League University hospitals.Limited hospital night staff can be overwhelmed by a sudden influx of gunshot trauma cases and force one to care for emergency patients outside one’s regular working expertise. Another time one could be working remote from the hospital’s fully equipped main operating room complex in a small-case specialty single operating room. Then a crisis arises needing additional drugs and devices taking 20 min to be transported to that remote venue. Innovative temporary medical measures will be required. Power failures can occur without backup electricity. Suction systems can fail. Gas delivery can fail. An anesthesia machine can fail. A device may develop a problem not foreseen by its designers. Low-resourced settings can occur in a flash moment anywhere in the world, even in rich countries.This book’s cases challenge anesthesiologists’ training, intellect, and resourcefulness. This book is rich in wisdom. Before doing “mission medical work,” all anesthesiologists should read this book. There is a summarizing list of pearls of wisdom in the book. Reading that list may save one patient’s life in your career. I read the book in 2 days. Reading this book should be mandatory for anesthesia trainees nearing graduation. Anesthesiologists at any career point will read lessons echoing some anesthesia mishap they have experienced and wish they had read this book earlier in their careers.The deficient resources can be:This is the most valuable case in the book.A 29-yr-old woman fell off a moving train. When she arrived at a midsize Somali hospital, she was hypotensive, in pain, and tachycardic. She had fractures of the T10 vertebra, right humerus, the pelvis, and five right-side ribs with a right-side hemopneumothorax. A large-bore right subclavian multi-lumen access cordis venous cannula and an intercostal chest drain were immediately inserted. The pleural cavity drained 1,500 ml of blood. Additional peripheral venous access catheters were inserted.The anesthesiologist administered 4 units of blood. The blood pressure improved, but the centralized venous pressure measured via the subclavian cannula stayed at zero. Intercostal blood continued to drain and worried the thoracic surgeon, who urgently wanted to operate to stop the bleeding. The international normalized ratio (INR) test for clotting, of a sample withdrawn for the right-subclavian vein cannula, measured 2.3 (N = less than 1.1 when not on warfarin).The anesthesiologist worried about the darkness of the ongoing draining chest blood and the inexplicable high INR test result. The thoracotomy found no active bleeding source. A repeat INR test sample drawn from the femoral vein revealed a normal INR test of 1.1. The right subclavian cannula was intrapleural, and the persistent draining dark blood was subclavian catheter transfused blood. The first INR test had been done on the trauma intrapleural blood.A patient underwent general anesthesia with intubation using a wire-reinforced flexible endotracheal tube. On awakening, the patient bit firmly on the tube and occluded it, bending the reinforcing wire. After the biting relaxed, the tube was still entirely blocked from the crimping of the reinforcing wire. The patient’s chest started to heave as he struggled to breathe past the sustained endotracheal tube obstruction.Fully deflate the endotracheal tube cuff. That frees up about 40% of the cross-sectional area of the trachea for the patient to breathe past the outside of the endotracheal tube.Soon this patient woke up and was safely extubated. The problem is preventable by initially placing a bite-block or a Guedel airway in the mouth beside the endotracheal tube.After reading this book, many will recall many forgotten pearls of wisdom. Dr. Brock-Utne is a rare and superbly trained physician anesthesiologist who has worked extensively in third-world circumstances. He is an Emeritus full clinical professor from Stanford University in California. He is the epitome of a clinically expert scientist. His book is recommended to read.

Interference in point-of-care international normalized ratio monitoring in patients with lupus anticoagulant is correlated with anti–β2-glycoprotein I antibody titers

