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These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years. The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation. The world health organization (WHO) standard definition then was the presence of two of three:
1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm
2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.
3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.
The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel. Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.
So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century. However, the role of biomarkers broadened. Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury. This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP). The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.
Thus, we have identified the use of traditional cardiac biomarkers for:
1. Diagnosis
2. Therapeutic monitoring
The story is only the beginning. Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic. This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium. The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease. Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.
While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature. There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require
1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement on multitest automated analyzers with high capability in proteomic measurement (MS, time of flight, MS-MS)
Summary: This portion of the Nitric Oxide series on PharmaceuticalIntelligence(wordpress.com) is the first of a two part treatment of platelets, the coagulation cascade, and protein-membrane interactions with low flow states, local and systemic inflammatory disease, and hematologic disorders. It is highly complex as the lines separating intrinsic and extrinsic pathways become blurred as a result of endothelial shear stress, distinctly different than penetrating or traumatic injury. In addition, other factors that come into play are also considered. The 2nd piece will be concerned with oxidative stress and the diverse effects on NO on the vasoactive endothelium, on platelet endothelial interaction, and changes in blood viscosity.
Coagulation Pathway
The workhorse tests of the modern coagulation laboratory, the prothrombin time (PT) and the activated partial thromboplastin time (aPTT), are the basis for the published extrinsic and intrinsic coagulation pathways. This is, however, a much simpler model than one encounters delving into the mechanism and interactions involved in hemostasis and thrombosis, or in hemorrhagic disorders.
We first note that there are three components of the hemostatic system in all vertebrates:
Platelets,
vascular endothelium, and
plasma proteins.
The liver is the largest synthetic organ, which synthesizes
albumin,
acute phase proteins,
hormonal and metal binding proteins,
albumin,
IGF-1, and
prothrombin, mainly responsible for the distinction between plasma and serum (defibrinated plasma).
According to WH Seegers [Seegers WH, Postclotting fates of thrombin. Semin Thromb Hemost 1986;12(3):181-3], prothrombin is virtually all converted to thrombin in clotting, but Factor X is not. Large quantities of thrombin are inhibited by plasma and platelet AT III (heparin cofactor I), by heparin cofactor II, and by fibrin. Antithrombin III, a serine protease, is a main inhibitor of thrombin and factor Xa in blood coagulation. The inhibitory function of antithrombin III is accelerated by heparin, but at the same time antithrombin III activity is also reduced. Heparin retards the thrombin-fibrinogen reaction, but otherwise the effectiveness of heparin as an anticoagulant depends on antithrombin III in laboratory experiments, as well as in therapeutics. The activation of prothrombin is inhibited, thereby inactivating any thrombin or other vulnerable protease that might otherwise be generated. [Seegers WH, Antithrombin III. Theory and clinical applications. H. P. Smith Memorial Lecture. Am J Clin Pathol. 1978;69(4):299-359)]. With respect to platelet aggregation, platelets aggregate with thrombin-free autoprothrombin II-A. Aggregation is dependent on an intact release mechanism since inhibition of aggregation occurred with adenosine, colchicine, or EDTA. Autoprothrombin II-A reduces the sensitivity of platelets to aggregate with thrombin, but enhances epinephrine-mediated aggregation. [Herman GE, Seegers WH, Henry RL. Autoprothrombin ii-a, thrombin, and epinephrine: interrelated effects on platelet aggregation. Bibl Haematol 1977;44:21-7.]
A tetrapeptide, residues 6 to 9 in normal prothrombin, was isolated from the NH(2)-terminal, Ca(2+)-binding part of normal prothrombin. The peptide contained two residues of modified glutamic acid, gamma-carboxyglutamic acid. This amino acid gives normal prothrombin the Ca(2+)-binding ability that is necessary for its activation.
