Idarucizumab For Dabigatran Reversal: Updated Results Of The Re-verse Ad Study

MedicalResearch.com Interview with:

Dr. Charles Pollack MD Professor of Emergency Medicine Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia.

Dr. Charles Pollack

Dr. Charles Pollack MD
Professor of Emergency Medicine
Sidney Kimmel Medical College at
Thomas Jefferson University, Philadelphia.

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: RE-VERSE AD™ is a multinational, open-label cohort Phase III trial studying the safety and efficacy of idarucizumab (PRAXBIND) to reverse the anticoagulant effects of dabigatran (PRADAXA) in patients with life-threatening or uncontrolled bleeding, or those who require emergency procedures.

It is the largest patient study investigating a reversal agent for a novel oral anticoagulant (NOAC) in real world emergency settings. At the American Heart Association’s Scientific Sessions 2016, we presented updated results from 494 patients participating in the ongoing study, showing that administration of 5g of idarucizumab immediately reversed the anticoagulant effect of dabigatran.

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Laser-Assisted Technology Allows Easier Removal of IVC Filters

MedicalResearch.com Interview with:

William T. Kuo, MD, FSIR, FCCP, FSVM Director, Stanford IVC Filter Clinic Director, IR Fellowship Program Founding Director, IR-DR Residency Program Associate Professor, Interventional Radiology Stanford University Medical Center Stanford, CA

Dr. William T. Kuo

William T. Kuo, MD, FSIR, FCCP, FSVM
Director, Stanford IVC Filter Clinic
Director, IR Fellowship Program
Founding Director, IR-DR Residency Program
Associate Professor, Interventional Radiology
Stanford University Medical Center
Stanford, CA

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: In the USA, over 250,000 IVC filters are now implanted each year, and rising filter use has led to an increase in filter-related morbidity and recognition of the potential complications from indwelling IVC filters. Consequently, the FDA has issued two safety communications alerting all physicians caring for patients with IVC filters to consider removing the filter as soon as protection from pulmonary embolism is no longer needed:

http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm221676.htm

http://www.fda.gov/MedicalDevices/Safety/AlertsandNotices/ucm396377.htm?so urce=govdelivery&utm_medium=email&utm_source=govdelivery

Despite heightened awareness, up to 40-60% of IVC filters cannot be easily removed using standard methods alone, after the filter becomes firmly embedded. Additionally, many patients have undergone prior placement of a permanent-type filter not even designed for retrieval, leaving them with few options for safe device removal. Although all of these patients can develop filter-related morbidity especially after chronic implantation, there is currently no routine option for removing embedded IVC filters refractory to standard retrieval methods. Our 5-year first-in-human study of a novel procedure—laser-assisted filter removal— demonstrates the safety and efficacy of this technique to treat such patients. In a cohort refractory to standard retrieval methods and high force, endovascular laser-assisted retrieval was overall safe and successful in removing a variety of filter types including permanent filters, regardless of dwell time and without the need for open surgery.

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Use of Oral Anticoagulation at Time of PCI Surgery Linked To Increase in Adverse Events

MedicalResearch.com Interview with:

Eric A. Secemsky, MD MSc Interventional Cardiology Fellow Massachusetts General Hospital, Harvard Medical School Fellow, Smith Center for Outcomes Research in Cardiology Beth Israel Deaconess Medical Center

Dr. Eric A. Secemsky

Eric A. Secemsky, MD MSc
Interventional Cardiology Fellow
Massachusetts General Hospital
Harvard Medical School
Fellow, Smith Center for Outcomes Research in Cardiology
Beth Israel Deaconess Medical Center

MedicalResearch.com: What is the background for this study?

Response: Use of oral anticoagulant (OAC) therapy prior to coronary stenting is a significant predictor of post-procedural bleeding events. Previous studies have estimated that the frequency of chronic OAC use among patients undergoing percutaneous coronary intervention (PCI) is between 3% to 7%. Yet many of these analyses examined select patient populations, such as those admitted with acute myocardial infarction or atrial fibrillation, and preceded the market approval of non-vitamin K antagonist oral anticoagulants (NOACs). As such, the contemporary prevalence of OAC use among all-comers undergoing PCI, as well as associated risks of adverse events, are currently unknown.

Therefore, we used PCI data from a large, integrated healthcare system to determine current use of  oral anticoagulant use among all-comers undergoing coronary stenting and the related short- and long-term risks of therapy.

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The GLORIA-AF Registry: Two Year Follow Up of Dabigatran for Non-Valvular A Fib Reported

MedicalResearch.com Interview with:

Menno Huisman, MD, PhD Associate professor Department of Medicine Leiden University Medical Center The Netherlands

Dr. Menno Huisman

Menno Huisman, MD, PhD
Associate professor
Department of Medicine
Leiden University Medical Center
The Netherlands

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: GLORIA™-AF is one of the largest ongoing global registry programs examining the use of oral antithrombotic agents in real-world clinical practice. The program is designed to characterize the population of newly diagnosed patients with non-valvular atrial fibrillation (NVAF) at risk for stroke, and to study patterns, predictors and outcomes of different regimens for stroke prevention.

