Low Therapeutic Range Research Articles

Opioid-free general anesthesia: considerations, techniques, and limitations.

To discuss the role of opioids during general anesthesia and examine their advantages and risks in the context of clinical practice. We define opioid-free anesthesia (OFA) as the absolute avoidance of intraoperative opioids. In most minimally invasive and short-duration procedures, nonopioid analgesics, analgesic adjuvants, and local/regional analgesia can significantly spare the amount of intraoperative opioid needed. OFA should be considered in the context of tailoring to a specific patient and procedure, not as a universal approach. Strategies considered for OFA involve several adjuncts with low therapeutic range, requiring continuous infusions and resources, with potential for delayed recovery or other side effects, including increased short-term and long-term pain. No evidence indicates that OFA leads to decreased long-term opioid-related harms. Complete avoidance of intraoperative opioids remains questionable, as it does not necessarily ensure avoidance of postoperative opioids. Multimodal analgesia including local/regional anesthesia may allow OFA for selected, minimally invasive surgeries, but further research is necessary in surgeries with high postoperative opioid requirements. Until there is definitive evidence regarding procedure and patient-specific combinations as well as the dose and duration of administration of adjunct agents, it is imperative to practice opioid-sparing approach in the intraoperative period.

Formulation development and characterization of Lecarnidipine hydrochloride niosomal transdermal patches

The bioavailability of Lercanidipine Hydrochloride (LCP) is about 44% and half-life of the drug is about 4.6 hours. LCP due to its low therapeutic dose range of 2.5 to 20mg and substantial biotransformation in liver becomes it ideal molecule in development of transdermal therapeutic system. The primary objective of the present research work was to develop Niosomal transdermal patch (NP) of Lecarnidipine. The LCP nanoparticles were prepared by solvent evaporation method and the optimized Nanoparticles formulation has shown 225nm particle size with a polydispersity index (PDI) of 0.120. LCP patches were prepared by incorporating nanoparticles dispersion, using varying concentrations of polymers HPMC E5, HPMC 5cps, HPMC 15cps, Carbopol 734 and Sodium alginate using solvent casting techniques and further optimized by central composite design(CCD) the effect of polymer on the various physico-chemical characteristics and in-vitro drug release studies, ex-vivo skin permeation studies is studied. On the basis of in-vitro drug release and ex-vivo skin permeation studies, the formulation containing (HPMC 15cps and HPMC 5cps) has shown sustained and extended drug release over a period of 24 hrs.
 Keywords: Lecarnidipine; Niosomes; Transdermal patch; Central composite Design, Controlled release; Bioavailability etc.

Abstract 9440: Acs in a Patient With Amegakaryocytic Thrombocytopenia: A Management Dilemma

Introduction: The management of Acute Coronary Syndrome (ACS) in thrombocytopenia is challenging. This abstract highlights the management dilemma of a patient who presented with high-risk ACS and was found to have Amegakaryocytic thrombocytopenia (AMT). Case Presentation: A fifty-five-year-old man with no cardiovascular risk factors was admitted with high-risk ACS with recurrent ischemic ECG changes and high troponin-T. He was found to have a low platelet count of 9 x10^3/uL. The initial impression was ACS and ITP. Course: No antiplatelet or anticoagulation was commenced. CT coronary angiography showed ostial left main (LM) severe stenosis. The patient received steroids and IVIG. A week later, cyclosporin and eltrombopag were added as the thrombocytopenia was refractory. Bone marrow biopsy showed AMT. His chest pain was persistent with ECG ischemic changes. A multidisciplinary team (MDT) decided that revascularization is urgently required, but the surgical option would have an extremely high bleeding risk. Alternatively, the Percutaneous option using radial access would have significantly less bleeding risk. However, he will need DAPT for at least the first week, which if interrupted, he will be at risk for stent thrombosis. The final decision was for platelet transfusion, then to proceed with the PCI once the platelet count is 50,000 or more, and to maintain the count > 15,000 by transfusion whenever required. Management: After the targeted transfusion, the patient was started on aspirin and clopidogrel, then successful IVUS guided PCI to ostial LM with new generation DES was done via radial access and low therapeutic ACT range. Post PCI, the patient remained asymptomatic; he was observed as an inpatient for 14 days, during which he required platelet transfusion once when his platelet count dropped < 15.000. DAPT was given for a week and then he was maintained on clopidogrel. In 3 months of follow-up, the patient had no cardiac complaints, no bleeding, and platelets were maintained between 15 to 30 on clopidogrel. Conclusion: ACS with severe thrombocytopenia is a management dilemma. Platelets transfusion, radial access, targeting low ACT, and using new generation stents for shorter DAPT duration might decrease the bleeding risk and thrombotic events.

