This document discusses anticoagulation and balancing efficacy and safety in treating blood clots. It covers various anticoagulant, antiplatelet, and antithrombotic drugs used in clinical practice like warfarin, aspirin, clopidogrel, dabigatran, and rivaroxaban. It also explains the coagulation pathway and how different drugs target different steps in coagulation like factor Xa or thrombin. Graphics show outcomes from clinical trials on drug combinations for preventing heart attacks and deaths in patients undergoing procedures.
This document provides an overview of acute renal failure (ARF), including definitions, epidemiology, diagnostic workup, specific syndromes, treatment, and prevention strategies. It discusses the etiology of ARF, including pre-renal, intra-renal, and post-renal causes. Pre-renal ARF can be caused by factors like volume depletion, NSAIDs, and ACE inhibitors. Intra-renal ARF includes vascular occlusion, glomerular diseases, tubular disorders like crystal nephropathy, and interstitial nephritis. Effective prevention strategies for ischemic acute tubular necrosis (ATN) include maintaining euvolemia through fluid hydration.
Session 12 - Introduction to Information ToolsMedXellence
This document summarizes tools for gathering performance improvement evidence, including the Template Analysis Tool (TAT). TAT provides clinic and provider-specific templates to analyze appointment categories, statuses, and dates. It summarizes appointment data for specific clinics, providers, and time periods to evaluate access and utilization. The document discusses using TAT and other sources like the Tricare Operations Center to examine metrics like empaneled patients, visits per 1000 patients, and provider availability. The goal is to provide actionable data to support decision making and demonstrate improvement tools for staff.
Meningitis antibiotics mechanism of actionMario Wilmath
This document discusses antibiotics used to treat bacterial meningitis. It describes four main mechanisms of antibiotic action: inhibiting cell wall synthesis, disrupting cell membranes, inhibiting protein synthesis, and inhibiting nucleic acid synthesis. Specific antibiotics are discussed for each category, including penicillins, cephalosporins, vancomycin, chloramphenicol, ciprofloxacin, and sulfisoxazole. Administration methods and dosages are provided. The case study discussed involved treating a patient with intravenous vancomycin and cefotaxime, while contacts received rifampin prophylaxis.
This review article summarizes the current literature on using ultrasound guidance for peripheral nerve blocks of the extremities and trunk in pediatric patients. It describes the techniques used in studies and case reports, highlighting how ultrasound guidance has enabled blocks that may have been difficult without image guidance due to proximity to vascular structures. The article provides ultrasound images and diagrams to demonstrate proper probe placement and needle insertion for various nerve blocks. The authors hope this review will stimulate further research on ultrasound-guided regional anesthesia in children.
Implications of the transfer ami trial for clinical practiceTrimed Media Group
The document discusses implications of the TRANSFER AMI trial for clinical practice based on a presentation. It summarizes that PCI centers should perform PCI in a timely manner (<90 minutes) and that short distance transfer patients should receive PCI within 120 minutes. For patients with expected delays, a pharmacoinvasive PCI strategy is an excellent option. However, the ideal regimen and timing remain unclear based on limitations of previous trials. Overall, reperfusion strategies should aim to restore flow in a timely fashion, as delays are associated with worse outcomes.
This document discusses anticoagulation strategies for transradial diagnostic and interventional cardiology cases. It finds that heparin is necessary to prevent radial artery occlusion but unfractionated heparin or bivalirudin are equally effective. For ad hoc transradial procedures, dividing the heparin dose and transitioning to bivalirudin if needed reduces bleeding risks. Bivalirudin monotherapy through transradial access reduces bleeding compared to transfemoral access without increasing thrombotic risks. Transradial access also improves outcomes for patients on anticoagulants like coumadin undergoing cardiac procedures.
1) The study examined outcomes in patients with heart failure who were at high risk, finding that at 6 months their risk was approximately 3.8 times higher.
2) Baseline characteristics were similar between the eplerenone and placebo groups, including average age of 64, 72% males, mean ejection fraction of 33%, and 32% with diabetes.
3) For the primary endpoints of total mortality and cardiovascular mortality or hospitalization, eplerenone demonstrated a 15% and 13% reduced risk respectively compared to placebo.
This document discusses a study called TALENT that compared operator radiation exposure from the right versus left radial approach for coronary procedures. The study found:
1) There was no significant difference in radiation dose to the body, thyroid, or shoulder between right and left radial approaches.
2) Radiation dose to the wrist was significantly lower with the left compared to the right radial approach.
3) Further evaluation is needed to confirm the possible advantage of lower wrist dose with the left radial access.
This document provides an overview of acute renal failure (ARF), including definitions, epidemiology, diagnostic workup, specific syndromes, treatment, and prevention strategies. It discusses the etiology of ARF, including pre-renal, intra-renal, and post-renal causes. Pre-renal ARF can be caused by factors like volume depletion, NSAIDs, and ACE inhibitors. Intra-renal ARF includes vascular occlusion, glomerular diseases, tubular disorders like crystal nephropathy, and interstitial nephritis. Effective prevention strategies for ischemic acute tubular necrosis (ATN) include maintaining euvolemia through fluid hydration.
Session 12 - Introduction to Information ToolsMedXellence
This document summarizes tools for gathering performance improvement evidence, including the Template Analysis Tool (TAT). TAT provides clinic and provider-specific templates to analyze appointment categories, statuses, and dates. It summarizes appointment data for specific clinics, providers, and time periods to evaluate access and utilization. The document discusses using TAT and other sources like the Tricare Operations Center to examine metrics like empaneled patients, visits per 1000 patients, and provider availability. The goal is to provide actionable data to support decision making and demonstrate improvement tools for staff.
Meningitis antibiotics mechanism of actionMario Wilmath
This document discusses antibiotics used to treat bacterial meningitis. It describes four main mechanisms of antibiotic action: inhibiting cell wall synthesis, disrupting cell membranes, inhibiting protein synthesis, and inhibiting nucleic acid synthesis. Specific antibiotics are discussed for each category, including penicillins, cephalosporins, vancomycin, chloramphenicol, ciprofloxacin, and sulfisoxazole. Administration methods and dosages are provided. The case study discussed involved treating a patient with intravenous vancomycin and cefotaxime, while contacts received rifampin prophylaxis.
This review article summarizes the current literature on using ultrasound guidance for peripheral nerve blocks of the extremities and trunk in pediatric patients. It describes the techniques used in studies and case reports, highlighting how ultrasound guidance has enabled blocks that may have been difficult without image guidance due to proximity to vascular structures. The article provides ultrasound images and diagrams to demonstrate proper probe placement and needle insertion for various nerve blocks. The authors hope this review will stimulate further research on ultrasound-guided regional anesthesia in children.
Implications of the transfer ami trial for clinical practiceTrimed Media Group
The document discusses implications of the TRANSFER AMI trial for clinical practice based on a presentation. It summarizes that PCI centers should perform PCI in a timely manner (<90 minutes) and that short distance transfer patients should receive PCI within 120 minutes. For patients with expected delays, a pharmacoinvasive PCI strategy is an excellent option. However, the ideal regimen and timing remain unclear based on limitations of previous trials. Overall, reperfusion strategies should aim to restore flow in a timely fashion, as delays are associated with worse outcomes.
This document discusses anticoagulation strategies for transradial diagnostic and interventional cardiology cases. It finds that heparin is necessary to prevent radial artery occlusion but unfractionated heparin or bivalirudin are equally effective. For ad hoc transradial procedures, dividing the heparin dose and transitioning to bivalirudin if needed reduces bleeding risks. Bivalirudin monotherapy through transradial access reduces bleeding compared to transfemoral access without increasing thrombotic risks. Transradial access also improves outcomes for patients on anticoagulants like coumadin undergoing cardiac procedures.
1) The study examined outcomes in patients with heart failure who were at high risk, finding that at 6 months their risk was approximately 3.8 times higher.
2) Baseline characteristics were similar between the eplerenone and placebo groups, including average age of 64, 72% males, mean ejection fraction of 33%, and 32% with diabetes.
3) For the primary endpoints of total mortality and cardiovascular mortality or hospitalization, eplerenone demonstrated a 15% and 13% reduced risk respectively compared to placebo.