BackgroundPatients with antiphospholipid syndrome (APS) receive anticoagulant therapy with vitamin K antagonists (VKAs) to prevent recurrent thrombosis. VKA treatment requires strict monitoring with an international normalized ratio (INR). It is known that lupus anticoagulants (LAs) can lead to elevated INR results with point-of-care-testing (POCT) devices, which could result in inadequate adaptation of anticoagulant therapy. ObjectiveTo determine discrepancies between POCT-INR and laboratory-INR in patients who are LA-positive on VKA therapy. MethodsPaired INR testing was performed with 1 POCT device (CoaguChek XS) and 2 laboratory assays (Owren and Quick method) in 33 patients with LA-positive APS on VKA in a single-center cross-sectional study. Patients were tested for anti–β2-glycoprotein I, anticardiolipin, and antiphosphatidylserine/prothrombin immunoglobulin (Ig) G and IgM antibodies. Agreement between assays was evaluated with Spearman’s correlation, Lin’s correlation coefficient, and Bland–Altman plots. Agreement limits were considered satisfactory if differences were ≤20% as determined by the Clinical and Laboratory Standards Institute. ResultsWe found poor agreement between POCT-INR and laboratory-INR based on Lin’s concordance correlation coefficient (ρc) of 0.42 (95% CI, 0.26-0.55) between POCT-INR and Owren-INR, a ρc of 0.64 (95% CI, 0.47-0.76) between POCT-INR and Quick-INR, and a ρc of 0.77 (95% CI, 0.64-0.85) between Quick-INR and Owren-INR. High anti-β2-glycoprotein I IgG antibody titers correlated with INR disagreement between POCT-INR and laboratory-INR. ConclusionThere is a disagreement between INR values measured with the CoaguChek XS and laboratory-INR in a proportion of patients with LA. Consequently, laboratory-INR monitoring should be preferred over POCT-INR monitoring in patients with LA-positive APS, especially in patients with high anti-β2-glycoprotein IgG antibody titers.

Effect of Mailing Educational Material to Patients With Atrial Fibrillation and Their Clinicians on Use of Oral Anticoagulants

Only about half of patients with atrial fibrillation (AF) who are at increased risk for stroke are treated with an oral anticoagulant (OAC), despite guideline recommendations for their use. Educating patients with AF about prevention of stroke with OACs may enable them as agents of change to initiate OAC treatment. To determine whether an educational intervention directed to patients and their clinicians stimulates the use of OACs in patients with AF who are not receiving OACs. The Implementation of a Randomized Controlled Trial to Improve Treatment With Oral Anticoagulants in Patients With Atrial Fibrillation (IMPACT-AFib) trial was a prospective, multicenter, open-label, pragmatic randomized clinical trial conducted from September 25, 2017, to May 1, 2019, embedded in health plans that participate in the US Food and Drug Administration's Sentinel System. It used the distributed database comprising health plan members to identify eligible patients, their clinicians, and outcomes. IMPACT-AFib enrolled patients with AF, a CHA2DS2-VASc (cardiac failure or dysfunction, hypertension, age 65-74 [1 point] or ≥75 years [2 points], diabetes, and stroke, transient ischemic attack or thromboembolism [2 points]-vascular disease, and sex category [female]) score of 2 or more, no evidence of OAC prescription dispensing in the preceding 12 months, and no hospitalization-related bleeding event within the prior 6 months. Randomization to a single mailing of patient and/or clinician educational materials vs control. Analysis was performed on a modified intention-to-treat basis. The primary end point was the proportion of patients with at least 1 OAC prescription dispensed or at least 4 international normalized ratio test results within 1 year of the intervention. Among 47 333 patients, there were 24 909 men (52.6%), the mean (SD) age was 77.9 (9.7) years, mean (SD) CHA2DS2-VASc score was 4.5 (1.7), 22 404 patients (47.3%) had an ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) bleeding risk score of 5 or more, and 8890 patients (18.8%) had a history of hospitalization for bleeding. There were 2328 of 23 546 patients (9.9%) in the intervention group with initiation of OAC at 1 year compared with 2330 of 23 787 patients (9.8%) in the control group (adjusted OR, 1.01 [95% CI, 0.95-1.07]; P = .79). Among a large population with AF with a guideline indication for OACs for stroke prevention who were randomized to a mailed educational intervention or to usual care, there was no clinically meaningful, numerical, or statistically significant difference in rates of OAC initiation. More-intensive interventions are needed to try and address the public health issue of underuse of anticoagulation for stroke prevention among patients with AF. ClinicalTrials.gov Identifier: NCT03259373.

