Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study

 FYI.  Ask your doctor what this means for you.

Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study

Gerrit M Grosse https://orcid.org/0000-0002-5335-9880, Anika Hüsing, […] on behalf of the PRODAST Investigators+13View all authors and affiliations

Volume 18, Issue 10

https://doi.org/10.1177/17474930231184366

• 
  

• • Abstract
  • Introduction
  • Aims
  • Methods
  • Results
  • Discussion
  • Acknowledgments
  • Declaration of conflicting interests
  • Funding
  • ORCID iDs
  • References
  • Supplementary Material
• PDF / ePub
• • Cite article
  • Share options
  • Information, rights and permissions
  • Metrics and citations
  • Figures and tables

Abstract

Background:

The optimal timing of initiating or resuming anticoagulation after acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is debated. Dabigatran, a non-vitamin K oral anticoagulant (NOAC), has shown superiority against vitamin K antagonists (VKA) regarding hemorrhagic complications.

Aims:

In this registry study, we investigated the initiation of dabigatran in the early phase after AIS or TIA.

Methods:

PRODAST (Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA) is a prospective, multicenter, observational, post-authorization safety study. We recruited 10,039 patients at 86 German stroke units between July 2015 and November 2020. A total of 3,312 patients were treated with dabigatran or VKA and were eligible for the analysis that investigates risks for major hemorrhagic events within 3 months after early (⩽ 7 days) or late (> 7 days) initiation of dabigatran or VKA initiated at any time. Further endpoints were recurrent stroke, ischemic stroke, TIA, systemic embolism, myocardial infarction, death, and a composite endpoint of stroke, systemic embolism, life-threatening bleeding and death.

Results:

Major bleeding event rates per 10,000 treatment days ranged from 1.9 for late administered dabigatran to 4.9 for VKA. Early or late initiation of dabigatran was associated with a lower hazard for major hemorrhages as compared to VKA use. The difference was pronounced for intracranial hemorrhages with an adjusted hazard ratio (HR) of 0.47 (95% confidence interval (CI): 0.10–2.21) for early dabigatran use versus VKA use and an adjusted HR of 0.09 (95% CI: 0.00–13.11) for late dabigatran use versus VKA use. No differences were found between early initiation of dabigatran versus VKA use regarding ischemic endpoints.

Conclusions:

The early application of dabigatran appears to be safer than VKA administered at any time point with regards to the risk of hemorrhagic complications and in particular for intracranial hemorrhage. This result, however, must be interpreted with caution in view of the low precision of the estimate.

Introduction

The timing of initiating or resuming of anticoagulation after an acute ischemic stroke (AIS) or transient ischemic attack (TIA) in patients with atrial fibrillation (AF) is still a matter of debate. Early initiation of anticoagulation may increase the risk of hemorrhagic transformation (HT) of the infarct and thus intracranial hemorrhage (ICH). Delaying the initiation of anticoagulation, however, may enhance the risk of recurrent ischemic events.¹ With one exception,² results from randomized controlled trials (RCTs) on the timing of anticoagulation^3–5 are not yet available and guidelines are currently based on expert opinion.^6–8 Surveys among stroke practitioners on timing of anticoagulation following AIS or TIA have shown no consensus in decision-making.^9,10

Observational studies on the initiation of anticoagulation after AIS or TIA in patients with AF yielded heterogeneous findings^1,11–14 and the majority of these studies were conducted in the era before non-vitamin K dependent anticoagulants (NOAC) replaced vitamin K antagonists (VKA). NOAC are safer compared to VKA with regard to major hemorrhagic complications.^15,16 However, the pivotal trials leading to the approval of NOAC in patients with AF excluded patients with AIS occurring 7–14 days before initiation of treatment.^17–20 Importantly, real-world data on the application of NOAC in the first week after AIS or TIA are scarce. We hypothesized that the hazards for major hemorrhages, most importantly ICH, may also be substantially lower in patients in whom NOAC are initiated early after AIS or TIA compared to patients who receive VKA.

Aims

The Prospective Record of the Use of Dabigatran in Patients with Acute Stroke or TIA (PRODAST; ClinicalTrials.gov Identifier: NCT02507856) study was initiated to provide real-world evidence on this issue. The main objective of PRODAST was the comparison of the 3-month rates of major hemorrhagic events between an early (⩽ 7 days) or late (> 7 days) initiation of dabigatran in comparison to treatment with VKA started at any time, in patients with AF and a recent AIS or TIA (⩽ 7 days). In addition to this primary objective, we investigated additional endpoints, such as ischemic stroke, TIA, systemic embolism, myocardial infarction, and HT, as well as the survival status depending on treatment. We aimed to provide real-world evidence on the early treatment with anticoagulants in this vulnerable phase of AIS and TIA.

Methods

Study design

Methods and the study design have been published in detail.²¹ PRODAST is a multi-center prospective, observational, non-interventional post-authorization safety study (PASS), which recruited patients with AF who experienced a recent (⩽ 7 days) AIS or TIA with AF at 86 German stroke units between July 2015 and November 2020. Inclusion criteria were age ⩾ 18 years at enrollment, written informed consent (IC), AIS or TIA within 7 days before enrollment and a diagnosis of non-valvular AF. Exclusion criteria included the presence of mechanical heart valves or valve disease that was expected to require valve replacement intervention (surgical or non-surgical) during the next 3 months. Patients who were participating in any RCT of an experimental drug or device, women of childbearing age without anamnestic exclusion of pregnancy, or who were not using an effective contraception, as well as nursing mothers, were also excluded. All therapeutic procedures were at the discretion of the treating physicians. Documentation of effective anticoagulation was also the responsibility of the respective study centers. For all patients, detailed demographic and clinical data were collected during their hospital stay, as previously described in detail.²¹ All patients except those discharged with an NOAC other than dabigatran underwent a standardized follow-up after 3 months as well as an assessment of vital status after one year, according to the scope of the PASS design. For the analysis of the primary study objective, all patients who were treated with dabigatran or VKA were considered and outcomes of patients on NOAC other than dabigatran, that is, factor Xa inhibitors, will be reported elsewhere.

