Newer Oral Anticoagulants: An Alternative to Warfarin
•Download as PPTX, PDF•
4 likes•480 views
New oral anticoagulant 2020
Recommended
More Related Content
What's hot
What's hot (20)
Similar to Newer Oral Anticoagulants: An Alternative to Warfarin
Similar to Newer Oral Anticoagulants: An Alternative to Warfarin (20)
More from Shivaom Chaurasia
More from Shivaom Chaurasia (20)
Recently uploaded
Recently uploaded (20)
Newer Oral Anticoagulants: An Alternative to Warfarin
- 1. Newer Oral Anticoagulant DR SHIVAOM CHAURASIA RESIDENT INTERNAL MEDICINE
- 2. • Whenever a blood vessel is severed or ruptured, hemostasis is achieved by • Vascular spasm • Platelet plug formation • Formation of blood clot • Growth of fibrous tissue into the blood clot. • Coagulation is a complex process by which blood forms clots. • Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis) Introduction
- 3. Platelet activation and thrombosis. • Platelets circulate in an inactive form in the vasculature. • Damage to the endothelium and/or external stimuli activates platelets that adhere to the exposed subendothelial von Willebrand factor and collagen. • Adhesion leads to activation of the platelet, shape change, and the synthesis and release of thromboxane (TxA2), serotonin (5-HT), and adenosine diphosphate (ADP). • Platelet stimuli cause conformational change in the platelet integrin glycoprotein (GP) IIb/IIIa receptor, leading to the high-affinity binding of fibrinogen and the formation of a stable platelet thrombus.
- 4. Summary of the coagulation pathways
- 6. Arterial vs Venous Thrombus Arterial Thrombus • Endothelial damage causes plts plug formation • Arterial platelet rich thrombus • Whitish • MI, Ischemic Stroke, PVD limb gangrene • Antiplatelets, Anticoagulants or fibrinolytics in acute conditions Venous Thrombus • Virchow’s Triad • Fibrin rich thrombus with trapped RBCs • Reddish • DVT, pulmonary embolism • Anticoagulants
- 8. ANTICOAGULANTS • An anticoagulant is a substance that prevents coagulation; that is, it stops blood from clotting. • The parenteral anticoagulants include • heparin, low-molecular-weight heparin (LMWH), fondaparinux (a synthetic pentasaccharide), lepirudin, desirudin, bivalirudin, and argatroban. • Currently available oral anticoagulants include • warfarin; • dabigatran etexilate - an oral thrombin inhibitor; and • rivaroxaban, apixaban, and edoxaban - oral factor Xa inhibitors.
- 9. Heparins- • A sulfated polysaccharide isolated from mammalian tissues rich in mast cells. • Acts by activating antithrombin and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa. • Only pentasaccharide-containing heparin chains composed of at least 18 saccharide units (~molecular weight 5400) are of sufficient length to bridge thrombin and antithrombin together.
- 10. Unfractionated Heparin LMWH Fondaparinux Activates antithrombin and acclerates the rate at which antithrombin inhibit factor Xa and thrombin Antithrombin, the obligatory plasma cofactor for heparin To activate antithrombin, heparin binds to the serpin via a unique pentasaccharide sequence mean molecular weight of 15,000, and a range of 5000– 30,000 Consisting of smaller fragments of heparin prepared from unfractionated heparin by controlled enzymatic or chemical depolymerization. Mean molecular weight ~ 5000, one-third the mean molecular weight of unfractionated heparin. synthetic analogue of the antithrombin-binding pentasaccharide sequence as effective as heparin or LMWH - DVT or PE Prophylaxis: 5000 units S/C bd – tds Therapeutic • MI: IV bolus 5000 u or 70 u/kg f/b infusion @ 12–15 u/kg/ hr • DVT: IV bolus of 80 u/kg f/b infusion @ 18 u/kg/ hr Monitoring- APTT-Therapeutic range:2-3 times of control value Anti factor Xa level :0.3-0.7 units/ml S/E- Bleeding, HIT,Osteoporosis Elevated Transaminases Antidote-Protamine Dosing- therapeutic dose-1mg/kg SC BD Prophylaxis-40mg SC OD Monitoring Usually not done • Anti factor Xa levels:0.2-0.5prophylaxis • 0.5 – 1.2 units/ml therapeutic • S/E-occurs rarely Antidote-Protamine only partially reverse • Complete bioavailability after SC (as no binding with endothelium or plasma protein) • Half life is longer than LMWH (OD dose) • Clearance – Renal (<30 GFR C/I) 2.5mg sc od - prophylaxis 5mg sc od - if less than 50 kg 10 mg sc if > 100kg Monitoring not needed major bleeding 50% lower enoxaparin; NO HIT No antidote
- 11. Parenteral Direct Thrombin Inhibitors • Directly to thrombin and block its interaction with its substrates. • Approved parenteral direct thrombin inhibitors include recombinant hirudins (lepirudin and desirudin), argatroban, and bivalirudin . • Lepirudin and Argatroban -HIT, • Desirudin - Thromboprophylaxis after elective hip arthroplasty, and • Bivalirudin - an alternative to heparin undergoing PCI, including those with HIT.