At the ESC Congress 2016, we presented the first Phase II results of GLORIA-AF from approximately 3,000 NVAF patients, which showed that treatment with PRADAXA was associated with low incidences of stroke, major bleeding and life threatening bleeding. Less than 1% of PRADAXA-treated patients experienced a stroke over two years (0.63%). Major bleeding occurred in 1.12% of PRADAXA-treated patients and 0.54% experienced a life-threatening bleed.

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Complex Stent Procedures May Require Longer Period of Antiplatelet Therapies

MedicalResearch.com Interview with:

Gennaro Giustino MD Resident Physician - Department of Medicine The Icahn School of Medicine at Mount Sinai

Dr. Gennaro Giustino

Gennaro Giustino MD
Resident Physician – Department of Medicine
The Icahn School of Medicine at Mount Sinai

MedicalResearch.com: What is the background for this study?

Response: A period of dual antiplatelet therapy (DAPT) is required after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). The pathophysiological rationale for DAPT after DES-PCI is predicated on the need to prevent stent-related thrombotic complications while vascular healing and platform endothelialization are ongoing, a process that seems to last between 1 and 6 months with new-generation DES. Whether to extend DAPT after this mandatory period in order to provide a broader atherothrombotic risk protection (for stent-related and non-stent-related atherothrombotic events) is currently a matter of debate. Current guidelines recommend at least 6 months of DAPT after PCI in patients with stable coronary artery disease (CAD) and at least 12 months of DAPT in patients presenting with acute coronary syndrome (ACS). While, several risk scores have been developed to guide clinical decision making for DAPT intensity and duration (namely the DAPT score and the PARIS risk scores) little attention has been payed so far to PCI complexity and the extent of CAD to guide duration of DAPT. In fact irrespective of clinical presentation, patients undergoing more complex PCI procedure (likely due to greater coronary atherosclerotic burden) may remain at greater risk for ischemic events and therefore may benefit of prolonged, or more intense, DAPT.

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Many Atrial Fibrillation Patients At Risk of Stroke Receive Aspirin Instead of Appropriate Anticoagulation

MedicalResearch.com Interview with:

Jonathan Hsu, MD, MAS, FACC, FAHA, FHRS Assistant Professor Cardiac Electrophysiology, Division of Cardiology University of California, San Diego (UCSD)

Dr. Jonathan Hsu

Jonathan Hsu, MD, MAS, FACC, FAHA, FHRS
Assistant Professor
Cardiac Electrophysiology, Division of Cardiology
University of California, San Diego (UCSD)

MedicalResearch.com: What is the background for this study?

Response: Atrial fibrillation (AF) is the most common cardiac arrhythmia worldwide and imparts significant stroke risk. In patients with AF determined to be at intermediate to high risk for thromboembolism, anticoagulation with warfarin (a vitamin K antagonist) or the newer non-vitamin K antagonist oral anticoagulants clearly reduces morbidity and mortality compared to aspirin. We sought to evaluate practice patterns of cardiovascular specialists in the United states to determine how often AF patients at risk for stroke are prescribed aspirin over oral anticoagulation, and predictors of this practice.

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Even on Anticoagulation Atrial Fibrillation Contributes to Dementia Risk

MedicalResearch.com Interview with:

T. Jared Bunch, MD Director of Heart Rhythm Research Medical Director for Heart Rhythm Services Intermountain Healthcare system

Dr. T. Jared Bunch

T. Jared Bunch, MD
Director of Heart Rhythm Research
Medical Director for Heart Rhythm Services
Intermountain Healthcare System

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Bunch: Approximately 6 years ago we found that patients with atrial fibrillation experienced higher rates of all forms of dementia, including Alzheimers disease.  At the time we started to ask the questions of why this association existed.  We know that atrial fibrillation patients experience higher rates of stroke.  These patients are placed on blood thinners, most commonly warfarin, to lower risk of stroke which at the same time expose that patient to a higher risk of intracranial bleeding.  One possibility to explain the association was that perhaps dementia in the manifestation of many small clots or bleeds in the brain that in total lead to cognitive decline.  If this is the case, then the efficacy and use of anticoagulation is very important in atrial fibrillation patients.

We conducted additional studies that showed this to be the case.  In patients with no history of dementia, managed long-term with warfarin anticoagulation, those that had levels that were frequently too higher or too low that resulted in poor times in therapeutic range, experienced significantly higher rates of dementia.  The risk was highest in younger atrial fibrillation patients that were less than 80 years of age.  We then found that in atrial fibrillation patients that were frequently over anticoagulated and also use an antiplatelet agent, aspirin or plavix, the dementia rates nearly doubled.  At this point we raised the question if atrial fibrillation increased the risk beyond anticoagulation, or does anticoagulation efficacy drive most of the risk.  This question formed the background of the current study.

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Idarucizumab– PRAXBIND Reverses Anticoagulant Effects of Dabigatran

MedicalResearch.com Interview with:

Dr. Charles Pollack MD MA Thomas Jefferson University Philadelphia, PA 19107

Dr. Charles Pollack

Dr. Charles Pollack MD MA
Thomas Jefferson University
Philadelphia, PA 19107

MedicalResearch.com: What is the background for this study? What are the main findings?

Dr. Pollack:: We are continuing research on PRAXBIND in the ongoing global phase III patient study, RE-VERSE AD™. RE-VERSE AD includes two groups of dabigatran patients: those who had serious bleeding or those who required an urgent procedure.