Outcomes

The primary endpoint was defined as major bleeding event within 3 months following the index event. Major bleeding events were defined as any of the following: a fatal bleeding; intracranial, intraocular, intraspinal, retroperitoneal, intraarticular or intramuscular bleeding causing a compartment syndrome; or clinically overt bleeding associated with either a decrease in hemoglobin concentration of > 2 g/dL, indication for transfusion of two or more units of whole blood or packed cells, or indication for surgical intervention. Secondary endpoints were recurrent strokes, recurrent ischemic strokes, TIA, systemic/pulmonary embolism, myocardial infarction, death, and the composite endpoint, which consisted of stroke, systemic embolism, life-threatening bleeding and death. Endpoints occurring during hospitalization were assessed by the respective study sites. Following central and on-site data verification, unclear outcome events were confirmed by an independent clinical adjudication committee, taking into account all available information. In addition, in unclear cases, medical records were retrieved from the general practitioner.

Ethical approval

All patients or their legal representatives provided written IC. In the case that IC could not be obtained in a timely manner due to the patient’s condition, the appropriate investigator was allowed to decide on study inclusion, whereupon the IC process was rescheduled as soon as possible. Ethical approval was provided by the institutional review board of the University of Duisburg-Essen (No. 15-6202-BO). All procedures were conducted in accordance with the national law, the 1964 Declaration of Helsinki and its later amendments, and the recommendations of the guidelines on Good Clinical Practice and Good Epidemiological Practice.

Statistical analysis

Two types of analyses were performed: First, we analyzed the initiation-time-specific effects of dabigatran therapy in comparison to VKA treatment. For this, a distinction was made between dabigatran treatment initiated early, that is, ⩽ 7 days, and late, that is, > 7 days, and exposure was statistically considered as persistent from the first day of dabigatran therapy until the end of the patient’s follow-up. Prevalent use of dabigatran at the time of the index event was considered as early dabigatran application. Second, we performed an analysis directly comparing events under actual (current) treatment with dabigatran with VKA independent of the initiation time. Each patient’s observed time under the respective treatment regimen was considered starting at the index event, from the day of treatment initiation, until the occurrence of the endpoint event, censoring due to treatment change, an alternative severe event (i.e. any endpoint, except TIA), or end of follow-up. Hazard ratios (HR) were estimated using crude and adjusted Cox-proportional hazards regression analyses. Crude models were adjusted for age, study site (as random effect), and time-varying antithrombotic medication in the categories NOAC, VKA, antiplatelets, and non-oral antithrombotic medication. Adjusted models included additional risk factors to correct for confounding or treatment by indication bias based on directed acyclic graphs (DAGs) as described previously²¹ (see online Supplemental Figure 1 and adjustment matrix Supplemental Table 1). To account for the varying duration of the effect of antithrombotic drugs beyond intake, the respective end of therapy was postponed by a lag time, as previously described²¹ (see online Supplemental Table 2).

All analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patients’ characteristics

We recruited 10,039 patients in the PRODAST study. A total of 3,312 patients were treated with dabigatran or VKA and were thus eligible for the analysis of the primary study objective. Analyses regarding administration of other anticoagulants will be published separately. Overall, 459 patient-years of dabigatran users and 337 patient-years of VKA users were analyzed. Demographical and clinical characteristics of the study population are shown in Table 1. Patients with late initiation of dabigatran more frequently underwent mechanical thrombectomy or thrombolysis, or had early HT shown by initial cranial imaging. Infarct volumes and the National Institutes of Health Stroke Scale (NIHSS) scores were higher in patients who received dabigatran late (median NIHSS score: 5) as compared to patients who received dabigatran early or VKA (median NIHSS score: 2 and 2, respectively). These observations are suggestive of confounding by indication. Supplemental Table 3 provides an overview on the actual treatment times of different anticoagulants according to the patient groups.

 

More at link

Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model

Will your incompetent stroke doctors and stroke hospital do nothing to ensure this is tested in humans? Firings should commence immediately, starting with the board of directors.

Long-Term Dabigatran Treatment Delays Alzheimer’s Disease Pathogenesis in the TgCRND8 Mouse Model

Marta Cortes-Canteli, Anna Kruyer, Irene Fernandez-Nueda, Ana Marcos-Diaz, Carlos Ceron, Allison T. Richards, Odella C. Jno-Charles, Ignacio Rodriguez, Sergio Callejas, Erin H. Norris, Javier Sanchez-Gonzalez, Jesus Ruiz-Cabello, Borja Ibanez, Sidney Strickland and Valentin Fuster

Author + information

Central Illustration

• Download figure
• Open in new tab
• Download powerpoint

Abstract

Background Alzheimer’s disease (AD) is a multifactorial neurodegenerative disorder with important vascular and hemostatic alterations that should be taken into account during diagnosis and treatment.

Objectives This study evaluates whether anticoagulation with dabigatran, a clinically approved oral direct thrombin inhibitor with a low risk of intracerebral hemorrhage, ameliorates AD pathogenesis in a transgenic mouse model of AD.

Methods TgCRND8 AD mice and their wild-type littermates were treated for 1 year with dabigatran etexilate or placebo. Cognition was evaluated using the Barnes maze, and cerebral perfusion was examined by arterial spin labeling. At the molecular level, Western blot and histochemical analyses were performed to analyze fibrin content, amyloid burden, neuroinflammatory activity, and blood–brain barrier (BBB) integrity.