The Effect of Switching From Warfarin to Novel Oral Anticoagulants on Patients' Satisfaction and the Travel Burden in a Rural Setting.

Introduction: New oral anticoagulants (NOACs) have shown comparable efficacy to warfarin in the treatment of patients with venous thromboembolism (VTE), stroke and atrial fibrillation (AF). Various studies on quality-of-life improvement in rural patients following the switch from vitamin K antagonists (VKAs) to NOACs have produced inconclusive results. The aim of the study is to assess the impact of switching from warfarin to NOACs on remotely living patients’ quality of life and the burden of travel.Methods: A questionnaire was provided to the patient by their pharmacists. The questionnaire assessed their travel burden and their level of satisfaction with their treatment.Results: The switch from warfarin to NOACs reduced the burden of travel in 75% of patients. A total of 66% of patients were hesitant about the efficacy of their warfarin treatment. The inconvenience caused due to international normalized ratio (INR) monitoring was reduced in 83% of patients; 70% and 72% of patients strongly agreed that NOACs improved their adherence and treatment satisfaction, respectively. The average number of patients’ travels for INR testing for warfarin monitoring was 7.27 trips/year. The average number of trips made by the patient to obtain their NOACs and warfarin scripts was 2.1 and 4.81 trips/year, respectively.Conclusion: The switch from warfarin, a VKA, to NOACs in patients who live in remote areas without medical services improved their quality of life, decreased their travel burden, and increased their treatment satisfaction and adherence. Switching to NOACs reduced the number of trips travelled by patients to obtain their anticoagulation scripts and/or to adjust their doses.

Can the preoperative hematologic factors play a role in predicting adult post-tonsillectomy hemorrhage?

OBJECTIVE: This study aimed to assess the preoperative hematologic factors for predicting post-tonsillectomy hemorrhage (PTH). METHODS: In the retrospective study, the records of 44 patients (21 males, 23 females; mean age 30.5±9.4 years; range, 18 to 55 years) who underwent tonsillectomy for chronic or recurrent tonsillar infections were reviewed. Age, sex, coagulation profile [international normalized ratio (INR), activated partial thromboplastin time (aPTT)], complete blood cell count [hematocrit (HTC), neutrophil (NEU) count, lymphocyte (LYMP) count, platelet (PLT) count, mean platelet volume (MPV), red cell distribution width (RDW)] such values have been recorded. Patients were divided into two groups according to the presence of PTH. Group A (8 males, 13 females; mean age 30.5±11.1 years) included patients without PTH and Group B (13 males, 10 females; mean age 30.5±7.8 years) was comprised of patients with PTH. RESULTS: In the evaluation of the coagulation profile, aPTT values were 24.5±1.9 sec in Group A and 26.4±17 sec in Group B (p= 0.017). Median value of INR was similar between the groups (p=0.60). No difference was detected between the groups regarding the following parameters of the complete blood count: HTC (p=0.49), NEU (p=0.17), LYMP (p=0.45), PLT (p=0.71), MPV (p=0.27), and RDW (p=0.29). CONCLUSION: It is important to perform relevant blood tests should in the preoperative period, in addition to INR and aPTT tests. New studies are needed to determine the relationship of MPV and RDW with PTH.

Correlation of prehospital point-of-care international normalized ratio to laboratory-based international normalized ratio in acute traumatic coagulopathy.