At ACC, we presented results from an updated interim analysis from 123 patients enrolled in RE-VERSE AD™, which showed a single 5g of PRAXBIND immediately reversed the anticoagulant effect of dabigatran in all patients evaluated.

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Physician Anticoagulant Strategies during PCI for Heart Attack Vary

MedicalResearch.com Interview with:

Eric Alexander Secemsky, M.D Research Fellow in Medicine Massachusetts General Hospital

Dr. Eric Secemsky

Eric Alexander Secemsky, MD, MSc
Fellow in Cardiovascular Medicine
Massachusetts General Hospital
Harvard Medical School
Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center

MedicalResearch.com: What is the background for this study?

Dr. Secemsky: Strategies to reduce bleeding, such as the selective use of procedural anticoagulants, have become an integral component of current percutaneous coronary intervention (PCI) practice to decrease adverse outcomes. For instance, previous randomized clinical trials had demonstrated that use of bivalirudin, a direct thrombin inhibitor, reduces major bleeding events following PCI among patients presenting with acute myocardial infarction (AMI) compared with unfractionated heparin (UFH). These findings resulted in a major increase in bivalirudin use during PCI.

However, more recent trials have contradicted these results and created uncertainty as to the relative safety and effectiveness of bivalirudin therapy. In addition, current United States guidelines do not endorse a primary antithrombotic strategy during PCI, leaving the choice of procedural anticoagulant to the discretion of the physician operator. As such, we wanted to determine how bivalirudin was currently being used among United States PCI operators and how usage may have changed in light of these trial findings.

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Does Metabolizer Status Matter in Acute Coronary Syndromes Treated With Prasugrel vs Clopidogrel?

MedicalResearch.com Interview with:

Professor Keith AA Fox Duke of Edinburgh Professor of Cardiology University of Edinburgh

Prof. Keith Fox

Professor Keith AA Fox
Duke of Edinburgh Professor of Cardiology
University of Edinburgh

Medical Research: What is the background for this study?

Prof. Fox: From previous reports, certain alleles of CYP2C19 are associated with reduced enzymatic function and reduced conversion of clopidogrel to the active metabolite. Patients carrying these reduced function alleles (reduced metabolizers) exhibit higher platelet reactivity when treated with clopidogrel, compared with patients without reduced-function alleles (extensive metabolizers). However, the relationship of CYP2C19 genotype and outcomes in medically managed patients with acute coronary syndromes (ACS) is not known.

Medical Research: What are the main findings?

Prof. Fox: There was no association between CYP2C19 metabolizer status (EM vs. RM) and the primary composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke (hazard ratio [HR]: 0.86). EM and RM patients had similar rates of the primary endpoint whether treated with prasugrel (HR: 0.82) or clopidogrel (HR: 0.91; p for
interaction non significant).

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What Normalizes Bleeding Time Best After Coumadin Related Brain Bleed?

MedicalResearch.com Interview with:

Thorsten Steiner, MD, PhD Klinikum Frankfurt Hoechst and Heidelberg University Hospital Germany

Dr. Thorsten Steiner

Thorsten Steiner, MD, PhD
Klinikum Frankfurt Hoechst and Heidelberg University Hospital
Germany

Medical Research: What is the background for this study? What are the main findings?

Dr. Steiner: Background of the study is intracranial hemorrhage (ICH) related to vitamin-K antagonists. The mortality rate is about 60%. Main reason for the high mortality rate is hematoma expansion which occurs in about 50% during the acute phase right after the start of symptoms. We performed an investigator initiated randomized controlled trial (RCT) and found that a 4-factor prothrombin complex (PCC) is superior to fresh frozen plasma (FFP) in normalizing the international normalized ratio (INR) and prevents hematoma expansion. This let to more deaths within 48 hours in the FFP-group but had no clinical impact at 3 months – but our study was powered to detect INR normalization and not a clinical endpoint.
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Is the Evidence for the Anticoagulant Rivaroxaban Valid?

MedicalResearch.com Interview with:

Dr. Deborah Cohen

Dr. Deborah Cohen

Dr. Deborah Cohen
Associate Editor BMJ
BMA House, Tavistock Square
London

Medical Research: What is the background for this study? What are the main findings?

Dr. Cohen: Anyone familiar with warfarin understands the critical role of INR values in determining the proper dose for warfarin patients. The INR value in an individual patient is the most important piece of information a doctor considers when determining the warfarin dose. If the doctor gives too little warfarin then the patient may be at undue risk of stroke; if too much, the patient may be at undue risk of a major bleed.

The BMJ investigation revealed that the INR device used to manage the ~7,000 warfarin patients in the ROCKET trial (which served as the basis for approval of the non-valvular atrial fibrillation indication) was defective.

As such – doctors were relying upon a defective device in determining the dose of the warfarin patients – which has a direct influence on the stroke and bleeding risk in that patient. Since this was a comparative trial – any deficiency in the performance of the comparator arm (warfarin) would skew the results in favour of the study drug (rivaroxaban).

Since INR directly influences strokes and bleeds – the primary efficacy and safety endpoints – it very much questions, if not undermines, the overall results of this trial.

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History of Bleeding Helps Predict Risk of Bleeding from Anticoagulants

More on Anticoagulants on MedicalResearch.com
MedicalResearch.com Interview with:

Prof. Raffaele De Caterina M.D., Ph.D University Cardiology Division G. d'Annunzio University

Prof. De Caterina

Prof. Raffaele De Caterina M.D., Ph.D
University Cardiology Division G. d’Annunzio University

Medical Research: What is the background for this study? What are the main findings?