Abnormal prothrombin, induced by the vitamin K antagonist, dicoumarol, lacks these modified glutamic acid residues and that this is the reason why abnormal prothrombin does not bind Ca(2+) and is nonfunctioning in blood coagulation. [Stenflo J, Fernlund P, Egan W, Roepstorff P. Vitamin K dependent modifications of glutamic acid residues in prothrombin. Proc Natl Acad Sci U S A. 1974;71(7):2730-3.]
Interestingly, a murine monoclonal antibody (H-11) binds a conserved epitope found at the amino terminal of the vitamin K-dependent blood proteins prothrombin, factors VII and X, and protein C. The sequence of polypeptide recognized contains 2 residues of gamma-carboxyglutamic acid, and binding of the antibody is inhibited by divalent metal ions. The antibody bound specifically to a synthetic peptide corresponding to residues 1-12 of human prothrombin that was synthesized as the gamma-carboxyglutamic acid-containing derivative, but binding to the peptide was not inhibited by calcium ion. This suggested that binding by divalent metal ions is not due simply to neutralization of negative charge by Ca2+. [Church WR, Boulanger LL, Messier TL, Mann KG. Evidence for a common metal ion-dependent transition in the 4-carboxyglutamic acid domains of several vitamin K-dependent proteins. J Biol Chem. 1989;264(30):17882-7.]
Role of vascular endothelium.
I have identified the importance of prothrombin, thrombin, and the divalent cation Ca 2+ (1% of the total body pool), mention of heparin action, and of vitamin K (inhibited by warfarin). Endothelial functions are inherently related to procoagulation and anticoagulation. The subendothelial matrix is a complex of many materials, most important related to coagulation being collagen and von Willebrand factor.
What about extrinsic and intrinsic pathways? Tissue factor, when bound to factor VIIa, is the major activator of the extrinsic pathway of coagulation. Classically, tissue factor is not present in the plasma but only presented on cell surfaces at a wound site, which is “extrinsic” to the circulation. Or is it that simple?
Endothelium is the major synthetic and storage site for von Willebrand factor (vWF). vWF is…
secreted from the endothelial cell both into the plasma and also
abluminally into the subendothelial matrix, and
acts as the intercellular glue binding platelets to one another and also to the subendothelial matrix at an injury site.
acts as a carrier protein for factor VIII (antihemophilic factor).
It binds to the platelet glycoprotein Ib/IX/V receptor and
mediates platelet adhesion to the vascular wall under shear. [Lefkowitz JB. Coagulation Pathway and Physiology. Chapter I. in Hemostasis Physiology. In ( ???), pp1-12].
Ca++ and phospholipids are necessary for all of the reactions that result in the activation of prothrombin to thrombin. Coagulation is initiated by an extrinsic mechanism that
generates small amounts of factor Xa, which in turn
activates small amounts of thrombin.
The tissue factor/factorVIIa proteolysis of factor X is quickly inhibited by tissue factor pathway inhibitor (TFPI).The small amounts of thrombin generated from the initial activation feedback
to create activated cofactors, factors Va and VIIIa, which in turn help to
generate more thrombin.
Tissue factor/factor VIIa is also capable of indirectly activating factor X through the activation of factor IX to factor IXa.
Finally, as more thrombin is created, it activates factor XI to factor XIa, thereby enhancing the ability to ultimately make more thrombin.
Coagulation Cascade
The procoagulant plasma coagulation cascade has traditionally been divided into the intrinsic and extrinsic pathways. The Waterfall/Cascade model consists of two separate initiations,
intrinsic (contact) and
The intrinsic pathway is initiated by a complex activation process of the so-called contact phase components,
prekallikrein,
high-molecular weight kininogen (HMWK) and
factor XII
Activation of the intrinsic pathway is promoted by non-biological surfaces, such as glass in a test tube, and is probably not of physiological importance, at least not in coagulation induced by trauma.