Direct Oral Anticoagulant Adherence of Patients With Atrial Fibrillation Transitioned from Warfarin.

BackgroundReduced time in international normalized ratio therapeutic range (TTR) limits warfarin safety and effectiveness. In patients switched from warfarin to direct oral anticoagulants (DOACs), patient factors associated with low TTR could also increase risk of DOAC nonadherence. We investigated the relationship between warfarin TTR and DOAC adherence in warfarin‐treated patients with atrial fibrillation switched to DOAC.Methods and ResultsUsing data from the Veterans Health Administration, we identified patients with atrial fibrillation switched from warfarin to DOAC (switchers) or treated with warfarin alone (non‐switchers). Logistic regression was used to evaluate association between warfarin TTR and DOAC adherence. We analyzed 128 605 patients (age, 71±9; 1.6% women; CHA2DS2‐VASc 3.5±1.6); 32 377 switchers and 96 228 non‐switchers. In 8016 switchers with international normalized ratio data to calculate 180‐day TTR before switch, TTR was low (median 0.45; IQR, 0.26–0.64). Patients with TTR <0.5 were more likely to be switched to DOAC (odds ratio [OR],1.68 [95% CI,1.62–1.74], P<0.0001), as were those with TTR <0.6 or TTR <0.7. Proportion of days covered ≥0.8 was achieved by 76% of switchers at 365 days. In low‐TTR individuals, proportion of days covered ≥0.8 was achieved by 70%, 72%, and 73% of switchers with TTR <0.5, 0.6, and 0.7, respectively. After multivariable adjustment, TTR <0.5 decreased odds of achieving 365‐day proportion of days covered ≥0.8 (OR, 0.49; 0.43–0.57, P<0.0001), with similar relationships for TTR <0.6 and TTR <0.7. In non‐switchers with TTR <0.5, long‐term TTR remained low.ConclusionsIn patients with atrial fibrillation switched from warfarin to DOAC, most achieved adequate DOAC adherence despite low pre‐switch TTRs. However, TTR trajectories remained low in non‐switchers. Patients with low warfarin TTR more consistently achieved treatment targets after switching to DOACs, although adherence‐oriented interventions may be beneficial.

Evaluating high serum digoxin concentration risk factors interaction between direct oral anticoagulant agents and digoxin

Aim:Digoxin is an anti-arrhythmic drug that also has a positive inotropic property. It is mainly used to control heart rate in nonvalvular atrial fibrillation, and improve ejection fraction in heart failure. In recent years, the frequency of digoxin and a combination of new drug using has been increasing. Therefore, to assess the pharmacokinetic interaction between direct oral anticoagulant agents and cardiovascular drugs is necessary for intoxications. Material and Methods:Patients Serum Digoxin Concentrations levels and digoxin intoxications were evaluated according to risk factors investigated retrospectively Patients Serum Digoxin Concentrations levels &amp;lt;1 ng/ml is accepted as low, 1-2 ng/ml therapeutic range, 2.1-2.4 ng/ml is high and &amp;gt;2.4 ng/ml toxicity. Results:The study consisted of 248 females (60.2%) and 160 males (39.2%). The mean age of the patients was 70.5 years. The average age of patients was 70.5 years. Serum digoxin concentrations of 408 patients; 44.81% were detected in the low therapeutic range, 34.41% in the therapeutic range, 6.23% in the high therapeutic range, 14.55% in the toxic therapeutic range. The mean glomerular filtration rate was 58.45, and the mean Serum Digoxin Concentration was 1.36 ng/ml. The statistically significant relationship between age and Patients Serum Digoxin Concentration was 16.3% (p &amp;lt;0.05). There was a statistically significant relationship between Glomerular Filtration Rate and Serum Digoxin Concentrations; one increased and the other decreased (p &amp;lt;0.05). In patients without atherosclerotic heart disease, Serum Digoxin Concentration was significantly lower than those with atherosclerotic heart disease(p&amp;lt; 0.05). Serum Digoxin Concentrations were significantly higher in patients treated with rivaroxaban, the proportions of which differ significantly from each other at the 0.05 level. Conclusion:Nowadays, the frequency of using digoxin and direct oral anticoagulants together is increasing. The narrow therapeutic level of digoxin necessitates close monitoring due to drug-drug interactions.