Results Anticoagulation with dabigatran prevented memory decline, cerebral hypoperfusion, and toxic fibrin deposition in the AD mouse brain. In addition, long-term dabigatran treatment significantly reduced the extent of amyloid plaques, oligomers, phagocytic microglia, and infiltrated T cells by 23.7%, 51.8%, 31.3%, and 32.2%, respectively. Dabigatran anticoagulation also prevented AD-related astrogliosis and pericyte alterations, and maintained expression of the water channel aquaporin-4 at astrocytic perivascular endfeet of the BBB.

Conclusions Long-term anticoagulation with dabigatran inhibited thrombin and the formation of occlusive thrombi in AD; preserved cognition, cerebral perfusion, and BBB function; and ameliorated neuroinflammation and amyloid deposition in AD mice. Our results open a field for future investigation on whether the use of direct oral anticoagulants might be of therapeutic value in AD.

Alzheimer’s disease (AD) is a progressive and multifactorial neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, tau tangles, neuroinflammation, and brain atrophy (1). AD is strongly linked with cardiovascular risk factors, and is often accompanied by an important vascular component (2–4). The cerebrovascular pathology present in AD includes blood–brain barrier (BBB) disruption, neurovascular unit dysfunction, neurovascular uncoupling, and cerebral blood flow (CBF) alterations (5–7). Furthermore, chronic dysregulated hemostasis is present in AD, with increased thrombin generation, presence of activated platelets, and leakage of plasma proteins into the brain parenchyma (8,9), favoring the formation and persistence of fibrin clots (10,11).

Fibrin(ogen) is up-regulated early in AD (12), is found intravascularly and extravascularly in areas of synaptic dysfunction and amyloid pathology (10,11), and interacts with Aβ (13,14) inducing the formation of resistant clots (10,15). Because decreasing systemic fibrin(ogen) levels in AD mice ameliorates disease progression (10,11,16), therapeutics that normalize the prothrombotic environment present in AD might be useful in combination with other strategies (17). Indeed, traditional anticoagulants have been reported to be beneficial for dementia patients (18,19) and AD mouse models (20,21). However, to overcome their important limitations, such as the necessity for close monitoring and the high risk of bleeding, direct oral anticoagulants (DOACs) have emerged as a useful alternative (22). Among these, dabigatran is a potent oral direct thrombin inhibitor already approved for several indications, such as the prevention of stroke in patients with nonvalvular atrial fibrillation and the treatment of venous thromboembolism (23). Dabigatran has minimal drug–drug interactions (22), a low risk of intracranial bleeding (24,25), a potent anti-inflammatory effect (26), and an effective reversal agent available (27).

Here, we present evidence that long-term anticoagulation with dabigatran ameliorates multiple features of AD pathogenesis. Dabigatran treatment preserved memory and cerebral perfusion in transgenic AD mice, which was accompanied by improved BBB integrity, together with lower levels of fibrin, amyloid deposition, and neuroinflammatory activity in the AD brain.

Real-World Study Confirms Lower Brain Bleed Risk with Dabigatran

For discussions with your doctor.
https://www.medpagetoday.com/cardiology/arrhythmias/69256?

Findings from post-marketing surveillance similar to clinical trial data

• by Salynn Boyles, Contributing Writer November 13, 2017
• This article is a collaboration between MedPage Today® and:
  

Action Points

• Real-world outcomes among patients with atrial fibrillation taking the anticoagulant dabigatran (Pradaxa) mimic those reported in clinical trials, with dabigatran use associated with lower rates of brain bleeds, and similar rates of stroke and extracranial hemorrhage as treatment with warfarin.
• Note that patients treated with dabigatran were more likely to have myocardial infarction, however the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition.

Real-world outcomes among patients with atrial fibrillation taking the anticoagulant dabigatran (Pradaxa) mimic those reported in clinical trials, with dabigatran use associated with lower rates of brain bleeds, and similar rates of stroke and extracranial hemorrhage as treatment with warfarin in a new study.
Researchers examined data from the Sentinel Initiative, which is a national electronic prescription-drug surveillance system established by the FDA to monitor the safety of newly approved drugs and medical products.
Dabigatran was approved by the FDA in 2010 to reduce stroke risk in patients with nonvalvular Afib, based on findings from the RE-LY clinical trial.
The new study, published Monday in Annals of Internal Medicine, compared stroke, bleeding and myocardial infarction rates in patients treated with dabigatran versus warfarin in more than 55,000 patients treated in clinical practices across the United States since the drug was approved.
"Our findings suggest that results from the trial do appear to translate pretty well into clinical practice in terms of similar rates of ischemic stroke compared to warfarin and (overall) bleeding and lower rates of brain bleeds," lead author Alan S. Go, MD, of Kaiser Permanente Northern California told MedPage Today.
As with the RE-LY data, there was a slightly higher rate of myocardial infarctions associated with dabigatran use in the study, but the association was not seen in all statistical analyses performed by the researchers. Subgroup analyses showed the association in men, but not women, and in older Afib patients.
"In the original trial used for FDA approval, they did notice more heart attacks in patients taking dabigatran, but this did not meet statistical significance," Go said. "We also saw a higher rate in clinical practice, but, depending on how we analyzed the data, it wasn't always statistically significant."
He added that more research is needed to better understand this observed association.
The retrospective cohort study included adults with Afib initiating dabigatran or warfarin therapy between November of 2010 and May 2014 within the Sentinel Initiative network, which includes a central coordinating center and 17 collaborating institutions and health care delivery systems.
The study included 25,289 patients starting dabigatran therapy and 25,289 propensity score-matched patients starting warfarin therapy.
The analysis revealed that:

• Dabigatran- and warfarin-treated patients did not have significantly different rates of ischemic stroke (0.80 versus 94 events per 100 person-years, HR 0.92; 95% CI 0.65-1.28)
• Similar rates of extracranial hemorrhage were also seen for the two drugs (2.12 versus 2.63 events per 100 person-years, HR 0.89; 95% CI 0.72-1.09)
• Dabigatran treatment was associated with a lower rate of intracranial bleeding (0.39 versus 0.77 events per 100 person-years, HR 0.51; 95% CI 0.33-0.79)
• Dabigatran treatment was associated with a higher rate of MI (0.77 versus 0.43 events per 100 person-years, HR 1.88; 95% CI 1.22-2.90)

"However, the strength and significance of the association between dabigatran use and myocardial infarction varied in sensitivity analyses and by exposure definition," the researchers wrote.
Gastrointestinal bleeding risk was also higher in older patient treated with dabigatran and in dabigatran-treated patients with kidney dysfunction.
Go said the main strength of the analysis was the use of the FDA surveillance system data, given that previous clinical practice studies have been largely limited to Medicare data.
"This provides a much more representative look across the age spectrum of patients with atrial fibrillation," he said.
Study limitations included the lack of information on outpatient international normalized ratios for most warfarin-treated patients, which limited the researchers' ability to characterize longitudinal exposure and quality of anticoagulation.
All the patients included in the study had health insurance, and the researchers warned that the findings may not be generalizable to uninsured patients.
Also, as in earlier studies, the duration of continuous exposure to dabigatran or warfarin was relatively short and drug adherence could not be directly measured.

The Sentinel Coordinating Center is funded by the U.S. Food and Drug Administration.
Researcher Alan Go reported receiving grants from the FDA during the trial. Other researchers reported fees from pharmaceutical companies not associated with the submitted work.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

• Primary Source

  Annals of Internal Medicine

  Source Reference: Go AS, et al "Outcomes of dabigatran and warfarin for atrial fibrillation in contemporary practice" Ann Intern Med 2017; DOI: 10.7326/M16-1157.

Some Blood Thinners May Increase Heart Attack Risk

Be careful out there. Hopefully your doctor has informed you of these risks. 

Some Blood Thinners May Increase Heart Attack Risk

A new study has examined whether different blood thinning medications prescribed to prevent strokes in patients with atrial fibrillation might increase the risk of heart attacks.

In the retrospective study of 30,146 patients, investigators found a twofold increased risk in patients taking direct acting oral anticoagulants (dabigatran and rivaroxaban) compared with those taking vitamin k antagonists such as warfarin. Heart attack risk was also higher in patients taking aspirin than in those taking warfarin.
"More research should be on-going as use of direct acting oral anticoagulants increases in the population," wrote the authors of the British Journal of Clinical Pharmacology study.
http://newsroom.wiley.com/press-release/british-journal-clinical-pharmacology/some-blood-thinners-may-increase-heart-attack-ri

• Full bibliographic informationBibliography
  Leo M Stolk MSc PharmD PhD, Frank de Vries PharmD PhD, Chiel Ebbelaar MSc, Anthonius de Boer MD PhD (3), Tom Schalekamp PhD, Patrick Souverein PhD,, Arina ten Cate-Hoek MD PhD, Andrea M Burden PhD. . Risk of myocardial infarction in patients with atrial fibrillation using vitamin K antagonists, aspirin or direct acting oral anticoagulants. British Journal of Clinical Pharmacology. DOI: 10.1111/bcp.13264.
  

All About Dabigatran(Pradaxa} Reversal in the ED

Just in case you are on this instead of warfarin, you will need to be lucid enough in the emergency room to tell your doctors what anti-clotting drug you are on.
https://www.medpagetoday.com/Blogs/EPMonthly/64573?