This document discusses a study called TALENT that compared operator radiation exposure from the right versus left radial approach for coronary procedures. The study found:
1) There was no significant difference in radiation dose to the body, thyroid, or shoulder between right and left radial approaches.
2) Radiation dose to the wrist was significantly lower with the left compared to the right radial approach.
3) Further evaluation is needed to confirm the possible advantage of lower wrist dose with the left radial access.
The document describes a study comparing primary angioplasty versus fibrinolysis for very elderly patients (≥75 years old) experiencing STEMI. The study aims to enroll 570 patients and will randomize them to either tenecteplase fibrinolysis or primary angioplasty. The primary endpoint is a composite of death, reinfarction, or disabling stroke at 30 days. Secondary endpoints include recurrent ischemia, mortality, bleeding, and outcomes at 12 months. The study seeks to determine the most effective reperfusion strategy for this elderly patient population.
1) Radial artery hemostasis is the easiest part of the transradial procedure due to the radial artery's location and collateral blood flow.
2) Maintaining radial artery patency during compression is critical to prevent radial artery occlusion. Devices and techniques aim to apply enough pressure for hemostasis while preserving flow.
3) Factors like pressure duration and monitoring patency can significantly impact radial artery outcomes. New protocols focus on active hemostasis, frequent patency checks, and adjusting compression to keep the artery open.
This document discusses management and treatment options for basal cell carcinoma (BCC). It summarizes several studies on photodynamic therapy (PDT) using methyl aminolevulinate (MAL-PDT) and its long-term outcomes and recurrence rates for different types of BCC compared to other treatments like surgery and cryotherapy. It also discusses the use of imiquimod cream and fluorouracil for treating BCC, as well as cryotherapy and oral agents currently in development for advanced BCC cases. The document concludes that having a choice of topical therapies is beneficial but they have non-specific modes of action, while pathway inhibitors taken orally show promise but have limiting side effect profiles.
Trial to assess chelation therapy (tact) slidesMarilyn Mann
The Trial to Assess Chelation Therapy (TACT) was a randomized controlled trial that compared chelation therapy (disodium EDTA injections) to placebo injections in 1708 patients with prior heart attacks. The primary goal was to see if chelation therapy reduced cardiovascular events like death, heart attack, stroke, and hospitalization. The trial found that chelation therapy reduced the primary composite endpoint compared to placebo with a hazard ratio of 0.82 and p-value of 0.035. A pre-specified subgroup analysis found the benefit was greater in patients with diabetes, with a hazard ratio of 0.61 and p-value of 0.002 for chelation therapy versus placebo in reducing cardiovascular events. The trial provides evidence that che
The document discusses hepatitis C and B infections in HIV patients. It finds that:
1) HCV and HBV coinfections are major causes of mortality and morbidity in HIV patients, with HCV being a leading cause of death.
2) Coinfected patients have more severe liver disease than mono-infected patients, with HIV accelerating liver fibrosis and damage from HCV and HBV.
3) The introduction of HAART has reduced mortality from liver disease in coinfected patients, but also increased the risk of liver flares due to immune reconstitution and potential drug hepatotoxicity.
4) Due to the higher risks, coinfected patients should be actively considered for HCV and HBV treatment.
Acute renal failure is a common condition in hospitalized patients with a high mortality rate. While many patients recover from ARF, a significant number do not survive. The document discusses the definitions, epidemiology, etiologies, diagnostic workup, treatment and prevention of ARF. It emphasizes that the most effective preventive strategy is to maintain proper fluid volume status in at-risk patients. Biomarkers are being investigated to aid early diagnosis but hydration remains the key prevention method.
This document discusses pulmonary hypertension (PH) associated with connective tissue diseases (CTDs). PAH may complicate several autoimmune diseases, most commonly systemic sclerosis. Early detection of PAH is important, as screening can identify milder cases. Biomarkers and exercise testing can help assess PAH severity and prognosis. PH associated with systemic sclerosis has a unique phenotype and is challenging to treat due to factors like older patient age and underlying interstitial lung disease. Screening for PAH is crucial in systemic sclerosis patients to enable early treatment.
1. The document introduces the antibiotic linezolid injection and tablets, marketed under the brand name Zyvox.
2. Clinical trials showed linezolid was more effective than vancomycin in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA), with higher cure rates and survival rates.
3. Linezolid achieves higher tissue concentrations than other antibiotics, resulting in better penetration and efficacy in treating pneumonia and other infections. It has a good safety and cost-effectiveness profile.
1) Breast cancer is heterogeneous with different subtypes defined by receptor status and gene expression profiles. The subtypes have different biological behaviors and clinical outcomes.
2) Accurate diagnosis requires biopsy (FNA or core) followed by receptor testing before treatment decisions. Surgery options include breast conserving therapy or mastectomy with/without reconstruction.
3) For early breast cancer, sentinel lymph node biopsy guides the need for further axillary lymph node dissection. Omission of further dissection may be adequate for sentinel node positive patients.
Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge.
Review a downloadable slide deck by Deborah K. Armstrong, MD, covering the most clinically relevant new data reported from The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds.
Target Audience
This activity has been designed to meet the unique learning needs of oncologists, surgeons, gynecologists, and other healthcare professionals involved in the treatment of patients with ovarian cancer.
Format: Microsoft PowerPoint (.ppt) | File size: 9.7 MB | Date posted: 8/06/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
Activity Overview
Although progress continues to be made in the treatment of ovarian cancer, making clinical decisions remains a challenge due to the many treatment options available in several different settings. Selective inhibitors of the VEGF/PDGF/FGF pathways have shown activity in patients with ovarian cancer in phase II and III clinical trials either as monotherapy or in combination with other chemotherapy. Community and academic oncologists who treat patients with ovarian cancer need to stay abreast of the latest research that can affect treatment decisions and patient outcomes.
As controversy still exists regarding how and when to incorporate the use of antiangiogenic agents into the treatment paradigm for ovarian cancer patients, this case-based activity developed by expert faculty will provide clinicians with the practical application of new data into community and academic practice settings.
This document discusses the use of neuromuscular blocking agents (NMBAs) for rapid sequence intubation (RSI) in emergency departments. It provides details on the Maharaj Nakorn Chiang Mai Hospital emergency department's experience with RSI, including:
1) They initially used etomidate + succinylcholine or etomidate + rocuronium for RSI, and now have over 150 experiences with RSI.
2) Common problems encountered include hypotension after the procedure, multiple intubation attempts due to inexperience or poor positioning
pleomorphic, sarcomatoid or
sarcomatous elements
The document discusses lung cancer (carcinoma pulmonar) and highlights several issues:
1) Lung cancer is stigmatized as being "self-inflicted" due to its strong association with tobacco use.
2) It receives little coverage in the media about treatment advances and attracts little celebrity interest.
3) Patients and families receive poor support from organizations and have pessimistic views of treatment outcomes held by doctors, patients, and families.
4) The document examines how oncologists treating lung cancer would choose to be treated themselves, finding increasing acceptance of chemotherapy over time.
Hépatites virales C et B et infection par le VIH.pdfodeckmyn
The document discusses the prevalence of hepatitis C and B viruses globally as well as their coinfection rates with HIV. It examines how HIV coinfection may accelerate liver fibrosis progression for hepatitis C and the importance of antiretroviral therapy in reducing liver-related mortality. New direct-acting antiviral drugs against hepatitis C virus are promising but treatment for HIV/hepatitis coinfection remains challenging due to drug interactions and side effects.
Hépatites virales C et B et infection par le VIH.pdfodeckmyn
The document discusses the prevalence of hepatitis C and B viruses globally as well as their coinfection rates with HIV. It also examines how HIV coinfection can affect the progression of hepatitis C-related liver disease and the treatment approaches for coinfected patients. Specifically, fibrosis is found to progress faster in HIV/HCV coinfected patients compared to HCV mono-infected individuals, though antiretroviral treatment can slow progression and improve outcomes.