Factor IX p.A37V mutation causes severe bleeding in a patient with phenprocoumon therapy

BackgroundBleeding is the most common complication of oral anticoagulants, due to inadequate dosing.Case presentationThis report describes the clinical course of a patient who developed severe bleeding under therapy with phenprocoumon, despite an INR in the lower therapeutic range. Strikingly, aPTT was prolonged, while factor IX activity was significantly reduced. Acquired hemophilia was excluded, due to missing detection of inhibitors. Finally, sequencing part of the factor IX gene including nucleotide position c.110 revealed a hemizygous factor IX mutation c.110C > T p (Ala37Val).ConclusionsIn rare cases, missense mutations in factor IX propeptide are associated with severe bleeding complications. The substitution of alanin at position 37 to either valin or threonin (Ala37Val or Ala37Thr) leads to hypersensitivity to vitamin k antagonists.

Time in therapeutic range is lower in women than in men and is not explained by differences in age or comorbidity

BackgroundTime in therapeutic range (TTR) measures the stability of the international normalized ratio in patients on vitamin K antagonists (VKA). Low values are associated with poor outcomes. Women were shown to have lower TTR than men, but the causes are poorly defined. It was suggested that women on VKA are older and more morbid than men, and this could affect the stability of anticoagulation. We aimed to identify variables that affect TTR differently in women and men. Materials and methodsThis is a retrospective study in patients referred to a University hospital anticoagulant clinic. Age, sex, comorbidities, number of daily medications, indication and type of anticoagulant, weekly dosage and distribution, were derived from electronic records. Differences by sex and regression analysis to identify significant modulators of TTR were computed. Results1182 women and 1281 men on VKA were studied. Women were older than men (81.5 yrs. ± 11.2 vs 78.4 yrs. ± 12.2), and had lower TTR (65% ± 20.3 vs 69% ± 19.8). Comorbidity was similar between sexes and negatively affected TTR in both. Mechanical valves as an indication to anticoagulation and acenocoumarol as an anticoagulant as opposed to warfarin had a strong negative influence on TTR, while age increased TTR. Being a man rather than a woman afforded more than three TTR points. Number of medications and average anticoagulant dose were equal between sexes. DiscussionWomen have a lower TTR than men, on average below the safety threshold. They were indeed older, but age positively influenced TTR. Since women and men were equally comorbid, neither age nor disease explains differences in TTR. None of the other variables included in the study could explain the gender gap in TTR. Since women are at increased risk of cardioembolic stroke in atrial fibrillation, an effort at defining other causes for the observed differences, closer monitoring and switching to direct anticoagulants whenever possible is warranted.

Expression profiling of DNA methyl transferase I (DNMT1) and efficacy of a DNA-hypomethylating agent (decitabine) in combination with chemotherapy in osteosarcoma

BackgroundAbnormality in the DNA methylation process is one of the hallmarks of cancer. Emerging evidence strongly supports the idea that defects in DNA methyl transferases (DNMTs) are involved in tumor development and progression. This alteration has major effects at the transcription level of various cancer-associated genes. MethodsExpression profiles of DNMT1 were investigated in fresh frozen tissues, patient-derived cells, and formalin-fixed paraffin-embedded tissues using immunoblotting and immunohistochemistry analysis. We also examined an anti-tumor effect of single DNA-hypomethylating agent (decitabine) and a combination of decitabine and chemotherapy in osteosarcoma cell lines. ResultsThe results showed an overexpression of DNMT1 in most cases compared to normal cells and tissue samples. DNMT1 was also expressed at the same levels in paired primary cells derived from biopsy and post-chemotherapy tissues. Expression patterns of DNMT1 were examined in 77 osteosarcoma patients of whom 82% had positive DNMT1 with an IRS score > 0. Most of the cases expressed low to moderate levels of DNMT1 (IRS range 1–8, median = 2.0). Furthermore, we found that a combination of decitabine and chemotherapy had a synergistic effect in most of the tested osteosarcoma cells at a low dose therapeutic range of decitabine. ConclusionsOur study revealed DNMT1 expression patterns that indicated potential roles of DNMT1 in osteosarcoma transformation and progression. This finding also suggests the efficacy of a combination therapy of decitabine with chemotherapy for osteosarcoma treatment.