- 12. Indications of Anticoagulant Therapy • Prevention and Treatment of Deep Venous Thrombosis • Treatment of Pulmonary Emboli • Prevention of stroke in patients with atrial fibrillation, artificial heart valves, established thrombosis (DVT, Cardiac) • Ischaemic heart disease • During procedures such as cardiac catheterisation
- 13. Copyrights apply
- 14. ORAL ANTICOAGULANTS • For many years, vitamin K antagonists such as warfarin were the only available oral anticoagulants. • This situation changed with the introduction of the direct oral anticoagulants (DOAC), which include • dabigatran, rivaroxaban, apixaban, and edoxaban.
- 15. Warfarin • Warfarin inhibits vitamin k epoxide reductase • Warfarin accumulates in the liver where the two isomers are metabolized via distinct pathways. • CYP2C9 mediates oxidative metabolism of the more active S isomer. • Polymorphisms in VKORC1 also can influence the anticoagulant response to warfarin. • VKORC1 variants are more prevalent than variants of CYP2C9. • Asians more common
- 16. MECHANISM OF ACTION • A racemic mixture of S- and R-enantiomers, S-warfarin is most active. • By blocking vitamin K epoxide reductase inhibits the conversion of oxidized vitamin K. • It inhibits vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X • As reduced vitamin K serves as a cofactor for γ-glutamyl carboxylase, • catalyzes the γ-carboxylation process, thereby converting prozymogens to zymogens capable of binding calcium and interacting with anionic phospholipid surfaces.
- 19. • Because of its delayed onset of action, patients with established OR high risk of thrombosis are given concomitant initial treatment with a rapidly acting parenteral anticoagulant, such as heparin, LMWH, or fondaparinux. • concomitant treatment should be continued until the INR has been therapeutic for at least 2 consecutive days. • A minimum 5-day course of parenteral anticoagulation is recommended • to ensure that the levels of factor Xa and prothrombin have been reduced into the therapeutic range with warfarin. • More frequent monitoring is necessary • when new medications are introduced as many drugs enhance or reduce the anticoagulant effects of warfarin.
- 20. Copyrights apply
- 25. Warfarin instead of the NOAC agents: • Patients already on warfarin who are comfortable with periodic INR measurement and whose INR has been well controlled with an annual time in the therapeutic range of greater than 65 percent. • Patients with mechanical heart valves of any type or those with severe mitral stenosis of any cause. • Patients who are not likely to comply with the twice daily dosing dabigatran or apixaban and who are unable to take once-a- day rivaroxaban or edoxaban.
- 26. • Patients for whom the NOAC agents will lead to an unacceptable increase in cost. • Patients with chronic severe kidney disease whose estimated glomerular filtration rate is less than 30 mL/min.(apixaban approved United States ). • Patients for whom the NOAC agents are contraindicated, including those on enzyme-inducing antiepileptic drugs (eg, phenytoin) and patients with human immunodeficiency virus infection (HIV) on protease inhibitor-based antiretroviral therapy.