Dr. De Caterina: There is uncertainty on how to predict bleeding upon treatment with anticoagulants, because bleeding risk scores and thromboembolic risk score fare very similarly in predicting bleeding, making the net clinical benefit difficult to assess in the single patient. Here we find that a history of bleeding – even minor bleeding – has an important prognostic value on the risk of future bleeding – virtually all sorts of future bleeding, with the notable exception of intracranial hemorrhage. Some novel oral anticoagulants (NOACs), such as apixaban, studied here, reduce the risk of major bleeding, and appear to benefit independent of the bleeding history.

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Study Finds Women Who Take Anticoagulants Can Use Hormonal Therapy

Ida Martinelli MD, PhD A Bianchi Bonomi Hemophilia and Thrombosis Center Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan, Italy

Dr. Martinelli

MedicalResearch.com Interview with:
Ida Martinelli MD, PhD
A Bianchi Bonomi Hemophilia and Thrombosis Center
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milan, Italy 

Medical Research: What is the background for this study? What are the main findings?

Dr. Martinelli: Hormonal therapies are associated with an increased risk of venous thromboembolism. Patients with acute deep-vein thrombosis or pulmonary embolism require anticoagulation, but women of childbearing potential require also an adequate contraception, as oral anticoagulants cross the placenta potentially leading to embryopathy or fetal bleeding. This study was aimed to evaluate the safety of hormonal therapies together with anticoagulant therapies in terms of recurrent venous thrombosis and uterine bleeding. We demonstrated for the first time that women who take oral anticoagulants can safely use hormonal therapies, as their risk of recurrent venous thromboembolism or uterine bleeding is not increased.

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For Medicare Patients, Dabigatran Offers Significant Cost Savings Over Warfarin

Geoffrey Barnes, MD, MSc Clinical Lecturer Cardiovascular Medicine and Vascular Medicine University of Michigan Health System

Dr. Barnes

MedicalResearch.com Interview with:
Geoffrey Barnes, MD, MSc
Clinical Lecturer
Cardiovascular Medicine and Vascular Medicine
University of Michigan Health System

Medical Research: What is the background for this study?

Dr. Barnes: Although warfarin has been the primary anticoagulant used for stroke prevention in atrial fibrillation for over 60 years, four new direct oral anticoagulants (DOACs) have been introduced into the market since 2010. Dabigatran, which directly inhibits thrombin, was found to have better prevention of ischemic stroke and a significant reduction in hemorrhagic stroke (bleeding strokes) for patients with atrial fibrillation at intermediate and high risk of stroke.  Prior cost-effectiveness studies have shown that dabigatran is cost-effective from both the societal and payer (usually Medicare) perspectives.  However, none of those studies looked at the patient’s out-of-pocket costs and the impact of prescription drug coverage

Medical Research: What are the main findings?

Dr. Barnes: We found that patients with prescription drug coverage (Medicare Part D) had significant cost savings when choosing dabigatran over warfarin.  This is primarily because of the reduction in both types of stroke as well not needing to have frequent blood draws, as are required by warfarin.  However, when patients do not have prescription drug coverage, the costs for dabigatran are quite high.  Continue reading

Study Compares Anticoagulation Risk Scores in Atrial Fibrillation

H.A. (Hendrika) van den Ham PharmD Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences Utrecht University The Netherlands.MedicalResearch.com Interview with:
H.A. (Hendrika) van den Ham PharmD

Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences
Utrecht University
The Netherlands.

Medical Research: What is the background for this study? What are the main findings?

Dr. van den Ham: Atrial fibrillation (AF) is associated with a substantial risk of ischemic stroke and thromboembolism. The CHADSand the CHA2DS2-VASc risk scores are developed to guide the decision to prescribe anticoagulants. Recently a new clinically-based risk score, the ATRIA study risk score, was developed. We compared the predictive ability of the ATRIA risk score with the CHADS2 and CHA2DS2-VASc risk scores in a large, independent, community-based cohort of Atrial fibrillation patients in the United Kingdom. We found that the ATRIA score more accurately identified low risk patients that the CHA2DS2-VASc score assigned to higher risk categories.  Such reclassification of stroke risk could prevent overuse of anticoagulants in very low stroke risk patients with Atrial fibrillation.

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Triple Anticoagulation Therapy Raises Bleeding Risk in Elderly Patients with AFib and Heart Attack

Connie N. Hess, MD, MHS Duke Clinical Research Institute Duke University Durham, North CarolinaMedicalResearch.com Interview with:
Connie N. Hess, MD, MHS
Duke Clinical Research Institute
Duke University
Durham, North Carolina

Medical Research: What is the background for this study? What are the main findings?

Dr. Hess: Guidelines recommend the use of anticoagulation for thromboembolic prophylaxis in atrial fibrillation and also recommend use of dual antiplatelet therapy to reduce cardiovascular events after myocardial infarction and percutaneous coronary intervention.  The use of triple therapy in patients with indications for DAPT and anticoagulation is challenging due to the increased bleeding risk associated with this regimen.  The optimal antithrombotic regimen in this population has not yet been defined.