Identification and Quantification of Antipsychotics in Blood Samples by LC-MS-MS: Case Reports and Data from Three Years of Routine Analysis.

Antipsychotic drugs (AP) are widely prescribed for the treatment of schizophrenia and psychosis. The pharmacological treatment of schizophrenia is often performed with the simultaneous use of two or more antipsychotic agents to achieve the desired control of psychotic symptoms Available AP include both conventional (typical) and new (atypical) antipsychotic medications. Atypical AP, such as quetiapine, now account for the vast majority of AP prescriptions. In forensic toxicology, AP are of considerable interest because of their potential abuse and their involvement in intoxications and suicides. The authors retrospectively examined AP positive cases detected in samples collected during autopsies performed in the Forensic Clinical and Pathology Service of National Institute of Legal Medicine and Forensic Sciences Centre Branch or in other autopsies carried out in the central region of Portugal, between January 2016 and December 2018. A quantitative liquid chromatography-tandem mass spectrometry assay was developed for the simultaneous determination of 16 AP (amisulpride, aripiprazole, chlorpromazine, clozapine, cyamemazine, fluphenazine, haloperidol, levomepromazine, melperone, olanzapine, paliperidone, promethazine, quetiapine, risperidone, sulpiride and ziprasidone) in blood samples of postmortem cases. The Laboratory of Forensic Chemistry and Toxicology received 3,588 requests for toxicological analysis: 1,413 cases were positive for drugs from which 351 (24.8%) cases were positive for AP, 60.1% from male individuals and 39.9% from female. Quetiapine was the most prevalent AP (36.5%) followed by olanzapine (20.8%). During this period, there were 25 postmortem cases with AP blood concentrations above therapeutic range, in which 36% of those are in agreement with the information received (psychological history or acute intoxication suspicion) and the manner of death was suicide. Our results point that antipsychotics are an increasingly prevalent class of drugs. AP must be measured not only in toxic concentrations but also in therapeutic levels in postmortem cases; therefore, it is important to come up with a sensitive method to cover the low therapeutic range in which AP are usually present.

A Novel Immunosuppressive Regiment for Cardiac Transplant Patients

Heart transplantation remains curative for end-stage heart failure. The choice between immunosuppressive regimens is guided by several principles: mitigating the risk of rejection early after transplantation, limiting drug toxicity of immunosuppressants, and minimizing over-suppression. We sought to investigate the efficacy of a novel immunosuppressive regimen targeting a lower therapeutic range (LTR) for Tacrolimus without antecedent induction therapy compared with a standard therapeutic range (STR). The protocol was implemented after 2016 and included the administration of Tacrolimus to a goal trough of 6-8 ng/mL immediately post transplant, Mycophenolate mofetil 1000-15000 mg BID, and Prednisone 1 mg/kg/day post-op divided into two doses and tapered by 5 mg Daily. A retrospective chart review was performed comparing transplant outcomes utilizing the novel LTR immunosuppression regimen compared to STR from 2008-2019. Primary outcomes included infection, bone marrow suppression and rejection within the first 3 years of transplantation. Of the 83 patients analyzed, 25 (30%) received the lower Tacrolimus dosing regimen (LDR), and 58 received the standard dosing regimen (SDR). Patients in the LDR group were younger (56.2 +/- 12.2 years vs 61.8 +/- 10.4 years) and less likely to be male (68% vs 87.9%). Rates of high risk CMV donor/recipient status was similar between the two groups. There was no statistically significant difference between the LDR group and SDR group with respect to rates of infection (44% vs 34.5%, p=0.41), bone marrow suppression (20% vs 13.8%, p=0.47), or > 2R CMR (24% vs 32.8%, p=0.42). In this single-center study we compared a conventional post-transplant immunosuppression regimen with one that utilized a lower Tacrolimus trough goal (6-8ng/mL). There was no statistical difference between the two groups in rates of rejection, bone marrow suppression, or infectious complications. We present a successful novel immunosuppression regiment that could serve to benefit patients with intolerance to higher doses of calcineurin inhibitors with no adverse outcomes. Future studies are needed to determine the impact of LTR on renal function.