Acute traumatic coagulopathy (ATC) is associated with increased mortality and hospital transfusion requirements. Accurate pre-hospital identification of ATC may improve outcomes by expediting care. Unlike clinical scores which may include subjective components, point of care (POC) international normalized ratio (INR) testing provides an objective value which in the non-trauma setting correlates well with laboratory INR (LABINR) results.The objective of this study was to evaluate the accuracy and ROC characteristics of pre-hospital sampled POC INR tests in trauma patients. Blood was drawn in the field for pre-hospital POCINR and comparative LABINR testing. Acute Traumatic Coagulopathy (ATC) was defined as LABINR31.3 and severe ATC LABINR31.5. Of 137 patients included in the analysis, ATC was present in 20 patients (14.6%) and severe ATC in six (4.7%). POCINR estimated LABINR with bias of 0.036 (95%CI: -0.297-0.369). ROC analysis for severe ATC demonstrated an AUC = 0.92 (95%CI: 0.83-1.00). Pre-hospital POCINR correlates well with for LABINR in trauma patients. It has excellent ROC characteristics for diagnosing trauma patients with an INR31.5. II/III.

Micro-mechanical blood clot testing using smartphones

Frequent prothrombin time (PT) and international normalized ratio (INR) testing is critical for millions of people on lifelong anticoagulation with warfarin. Currently, testing is performed in hospital laboratories or with expensive point-of-care devices limiting the ability to test frequently and affordably. We report a proof-of-concept PT/INR testing system that uses the vibration motor and camera on smartphones to track micro-mechanical movements of a copper particle. The smartphone system computed the PT/INR with inter-class correlation coefficients of 0.963 and 0.966, compared to a clinical-grade coagulation analyzer for 140 plasma samples and demonstrated similar results for 80 whole blood samples using a single drop of blood (10 μl). When tested with 79 blood samples with coagulopathic conditions, the smartphone system demonstrated a correlation of 0.974 for both PT/INR. Given the ubiquity of smartphones in the global setting, this proof-of-concept technology may provide affordable and effective PT and INR testing in low-resource environments.

Assessment of Stability of Prothrombin Time, International Normalized Ratio, and Activated Partial Thromboplastin Time Under Different Storage Conditions in Human Plasma.

BackgroundIn this study, we aimed to determine the effects of storage time and temperature on commonly performed coagulation tests such as prothrombin time (PT), international normalized ratio (INR), and activated partial thromboplastin time (APTT) in human plasma.MethodologyWhole blood samples from 100 patients were collected in a 3.2% sodium citrate vacutainer. The blood was centrifuged within two hours of collection at 2,000 g for 10 minutes, and the platelet-poor plasma (PPP) obtained was analyzed for PT, INR, and APTT tests at zero hours (baseline) and repeated at 12 hours, 24 hours, and 36 hours on a fully automated coagulation analyzer at various storage conditions (room temperature, refrigerator, and freezer). The results were categorized into two groups: group 1 comprised results with normal coagulation profile and group 2 comprised results with abnormal coagulation profile. The percentage change of the results from baseline (zero hours) for PT, INR, and APTT tests was also studied. A percentage change of more than ±10% from baseline was considered as a clinically significant change.ResultsIn this study, a total of 95 PPP samples were evaluated. The median age of all patients was 44 years (range: 19-65 years). The male-to-female ratio was 0.9:1. The baseline PT, INR, and APTT values were 12.1 seconds, 1.06, and 26.5 seconds, respectively, in group 1, whereas the baseline PT, INR, and APTT values were 19.1 seconds, 1.80, and 36.0 seconds, respectively, in group 2. In the freezer, the samples were stable for PT, INR, and APTT tests at 12 hours, 24 hours, and 36 hours showing a change of <10% from baseline at all three time-points. In the refrigerator, the samples were stable for PT and INR tests for up to 24 hours showing a change of <10% from baseline. In comparison, the samples for the APTT test were not stable at 12 hours, 24 hours, and 36 hours showing a change of 12.1%, 15.5%, and 17.9%, respectively, from the baseline (zero hours). Finally, at room temperature, the samples deteriorated at 12 hours for all coagulation parameters (PT, INR, and APTT).ConclusionsThe patient plasma samples for PT, INR, and APTT tests could be safely stored for up to 36 hours in the freezer. In the refrigerator, samples for PT and INR tests could be safely stored for up to 24 hours while the samples for APTT deteriorated at 12 hours. All patient samples for PT, INR, and APTT tests deteriorated at 12 hours at room temperature.