This study specifically focused on older patients, a population that is at greater risk for Atrial Fibrillation-related stroke and recurrent events after MI but also higher risk for bleeding. Despite a growing population of older patients with indications for triple therapy, these patients have been underrepresented in clinical trials and are therefore understudied.

We found that relative to DAPT, patients on triple therapy had a similar risk of 2-year major adverse cardiac events but a significantly increased risk of bleeding requiring hospitalization, including greater risk of intracranial hemorrhage.

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Oral Anticoagulation Medications Have Led To More Patients Treated For Atrial Fibrillation

Dr-Geoffrey-BarnesMedicalResearch.com Interview with:
Geoffrey Barnes, MD, MSc
Clinical Lecturer
Cardiovascular Medicine and Vascular Medicine
University of Michigan Health System

Medical Research: What is the background for this study? What are the main findings?

Dr. Barnes: While warfarin has been the primary oral anticoagulant used for over 60 years, a new class of anticoagulants known as ‘direct oral anticoagulants’ (including dabigatran, rivaroxaban and apixaban) have been introduced within the last 5 years.  These newer medications were developed to be easier for patients and physicians to use.  While early data suggested quick adoption of these medications, there had not been a nation-wide assessment of their use and how specific diseases influenced the use of specific oral anticoagulants.

Using a national sample of office visits, we generated national estimates of oral anticoagulant use for patients between 2009 and 2014.  The primary finding is that total number of office visits where an anticoagulant was used increased from 2.05 million to 2.83 million between 2009 and 2014, largely driven by a rapid increase in the use of the direct oral anticoagulant medications.  Specifically among patient visits for atrial fibrillation, the total number of visits where an oral anticoagulant was used increased from 52% to 67%.  This is important because there has long been concern about “under treatment” of atrial fibrillation and the risk of stroke for patients who do not receive anticoagulation.  This study suggests that the direct oral anticoagulants may be helping to protect more patients with atrial fibrillation from strokes.

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Duration of Anticoagulation After Primary Pulmonary Embolism Clarified

Professor Francis Couturaud, MD, PhD Department of Internal Medicine and Chest Diseases University Hospital Center of Brest Brest, FranceMedicalResearch.com Interview with:
Professor Francis Couturaud, MD, PhD
Department of Internal Medicine and Chest Diseases
University Hospital Center of Brest
Brest, France

Medical Research: What is the background for this study? What are the main findings?

Dr. Couturaud: Patients who have completed 3 to 6 months of anticoagulation for a first episode of pulmonary embolism that was not provoked by a major transient risk factor, such as surgery or prolonged immobilization, have a high risk of recurrent venous thromboembolism after stopping anticoagulation. In this high-risk population, extending anticoagulation beyond 3 to 6 months is associated with a major reduction in recurrences as long as the treatment is continued. However, whether this benefit is maintained thereafter remains uncertain, as in most previous studies, patients were not followed after treatment discontinuation. In addition, while extending anticoagulation is very effective in preventing recurrent venous thromboembolism, anticoagulation is also associated with an increased risk of bleeding. Therefore, in patients with a first episode of unprovoked pulmonary embolism, the optimal duration of anticoagulation remains uncertain.

In the PADIS-PE multicenter, double-blind, randomized trial that included 371 patients with a first episode of unprovoked pulmonary embolism initially treated during 6 months, we aimed to evaluate the benefit and risk of an additional 18 months of warfarin therapy versus placebo during the 18-month study treatment period and during an additional 2 years of follow-up after study treatment discontinuation.

The main findings are the followings: during the study treatment period, we found a 80% reduction in the relative risk of recurrent venous thromboembolism or major bleeding, mainly driven by the 90% risk reduction of recurrences; however, during the post-treatment follow-up period of two years, the benefit was lost, and the risks of recurrent venous thromboembolism and major bleeding were not different between the 2 groups. In addition, recurrent venous thromboembolism occurred as pulmonary embolism in 80% of cases (8% were fatal) and were unprovoked in 90% of cases.

Medical Research: What should clinicians and patients take away from your report?

Dr. Couturaud: Our study provides convincing result that extended but limited duration of anticoagulation does not improve the long-term prognosis of a first episode of unprovoked pulmonary.

The consequences for clinicians are the followings:

First, only two options of management should be discussed: either a conventional duration of 3 to 6 months or an indefinite duration of anticoagulation.

Second, more than ever, the individual risk factors of recurrent VTE if anticoagulation is stopped and risk factors of bleeding if anticoagulation is continued should be carefully identified and weighted in order to propose the most adequate long-term secondary prevention (long-term anticoagulation or specific prophylactic counseling in high-risk situations). This evaluation should also included patient’s preference.

Third, the benefit risk ratio of indefinite anticoagulation should be serially evaluated in these patients not only if indefinite anticoagulation is decided but also if anticoagulation is stopped as patient’s profile will change over the time (age, additional comorbidities, etc.) and in order to determine if anticoagulation should be stopped or started again.

For the patients, once the first episode of unprovoked pulmonary embolism, they should be informed about their high risk of recurrent venous thromboembolism if anticoagulation is stopped and their risk of bleeding if anticoagulation is continued. They also should be informed that recurrent venous thromboembolism occurs more often as pulmonary embolism; in this setting, patients should be informed about clinical symptoms of pulmonary embolism but also of deep vein thrombosis and the links between these two entities. This will help people to express their preferences.