Pancreatic carcinoma underlying a complex presentation in late pregnancy: a case report

BackgroundGestational diabetes mellitus is strongly related to the risk of pancreatic cancer in pregnant women, but gestational diabetes can precede a diagnosis of pancreatic cancer by many years. Women with a history of gestational diabetes showed a relative risk of pancreatic cancer of 7.1. Pancreatic adenocarcinoma is one of the most common malignancies associated with thromboembolic events. A clinical study showed that thromboembolic events were detected in 36% of patients diagnosed as having pancreatic cancer. Studies showed that gestational diabetes mellitus could be one of the important risk factors for pancreatic cancer.Case presentationGestational diabetes mellitus is associated with increased risk of breast and pancreatic cancer. This case report describes a 29-year-old Chinese woman who presented with: gestational diabetes mellitus; International Society on Thrombosis and Haemostasis criteria suggested disseminated intravascular coagulation with a score of 5; hemolysis, elevated liver enzymes, low platelet count syndrome; and pulmonary hypertension. After an intravenous injection of fibrinogen, she gave birth to a normal baby and following delivery, her blood pressure reached 180/110 mmHg. Laboratory analysis results showed elevated lactic dehydrogenase, decreased platelets and fibrinogen, and urine protein was positive. She was transfused with fresh frozen plasma, blood coagulation factor, and fibrinogen. Subsequently, she was transferred to a maternity intensive care unit, where magnesium sulfate seizure prophylaxis was continued for 24 hours to keep her magnesium level at a low therapeutic range. However, continuous oxygen therapy was needed to maintain her oxygenation. Further laboratory investigations revealed elevated carcinoembryonic antigen, carbohydrate antigen 19-9, and carbohydrate antigen 72-4. Positron emission tomography-computed tomography showed malignant carcinoma in the head of her pancreas with lymph node involvement along with bone, peritoneal, and left adrenal metastasis, as well as double lung lymphangitic carcinomatosis.ConclusionA differential diagnosis of digestive system neoplasm should be considered when a pregnant patient presents with gestational diabetes mellitus and disseminated intravascular coagulation, where the disseminated intravascular coagulation has no specific cause and cannot be readily resolved.

Rapid determination of anticoagulating effects of dabigatran in whole blood with rotational thromboelastometry and a thrombin‐based trigger

Essentials A rapid test to detect thrombin inhibition by dabigatran would be valuable in acute situations. A thrombin-based trigger was applied in whole blood using rotation thromboelastometry. Effects of dabigatran were assessed invitro and in samples from patients on dabigatran. The test produced data rapidly and was sensitive to dabigatran concentrations from 20 to 500ngmL-1 . SUMMARY: Background Rapid determination of the anticoagulant effect of dabigatran is essential in emergency situations. Objective To study a viscoelastic test (rotational thromboelastometry [ROTEM]) for rapid determination of dabigatran effects in whole blood samples. Method ROTEM measurements were performed with comparison of two triggers (thrombin-based versus the commercial tissue factor-based trigger Ex-tem) in samples from 10 healthy donors spiked with dabigatran (20-500ngmL-1 ) and in samples from 35 patients receiving dabigatran treatment; 10 healthy subjects served as controls. Clotting time (CT) and the difference in CT without versus with addition of the dabigatran antidote idarucizumab (CTdiff ) were measured. Addition of idarucizumab reveals the contribution of dabigatran to ROTEM measurements and its potential reversibility. Results Invitro studies showed that thrombin CT and thrombin CTdiff were more sensitive than Ex-tem CT and Ex-tem CTdiff in detecting dabigatran in whole blood samples. In patient samples, when thrombin CT and thrombin CTdiff were used, it was possible to detect dabigatran with a cut-off of dabigatran at 20ngmL-1 , whereas, when Ex-tem CT and Ex-tem CTdiff were used, the method was less sensitive. Data from patient samples were obtained within 15min of blood sampling. Conclusions ROTEM CT with a thrombin-based trigger is more sensitive to dabigatran effects than Ex-tem CT, and detects anticoagulant effects of drug concentrations in the low-very low therapeutic range. Analysis with idarucizumab (CTdiff ) reveals dabigatran-specific effects. As data are rapidly obtained, this method could, with further development and validation of its performance, be suitable for detecting clinically significant dabigatran effects in emergency situations.