This document discusses the treatment of metastatic disease in lung cancer. It emphasizes the importance of determining histology (squamous vs. non-squamous) and biomarkers to guide treatment decisions. For squamous cell carcinoma, EGFR/ALK testing is not recommended and treatment involves platinum-based doublets or cetuximab-containing regimens. For non-squamous, testing for EGFR/ALK is recommended, and if negative, initial treatment with carboplatin/pemetrexed is an option. The prognostic value of TTF-1 is also discussed, as its negativity highly predicts EGFR mutation negativity. Treatment decisions should incorporate histology, biomarker status, and other clinical factors.
This document describes the case of an 82-year-old man with chest pain and pulmonary edema who was found to have multi-vessel coronary artery disease including a distal left main lesion. Due to his advanced age and high surgical risk, percutaneous coronary intervention (PCI) was chosen over coronary artery bypass grafting (CABG). The staged PCI procedure involved initially stenting the right coronary artery, followed by a complex multi-stent strategy including a mini-crush stent for the left main lesion and additional stents in the circumflex and left anterior descending arteries. The final result demonstrated successful revascularization.
This document summarizes prescription statistics from October 2012 for different departments at a hospital. It shows the total number of prescriptions, prescriptions containing more than 10 items, and the percentage of prescriptions over 10 items for each department. Nephrology had the highest percentage at 100%, while departments like ENT, ER, and OBG had the lowest percentages between 0-0.1%.
Taiwan has a population of over 23 million people with a GDP per capita of $18,603. The country implemented a National Health Insurance program in 1995 that provides coverage for inpatient, outpatient, and limited home care. Thalassemia is prevalent in Taiwan, with carrier rates of 5-8% for various types. The country has a national prevention program that screens pregnant women and provides confirmatory testing and genetic counseling. Treatment for thalassemia major includes regular blood transfusions paid for by National Health Insurance as well as iron chelation therapy. Multidisciplinary expert centers provide coordinated care and management for patients.
Statin Use Cancer Related Mortality M Wilmath Nov2012 Whh Adult MedMario Wilmath
1. Researchers examined the association between statin use and cancer-related mortality using Danish national registries containing data on cancer diagnoses, prescriptions, and deaths from 1995-2007.
2. They found that cancer patients who used statins had a 15% lower risk of death from cancer compared to non-users.
3. The potential benefits were highest for colon, liver, esophageal, and prostate cancers. However, the study had limitations such as lacking treatment data for most patients and being limited to Denmark. Further research is still needed.
This document discusses managing opioid-induced bowel dysfunction. It describes the physiology behind constipation, measures for assessing treatment impact, and risks of undertreatment. New treatment modalities like Relistor, Amitizia, Entereg, and Linzess are outlined with their mechanisms of action, dosing, side effects, efficacy, and outcomes. Universal precautions for prescribing opioids include diagnosis, goals, monitoring, education, and documentation. Established medications like bulking agents, laxatives, and cathartics are also reviewed with cautions.
More Related Content
Similar to New approaches to chronic anticoagulatio na
The document describes a study comparing primary angioplasty versus fibrinolysis for very elderly patients (≥75 years old) experiencing STEMI. The study aims to enroll 570 patients and will randomize them to either tenecteplase fibrinolysis or primary angioplasty. The primary endpoint is a composite of death, reinfarction, or disabling stroke at 30 days. Secondary endpoints include recurrent ischemia, mortality, bleeding, and outcomes at 12 months. The study seeks to determine the most effective reperfusion strategy for this elderly patient population.
1) Radial artery hemostasis is the easiest part of the transradial procedure due to the radial artery's location and collateral blood flow.
2) Maintaining radial artery patency during compression is critical to prevent radial artery occlusion. Devices and techniques aim to apply enough pressure for hemostasis while preserving flow.
3) Factors like pressure duration and monitoring patency can significantly impact radial artery outcomes. New protocols focus on active hemostasis, frequent patency checks, and adjusting compression to keep the artery open.
This document discusses management and treatment options for basal cell carcinoma (BCC). It summarizes several studies on photodynamic therapy (PDT) using methyl aminolevulinate (MAL-PDT) and its long-term outcomes and recurrence rates for different types of BCC compared to other treatments like surgery and cryotherapy. It also discusses the use of imiquimod cream and fluorouracil for treating BCC, as well as cryotherapy and oral agents currently in development for advanced BCC cases. The document concludes that having a choice of topical therapies is beneficial but they have non-specific modes of action, while pathway inhibitors taken orally show promise but have limiting side effect profiles.
Trial to assess chelation therapy (tact) slidesMarilyn Mann
The Trial to Assess Chelation Therapy (TACT) was a randomized controlled trial that compared chelation therapy (disodium EDTA injections) to placebo injections in 1708 patients with prior heart attacks. The primary goal was to see if chelation therapy reduced cardiovascular events like death, heart attack, stroke, and hospitalization. The trial found that chelation therapy reduced the primary composite endpoint compared to placebo with a hazard ratio of 0.82 and p-value of 0.035. A pre-specified subgroup analysis found the benefit was greater in patients with diabetes, with a hazard ratio of 0.61 and p-value of 0.002 for chelation therapy versus placebo in reducing cardiovascular events. The trial provides evidence that che
The document discusses hepatitis C and B infections in HIV patients. It finds that:
1) HCV and HBV coinfections are major causes of mortality and morbidity in HIV patients, with HCV being a leading cause of death.
2) Coinfected patients have more severe liver disease than mono-infected patients, with HIV accelerating liver fibrosis and damage from HCV and HBV.
3) The introduction of HAART has reduced mortality from liver disease in coinfected patients, but also increased the risk of liver flares due to immune reconstitution and potential drug hepatotoxicity.
4) Due to the higher risks, coinfected patients should be actively considered for HCV and HBV treatment.
Acute renal failure is a common condition in hospitalized patients with a high mortality rate. While many patients recover from ARF, a significant number do not survive. The document discusses the definitions, epidemiology, etiologies, diagnostic workup, treatment and prevention of ARF. It emphasizes that the most effective preventive strategy is to maintain proper fluid volume status in at-risk patients. Biomarkers are being investigated to aid early diagnosis but hydration remains the key prevention method.
This document discusses pulmonary hypertension (PH) associated with connective tissue diseases (CTDs). PAH may complicate several autoimmune diseases, most commonly systemic sclerosis. Early detection of PAH is important, as screening can identify milder cases. Biomarkers and exercise testing can help assess PAH severity and prognosis. PH associated with systemic sclerosis has a unique phenotype and is challenging to treat due to factors like older patient age and underlying interstitial lung disease. Screening for PAH is crucial in systemic sclerosis patients to enable early treatment.
1. The document introduces the antibiotic linezolid injection and tablets, marketed under the brand name Zyvox.
2. Clinical trials showed linezolid was more effective than vancomycin in treating infections caused by methicillin-resistant Staphylococcus aureus (MRSA), with higher cure rates and survival rates.
3. Linezolid achieves higher tissue concentrations than other antibiotics, resulting in better penetration and efficacy in treating pneumonia and other infections. It has a good safety and cost-effectiveness profile.
1) Breast cancer is heterogeneous with different subtypes defined by receptor status and gene expression profiles. The subtypes have different biological behaviors and clinical outcomes.
2) Accurate diagnosis requires biopsy (FNA or core) followed by receptor testing before treatment decisions. Surgery options include breast conserving therapy or mastectomy with/without reconstruction.
3) For early breast cancer, sentinel lymph node biopsy guides the need for further axillary lymph node dissection. Omission of further dissection may be adequate for sentinel node positive patients.
Downloadable slide decks are a great tool for self study and teaching purposes. They are non-certified resources available to enhance your knowledge.
Review a downloadable slide deck by Deborah K. Armstrong, MD, covering the most clinically relevant new data reported from The Future of Antiangiogenic Therapies in Ovarian Cancer: A Series of Community and Academic Grand Rounds.
Target Audience
This activity has been designed to meet the unique learning needs of oncologists, surgeons, gynecologists, and other healthcare professionals involved in the treatment of patients with ovarian cancer.
Format: Microsoft PowerPoint (.ppt) | File size: 9.7 MB | Date posted: 8/06/2012
Slide Deck Disclaimer
This slide deck in its original and unaltered format is for educational purposes and is current as of August 2012. All materials contained herein reflect the views of the faculty, and not those of IMER, the CME provider, or the commercial supporter. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. Readers should not rely on this information as a substitute for professional medical advice, diagnosis, or treatment. The use of any information provided is solely at your own risk, and readers should verify the prescribing information and all data before treating patients or employing any therapeutic products described in this educational activity.