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Couturaud: : The first issue is to identify, among patients with unprovoked venous thromboembolism, those who have a lower risk of recurrence that may not justify indefinite anticoagulation. Several predictive scores, combining clinical variables such at gender, age, and tests such as D-dimer have been derived but prospective validation is not yet available.
The second issue is to explore long-term secondary thrombo-prophylaxis strategies with a lower risk of bleeding and a similar efficacy. This is currently the case with aspirin and low dose of Direct Oral Anticoagulants. However, additional studies are needed to determine if such strategies have a better benefit risk ratio than conventional anticoagulation.

Citation:

Professor Francis Couturaud, MD, PhD, & Department of Internal Medicine and Chest Diseases (2015). Duration of Anticoagulation After Primary Pulmonary Embolism Clarified 

RE-VERSE AD: Anticoagulant Effect of Dabigatran Reversed By New Drug

MedicalResearch.com Interview with:
Dr. Charles Pollack Jr., MA, MD, FACEP
Thomas Jefferson University
Clinical Professor of Emergency Medicine
Philadelphia, PA 19107

MedicalResearch: What is the background for this study? What are the main findings?

Dr. Pollack: There are currently no approved specific reversal agents for non–vitamin K antagonist oral anticoagulants. Idarucizumab, an antibody fragment, was developed to specifically reverse the anticoagulant effects of the oral thrombin inhibitor, dabigatran.

RE-VERSE AD is an ongoing, global Phase III patient study initiated in 2014 to investigate idarucizumab in emergency settings in patients taking dabigatran. We undertook this prospective cohort study to determine the safety of 5 g of intravenous idarucizumab and its capacity to reverse the anticoagulant effects of dabigatran in patients who either presented with serious bleeding (group A) or required an urgent invasive procedure (group B) which could not be delayed by eight hours. We intentionally designed the study with very broad inclusion criteria to reflect the types of patients who would require urgent anticoagulant reversal in real-world emergency settings.

The primary end point was the maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours after the administration of idarucizumab, on the basis of the determination at a central laboratory of the dilute thrombin time or ecarin clotting time. We also diligently collected clinical outcomes as secondary outcomes, being conscious that these may vary considerably due to the heterogeneity of the patients we included in the study.

In our publication in the New England Journal of Medicine, we present the first results from the study, in an interim analysis of the data from the first 90 patients. The data showed that idarucizumab rapidly and completely reversed the anticoagulant effect of dabigatran in 88 to 98% of the patients who had had elevated clotting times at baseline. The reversal effect was evident within minutes. There were no safety concerns related to idarucizumab among the 90 patients involved in this study – including patients who were given idarucizumab on clinical grounds but were later found to have had normal results on clotting tests at baseline. This is consistent with the experience from the more than 200 volunteers who were administered idarucizumab in previous studies.

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Anticoagulation Bridge Therapy May Be Unnecessary For Low Risk Venous Thromboembolism Patients


MedicalResearch.com Interview with:
Nathan Clark, PharmD
Clinical pharmacy supervisor, anticoagulation and anemia management services and
Thomas Delate, PhD
Clinical research scientist
Kaiser Permanente Colorado

MedicalResearch: What is the background for this study? What are the main findings?

Response: Patients with a history of blood clots are commonly prescribed warfarin, an anticoagulant, to decrease the body’s ability to form additional clots. Clinicians typically stop the use of warfarin in patients to reduce the risk of serious bleeding when invasive procedures, such as colonoscopy or orthopedic surgery are scheduled. However, when warfarin interruptions occur, patients are exposed to an increased risk of blood clots three to five days before and five or more days after invasive procedures. Bridge therapy with another, faster acting anticoagulant is often initiated in an attempt to reduce the patients’ risk for developing blood clots during that gap.

Bridging has been a part of standard therapy for venous thromboembolism (VTE) patients undergoing invasive procedures for many years. But only limited data outlining the rates of bleeding and VTE recurrence were available to help clinicians analyze the risks and benefits of bridge therapy.

We examined the electronic medical records of 1,178 patients with VTE who underwent 1,812 invasive diagnostic or surgical procedures between January 2006 and March 2012 that required the interruption of warfarin therapy. Study patients were categorized into three groups based on their annual risk of VTE recurrence without anticoagulant therapy. Within those groups, a total of 555 patients – 28.7 percent of low-risk, 33.6 percent of moderate-risk and 63.2 percent of high-risk patients – received bridging anticoagulant therapy. The 1,257 patients who did not receive bridge therapy interrupted their warfarin use and received no other anticoagulants during the perioperative period. The use of bridge therapy resulted in a 17-fold higher risk of bleeding without a significant difference in the rate of blood clot formation compared to patients who didn’t receive bridge therapy. In addition, there were no significant differences in the rates of blood clot occurrence or death between the bridged and non-bridged patient groups. Continue reading

Study Weighs Risks/Benefits of Oral Anticoagulation for Atrial Fibrillation in Hemodialysis Patients

Dr. Simonetta Genovesi MD Department of Health Science University of Milano-Bicocca, Monza Italy Nephrology Unit San Gerardo Hospital, Monza, ItalyMedicalResearch.com Interview with: Dr. Simonetta Genovesi MD
Department of Health Science
University of Milano-Bicocca, Monza
Italy Nephrology Unit
San Gerardo Hospital, Monza, Italy

MedicalResearch: What is the background for this study?  