Instead, the physiological activation of coagulation is mediated exclusively via the extrinsic pathway, also known as the tissue factor pathway.
extrinsic pathways,
Tissue factor (TF) is a membrane protein which is normally found in tissues. TF forms a procoagulant complex with factor VII, which activates factor IX and factor X.
which ultimately merge at the level of Factor Xa (common pathway).
Regulation of thrombin generation. Coagulation is triggered (initiation) by circulating trace amounts of fVIIa and locally exposed tissue factor (TF). Subsequent formations of fXa and thrombin are regulated by a tissue factor pathway inhibitor (TFPI) and antithrombin (AT). When the threshold level of thrombin is exceeded, thrombin activates platelets, fV, fVIII, and fXI to augment its own generation (propagation).
Activated factors IX and X (IXa and Xa) will activate prothrombin to thrombin and finally the formation of fibrin. Several of these reactions are much more efficient in the presence of phospholipids and protein cofactors factors V and VIII, which thrombin activates to Va and VIIIa by positive feedback reactions.
We depict the plasma coagulation emphasizing the importance of membrane surfaces for the coagulation processes. Coagulation is initiated when tissue factor (TF), an integral membrane protein, is exposed to plasma. TF is expressed on subendothelial cells (e.g. smooth muscle cells and fibroblasts), which are exposed after endothelium damage. Activated monocytes are also capable of exposing TF.
A small amount, approximately 1%, of activated factor VII (VIIa) is present in circulating blood and binds to TF. Free factor VIIa has poor enzymatic activity and the initiation is limited by the availability of its cofactor TF. The first steps in the formation of a blood clot is the specific activation of factor IX and X by the TF-VIIa complex. (Initiation of coagulation: Factor VIIa binds to tissue factor and activates factors IX and X). Coagulation is propagated by procoagulant enzymatic complexes that assemble on the negatively charged membrane surfaces of activated platelets. (Propagation of coagulation: Activation of factor X and prothrombin). Once thrombin has been formed it will activate the procofactors, factor V and factor VIII, and these will then assemble in enzyme complexes. Factor IXa forms the tenase complex together with its cofactor factor VIIIa, and factor Xa is the enzymatic component of the prothrombinase complex with factor Va as cofactor.
Activation of protein C takes place on the surface of intact endothelial cells. When thrombin (IIa) reaches intact endothelium it binds with high affinity to a specific receptor called thrombomodulin. This shifts the specific activity of thrombin from being a procoagulant enzyme to an anticoagulant enzyme that activates protein C to activated protein C (APC). The localization of protein C to the thrombin-thrombomodulin complex can be enhanced by the endothelial protein C receptor (EPCR), which is a transmembrane protein with high affinity for protein C. Activated protein C (APC) binds to procoagulant surfaces such as the membrane of activated platelets where it finds and degrades the procoagulantcofactors Va and VIIIa, thereby shutting down the plasma coagulation. Protein S (PS) is an important nonenzymatic cofactor to APC in these reactions. (Degradation of factors Va and VIIIa).
The common theme in activation and regulation of plasma coagulation is the reduction indimensionality. Most reactions take place in a 2D world that will increase the efficiency of the reactions dramatically. The localization and timing of the coagulation processes are also dependent on the formation of protein complexes on the surface of membranes. The coagulation processes can also be controlled by certain drugs that destroy the membrane binding ability of some coagulation proteins – these proteins will be lost in the 3D world and not able to form procoagulant complexes on surfaces.
Assembly of proteins on membranes – making a 3D world flat
• The timing and efficiency of coagulation processes are handled by reduction in dimensionality
– Make 3 dimensions to 2 dimensions
• Coagulation proteins have membrane binding capacity
• Membranes provide non-coagulant and procoagulant surfaces
– Intact cells/activated cells
• Membrane binding is a target for anticoagulant drugs
– Anti-vitamin K (e.g. warfarin)
Modern View
It can be divided into the phases of initiation, amplification and propagation.
In the initiation phase, small amounts of thrombin can be formed after exposure of tissue factor to blood.