Usage Rights
This slide deck is provided for educational purposes and individual slides may be used for personal, non-commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published in print or electronically as a promotional or certified educational activity without prior written permission from IMER. Additional terms may apply. See Terms of Service on IMERonline.com for details.
Activity Overview
Although progress continues to be made in the treatment of ovarian cancer, making clinical decisions remains a challenge due to the many treatment options available in several different settings. Selective inhibitors of the VEGF/PDGF/FGF pathways have shown activity in patients with ovarian cancer in phase II and III clinical trials either as monotherapy or in combination with other chemotherapy. Community and academic oncologists who treat patients with ovarian cancer need to stay abreast of the latest research that can affect treatment decisions and patient outcomes.
As controversy still exists regarding how and when to incorporate the use of antiangiogenic agents into the treatment paradigm for ovarian cancer patients, this case-based activity developed by expert faculty will provide clinicians with the practical application of new data into community and academic practice settings.
This document discusses the use of neuromuscular blocking agents (NMBAs) for rapid sequence intubation (RSI) in emergency departments. It provides details on the Maharaj Nakorn Chiang Mai Hospital emergency department's experience with RSI, including:
1) They initially used etomidate + succinylcholine or etomidate + rocuronium for RSI, and now have over 150 experiences with RSI.
2) Common problems encountered include hypotension after the procedure, multiple intubation attempts due to inexperience or poor positioning
pleomorphic, sarcomatoid or
sarcomatous elements
The document discusses lung cancer (carcinoma pulmonar) and highlights several issues:
1) Lung cancer is stigmatized as being "self-inflicted" due to its strong association with tobacco use.
2) It receives little coverage in the media about treatment advances and attracts little celebrity interest.
3) Patients and families receive poor support from organizations and have pessimistic views of treatment outcomes held by doctors, patients, and families.
4) The document examines how oncologists treating lung cancer would choose to be treated themselves, finding increasing acceptance of chemotherapy over time.
Hépatites virales C et B et infection par le VIH.pdfodeckmyn
The document discusses the prevalence of hepatitis C and B viruses globally as well as their coinfection rates with HIV. It examines how HIV coinfection may accelerate liver fibrosis progression for hepatitis C and the importance of antiretroviral therapy in reducing liver-related mortality. New direct-acting antiviral drugs against hepatitis C virus are promising but treatment for HIV/hepatitis coinfection remains challenging due to drug interactions and side effects.
Hépatites virales C et B et infection par le VIH.pdfodeckmyn
The document discusses the prevalence of hepatitis C and B viruses globally as well as their coinfection rates with HIV. It also examines how HIV coinfection can affect the progression of hepatitis C-related liver disease and the treatment approaches for coinfected patients. Specifically, fibrosis is found to progress faster in HIV/HCV coinfected patients compared to HCV mono-infected individuals, though antiretroviral treatment can slow progression and improve outcomes.
This document discusses the treatment of metastatic disease in lung cancer. It emphasizes the importance of determining histology (squamous vs. non-squamous) and biomarkers to guide treatment decisions. For squamous cell carcinoma, EGFR/ALK testing is not recommended and treatment involves platinum-based doublets or cetuximab-containing regimens. For non-squamous, testing for EGFR/ALK is recommended, and if negative, initial treatment with carboplatin/pemetrexed is an option. The prognostic value of TTF-1 is also discussed, as its negativity highly predicts EGFR mutation negativity. Treatment decisions should incorporate histology, biomarker status, and other clinical factors.
This document describes the case of an 82-year-old man with chest pain and pulmonary edema who was found to have multi-vessel coronary artery disease including a distal left main lesion. Due to his advanced age and high surgical risk, percutaneous coronary intervention (PCI) was chosen over coronary artery bypass grafting (CABG). The staged PCI procedure involved initially stenting the right coronary artery, followed by a complex multi-stent strategy including a mini-crush stent for the left main lesion and additional stents in the circumflex and left anterior descending arteries. The final result demonstrated successful revascularization.
This document summarizes prescription statistics from October 2012 for different departments at a hospital. It shows the total number of prescriptions, prescriptions containing more than 10 items, and the percentage of prescriptions over 10 items for each department. Nephrology had the highest percentage at 100%, while departments like ENT, ER, and OBG had the lowest percentages between 0-0.1%.
Taiwan has a population of over 23 million people with a GDP per capita of $18,603. The country implemented a National Health Insurance program in 1995 that provides coverage for inpatient, outpatient, and limited home care. Thalassemia is prevalent in Taiwan, with carrier rates of 5-8% for various types. The country has a national prevention program that screens pregnant women and provides confirmatory testing and genetic counseling. Treatment for thalassemia major includes regular blood transfusions paid for by National Health Insurance as well as iron chelation therapy. Multidisciplinary expert centers provide coordinated care and management for patients.
Similar to New approaches to chronic anticoagulatio na (20)
Statin Use Cancer Related Mortality M Wilmath Nov2012 Whh Adult MedMario Wilmath
1. Researchers examined the association between statin use and cancer-related mortality using Danish national registries containing data on cancer diagnoses, prescriptions, and deaths from 1995-2007.
2. They found that cancer patients who used statins had a 15% lower risk of death from cancer compared to non-users.
3. The potential benefits were highest for colon, liver, esophageal, and prostate cancers. However, the study had limitations such as lacking treatment data for most patients and being limited to Denmark. Further research is still needed.
This document discusses managing opioid-induced bowel dysfunction. It describes the physiology behind constipation, measures for assessing treatment impact, and risks of undertreatment. New treatment modalities like Relistor, Amitizia, Entereg, and Linzess are outlined with their mechanisms of action, dosing, side effects, efficacy, and outcomes. Universal precautions for prescribing opioids include diagnosis, goals, monitoring, education, and documentation. Established medications like bulking agents, laxatives, and cathartics are also reviewed with cautions.
Certain drugs can negatively impact nutrition by interfering with nutrient absorption or decreasing appetite. Drugs that interact with calcium, magnesium, iron, or zinc can lower absorption of other medications. Medications that alter taste or decrease saliva production can decrease oral intake and appetite. Choosing medications with established efficacy and safety, a low risk of drug interactions, and compatibility with disease states can help prevent malnutrition. Maintaining a nutrient-rich diet with antioxidants, B-vitamins, calcium, fiber, and minerals can also help offset potential nutrient-drug interactions.
Guillain-Barré syndrome is an acute inflammatory polyneuropathy typically presenting with progressive ascending motor weakness. Intravenous immunoglobulin and plasma exchange are first-line treatments aimed at hastening recovery. While some vaccinations have a temporal association with Guillain-Barré syndrome, the causal relationship remains unclear and risks must be weighed against benefits of preventing severe infectious diseases. Careful supportive care including respiratory monitoring is important given potential respiratory complications.
This document discusses key principles of pharmacokinetics including drug absorption, distribution, metabolism, and elimination. It provides examples of drugs that require therapeutic drug monitoring for several disease states, such as digoxin for cardiovascular issues, aminoglycosides for infectious diseases, and theophylline for pulmonary conditions. The document also outlines factors that influence pharmacokinetic parameters like body size, age, disease state, and drug interactions. Equations for calculating pharmacokinetic measures like loading dose, maintenance dose, and drug clearance are presented.
Cimzia is a TNF blocker used to treat rheumatoid arthritis. In pivotal clinical studies, patients treated with Cimzia experienced significant improvements in symptoms like joint swelling and tenderness. These improvements were rapid, occurring within 1 week, and sustained over 24-52 weeks. Patients also reported improvements in pain, fatigue, disability, and quality of life when treated with Cimzia. However, Cimzia can lower the immune system's ability to fight infections, and serious infections have occurred in some patients treated with Cimzia.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
Our backs are like superheroes, holding us up and helping us move around. But sometimes, even superheroes can get hurt. That’s where slip discs come in.
One health condition that is becoming more common day by day is diabetes.
According to research conducted by the National Family Health Survey of India, diabetic cases show a projection which might increase to 10.4% by 2030.