Severe Hyperkalemia Complicating Voriconazole Treatment in a Kidney Transplant Recipient With Histoplasmosis: A Case Report

Voriconazole is an antifungal agent that is commonly used in immunocompromised patients who develop fungal infections. We report a case of severe recurrent hyperkalemia that developed after starting voriconazole for the treatment of histoplasmosis in a kidney transplant patient who was maintained on tacrolimus-based immunosuppression. Hyperkalemia developed despite reducing the tacrolimus dose to maintain levels in a low therapeutic range. Although interactions between azoles and calcineurin inhibitors are widely recognized, this is the 1st report describing new-onset hyperkalemia following initiation of voriconazole in a kidney transplant patient receiving tacrolimus.

Intensity of anticoagulation and risk of thromboembolism after elective cardioversion of atrial fibrillation

BackgroundElective cardioversion (ECV) for atrial fibrillation (AF) is associated with a relatively low risk of thromboembolic complications. However, the optimal intensity of anticoagulation for ECV is unknown. We sought to assess the risk of thromboembolism in low (INR 2.0–2.4) vs. high (INR≥2.5) therapeutic range in a large retrospective cohort study. MethodsThis multi-centre “real world” study included 1424 ECVs in 1021 patients. The primary outcome was a stroke or a transient ischaemic attack (TIA) or a systemic embolus during the 30-day follow-up after ECV. ResultsAltogether 4 (0.3%) strokes, 2 (0.1%) TIAs and 2 (0.1%) bleeds were detected during the 30-day follow-up after ECV. No systemic emboli were detected. There were 2 deaths (0.1%), one associated with a stroke. Median time to stroke/TIA was 4 (IQR 9.5) days and the median CHA2DS2-VASc-score was 2 (IQR 1.25) among patients with thromboembolic events. Mean INR at ECV was 2.7 (SD 0.54) in the study cohort. Patients with INR 2.0–2.4 at ECV had more thromboembolic events compared with patients with INR≥2.5 (5/529 (0.9%) vs. 1/895 (0.1%), p=0.03). Comprehensive postprocedural INR data was available for 733 (71.8%) patients and 1007 cardioversions. At least one subtherapeutic (<2.0) INR value was detected within 21days after 230 (22.8%) ECVs and this drop in INR level was associated with a higher risk for thromboembolic events compared with continuous therapeutic post-cardioversion anticoagulation (1.7% vs 0.3%, p=0.03). ConclusionsOur results suggest that the intensity of periprocedural anticoagulation is associated with the risk of thromboembolic events after ECV.

Association of outcomes and anti-Xa levels in the treatment of pediatric venous thromboembolism.

There are few data in the pediatric population evaluating the relationship between measured anti-Xa levels during enoxaparin therapy and thrombotic outcomes. To determine whether there is a difference in outcomes in children who receive enoxaparin with mean anti-Xa levels between 0.45 and 0.79 unit/ml (low therapeutic range) versus between 0.80 and 1.05 unit/ml (high therapeutic range) throughout their course of their treatment. We retrospectively identified subjects with uncomplicated venous thromboembolism treated with enoxaparin. Of 69 patients with any response to therapy, 48 (70%) had mean anti-Xa levels in the low therapeutic range and 21 (30%) had mean anti-Xa levels in the high therapeutic range. Of 20 patients with no documented response to therapy, 13 (65%) had mean anti-Xa levels in the low therapeutic range and 7 (35%) had mean anti-Xa levels in the high therapeutic range. Forty-eight (79%) of the 61 patients with low-range mean anti-Xa level had any response to therapy. Twenty-one (75%) of the 28 patients with high-range mean anti-Xa level had any response to therapy. Chi-square test (P = 0.080) and logistic regression (OR = 1.23, P = 0.70) demonstrated no significant association between mean anti-Xa range (lower vs. upper) and therapy response. There was no statistically significant difference between low-range versus high-range mean anti-Xa levels and thrombus resolution. Empiric clinical practices of targeting anti-Xa levels in the higher therapeutic range to achieve better outcomes may not be warranted.

Evaluation of a pharmacogenetic-based warfarin dosing algorithm in patients with low time in therapeutic range - study protocol for a randomized controlled trial.