In the amplification phase, the traces of thrombin will be inactivated or used for amplification of the coagulation process.
At this stage there is not enough thrombin to form insoluble fibrin. In order to proceed further thrombin activates platelets, which provide a procoagulant surface for the coagulation factors. Thrombin will also activate the vital cofactors V and VIII that will assemble on the surface of activated platelets. Thrombin can also activate factor XI, which is important in a feedback mechanism.
In the final step, the propagation phase, the highly efficient tenase and prothrombinase complexes have been assembled on the membrane surface. This yields large amounts of thrombin at the site of injury that can cleave fibrinogen to insoluble fibrin. Factor XI activation by thrombin then activates factor IX, which leads to the formation of more tenase complexes. This ensures enough thrombin is formed, despite regulation of the initiating TF-FVIIa complex, thus ensuring formation of a stable fibrin clot. Factor XIII stabilizes the fibrin clot through crosslinking when activated by thrombin.
English: Gene expression pattern of the VWF gene. (Photo credit: Wikipedia)
Coagulation cascade (Photo credit: Wikipedia)
Fibrinolytic pathway
Fibrinolysis is the physiological breakdown of fibrin to limit and resolve blood clots. Fibrin is degraded primarily by the serine protease, plasmin, which circulates as plasminogen. In an auto-regulatory manner, fibrin serves as both the co-factor for the activation of plasminogen and the substrate for plasmin.
In the presence of fibrin, tissue plasminogen activator (tPA) cleaves plasminogen producing plasmin, which proteolyzes the fibrin. This reaction produces the protein fragment D-dimer, which is a useful marker of fibrinolysis, and a marker of thrombin activity because fibrin is cleaved from fibrinogen to fibrin.
Bleeding after Coronary Artery bypass Graft
Cardiac surgery with concomitant CPB can profoundly alter haemostasis, predisposing patients to major haemorrhagic complications and possibly early bypass conduit-related thrombotic events as well. Five to seven percent of patients lose more than 2 litres of blood within the first 24 hours after surgery, between 1% and 5% require re-operation for bleeding. Re-operation for bleeding increases hospital mortality 3 to 4 fold, substantially increases post-operative hospital stay and has a sizeable effect on health care costs. Nevertheless, re-exploration is a strong risk factor associated with increased operative mortality and morbidity, including sepsis, renal failure, respiratory failure and arrhythmias.
(Gábor Veres. New Drug Therapies Reduce Bleeding in Cardiac Surgery. Ph.D. Doctoral Dissertation. 2010. Semmelweis University)
Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported
Reporter: Aviva Lev-Ari, PhD, RN
UPDATED on 8/17/2018
NOAC’s Brain Bleed Risk Outside Afib May Be Dose-Dependent
Higher risk seen only with higher rivaroxaban doses in meta-analysis
by Ashley Lyles, MedPage Today Intern
The findings indicate the following risk of intracranial hemorrhage versus aspirin:
10 mg of rivaroxaban taken once per day or 5 mg taken two times a day (three trials, OR 1.43, 95% CI 0.93-2.21)
5 mg of apixaban twice daily (one trial, OR 0.84, 95% CI 0.38-1.88)
The study also showed that 15 mg to 20 mg of rivaroxaban each day was linked with an increased risk of fatal bleeding (two trials, OR 2.37, 95% CI 1.30-4.29). On the other hand, 10 mg of rivaroxaban each day or 5 mg taken twice a day (three trials, OR 1.47, 95% CI 0.72-2.97) and 5 mg of apixaban taken twice per day (one trial, OR 0.66, 95 % CI 0.19-2.35) were not linked with an increased risk.
Increased risk of major bleeding compared with aspirin was seen with 15 mg to 20 mg dose of rivaroxaban each day (two trials, OR 2.64, 95% CI 1.68-4.16) and a 10 mg dose of rivaroxaban once a day or 5 mg twice per day (three trials, OR 1.56, 95% CI 1.31-1.85).