These lecture slides, by Dr Sidra Arshad, offer a simplified look into the mechanisms involved in the regulation of respiration:
Learning objectives:
1. Describe the organisation of respiratory center
2. Describe the nervous control of inspiration and respiratory rhythm
3. Describe the functions of the dorsal and respiratory groups of neurons
4. Describe the influences of the Pneumotaxic and Apneustic centers
5. Explain the role of Hering-Breur inflation reflex in regulation of inspiration
6. Explain the role of central chemoreceptors in regulation of respiration
7. Explain the role of peripheral chemoreceptors in regulation of respiration
8. Explain the regulation of respiration during exercise
9. Integrate the respiratory regulatory mechanisms
10. Describe the Cheyne-Stokes breathing
Study Resources:
1. Chapter 42, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 36, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 13, Human Physiology by Lauralee Sherwood, 9th edition
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Integrating Ayurveda into Parkinson’s Management: A Holistic ApproachAyurveda ForAll
Explore the benefits of combining Ayurveda with conventional Parkinson's treatments. Learn how a holistic approach can manage symptoms, enhance well-being, and balance body energies. Discover the steps to safely integrate Ayurvedic practices into your Parkinson’s care plan, including expert guidance on diet, herbal remedies, and lifestyle modifications.
Cell Therapy Expansion and Challenges in Autoimmune DiseaseHealth Advances
There is increasing confidence that cell therapies will soon play a role in the treatment of autoimmune disorders, but the extent of this impact remains to be seen. Early readouts on autologous CAR-Ts in lupus are encouraging, but manufacturing and cost limitations are likely to restrict access to highly refractory patients. Allogeneic CAR-Ts have the potential to broaden access to earlier lines of treatment due to their inherent cost benefits, however they will need to demonstrate comparable or improved efficacy to established modalities.
In addition to infrastructure and capacity constraints, CAR-Ts face a very different risk-benefit dynamic in autoimmune compared to oncology, highlighting the need for tolerable therapies with low adverse event risk. CAR-NK and Treg-based therapies are also being developed in certain autoimmune disorders and may demonstrate favorable safety profiles. Several novel non-cell therapies such as bispecific antibodies, nanobodies, and RNAi drugs, may also offer future alternative competitive solutions with variable value propositions.
Widespread adoption of cell therapies will not only require strong efficacy and safety data, but also adapted pricing and access strategies. At oncology-based price points, CAR-Ts are unlikely to achieve broad market access in autoimmune disorders, with eligible patient populations that are potentially orders of magnitude greater than the number of currently addressable cancer patients. Developers have made strides towards reducing cell therapy COGS while improving manufacturing efficiency, but payors will inevitably restrict access until more sustainable pricing is achieved.
Despite these headwinds, industry leaders and investors remain confident that cell therapies are poised to address significant unmet need in patients suffering from autoimmune disorders. However, the extent of this impact on the treatment landscape remains to be seen, as the industry rapidly approaches an inflection point.
2. Anticoagulation: The Art of Balance
Both efficacy and safety are
important, imbalance in
efficacy and safety may result
in patient harm
3. 1. Safety versus Efficacy
2. Thrombosis = Clotting + Coagulation
3. AntiThrombotics That Have Changed Clinical Practice
a) Anticoagulants
b) Antiplatelets
c) Anticlotting
4. AntiCoagulants
a) Aspirin
b) Warfarin
5. AntiPlatelets
a) Clopidogrel
b) Ticragrelor
c) Bivalrudin
6. AntiClotting
a) Dabigatran
b) Apixiban
c) Rivaroxaban
5. TF (Tissue Factor)
XI XIa
Intrinsic Pathway
IX IXa VIIa + TF VII
VIIIa Extrinsic Pathway
X Xa
Intrinsic or Extrinsic pathway
activation leads to thrombin Va
formation via the final common II IIa (Thrombin)
coagulation pathway
Fibrinogen Fibrin
8. <48 hrs after rand PCI ≥ 48 hrs from rand and PCI after hospital
during initial hosp discharge
0.20 0.20 0.20
Cumulative Hazard Rates Death / MI
Denotes median
Time to PCI ASA
ASA
0.15 0.15 0.15
ASA
0.10 0.10 0.10
ASA + Clopidogrel ASA + Clopidogrel
0.05 0.05 0.05
ASA + Clopidogrel
RR:0.53 (0.27-1.06) RR:0.72 (0.51-1.01) RR:0.70 (0.48-1.02)
0.0 0.0 0.0
0 100 200 300 0 100 200 300 0 100 200 300
Days of Follow-up Days of Follow-up Days of Follow-up
Lewis BS, et al. Am Heart J. 2005;150:1177-1184.
9. Angioscopic findings
100%
83%
suggestive of plaque
79%
80% instability are extremely
70% 71%
frequent (75% to 80% of
60% the study population) as
is the presence of clot
s ub m r h T y poc o gn A n o
40% even in the absence of
clinical symptoms.
20%
% s i
Only 16% of clot seen
0% on angio
< 8 Days 8<& 10 < & > 15 Days
(n=18) < 10 Days < 15 Days (n=14)
o
(n=10) (n=14)
Days after lysis or medical therapy Van Belle et al. Circulation. 1998;97:26-
33.
11. 999 Pts within 8 wks of UA or Acute MI
Rx : ASA 80 mg; Coumadin (INR 3-4); or Combination: ( INR 2-2.5)+ ASA 80 mg
Efficacy Safety
30
Major Bleed
Death,MI,CVA
Tranfusion
20
Minor Bleed 15
%
10 8
5
1 1 1 1 2 1
0
ASA Coumadin Combo
Rate of
Discontinuation
10% 19% 20%
van Es et al Lancet 360:109,2002
15. ⇒ Effective
Rapid onset and offset of action
⇒ Safe
Predictable PK and PD
Wide therapeutic window
⇒ Easy
No need for monitoring
Oral, preferably once daily
Fixed doses
Low propensity for food and drug interactions
17. ORAL PARENTERAL
TF/VIIa TFPI (tifacogin)
TTP889
X IX
Rivaroxaban IXa APC (drotrecogin alfa)
Apixaban VIIIa sTM (ART-123)
LY517717
Va
YM150 AT Fondaparinux
DU-176b Xa
Idraparinux
Betrixaban
TAK 442
II DX-9065a
Dabigatran IIa
Fibrinogen Fibrin
apted from Weitz & Bates, J Thromb Haemost 2007
18. Tissue
XIIa factor
XIa VIIa
IXa
Xa
II
×Factor IIa
(thrombin)
Dabigatran
19. Dabigatran doses of 150 and 220 mg once daily (od) were
investigated in all three studies
Study Type of Comparator Number of Time to 1st Treatment
surgery patients administration duration
of dabigatran
RE-MODEL TKR Enoxaparin 2010 1–4 hours 6–10 days
40 mg od, starting post-surgery
evening before
surgery
RE-MOBILIZE TKR Enoxaparin 2615 6–12 hours 12–15 days
30 mg bid, starting post-surgery
12–24 hours post-
surgery
RE-NOVATE THR Enoxaparin 3494 1–4 hours 28–35 days
40 mg od, starting post-surgery
evening before
surgery
TKR: total knee replacement; THR: total hip replacement
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
20. Enoxaparin Dabigatran Dabigatran
(150 mg) (220 mg)
DVT, PE and all-cause mortality (%)
RE-NOVATE 6.7 8.6 6.0
p<0.0001* p<0.0001*
RE-MOBILIZE 25.3 33.7 31.1
p=0.0009 †
p=0.02†
RE-MODEL 37.7 40.5 36.4
p=0.0005* p=0.0345*
Major bleeding (%)
RE-NOVATE 1.6 1.3 2.0
RE-MOBILIZE 1.4 0.6 0.6
RE-MODEL 1.3 1.3 1.5
*Non-inferior to enoxaparin; †inferior to enoxaparin
Eriksson et al. Blood 2006; Friedman et al. J Thromb Haemost 2007; Eriksson et al. J Thromb Haemost 2007
21. Tissue
XIIa factor
×
XIa VIIa
IXa
Rivaroxaban
Xa
Apixaban
YM150
DU-176b
LY517717
Factor II Betrixaban
(prothrombin) TAK 442
Fibrinogen Fibrin clot
22. Oral, direct, selective factor Xa
O
inhibitor
Produces concentration-dependent N NH2
anticoagulation N
No formation of reactive
intermediates
O O N
No organ toxicity or LFT abnormalities