Agent now available for reversing new oral anticoagulant in bleeding patients

• by MedPage Today Staff
  April 15, 2017

A 67-year-old woman is brought in by EMS after she developed a severe headache at home with associated vomiting and altered mental status. Her past medical history is significant for hypertension and atrial fibrillation, for which she takes atenolol and dabigatran (Pradaxa). The patient is somnolent, and after quickly securing her airway, you send her for a stat head CT. The CT shows an intraparenchymal hemorrhage. After paging your neurosurgeon on call, you consider your options for reversal of anticoagulation. You know you need to reverse her anticoagulation, but how?
The new oral anticoagulants (NOACs) are skyrocketing in popularity, displacing warfarin as first-line anticoagulants for many patients. Dabigatran is a direct thrombin inhibitor used for stroke prevention in patients with atrial fibrillation and for treatment and secondary prevention of venous thromboembolism. Dabigatran and other NOACs have several advantages over warfarin. Their pharmacokinetics are simpler, they don't have the pesky food and drug interactions that plague warfarin, they don't require monitoring and frequent dose adjustments, and importantly, they carry a lower risk of major bleeding complications.
However, a major concern is that unlike warfarin, which can be reversed with Prothrombin Complex Concentrates (PCC) or fresh frozen plasma and vitamin K, dabigatran and the other NOACs lacked a dedicated reversal agent. This made emergency physicians and others who anticipate worst-case scenarios somewhat nervous. Although the NOACs are associated with fewer serious bleeding complications than warfarin, life-threatening bleeding can still occur. How should we manage the patient on dabigatran with an intracranial hemorrhage? Or the trauma patient who requires emergent surgery for their liver laceration who happens to be on dabigatran? Alternative reversal methods have been proposed, such as use of three- or four-factor PCC, fresh frozen plasma, or even emergent hemodialysis to remove circulating anticoagulant. However, the efficacy of these methods has been questioned, and safety concerns have been raised regarding thrombotic risk of PCC.
In October 2015 the U.S FDA approved a target-specific reversal agent for dabigatran. Idarucizumab, marketed as Praxbind, is a monoclonal antibody fragment (Fab) that binds directly to dabigatran, neutralizing its activity. It is approved for reversal of anticoagulation in patients on dabigatran requiring emergent or urgent surgery or in patients with life-threatening bleeding. Dabigatran inhibits thrombin, which catalyzes one of the final steps in the clotting cascade. Idarucizumab reverses dabigatran's anticoagulant effects by binding tightly to dabigatran with an affinity 350 times greater than thrombin, thus freeing thrombin's functionality in the clotting cascade.
Studies show that administration of idarucizumab to healthy young volunteers, older volunteers ages 65-80, and volunteers ages 45-80 with mild or moderate renal impairment resulted in complete reversal of dabigatran's anticoagulant effects within minutes without any procoagulant effects. This reversal of anticoagulation lasts 24 hours, which is an advantage over PCC, which has more transient effects. One important caveat is that there must be dabigatran in the bloodstream for idarucizumab to have any effect. Once the dabigatran is cleared by the kidney, idarucizumab will have nothing to bind to and will have no effect. It is recommended to give it if the last dose of dabigatran was in the last 24-48 hours. There may be some benefit of longer time frames in patients with renal failure, who will have a slower clearance rate of the dabigatran. Finally, since it is a monoclonal antibody, it is highly specific for dabigatran. It will not reverse the anticoagulant effects of coumadin, plavix, or other NOACs such as rivaroxaban.
The data on idarucizumab in patients who are actually bleeding or being operated on looks favorable as well. The Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial, a large international prospective cohort study of patients on dabigatran who receive idarucizumab either for serious bleeding or prior to an urgent surgical procedure, is still ongoing. A preliminary analysis of the first 90 patients revealed that idarucizumab rapidly and completely restored coagulation parameters in 88-98% of patients who had elevated clotting times at baseline. Among patients who underwent surgery, normal hemostasis was reported in 92%, with mild to moderate impairment in 8%. Only one of 90 patients (1%) had a thrombotic event within 72 hours of administration of idarucizumab. These data mirror the safety and efficacy data on idarucizumab from earlier human and animal studies.
Dosing
The FDA-approved dose for idarucizumab is 5 mg, which is administered as two separate 2.5 mg IV doses infused over 5 minutes. The second dose should be administered within 15 minutes of the first infusion. There is no dosing change needed for renal or hepatic impairment.
Adverse Events
Adverse reactions are rare and include headache (5%) and hypokalemia (7%). There are case reports of serious complications in patients receiving idarucizumab, including acute ischemic stroke, cardiac arrest, NSTEMI, DVT, and PE, but the incidence is thought to be extremely low.
Cautions
Contraindications include hypersensitivity to idarucizumab or any components of the formulation. Risks/benefits of anticoagulation should be considered before reversing anticoagulation with idarucizumab, since the underlying disease state may predispose to thrombotic events. However, since it is typically reserved for life-threatening bleeds, the scale typically would favor its use. Cost is also a consideration. Not all emergency departments may be able to stock idarucizumab due to the infrequent need for it and its cost.
Pregnancy
There are no studies of human or animal models of pregnancy. It is unknown if idarucizumab is excreted in breast milk.
Cost
A single 2.5 mg/50 mL dose of idarucizumab costs $2,100, so recommended treatment with two doses costs $4,200. This is slightly cheaper than four-factor PCC, which costs about $5,000 for an 80 kg patient.
Karen Serrano, MD, and Christina Shenvi, MD, are assistant professors of emergency medicine at the University of North Carolina. Shenvi authors RX Pad each month in EPM. A version of this article originally appeared at Emergency Physicians Monthly.

The authors of this column receive no funding or incentives from any pharmaceutical company, and have no conflicts of interest related to the topics of their articles. Furthermore, Praxbind is not an advertising client of Emergency Physicians Monthly.

• Primary Source

  New England Journal of Medicine

  Source Reference: Connolly SJ, et al. "Dabigatran versus warfarin in patients with atrial fibrillation" N Engl J Med 2009; DOI: 10.1056/NEJMoa0905561

• Secondary Source

  Emergency Medicine Journal

  Source Reference: Alikhan R, et al. "The acute management of hemorrhage, surgery and overdose in patients receiving dabigatran" Emerg Med J 2014; DOI: 10.1136/emermed-2012-201976.

• Additional Source

  Anesthesiology

  Source Reference: Honickel M, et al. "Prothrombin complex concentrate is effective in treating the anticoagulant effects of dabigatran in a porcine polytrauma model" Anesthesiology 2015; DOI: 10.1097/ALN.0000000000000863

Risk of hemorrhage with statins and stroke prevention drug combination

Is you are on these, how long before your doctor warns you?
http://medicalxpress.com/news/2016-11-hemorrhage-statins-drug-combination.html
Two commonly prescribed statins appear to be associated with a higher risk of bleeding than others when combined with dabigatran, a drug often used for preventing strokes in patients with atrial fibrillation, according to a study published today in the Canadian Medical Association Journal.