BackgroundTime in therapeutic range (TTR) is a measurement of quality of warfarin therapy and lower TTR values (<50%) are associated with greater risk of thromboembolic and bleeding events. Recently, we developed a pharmacogenetic-based warfarin dosing algorithm specifically calibrated for a Brazilian patient sample. The aims of this study are: to evaluate the impact of a genetic-based algorithm, compared to traditional anticoagulation, in the time to achieve the therapeutic target and in TTR percentage; and to assess the cost-effectiveness of genotype-guided warfarin dosing in a specific cohort of patients with low TTR (<50%) from a tertiary cardiovascular hospital.Methods/designThis study is a randomized controlled trial in patients (n = 300) with atrial fibrillation with TTR < 50%, based on the last three INR values. At the first consultation, patients will be randomized into two groups: TA group (traditional anticoagulation) and PA group (pharmacogenetic anticoagulation). For the first group, the physician will adjust the dose according to current INR value and, for the second group, a pharmacogenetic algorithm will be used. At the second, third, fourth and fifth consultations (with an interval of 7 days each) INR will be measured and, if necessary, the dose will be adjusted based on guidelines. Afterwards, patients who are INR stable will begin measuring their INR in 30 day intervals; if the patient’s INR is not stable, the patient will return in 7 days for a new measurement of the INR. Outcomes measures will include the time to achieve the therapeutic target and the percentage of TTR at 4 and 12 weeks. In addition, as a secondary end-point, pharmacoeconomic analysis will be carried out. Ethical approval was granted by the Ethics Committee for Medical Research on Human Beings of the Clinical Hospital of the University of São Paulo Medical School.DiscussionThis randomized study will include patients with low TTR and it will evaluate whether a population-specific genetic algorithm might be more effective than traditional anticoagulation for a selected group of poorly anticoagulated patients.Trial registrationClinicalTrials.gov, NCT02592980. Registered on 29 October 2015.

Warfarin utilisation and anticoagulation control in patients with atrial fibrillation and chronic kidney disease

ObjectiveTo evaluate warfarin prescription, quality of international normalised ratio (INR) monitoring and of INR control in patients with atrial fibrillation (AF) and chronic kidney disease (CKD).MethodsWe performed a retrospective cohort...

Atrial Fibrillation Patients Treated With Long-Term Warfarin Anticoagulation Have Higher Rates of All Dementia Types Compared With Patients Receiving Long-Term Warfarin for Other Indications.

BackgroundThe mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. We previously found a significantly increased risk of dementia in AF patients taking warfarin with a low percentage of time in therapeutic range. The purpose of this study was to determine the extent to which AF itself increases dementia risk, in addition to long‐term anticoagulation exposure.Methods and ResultsA total of 10 537 patients anticoagulated with warfarin (target INR 2–3), managed by the Clinical Pharmacist Anticoagulation Service with no history of dementia were included. Warfarin indication was for AF (n=4460), thromboembolism (n=5868), and mechanical heart valve(s) (n=209). Patients in the latter 2 categories were included only if they had no prior history of AF. The primary outcome was dementia. Patients with AF were older and had higher rates of hypertension, diabetes, heart failure, and stroke. AF patients experienced higher rates of total dementia (5.8% versus 1.6%, P<0.0001), Alzheimer disease (2.8% versus 0.9%, P<0.0001), and vascular dementia (1.0% versus 0.2%, P<0.0001). A propensity analysis of 6030 patients was performed to account for baseline demographics differences. Long‐term risk of dementia remained significant in AF patients compared with matched non‐AF patients (total dementia: hazard ratio [HR]=2.42 [1.85–3.18], P<0.0001; Alzheimer: HR=2.04 [1.40–2.98], P<0.0001; senile: HR=2.46 [1.58–3.86], P<0.0001). Low percent therapeutic range compared with a higher percent therapeutic range was associated with dementia risk in both AF (26–50% versus >75%: HR=2.51, P=0.005) and non‐AF groups (≤25% versus >75%: HR=3.92, P<0.0001).ConclusionsThe presence of AF significantly increases risk of dementia, including Alzheimer's disease, compared with matched patients receiving warfarin anticoagulation for other reasons. Quality of anticoagulation management remains an important risk factor for dementia in all patients.