Rivaroxaban (Xarelto) flopped for preventing recurrent strokes and increased bleeding compared with aspirin in top-line results from the phase III NAVIGATE ESUS trial, Bayer and Janssen announced. (Genetic Engineering and Biotechnology News)
Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation, increase in Gastrointestinal (GI) Bleeding Reported compared with Coumadin
Rivaroxaban Gains FDA Indications For The Treatment And Prevention Of DVT And PE
The FDA today expanded the indication for rivaroxaban (Xarelto, Johnson & Johnson) to include the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) and to reduce the risk of recurrent DVT and PE.
The oral anticoagulant is already approved to reduce the post-surgical risk of DVT and PE after hip and knee replacement surgery and to reduce the risk of stroke in people with atrial fibrillation. The new indication was granted under the FDA’s priority review program.
“Xarelto is the first oral anti-clotting drug approved to treat and reduce the recurrence of blood clots since the approval of warfarin nearly 60 years ago,” said Richard Pazdur, director of the FDA’s Office of Hematology and Oncology Products, in an FDA press release.
Here is the FDA press release:
FDA expands use of Xarelto to treat, reduce recurrence of blood clots
The U.S. Food and Drug Administrationtoday expanded the approved use of Xarelto (rivaroxaban) to include treating deep vein thrombosis (DVT) or pulmonary embolism (PE), and to reduce the risk of recurrent DVT and PE following initial treatment.Blood clots occur when blood thickens and clumps together. DVT is a blood clot that forms in a vein deep in the body. Most deep vein blood clots occur in the lower leg or thigh. When a blood clot in a deep vein breaks off and travels to an artery in the lungs and blocks blood flow, it results in a potentially deadly condition called PE.Xarelto is already FDA-approved to reduce the risk of DVTs and PEs from occurring after knee or hip replacement surgery (July 2011), and to reduce the risk of stroke in people who have a type of abnormal heart rhythm called non-valvular atrial fibrillation (November 2011).
The FDA reviewed Xarelto’s new indication under the agency’s priority review program, which provides an expedited six-month review for drugs that offer major advances in treatment or that provide treatment when no adequate therapy exists.
“Xarelto is the first oral anti-clotting drug approved to treat and reduce the recurrence of blood clots since the approval of warfarin nearly 60 years ago,” said Richard Pazdur, M.D., director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.
Other drugs approved by FDA to treat or reduce the risk of blood clots include Lovenox (enoxaparin), generic versions of enoxaparin, Arixtra (fondaparinux), Fragmin (dalteparin), Coumadin (warfarin), and heparin.
The safety and effectiveness of Xarelto for the new indications were evaluated in three clinical studies. A total of 9,478 patients with DVT or PE were randomly assigned to receive Xarelto, a combination of enoxaparin and a vitamin K antagonist (VKA), or a placebo. The studies were designed to measure the number of patients who experienced recurrent symptoms of DVT, PE or death after receiving treatment.
Results showed Xarelto was as effective as the enoxaparin and VKA combination for treating DVT and PE. About 2.1 percent of patients treated with Xarelto compared with 1.8 percent to 3 percent of patients treated with the enoxaparin and VKA combination experienced a recurrent DVT or PE. Additionally, results from a third study showed extended Xarelto treatment reduced the risk of recurrent DVT and PE in patients. About 1.3 percent of patients treated with Xarelto compared with 7.1 percent of patients receiving placebo experienced a recurrent DVT or PE.
The major side effect observed with Xarelto is bleeding, similar to other anti-clotting drugs.
Xarelto is marketed by Raritan, N.J.-based Janssen Pharmaceuticals Inc.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.
ATLANTA, Georgia — Patients with atrial fibrillation receiving anticoagulant therapy are more likely to experience gastrointestinal (GI) bleeding when treated with rivaroxaban than when treated with warfarin, according to a new analysis of data from ROCKET AF.