Hemorrhage, or bleeding in a critical area or organ, is a possible side effect of dabigatran (brand name Pradaxa) and occasionally can be severe enough to warrant hospital admission or emergency department visits. Cholesterol-lowering statins such as lovastatin and simvastatin may increase the amount of dabigatran absorbed by the body and thereby increase the risk of bleeding, something other statins would not be expected to do.
Researchers conducted two studies on Ontario residents over age 65 who started taking dabigatran between 2012 and 2014. Of the 45,991 patients, 397 experienced a stroke and 1,117 had major hemorrhage. The risk of bleeding went up by more than 40 per cent in patients taking lovastatin or simvastatin, compared with those who were given other statins.
"We found no difference in the risk of stroke in patients receiving dabigatran who were prescribed lovastatin or simvastatin versus other statins," said Dr. Tony Antoniou, a pharmacist at St. Michael's Hospital and researcher in its La Ka Shing Knowledge Institute and an adjunct scientist at the Institute for Clinical Evaluative Sciences.
"However, an increase in the risk of bleeding requiring hospital admission or emergency department visits was seen with lovastatin and simvastatin compared with the other statins," Dr. Antoniou said.
These results suggest that a clinically important drug interaction exists between dabigatran and both simvasatatin and lovastatin, he said, and that other statins should be considered instead for patients with atrial fibrillation, a condition involving an irregular heart rhythm known as an arrhythmia. According to the Heart and Stroke Foundation of Canada it is the most common type of arrhythmia, affecting approximately 350,000 Canadians. One of the main complications of atrial fibrillation is stroke. Individuals with atrial fibrillation have a risk of stroke that is 3 to 5 times greater than those without atrial fibrillation.

Explore further: Enrollment completed for RE-DUAL PCI study of 2,700 atrial fibrillation patients

More information: Canadian Medical Association Journal, www.cmaj.ca/lookup/doi/10.1503/cmaj.160303

Journal reference: Canadian Medical Association Journal
Provided by: Canadian Medical Association Journal

Stroke Prevention for Patients With Atrial Fibrillation Similar With Warfarin, Newer Oral Anticoagulants

Didn't answer the outstanding question that there is no reversal agent for the newer ones. How many died or had negative outcomes because of no reversal agent? Can't these people even think of the correct questions to answer while doing research? Must I do everything? Think and wipe their ass? 

Stroke Prevention for Patients With Atrial Fibrillation Similar With Warfarin, Newer Oral Anticoagulants

An observational study comparing new oral anticoagulants with warfarin found stroke prevention to be similar, but the newer anticoagulants provided reduced intracranial bleeding, according to a study presented here at the 2016 Annual Meeting of the European Society of Cardiology (ESC).
The study included 43,299 patients with atrial fibrillation who were recruited from Danish nationwide administrative registries. In the cohort, 42% of patients were taking warfarin, 29% were taking dabigatran, 16% were on apixaban, and 13% were taking rivaroxaban.
“There has been a need to investigate safety and effectiveness of new oral anticoagulants versus warfarin in a ‘real world’ population and our Danish registries provide this opportunity,” said Laila Staerk, MD, Herlev and Gentofte University Hospitals, Herlev, Denmark.
Efficacy outcomes were stroke and all-cause mortality. Patients were followed until outcome, death, switch or discontinuation of initiated anticoagulant treatment, emigration, or study end.
During treatment, stroke occurred in 1,850 (4%) patients and there were 6,477 (15%) deaths.
The absolute stroke risk at 1 year of initiating treatment was similar for each of the 4 groups, at 2.01% for warfarin, 2.12% for dabigatran, 2.06% for rivaroxaban, and 2.46% for apixaban.
Absolute risk of all-cause mortality at 1 year after initiation of warfarin was 18.0%, dabigatran 11.5%, rivaroxaban 14.7%, and apixaban 14.9%.
Standardised absolute risk of intracranial bleeding at 1 year was reduced in patients who were taking the newer oral anticoagulants. Absolute risk was 0.60% for warfarin, 0.26% for dabigatran (P =0.05 vs warfarin), 0.47% for rivaroxaban, and 0.40% for apixaban (P = .05 vs warfarin).
“Among patients with atrial fibrillation who were new users of oral anticoagulation, while treatment with [these newer drugs] was not associated with a significantly lower risk of stroke, treatment with dabigatran and apixaban was associated with a significantly lower risk of intracranial bleeding compared with warfarin,” said Dr. Staerk.
[Presentation title: Stroke and All-Cause Mortality With Non-Vitamin K Antagonist Oral Anticoagulation Versus Warfarin in Atrial Fibrillation: a Nationwide Study. Abstract 1875]

Dabigatran Versus Warfarin for Atrial Fibrillation in Real-World Clinical Practice

In case you need to be informed on this.
http://circoutcomes.ahajournals.org/content/9/2/126.abstract?etoc

A Systematic Review and Meta-Analysis

1. Robert J. Romanelli, PhD, MPH,
2. Laura Nolting, BS,
3. Marina Dolginsky, BS,
4. Eunice Kym, PharmD and
5. Kathleen B. Orrico, PharmD

+ Author Affiliations

1. From the Palo Alto Medical Foundation Research Institute, Palo Alto, CA (R.J.R., L.N., M.D.); and Department of Clinical Pharmacy, University of California, San Francisco (E.K., K.B.O.).

1. Correspondence to Robert J. Romanelli, PhD, MPH, Palo Alto Medical Foundation Research Institute, 795 El Camino Real Ames Bldg, Palo Alto, CA 94301. E-mail romanellir@pamfri.org

Abstract

Background—Trial data for the benefits and risks of dabigatran versus warfarin in the treatment of nonvalvular atrial fibrillation are lacking. We sought to review real-world observational evidence for the comparative effectiveness and safety of these agents.