Dr. Genovesi: The prevalence of atrial fibrillation (AF) in patients
with end-stage renal disease (ESRD) on hemodialysis (HD)
is high. The presence of atrial fibrillation increases the risk of
thrombo-embolic stroke in the general population. The
treatment of choice for reducing thrombo-embolic risk in
AF patients is oral anticoagulant therapy (OAT) with
warfarin. However, the use of warfarin in HD patients is
controversial because of the high risk of bleeding and the
fact that it is not demonstrated a clear protection
against the risk of stroke in this population. The purpose
of the study was to prospectively evaluate the effect of
OAT on the risk of mortality, stroke and bleeding in HD
population.

MedicalResearch: What are the main findings?  

Dr. Genovesi: In our hemodialysis population oral anticoagulant therapy does not increase the risk of total mortality, while antiplatelet agents are associated
with an increased risk of death of about 70%. The
continuous use of warfarin tends to be associated with
improved survival as compared with individuals who
discontinued the medication during the follow-up, but the
incidence of thrombo-embolic events is not different in
OAT subjects as compared with those who do not take it.
Moreover, bleeding events are more frequent in patients
taking warfarin, although the maintenance over time of an
INR in the therapeutic range wards against the risk of
bleeding.
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JAMA Study Confirms Better Anticoagulation Choice After Myocardial Infarction

Karolina Szummer, MD, PhD Section of Cardiology, Department of Medicine Karolinska Institutet Karolinska University Hospital Stockholm, Sweden MedicalResearch.com Interview with:
Karolina Szummer, MD, PhD
Section of Cardiology, Department of Medicine
Karolinska Institutet Karolinska University Hospital
Stockholm, Sweden

Please note: This work is comparing the anticoagulant fondaparinux with low-molecular-weight heparin (not heparin).

Medical Research: What is the background for this study? What are the main findings?

Dr. Szummer: Since the publication of the OASIS-5 trial in 2006, many hospitals chose to change their medical practice and start using fondaparinux instead of low-molecular-weight heparin in the treatment of myocardial infarctions. In this study from the nation-wide near-complete myocardial infarction registry we were able to follow how the use of fondaparinux instead of low-molecular-weight heparin translated in clinical life was associated to a reduction in bleeding events and death. It is a very satisfying study, that confirms that the randomized clinical trial results are transferred with improvements in outcome to the treated patients.

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Study Highlights Unpredictable Anticoagulation With Warfarin

Winnie Nelson PharmD, MS, MBA Director, Health Economics & Outcomes Research Janssen PharmaceuticalsMedicalResearch.com Interview with:
Winnie Nelson PharmD, MS, MBA

Director, Health Economics & Outcomes Research
Janssen Pharmaceuticals

Medical Research: What is the background for this study? What are the main findings?

Dr. Nelson: Although warfarin has long served as the standard of care for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF), research has shown nearly one-third of international normalized ratio (INR) levels among stabilized patients on warfarin are out-of-range. Data recently published in the International Journal of Clinical Pharmacy underscores the potential complications of out-of-range INRs, with the aim of informing patient care.

The analysis of a U.S. Veterans Health Administration dataset showed out-of-range INRs were associated with a significantly increased risk of adverse clinical outcomes, including stroke and major bleeding. Of particular interest, the study also showed the magnitude of risk of thromboembolic events – such as ischemic stroke – was several folds higher in sub-therapeutic INR levels (i.e., INR <2) than risk of bleeding events when INR measures were >3. In another words, the research found more risks to patients when INRs were too low than when INRs were too high.
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Anticoagulation in Chronic Kidney Disease Patients with Atrial Fibrillation

Anders Nissen Bonde MBs Department of Cardiology Copenhagen University Hospital Gentofte, Gentofte, Denmark MedicalResearch.com Interview with:
Anders Nissen Bonde MBs
Department of Cardiology
Copenhagen University Hospital Gentofte,
Gentofte, Denmark

Medical Research: What is the background for this study? What are the main findings?

Response: Patients with severe chronic kidney disease have been excluded from
randomized trials of antithrombotic therapy in atrial fibrillation.They
represent a very fragile group as they are both at increased risk of
stroke/thromboembolism and major bleedings, and previous observational
studies have had conflicting conclusions regarding the safety and benefits
of the treatment. A previous study from our department reported both
increased risk of bleeding and reduced risk of stroke with warfarin.

We wanted to assess the net clinical benefit of aspirin and warfarin in
these patients, balancing stroke and major bleeding associated with the
treatment.

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Monoclonal Idarucizumab Antibody May Reverse Dabigatran Anticoagulation

MedicalResearch.com Interview with:
Dr. Joanne van Ryn, PhD
Department of CardioMetabolic Disease Research
Boehringer Ingelheim GmbH & Co., Germany

MedicalResearch: What is the background for this study? What are the main findings?

Response: Idarucizumab is a humanized antibody fragment, or Fab, being investigated as a specific antidote to reverse the anticoagulant effect of dabigatran. Currently, there are no specific antidotes available for any of the newer oral anticoagulants, or NOACs, to complement the existing range of bleed management options during critical care situations. Idarucizumab is being developed to provide physicians with an additional therapeutic option they could consider should a patient require emergency intervention or if a patient experiences uncontrolled bleeding.