Association of Outcomes and Anti-Xa Monitoring in Treatment of Pediatric Venous Thromboembolism

BACKGROUND/INTRODUCTION: With the increased use of venous catheters and improved survival from previously life-threatening pediatric disorders (e.g., congenital heart disease, cancer), the incidence of venous thromboembolism and the need for anticoagulation have also increased.While unfractionated heparin and warfarin were once considered the standards of care, enoxaparin has now become the drug of choice in many pediatric institutions, given improved efficacy, fewer bleeding complications, minimal interaction with concurrent medications, and a more favorable pharmacokinetic profile.Regular monitoring of Anti-Xa activity is generally recommended in children treated with enoxaparin. Though the published therapeutic range for Anti-Xa levels is 0.5 - 1.0 unit/mL, there is little data in the pediatric population regarding the outcomes associated with maintaining Anti-Xa levels at the higher versus lower end of the therapeutic range.OBJECTIVES: The purpose of this study was to determine whether there was a difference in diagnostic outcomes when children received enoxaparin with Anti-Xa levels between 0.5 - 0.79 unit/mL (low therapeutic range) versus between 0.8 - 1.0 unit/mL (high therapeutic range) throughout their course of their treatment.METHODS: Using the TCH DVT Registry, we retrospectively identified 107 subjects diagnosed with uncomplicated VTE and treated with enoxaparin. Demographic information, Anti-Xa levels, dose modifications, and diagnostic outcomes were abstracted using the electronic medical record (Epic®) and analyzed.RESULTS: We evaluated 103 patients with therapeutic Anti-Xa levels at the time of hospital discharge, of whom 93 had outcomes data. Of these 93 subjects, 38% (N = 35) had complete resolution after 3 months of therapy, 40% (N = 37) had partial resolution, 20% (N = 19) were unchanged, and 2% (N = 2) had progression of their initial thrombus. Of the 72 patients with any response to therapy (complete or partial resolution), 68% (N = 49) had a mean Anti-Xa level in the low therapeutic range and 32% (N = 23) had a mean Anti-Xa level in the high therapeutic range. In comparison, of the 21 patients with no documented response to therapy (unchanged or progression), 67% (N = 14) had a mean Anti-Xa level in the low therapeutic range, and 33% (N = 7) had a mean Anti-Xa level in the high therapeutic range.Of the 93 subjects with outcomes data, all but one had a mean Anti-Xa level within the therapeutic range throughout their treatment course. Of these 92 patients, 68% (N = 63) had mean Anti-Xa levels in the low therapeutic range. 78% (N = 49) had any response (complete or partial resolution) after 3 months of therapy, and 22% (N = 14) had no documented response to therapy (unchanged or progression). Of the 92 patients, 32% (N = 29) had mean Anti-Xa levels in the high therapeutic range. 76% (N = 22) had any response to therapy and 24% (N = 7) had no response to therapy.CONCLUSIONS: There does not appear to be a statistically significant difference between low versus high range mean therapeutic Anti-Xa levels and the incidence of thrombus resolution. Empiric clinical practices of targeting Anti-Xa levels in the high end of the therapeutic range may not be warranted. DisclosuresOff Label Use: Enoxaparin use as an anticoagulant in pediatric patients with venous thromboembolism.

P14 – 2314: Carbamazepine overdosage despite low residual plasma concentration?

Introduction Carbamazepine (CBZ) is an anti-epileptic drug and the rapid-release oral suspension (OS) is regularly used in the pediatric population. Case description We present a 4.5-year-old boy with temporal epilepsy since the age of 12 months. Treatment by valproic acid was inefficient, and levetiracetam was complicated by behavioral troubles. Therefore, CBZ OS twice a day was introduced. After 8 months without seizures despite low residual plasma dosage of 2.3 mg/l (normal 4–10 mg/l), seizures reappeared and treatment dose was increased. Nevertheless, after increase to 15 mg/kg/day with plasma level Discussion The patient described in this case report presented partial seizures controlled by extended-release CBZ. Despite high-dose CBZ the patient had a residual plasma level in the lower therapeutic range suggesting rapid metabolism. In addition, the patient experienced symptoms of CBZ overdosage 2 hours after administration of rapid-release oral suspension, but not with CBZ tablets, and despite infratherapeutic basal plasma level, compatible with the hypothesis of very rapid metabolism. Indeed, peak CBZ plasma concentrations are observed 2 hours after the administration of oral suspension, 12 hours after tablets and 24 hours after extended-release CBZ tablets. Conclusion In contrast to CBZ oral solution, CBZ tablets at the same dose might be efficient for seizure control. In addition, symptoms of CBZ overdosage might be observed despite low residual CBZ plasma level during OS treatment as the consequence of very rapid metabolisation. Nevertheless, there is currently no extended-release formulation available for small children and patients with swallow difficulties.