in chronic toxicology studies
Low likelihood of drug interactions or
QTc prolongation
Good oral bioavailability N O
No food effect
Balanced elimination (~25% renal)
Half-life ~12 hrs
He et al., ASH, 2006, Lassen, et al ASH, 2006
23. Apixaban od and bid (total daily doses 5-20mg) were assessed
relative to enoxaparin and warfarin, in 1,217 patients
Total VTE and All-Cause Mortality (%)
Total VTE and All-Cause Mortality (%) Major Bleeding (%)
Major Bleeding (%)
30 26.6 30
25 25
Percent
Percent
20 20
15.6
15 15
10.6
10 8.6 10
6.8
5 5 3.0
1.3 1.6
0 0
0 0
Enoxaparin Enoxaparin
5mg 10mg20mg Warfarin
(INR (30mg bid) 5mg 10mg20mg Warfarin
(INR (30mg bid)
Apixaban 1.8-3.0) Apixaban 1.8-3.0)
(Total Daily Dose) (Total Daily Dose)
Lassen et al. Blood 2006
24. Apixaban bid (5 and 10mg) and od (20mg) were assessed
relative to low molecular weight heparin (LMWH) or
fondaparinux followed by VKA, in 520 patients
Composite of Symptomatic
Composite of Symptomatic
Recurrent VTE and Deterioration
Recurrent VTE and Deterioration Major Bleeding (%)
Major Bleeding (%)
of Thrombotic Burden (%)
of Thrombotic Burden (%)
10 10
8 8
6.0
6 5.6 6
Percent
Percent
4.2
4 4
2.6
2 2 0.8
0.8
0 0
0 0
5mg 10mg 20mg LMWH/ 5mg 10mg 20mg LMWH/
fondaparinux fondaparinux
bid bid bid + VKA bid bid bid + VKA
Apixaban Apixaban
Büller, Eur Heart J 2006
25. Agent Disadvantages
Heparin • Parenteral administration
• Risk of heparin-induced thrombocytopenia (HIT)
• Narrow therapeutic window (low bioavailability, short
half-life)
Warfarin • Requires frequent monitoring due to:
– Narrow therapeutic window
– Unpredictable pharmacology
– Multiple drug–drug and food–drug interactions
– Increased risk of major and minor bleeds
LMWH • Parenteral administration
• Risk of heparin-induced thrombocytopenia (HIT)
Indirect Xa • Parenteral administration
Inhibitor • Long half-life
(e.g. fondaparinux) • Limitations related to special patient populations
Direct • Parenteral administration
Thrombin • Current applications limited to cardiovascular
Inhibitors management
Albans S et al. Eur J Clin Invest 2005;35(Suppl 1):12-20.
26. Predictable O
Cl
pharmacology
O S
O N N H
N
O
O
Rivaroxaban® – rivaroxaban
High bioavailability
Low risk of drug–drug
interactions
Fixed dose
No requirement for
monitoring
Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007; Roehrig et al, 2005
27. Direct, specific, competitive Factor Xa inhibitor
Inhibits free and fibrin-bound Factor Xa activity,
and prothrombinase activity
Does not directly inhibit thrombin, but inhibits
thrombin generation via inhibition of Factor Xa
activity
Does not affect agonist-induced platelet
aggregation,
and therefore has no direct effect on primary
hemostasis
Does not require a cofactor
No interaction with aspirin, enoxaparin, digoxin,
naproxen, ranitidine, or antacids
Perzborn et al., J Thromb Haemost 2005; ICT 2004; Depasse et al., ISTH 2005;
Kubitza et al., J Clin Pharmacol 200; ASH 2005; Fareed et al., ISTH 2005
28. XIa TF (Tissue Factor)
XI
Intrinsic Pathway
IX IXa VIIa + TF VII
Extrinsic Pathway
VIIIa
X Xa
If either Intrinsic or Extrinsic
pathway is activated, Rivaroxaban Va
blocks the final common II IIa (Thrombin)
coagulation pathway leading to
thrombin formation by blocking
Factor Xa Fibrinogen Fibrin
29. Two large, phase II studies of rivaroxaban for 3 mo for
treatment and long-term secondary VTE prevention:
› ODIXa-DVT : Rivaroxaban 10–30 mg bid
and 40 mg od
› EINSTEIN DVT : Rivaroxaban 20–40 mg od
› LMWH followed by VKA comparator in both studies
Agnelli et al. Circulation 2007; Büller. Eur Heart J 2006
30. Oral rivaroxaban compared with
subcutaneous enoxaparin for
extended thromboprophylaxis after
total hip arthroplasty
31. 5
Rivaroxaban 10 mg once daily
Total VTE Enoxaparin 40 mg once daily
4 RRR 70%
Incidence (%)
3
Major VTE
RRR 88%
2
Symptomatic VTE
1 Major
bleeding
3.7% 1.1% 2.0% 0.2% 0.5% 0.1%
0.3% 0.3%
0
33. 10
Total VTE Rivaroxaban 10 mg once daily
Enoxaparin 40 mg once daily
8
Incidence (%)
6
Major VTE
4
Symptomatic
RRR 78.9% VTE
2 Major bleeding
RRR 87.8%
RRR 80.1%
9.3% 2.0% 5.1% 0.6% 1.2% 0.2% 0.1% 0.1%
0
34. Rivaroxaban – an oral, direct Factor Xa inhibitor –
for the prevention of venous thromboembolism in
total knee arthroplasty surgery
35. Total VTE
20
RRR 49%
Enoxaparin 40 mg
od
Rivaroxaban 10
15 mg od
Incidence (%)
10
Major VTE
5 Symptomatic VTE
Major bleeding
RRR 62% RRR 65%
NS
18.9% 9.6% 2.6% 1.0% 2.0% 0.7% 0.5% 0.6%
0
36. 70
Rivaroxaban 1.25 mg (n=8)
Rivaroxaban 5 mg (n=6)
60
Rivaroxaban 10 mg (n=8)
50
Anti-Xa Activity Rivaroxaban 20 mg (n=7)
% Inhibition of Factor Xa
Rivaroxaban 40 mg (n=8)
40 Rivaroxaban 80 mg (n=6)
Placebo (n=25)
30
20
10
0
-10
0 2 4 6 8 10 12 14 16 18 20 22 24
Time (hours)
► All once-daily dosage regimens demonstrated
Xa inhibition for out to 24 hours
► These results provided foundation for selection of
Kubitza, et al. Clin Pharmacol Ther 2005;78(4):412-21. once-daily dosing regimen for Phase III programs
37. Specific, competitive,
direct FXa inhibitor
Inhibits free and clot-
associated FXa activity, 100
and prothrombinase
Inhibition of Factor Xa activity (%)
activity 80
Inhibits thrombin
generation via inhibition of
FXa activity 60
◦ Prolongs time to thrombin 40
generation
◦ Inhibits peak thrombin 20
Free FXa
generation Prothrombinase activity
Clot-associated FXa
◦ Reduces the total amount 0
of thrombin generated 0.01 0.1 1 10 100 1000
Rivaroxaban (nM)
Does not require a
cofactor
Perzborn et al. J Thromb Haemost 2005; ICT 2004; Depasse et al. ISTH 2005; Kubitza et al. Clin Pharmacol Ther
2005; Br J Clin Pharmacol, 2007; Graff et al. In press
38. • Dose peaks in 2.5–4 hrs, t1/2=5-9 hrs (11-13 hrs in elderly)
• One dose will be selected for clinical use
• No monitoring required given consistent dose response
• Dual modes of excretion
•Renal (66%), no excess bleeding associated with CrCl
•Fecal/biliary (28%)
• Minimal drug/drug interactions, no major circulating
metabolites, no drug accumulation
Kubitza et al., Eur J Clin Pharmacol 2005; Eriksson et al., J Thromb Haemost 2006; Turpie et al., J Thromb
Haemost 2005; Kubitza et al., ISTH 2005; Kubitza et al., ASH 2005; Kubitza et al., J Clin Pharmacol 2006
40. Primary
Total venous thromboembolism (VTE): any
deep vein thrombosis (DVT), non-fatal
pulmonary embolism (PE), and all-cause
mortality
Secondary
Major VTE: proximal DVT, non-fatal PE, and
VTE-related death
DVT: any, proximal, distal
Symptomatic VTE
All endpoints were adjudicated centrally by independent, blinded committees
41. Rivaroxaban Safety: Bleeding Time
Tail Transection Bleeding Time in Rats
X-fold prolongation of
Compound bleeding time at ED50
(control =1)
Rivaroxaban [po] 1.8
Enoxaparin [sc] 2.2
Ximelagatran [po] 3.7
Dabigatran [po] 4.9
Warfarin [po] > 6.3
Bleeding time comparable to enoxaparin
Lower compared to thrombin inhibitors or
warfarin
42. Main
Major bleeding starting after the first blinded dose
and
≤2 days after last dose
◦ Bleeding that was fatal, into a critical organ or required
re-operation
◦ Extra-surgical-site bleeding associated with a drop in
hemoglobin ≥2 g/dL or requiring transfusion of ≥2 units
blood
Other
Any bleeding on treatment*
Non-major bleeding*
Hemorrhagic wound complications*
Cardiovascular adverse events
Liver enzyme levels
All endpoints were adjudicated centrally by independent, blinded committees
*Up to 2 days after last dose of study medication
43. Rivaroxaban: Bleeding Time with
Combination Therapy
Tail Transection Bleeding Time in Rats
X-fold prolongation
Compounds
of bleeding time
Clopidogrel 1 mg/kg [po]
2.1 +/- 0.3
Aspirin 3 mg/kg [po]