Methods and Results—A systematic search of multiple databases was conducted from first available date to March 10, 2015 for longitudinal, observational studies comparing dabigatran with warfarin. Two reviewers evaluated studies for eligibility and extracted hazard ratios for ischemic stroke and gastrointestinal and intracranial bleeding. hazard ratios were pooled using random-effects meta-analysis. Metaregression was performed to assess treatment-effect heterogeneity. We identified 232 unique citations. Seven retrospective cohort studies met study eligibility criteria, with 348 750 patients and a mean follow-up of 2.2 years. In pooled analyses, dabigatran-150 mg was not superior to warfarin in preventing stroke (hazard ratio, 0.92; 95% confidence interval, 0.84–1.01; P=0.066), but had a significantly lower hazard of intracranial bleeding (0.44; 0.34–0.59; P<0.001). Dabigatran-150 mg had a significantly greater hazard of gastrointestinal bleeding than warfarin (1.23; 1.01–1.50; P=0.041), which was potentiated in studies of older (elderly) versus younger populations (median/mean age, ≥75 versus <75 years; β=1.53; 95% confidence interval, 1.10–2.14; P=0.020).

Conclusions—In real-world clinical practice, dabigatran is comparable with warfarin in preventing ischemic stroke among patients with nonvalvular atrial fibrillation. However, dabigatran is associated with a lower risk for intracranial bleeding relative to warfarin, but—particularly among the elderly—a greater risk for gastrointestinal bleeding. Bleeding outcomes from observational studies are consistent with those from the pivotal Randomized Evaluation of Long-Term Anticoagulation Therapy trial.

Idarucizumab rapidly reverses anticoagulant effect of dabigatran, restores hemostasis

Just in case your doctor put you on the newer class of anticoagulants.
http://www.healio.com/hematology-oncology/hematology/news/online/%7B2e6dea88-9ca9-4c09-adb5-1a3bdae34f87%7D/idarucizumab-rapidly-reverses-anticoagulant-effect-of-dabigatran-restores-hemostasis?

Idarucizumab instantly and completely reversed the anticoagulant effect of dabigatran in patients requiring urgent procedures or with serious hematologic complications, according to interim results of a phase 3 study.

Few specific reversal agents exist for non-vitamin K oral anticoagulants, according to study background. Researchers developed idarucizumab (Boehringer Ingelheim) to reverse the anticoagulant effects of dabigatran (Pradaxa, Boehringer Ingelheim).

Charles V. Pollack, Jr., MD, chair of the department of emergency medicine at Pennsylvania Hospital and professor of emergency medicine at the Hospital of the University of Pennsylvania, and colleagues conducted the prospective, phase 3 RE-VERSE AD study to observe the safety and efficacy of idarucizumab in reversing the effects of dabigatran.

Pollack and colleagues divided the study into two arms: patients experiencing severe bleeding (group A) and patients who required an urgent procedure (group B).

The researchers assigned 5 mg IV idarucizumab to patients in both groups.

The maximum percentage reversal of the anticoagulant effect of dabigatran — evaluated with the dilute thrombin time or ecarin clotting time — within 4 hours of idarucizumab administration served as the primary endpoint. Restoration of hemostasis served as a secondary endpoint.

The interim analysis included data from 90 patients (group A, n = 51; group B, n = 39).

At baseline, 68 patients had an elevated dilute thrombin time and 81 had an elevated ecarin clotting time. The study achieved its primary endpoint, with 100% of these patients (95% CI, 100-100) reaching maximum percentage reversal following idarucizumab administration.

Idarucizumab normalized the dilute thrombin time in 98% of patients in group A and 93% in group B, as well as the ecarin clotting time in 89% of patients in group A and 88% of patients in group B.  In most cases, researchers observed these effects within minutes of administration.

Concentrations of unbound dabigatran stayed below 20 ng/mL in 79% of patients after 24 hours.

The researchers assessed hemostasis in 35 patients in group A and 36 patients in group B. Among patients in group A, hemostasis restoration occurred at a median of 11.4 hours. Thirty-three patients in group B who underwent a procedure experienced normal intraoperative hemostasis, whereas two patients experienced mildly abnormal hemostasis and one patient experienced moderately abnormal hemostasis.

A total of 18 patients died (n = 9 for each arm). Ten patients died from vascular causes, with five deaths attributed to bleeding events. Eleven patients died within 96 hours of treatment; however, their deaths appeared to be related to their index event.

Five patients experienced thrombotic events, including deep vein thrombosis and pulmonary embolism in one patient within 72 hours of idarucizumab administration.

Twenty-one patients (group A, n = 13; group B, n = 8) experienced serious adverse events, including gastrointestinal hemorrhage (n = 2), postoperative wound infection, delirium, right ventricular failure and pulmonary edema (n = 1 for all).

The researchers identified the lack of a control group as a limitation of their study.

“The interim analysis from RE-VERSE AD is important for the healthcare professionals as it provides the first insights into the effect of a specific reversal agent to a non–vitamin K antagonist oral anticoagulant during real-word emergency situations,” Pollack said in a press release. “These data demonstrate that use of idarucizumab can help physicians focus on other vital aspects of emergency management beyond anticoagulant reversal in dabigatran-treated patients.” – by Cameron Kelsall

Evaluate the reversal of the anticoagulant effects of dabigatran by IV administration of 5.0g idarucizumab in patients treated with dabigatran etexilate who have uncontrolled bleeding or require emergency surgery or procedures.

So maybe my friend who refused to go on Pradaxa because of no reversal agent might be able to change her mind.
The trial here:
https://clinicaltrials.gov/show/NCT02104947

A discussion of preliminary results here:

NOAC Antidote Promising in Phase III Trial

Idarucizumab restored clotting in most patients on the new oral anticoagulant (NOAC) dabigatran (Pradaxa) who had serious bleeding or required urgent surgery, according to interim results of the phase III RE-VERSE AD trial.
The median maximum percentage reversal of the anticoagulant effect of dabigatran within 4 hours of administration was 100%, based on central laboratory analysis of dilute thrombin time or ecarin clotting time.

Advertisement

"Idarucizumab normalized the test results in 88% to 98% of the patients, an effect that was evident within minutes," Charles V. Pollack Jr., MD, of the Pennsylvania Hospital in Philadelphia, and colleagues found.