Pre-clinical studies indicated idarucizumab binds specifically to and inhibits dabigatran. Phase I data with idarucizumab in healthy volunteers demonstrated the potential of idarucizumab to achieve immediate, complete and sustained reversal of dabigatran-induced anticoagulation. In that placebo-controlled study, idarucizumab did not cause any clinically relevant side effects.

This phase I sub-study in 35 healthy volunteers showed that idarucizumab restores dabigatran-induced inhibition of fibrin formation at a small wound site. Fibrin, the main component of a blood clot, was assessed by measuring levels of fibrinopeptide A (FPA), a substance that is released when fibrin is formed. Fibrin formation was assessed after a small scratch, similar to a paper cut, was made. Measurements were conducted at baseline, after administration of dabigatran, and after subsequent administration of idarucizumab or placebo. The results showed that dabigatran almost completely inhibited the production of FPA at the wound site, and that idarucizumab restored FPA production:

  • At baseline, before the volunteers took dabigatran, the average level of FPA was 3981 ng/mL.
  • On day three, 2.5 hours after the volunteers took dabigatran, the average level of FPA was 208 ng/mL, an approximate 95 percent decrease compared to baseline.
  • On day four, 2.5 hours after the volunteers took dabigatran and 30 minutes after they were infused with 1 g, 2 g or 4 g of idarucizumab, FPA levels were 24 percent, 45 percent and 95 percent, respectively, of the average baseline level.

The restored fibrin production at the wound site after idarucizumab dosing with 2g or 4g also correlated with reversal of the dabigatran-anticoagulation activity in circulating blood.

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Dabigatran vs Warfarin in Non-Valvular Atrial Fibrillation

dr_John-SeegerMedicalResearch.com Interview with:
Dr. John Seeger
, PharmD, DrPH
Department of Medicine, Brigham and Women’s Hospital

Dr. Seeger: What is the background for this study? What are the main findings?

Response: This study is part of an ongoing research program initiated in 2013 to assess prescribing patterns and real-world safety and effectiveness of oral anticoagulants, including dabigatran, for the reduction of stroke risk. The study program is expected to run through the end of 2016. Boehringer Ingelheim and Brigham and Women’s Hospital are aiming to gather data from more than 100,000 U.S. NVAF patients.

Using a sequential matched cohort design, the safety and effectiveness of dabigatran compared to warfarin among patients with non-valvular atrial fibrillation (NVAF) receiving these medications in routine care settings can be assessed periodically. The interim findings at this stage come from 38,378 non-valvular atrial fibrillation patients in two health insurance databases, MarketScan (31,058 patients) and UnitedHealth (7,320 patients). The primary analysis follows patients from start of therapy until a switch or discontinuation of the anticoagulant, an outcome event, or disenrollment. The average follow-up was five months for patients in the dabigatran group and four months for those taking warfarin. The primary outcomes measured in the analysis are stroke and major hemorrhage.

Interim findings from the combined databases showed a 25 percent reduction in the rate of major hemorrhage (hazard ratio [HR] 0.75, 95 percent confidence interval [CI] 0.65-0.87, 354 vs. 395 events) and a 23 percent reduction in strokes (HR 0.77, CI 0.54-1.09, 62 vs 69 events) for dabigatran compared to warfarin among these patients with NVAF. The database-specific results indicate a reduction in the rate of major hemorrhage with dabigatran (MarketScan: HR 0.78, CI 0.67- 0.91; UnitedHealth: HR 0.56, CI 0.36-0.86). In the larger MarketScan database, dabigatran reduced the stroke rate by 36 percent (HR 0.64, CI 0.44-0.95), while in the smaller UnitedHealth database, stroke rates were not different between the two anticoagulants, as there were only 26 strokes in total which led to wide confidence intervals (HR=1.62, CI 0.72-3.66).
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Warfarin Dosing: Do Genotype-Based Algorithms Improve Outcomes?

MedicalResearch.com Interview with:
David Ldr_david_l_brown. Brown, MD, FACC
Professor of Medicine
Cardiovascular Division
Washington University School of Medicine
St. Louis, MO 63110

MedicalResearch: What are the main findings of the study?

Dr. Brown: This meta-analysis of randomized controlled trials showed that using a genotype-based warfarin dosing algorithm did not improve the process or outcomes of anticoagulation compared to using a clinical dosing algorithm.
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Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism

 Author Interview: Sam Schulman M.D., FRCPC(C) Professor, Division of Hematology and Thromboembolism, Department of Medicine Associate Professor, Medicine, Karolinska Institute, Stockholm, Sweden Director, Clinical Thromboembolism Program Hamilton Health Sciences, Hamilton General Hospital, Hamilton, OntarioMedicalResearch.com  Author Interview: Sam Schulman M.D., FRCPC(C)
Professor, Division of Hematology and Thromboembolism, Department of Medicine
Associate Professor, Medicine, Karolinska Institute, Stockholm, Sweden
Director, Clinical Thromboembolism Program Hamilton Health Sciences, Hamilton General Hospital, Hamilton, Ontario

MedicalResearch.com: What are the main findings of the study?

Response: Similar effect of dabigatran  as warfarin, 92% risk reduction compared to placebo. The risk of bleeding is reduced by almost 50% compared to warfarin but in comparison with placebo there is an increased risk of minor bleeding. No routine coagulation monitoring or dose adjustments are required, making the treatment convenient for patients and physicians.
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