Christopher Nessel, MD, from research and development at Johnson & Johnson in Raritan, New Jersey, reported the findings here at CHEST 2012: American College of Chest Physicians Annual Meeting.
“Compared with warfarin, the risk of GI bleeding is increased with rivaroxaban, but the incidence of life-threatening or fatal GI bleeding is lower,” Dr. Nessel told Medscape Medical News. “A careful benefit/risk assessment is needed prior to prescribing rivaroxaban for high-risk patients,” he added.
The analysis examined the incidence and outcomes of GI hemorrhage in 14,264 patients with nonvalvular atrial fibrillation enrolled in ROCKET AF.
The patients were randomized to either rivaroxaban or dose-adjusted warfarin. All GI bleeding events were recorded during treatment and for 2 days after the last dose was administered. Severity of bleeding was defined by a corresponding drop in hemoglobin or transfusion of more than 2 units of red cells.
The composite principal safety end point for GI bleeding events (upper GI, lower GI, and rectal bleeding) occurred more frequently in the 394 patients receiving rivaroxaban than in the 290 receiving warfarin (3.61% vs 2.60% per year; hazard ratio [HR], 1.39; 95% confidence interval [CI], 1.19 to 1.61). Major bleeding was more frequent with rivaroxaban than with warfarin (2.00% vs 1.24% per year; HR, 1.61; 95% CI, 1.30 to 1.99), as was clinically relevant nonmajor bleeding (1.75% vs 1.39% per year; HR, 1.26; 95% CI, 1.20 to 1.55).
Patients who experienced major GI bleeding were more likely to have experienced GI bleeding in the past, to have mild anemia, to have a lower creatinine clearance, to be previous or current smokers, and to be older than patients who did not experience a GI bleeding during the trial (n = 13,552). They were also less likely to be female and to have previously experienced a stroke or transient ischemic attack.
The incidence of severe bleeding (transfusion of at least 4 units) was similar in the rivaroxaban and warfarin groups (49 vs 47). Six patients developed fatal bleeding: 1 in the rivaroxaban group and 5 in the warfarin group.
Data May Give Clinicians Pause When Considering Rivaroxaban
“The data presented extend the observations from the ROCKET AF clinical study,” Dr. Nessel said. “Specifically, the analyses identified characteristics of nonvalvular atrial fibrillation patients that may predispose them to the occurrence of GI hemorrhage. The data also indicated that the overall fatality rates for bleeds of this nature are very low.”
Independent commentator James Wisler, MD, from the division of cardiovascular disease at Duke University Medical Center in Durham, North Carolina, pointed out that this study underscores the importance of critically evaluating these newer anticoagulants when considering their use in a given patient.
“The decision regarding which anticoagulant to use for a given patient is complex, and risks and benefits need to be considered thoughtfully,” he told Medscape Medical News. He added that the results of this study might give some physicians pause about initiating a newer anticoagulant, such as rivaroxaban, in a given patient with atrial fibrillation and an unfavorable risk profile, such as those with a previous GI bleed.
“While the previously published results from ROCKET AF suggested that the risk profiles were similar between rivaroxaban and warfarin, these results demonstrate that there is indeed a subpopulation of patients who may be better served with warfarin than rivaroxaban,” he explained.
According to Dr. Wisler, both this analysis and the initial ROCKET AF study demonstrate that rivaroxaban is associated with fewer episodes of severe or fatal bleeding events, despite the increase in major and clinically relevant nonmajor bleeding observed in the specific subgroup of this study. “Currently, it is unclear why this discrepancy exists,” he added.
He recommends that clinicians take a careful patient history to assess bleeding risk factors when considering the initiation of a newer anticoagulant such as rivaroxaban.
“While perhaps more convenient and efficacious, certain patient populations, such as that evaluated in this study, may receive net harm from these newer agents,” he said.
SOURCE:
CHEST 2012: American College of Chest Physicians Annual Meeting. Presented October 22, 2012.
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