 

Fatal gastrointestinal hemorrhage after a single dose of dabigatran.

Be careful out there on those Warfarin replacements. Has your doctor told you all the side effects of Warfarin vs. Pradaxa?  Don't listen to me, if your doctor doesn't tell you about these problems s/he must not consider them worthwhile or even worse does not know about the problems.
A good friend of mine refused to go on Pradaxa because of the lack of a reversal agent.
https://us-mg5.mail.yahoo.com/neo/launch?.rand=5gfa04d2d1oug#4477885065

Dabigatran: Australia issues bleeding warning

The replacement for Warfarin. Be careful out there.
http://www.theheart.org/article/1291757.do
The Australian regulatory authority, the Therapeutic Goods Administration (TGA), has issued a "safety advisory" on the new oral anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) because of an increase in the number of bleeding-related adverse events reports received since more people starting taking the drug [1].

Dabigatran was first approved in Australia in November 2009 for the prevention of venous thromboembolic events in patients who have undergone major orthopedic surgery of the lower limb. It is reimbursed for this indication, with limited usage, the TGA reports. In April of this year, the indications were expanded to include the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) and at least one risk factor for stroke. An increase in adverse-event reports occurred after this extension of indications.

The TGA says it has received a total of 203 adverse-event reports for dabigatran since 2009. Of these, 124 were for serious adverse events; 47 are described as serious bleeding adverse events, 30 related to serious gastrointestinal bleeding and six documented serious intracranial bleeding. There have been a total of 121 adverse events reported in patients aged 75 years or older, of which 76 have been described as serious.

The TGA adds that its analysis shows that some of the bleeding adverse events occurred during the transition from warfarin to dabigatran. Many of the adverse events are occurring in patients on the reduced-dosage regimen, and the most common site of serious bleeding for dabigatran is the gastrointestinal tract, whereas for warfarin it is intracranial.

The agency notes that in clinical trials the risk of bleeding per year of treatment with dabigatran was 16.6% (one in six patients) when taking 150 mg twice daily and 14.7% (one in 6.8 patients) taking 110 mg twice daily, compared with 18.4% (one in 5.4 patients) for warfarin.

Consider suitability of patients carefully

It urges clinicians to give careful consideration to the suitability of their patients for dabigatran, "particularly with regard to the risks of bleeding and their current stability on warfarin or other anticoagulants." And it adds that "special consideration should be given to the perioperative management of patients taking Pradaxa."

The advisory notes that Australian experts are currently developing guidelines for the management of bleeding in patients taking dabigatran, but in the meantime it refers clinicians to the New Zealand guidelines on the subject [2].

Coagulation assays for emergency use

It says that while existing standard laboratory tests are not validated for use with dabigatran, in cases of emergency, the most accessible qualitative tests are thrombin time (TT) and activated partial thromboplastin time (aPTT). An aPTT >80 seconds is associated with a higher bleeding risk. Prothrombin time (INR) should not be used. Interpretation of coagulation assay results should consider time of dabigatran administration relative to time of blood sampling.

A safety advisory on dabigatran was also issued in Japan in August this year warning of serious side effects, including gastrointestinal bleeding, following the deaths of five patients.

Adverse-drug-reaction data is difficult to interpret

Asked to comment on the latest advisory for heartwire, Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA) said it was difficult to interpret these data. He explained that while randomized trials allow side effects to be evaluated properly and placed in context, they often exclude high-risk patients, noncompliant patients, and other challenging patient subsets. "Thus, when new drugs are initially introduced into real life, there is often a spike in the number of adverse events reported compared with the older drug—but without a valid comparator arm, it is impossible to know whether the new drug really is responsible for the reported events." He added that, as in this case, the number of events reported is often given without knowing the total number of patients treated, including those who are doing well, so it is difficult to know whether the adverse-event rate is really higher with the new therapy.

Another issue, Bhatt pointed out, is that when drugs are new, they may be used in the most difficult patients, including subsets that are off-label or even contraindicated, and this too can lead to a higher-than-expected event rate. "Warfarin under- and overanticoagulation leads to adverse events as well, and careful monitoring reduces this risk but does not eliminate it. However, at this point in time, hardly anyone will report a warfarin-related adverse event. So, a combination of factors likely leads to the reports of more adverse events with new drugs, and it certainly does slow down their uptake—at times appropriately and at other times inappropriately."

New Zealand focus on dabigatran deaths

Separately, a New Zealand newspaper is reporting the launch of a coroner's investigation into the deaths of at least five patients who were taking dabigatran [3]. The investigation has been instigated by Bay of Plenty regional coroner Wallace Bain, who is said to be concerned that the deaths were signed off without coroner's hearings. The New Zealand Sunday Star-Times says it has been notified of five deaths of patients taking dabigatran, all of whom were elderly. It reports the Centre for Adverse Reactions Monitoring (CARM) at Otago University has received four such reports, but it is unclear whether they relate to the same patients. Dabigatran became widely available in New Zealand in July. The newspaper also reports having heard of concerns about dabigatran among doctors relating to the fact that it is not monitored like warfarin and the lack of an antidote if a major bleed occurs. It says there is also evidence that dabigatran has been prescribed to those at higher risk, such as patients over 75 with poor kidney function, low weight, and replacement heart valves. Although the New Zealand Medicines and Medical Devices Safety Authority has said the benefits of the drug outweigh the risks and CARM has stated that the deaths it investigated were caused by other factors, such as infections, the Star-Times quotes families of the affected patients saying the troubles began when they switched from warfarin to dabigatran, and infections were only the last straw. But CARM director Dr Michael Tatley is quoted as saying that there is no obvious mechanism by which an anticoagulant could cause death by infection.