Clopidogrel 1 mg/kg [po]
Aspirin 3 mg/kg [po]
2.5 +/- 1
+
Rivaroxaban 0.1 mg/kg [iv]
Similiar Bleeding Times
44. DVT, PE, and all-cause mortality Major, post-operative bleeding
30
Incidence rate %
20
10
0
0 5 10 15 20 25 30 35 40 Enoxaparin
40 mg
Total daily dose (mg) of Rivaroxaban
Eriksson et al., Circulation 2006
45. Rivaroxaban was well tolerated, with similar incidence of AEs as
enoxaparin
Rivaroxaban did not affect ECG parameters
Rivaroxaban did not have any substance-specific effects on
laboratory parameters (except for clotting tests)
LFT increases with BAY 59-7939 did not exceed the level observed
with enoxaparin
› There was no dose-dependent increase in transaminase levels
Liver function
test (LFT) Rivaroxaban Enox
5 mg 10 mg 20 mg 30 mg 40 mg 40 mg
ALT > 3× ULN 5/119 6/133 4/133 7*/129 5/127 10/140
% 4.2 4.5 3.0 5.4 3.9 7.1
*One patient had ALT >3× ULN and bilirubin >2× ULN (occurring before first intake of study
drug)
46. Phase II Phase III
VTE prevention after major ODIXa-HIP1
orthopaedic surgery ODIXa-HIP2
ODIXa-KNEE RECORD1
ODIXa-OD-HIP RECORD2
RECORD3
RECORD4
VTE prevention in
hospitalized medically ill
patients
VTE treatment ODIXa-DVT
EINSTEIN-DVT EINSTEIN-DVT
EINSTEIN-PE
EINSTEIN-EXT
Stroke prevention in atrial
fibrillation Japanese Phase III study
Secondary prevention of
acute coronary syndromes
~8,000 >42,000
48. Safety
Rivaroxaban
Efficacy Ease
CM Gibson 2007
49. Is a selective, reversible, active-site directed Factor
Xa inhibitor that inhibits coagulation triggered by both
the collagen (intrinsic) and tissue factor (extrinsic)
pathways
Reduces thrombus formation in both venous and
arterial thrombosis models
Has a bleeding risk comparable to Enoxaparin, and
lower compared to thrombin inhibitors and Warfarin, in
preclinical in vivo models
CM Gibson 2007
50. Reaches Peak (Cmax)) in 2.5–4 hours; half-life of 5–9 hours
at steady state (little longer in older)
Dual modes of excretion: Renal (66%) & Faecal /
biliary (28%)
No substantial accumulation after multiple dosing, few
drug interactions
Dose dependent prolongation of prothrombin time
CM Gibson 2007
51. • Ongoing evaluation in acute
and chronic settings for Target Enrollment Phase II-III
prevention and treatment
of multiple venous and
35,000 - 40,000
arterial indications
CM Gibson 2007
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Editor's Notes
Lewis et al examined data from the 2658 PCI-CURE patients to evaluate the benefit of clopidogrel according to the timing of PCI after randomization. Rates of outcome events (CV death or myocardial infarction) were lower in patients treated with clopidogrel than with placebo, irrespective of the timing of intervention. The lowest absolute event rates were seen in patients treated with clopidogrel who underwent PCI within 48 hours of randomization. Lewis BS, Mehta SR, Keith AA, et al. Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events study. Am Heart J. 2005;150:1177-1184.
Lecture Notes Unfortunately, coronary angiography may underestimate the true incidence of thrombus. The impact of thrombolytic therapy on the true incidence of thrombus as assessed using direct visualization of thrombus via angioscopy is shown here. While the 30 day incidence of protruding thrombus was reduced from 70% to 30% in thrombolytic patients, all thrombolytic patients (n=40) had some form of thrombus (laminated shown here in red). Thus, thrombolysis reduces thrombus burden but thrombus remains, thrombolysis exposes underlying ulcerated lesions, and angioscopic evidence of plaque instability is more frequent in patients treated with thrombolysis. The high frequency of thrombotic lesions underscore the need for effective antithrombotic therapy following thrombolytic administration. Antithrombotic therapies in acute MI may therefore reduce the incidence of reocclusion or reinfarction. References 1. Van Belle et al. Circulation. 1998;97:26-33.
The ASPECT II study enrolled a broader population of pts including those within 8 wks of UA or Acute MI. Although the study planned to enroll 8700 pts enrollment was slow and was stopped after 999 pts were randomized to either ASA 80 mg, Coumadin (INR 3-4) , or a Combination of Coumadin (INR 2-2.5) + ASA 80 mg. ANIMATE As expected, and by design, the INR values were higher in the Coumadin alone group than in the combination therapy group but were in range in only 40-50 % of pts. ANIMATE Both OA arms showed significantly lower rates of D/MI/CVA than the ASA alone control arm. ANIMATE Although the rate of major bleeding was similarly low across all 3 grouprs those pts receiving OA had higher rates of txn and minor bleeds. ANIMATE Note also that the rate of discontinuation of treatement was 10% in the ASA alone arm but double that in the OA arms---a pattern seen in other trials.
There are many targets for novel anticoagulants in the coagulation pathway: Tissue factor pathway inhibitor (TFPI) bound to Factor Xa inactivates the tissue factor (TF)–Factor VIIa complex, preventing initiation of coagulation Activated protein C (APC) degrades Factors Va and VIIIa, and thrombomodulin (soluble; sTM) converts thrombin (Factor IIa) from a procoagulant to a potent activator of protein C Fondaparinux and idraparinux indirectly inhibit Factor Xa, requiring antithrombin (AT) as a cofactor Direct (AT-independent) inhibitors of Factor Xa include rivaroxaban (BAY 597939), LY517717, YM150 and DU-176b (all orally available), and DX-9065a (intravenous) Oral, direct thrombin inhibitors include ximelagatran (now withdrawn) and dabigatran Weitz JI & Bates SM. New anticoagulants. J Thromb Haemost 2005;3:1843–1853
Rivaroxaban is a novel, oral, direct Factor Xa inhibitor 1 Rivaroxaban has predictable dose-proportional pharmacokinetics and pharmacodynamics in healthy subjects, and showed no evidence of accumulation after multiple dosing 2 Studies in healthy subjects showed that rivaroxaban had no clinically relevant interactions with acetylsalicylic acid or naproxen. 3,4 Further studies demonstrated that the pharmacology of rivaroxaban was not affected by age, gender or weight to a clinically relevant degree, suggesting that fixed dosing should be possible for all patients 5,6 The phase II development programme of rivaroxaban involved four studies of rivaroxaban for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery 7–10 All of the doses investigated in the three double-blind studies of rivaroxaban in this indication (5–60 mg), had similar efficacy compared with the low molecular weight heparin enoxaparin 8–10 There were dose–response relationships between rivaroxaban and major bleeding in all of the studies; however, there were no significant differences in the observed incidence of major bleeding between rivaroxaban and enoxaparin in any study 8–10 These findings suggest that rivaroxaban has a wide therapeutic window When efficacy and safety were considered together, rivaroxaban 10 mg once daily (od) was selected for further investigation in the RECORD programme 10 1. Perzborn E et al. J Thromb Haemost 2005;3:514–521. 2. Kubitza D et al. Eur J Clin Pharmacol 2005;61:873–880. 3. Kubitza D et al. J Clin Pharmacol 2006;46:981–990. 4. Kubitza D et al. Br J Clin Pharmacol 2007;63:469–476. 5. Kubitza D et al. J Clin Pharmacol 2007;47:218–226. 6. Kubitza D et al. Blood 2006;108:Abstract 905. 7. Eriksson BI et al. Thromb Res 2007;doi:10.1016/j.thromres.2006.12.025. 8. Eriksson BI et al. J Thromb Haemost 2006;4:121–128. 9. Turpie AG et al. J Thromb Haemost 2005;3:2479–2486. 10. Eriksson BI et al. Circulation 2006;114:2374–2381.
Two phase IIb, dose-finding studies of rivaroxaban for the treatment and secondary prevention of DVT were undertaken. 1,2 The studies enrolled >1150 patients with acute, symptomatic proximal DVT In ODIXa-DVT (bid study), the primary endpoint was an improvement in thrombus burden (assessed by ultrasound) without recurrent VTE (recurrent DVT, PE or VTE-related death), after 3 weeks’ treatment In EINSTEIN-DVT (od study), the primary endpoint was a deterioration in thrombus burden (on either CUS or PLS) with recurrent VTE, after 3 months’ treatment In ODIXa-DVT, the incidences of improved thrombus burden with the bid rivaroxaban doses after 3 weeks’ treatment were greater than with od rivaroxaban and standard therapy After 3 months’ treatment, all rivaroxaban doses and regimens, in both studies, had similar efficacy to standard therapy for the prevention of recurrent VTE Incidences of major bleeding with rivaroxaban were low in ODIXa-DVT (1.7–3.3% vs 0% with standard therapy) Incidences of clinically relevant bleeding (the composite of major and clinically relevant, non-major bleeding) with rivaroxaban were low in EINSTEIN-DVT and similar to standard therapy (2.2–6.0% vs 8.8% with standard therapy) The greater efficacy of bid rivaroxaban for thrombus regression early after DVT formation, relative to od rivaroxaban, suggest that a bid regimen may offer the optimum benefit to the patient in the first few weeks of treatment. Lower bleeding incidences with long-term od rivaroxaban, and improved compliance with od regimens, suggest that an od regimen would be the best choice for long-term treatment and secondary prevention of VTE. This approach is being investigated in phase III studies Agnelli G et al . Treatment of acute, symptomatic, proximal deep vein thrombosis with the oral, direct Factor Xa inhibitor rivaroxaban (BAY 59-7939) – the ODIXa-DVT dose-ranging study. Eur Heart J 2006;27(Abstract Supplement):761 Buller HR. Once-daily treatment with an oral, direct Factor Xa inhibitor – rivaroxaban (BAY 59-7939) – in patients with acute, symptomatic deep vein thrombosis. The EINSTEIN-DVT dose-finding study. Eur Heart J 2006;27(Abstract Supplement):761
summarizes main efficacy and safety results of trial. rivaroxaban regimen significantly superior to enoxaparin for: Prevention of total VTE, with an RRR of 78.9% Prevention of major VTE, with an RRR of 87.8% The incidence of major bleeding was very low and similar for both groups
Information for speakers: most of the following slides contain important notes to accompany the presentation
This slide summarizes the main efficacy and safety results of this trial Rivaroxaban was significantly superior to enoxaparin for the prevention of the composite of DVT, PE and all-cause mortality, with a RRR of 49% Rivaroxaban was significantly superior to enoxaparin for the prevention of major VTE, with a RRR of 62% The incidence of major bleeding was low and similar for both drugs
Results of in vitro studies have shown that rivaroxaban is a direct, specific, competitive Factor Xa inhibitor. 1 Studies in healthy subjects demonstrated that it has no direct effect on thrombin and does not require a cofactor 2 Rivaroxaban inhibits free and fibrin-bound Factor Xa activity, prothrombinase activity, and Factor Xa generated via the intrinsic or extrinsic coagulation pathway in human plasma 1,3 Rivaroxaban has potent anticoagulant effects, as demonstrated by its effects on global clotting tests (prothrombin time, activated partial thromboplastin time) 2,4 Rivaroxaban does not affect platelet aggregation 5–7 Recombinant FVIIa, given after the initiation of bleeding, partially reversed the anticoagulant effect of high-dose rivaroxaban 8 Perzborn E et al . In vitro and in vivo studies of the novel antithrombotic agent BAY 597939—an oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3:514–521 Kubitza D et al . Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 597939, an oral, direct Factor Xa inhibitor. Clin Pharmacol Ther 2005;78:412–421 Depasse F et al . Effect of BAY 59-7939 – a novel, oral, direct Factor Xa inhibitor – on clot-bound Factor Xa activity in vitro . J Thromb Haemost 2005;3(S1):Abstract P1104. Poster presentation at the International Society on Thrombosis and Haemostasis XXth Congress, Sydney, Australia, August 6–12, 2005 Kubitza D et al . Safety, pharmacodynamics and pharmacokinetics of BAY 597939 – an oral, direct Factor Xa inhibitor – after multiple dosing in healthy male subjects. Eur J Clin Pharmacol 2005;61:873–880 Perzborn E et al . Biochemical and pharmacologic properties of BAY 59-7939, an oral, direct Factor Xa inhibitor. Pathophysiol Haemost Thromb 2004;33(S2):Abstract PO079. Poster presentation at the 18th International Congress on Thrombosis, Ljubljana, Slovenia, June 20–24, 2004 Fareed J et al . Antithrombotic mechanism of action of BAY 597939 – a novel, oral, direct Factor Xa inhibitor. J Thromb Haemost 2005;3(S1):abstract P0518. Poster presentation at the XXth International Society on Thrombosis and Haemostasis Congress, Sydney, Australia, August 6–12, 2005 Kubitza D et al . Rivaroxaban (BAY 59‑7939) – an oral, direct Factor Xa inhibitor – has no clinically relevant interaction with naproxen. Br J Clin Pharmacol , 2007;63:469–474 Tinel H, Huetter J, Perzborn E. Partial reversal of the anticoagulant effect of high-dose rivaroxaban – an oral, direct Factor Xa inhibitor – by recombinant Factor VIIa in rats. Blood 2006;108(11):Abstract 915
The primary efficacy endpoint was the incidence of the composite of any deep vein thrombosis (DVT) (as detected by mandatory bilateral venography), non-fatal pulmonary embolism (PE) and all-cause mortality by day 13 +4 (total VTE) The main secondary efficacy endpoint was major VTE – the composite of proximal DVT, non-fatal PE and VTE-related death Further efficacy endpoints included the incidence of DVT, symptomatic VTE and events occurring during the follow-up period
The main safety endpoint was the incidence of major bleeding events beginning after the first blinded dose of study medication and up to 2 days after the last dose Major bleeding included Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Clinically overt extra-surgical-site bleeding associated with a fall in haemoglobin of ≥2 g/dl or requiring the infusion of >2 units of blood or packed cells Other safety endpoints included Any on-treatment bleeding Any on-treatment, non-major bleeding (any on-treatment bleeding event not adjudicated as major bleeding) Haemorrhagic wound complications (the composite of excessive wound hematoma and surgical-site bleeding) Further safety endpoints also included liver enzyme monitoring and cardiovascular adverse events occurring during and after therapy
Rivaroxaban has a wide therapeutic window When efficacy and safety are considered together, this study suggests that 10 mg once daily is the optimum dose of Rivaroxaban
In the post-surgical setting, after short-term use