- 28. Features of an ideal anticoagulant • High efficacy to safety index • Predictable dose response • Administration by parenteral and oral routes • Rapid onset of action • Availability of a safe antidote • Freedom from side effects • Minimal interactions
- 29. Direct Oral Anticoagulants • An alternatives to warfarin. • These agents include • Dabigatran - inhibits thrombin, and • rivaroxaban, apixaban, and edoxaban - inhibit factor Xa. • All of these drugs have • a rapid onset and offset of action and • half-lives that permit once- or twice-daily administration. • produce a predictable level of anticoagulation,
- 30. MECHANISMS OF ACTION Sites of action — The direct thrombin inhibitors and direct factor Xa inhibitors block major procoagulant activities involved in the generation of a fibrin clot . • Thrombin – • Thrombin (factor IIa) is the final enzyme of the clotting cascade that produces fibrin; • formed by the proteolytic cleavage of prothrombin by factor Xa. • Thrombin has a central role in coagulation: • it cleaves fibrinogen to fibrin; • activates other procoagulant factors including factors V, VIII, XI, and XIII; and activates platelets . • enhance the specificity of the enzyme . • active in both circulating and clot-bound forms
- 31. • Factor Xa – • acts at the convergence point of the intrinsic and extrinsic coagulation pathways; • formed by the proteolytic cleavage of factor X . • active in circulating and clot-bound forms. • Inhibition can prevent amplified thrombin generation • as one molecule of factor Xa can cleave over 1000 molecules of prothrombin to thrombin . • Direct factor Xa inhibitors are able to block the action of both forms of factor Xa, • whereas indirect factor Xa inhibitors such as heparin and fondaparinux (the antithrombin-binding pentasaccharide) are only able to inactivate factor Xa in the fluid phase, via antithrombin
- 32. INDICATIONS • Venous thromboembolism (VTE) prophylaxis & TREATMENT • Atrial fibrillation (AF) • Acute coronary syndromes (ACS) • Heparin-induced thrombocytopenia (HIT) • These agents are not used in individuals with prosthetic heart valves, severe renal insufficiency, pregnancy, or antiphospholipid syndrome (APS)
- 34. • Rivaroxaban and apixaban simplify treatment and facilitate out-of-hospital management of most patients with DVT and many with PE • With these advantages, clinical guidelines now endorse the direct oral anticoagulants • first-line treatment of venous thromboembolism in patients without active cancer. • For those with active cancer - LMWH remains the preferred therapy.
- 35. MONITORING • Designed to be administered without routine monitoring, • Situations where determination of the anticoagulant activity of the new oral anticoagulants can be helpful. • assessment of adherence, detection of accumulation or overdose, identification of bleeding mechanisms, and determination of activity prior to surgery or intervention. • Qualitative assessment of anticoagulant activity, • Prothrombin time - factor Xa inhibitors and • aPTT - dabigatran.
- 36. SIDE EFFECTS • Bleeding is the most common side effect. • The new oral anticoagulants has increased risk of gastrointestinal bleeding. • likely occurs because unabsorbed active drug in the gut exacerbates bleeding from lesions. • Less intracranial bleeding than warfarin. • The direct oral anticoagulants target downstream coagulation enzymes, • produce less impairment of hemostatic plug formation at sites of vascular injury
- 37. • Dabigatran etexilate • a prodrug, only 7% is absorbed and the remainder passes through the gut • where at least two-thirds is metabolically activated to dabigatran by gut esterases. • Dyspepsia occurs in up to 10% of patients treated with dabigatran - improves with time and can be minimized by administering the drug with food. • Dyspepsia is rare • rivaroxaban, apixaban, and edoxaban.
- 38. PERIPROCEDURAL MANAGEMENT • Like warfarin, the new oral anticoagulants must be stopped before procedures associated with a moderate or high risk of bleeding. • held for 1–2 days, or longer - renal function is impaired. • Assessment of residual anticoagulant activity before procedures associated with a high bleeding risk is prudent.
- 41. • P-gp inhibitors :Concomitant administration of strong P-gp inhibitors (such as amiodarone, verapamil, quinidine, ketoconazole and clarithromycin) is expected to result in increased dabigatran plasma concentrations. • P-gp inducers : Concomitant administration of a P-gp inducer (such as rifampicin, St. John´s wort (Hypericum perforatum),carbamazepine, or phenytoin) is expected to result in decreased dabigatran concentrations and should be Avoided. Interaction- Dabigatran
- 42. • CYP3A4 and P-GP inhibitors • May ↑ the serum concentration of rivaroxaban • CYP3A4 and P-GP inducers • May ↓ the serum concentration of rivaroxaban • Anticoagulants • ↑ risk of bleeding • NSAIDs and platelet aggregation inhibitors • ↑ risk of bleeding Drug Interactions- Rivaroxaban
- 43. Copyrights apply
- 44. MANAGEMENT OF BLEEDING • With minor bleeding, • holding one or two doses of drug is usually sufficient. • Serious bleeding • similar to that with warfarin except that vitamin K administration is of no benefit. • The anticoagulant and antiplatelet drugs should be held, • Resuscitation with fluids and blood products as necessary, and, • if possible, the bleeding site should be identified and managed.
- 45. • Timing of the last dose of anticoagulant is important; • Administration of oral activated charcoal • may help to prevent absorption of drug administered in the past 2–4 h. • Anticoagulant reversal should be considered • life-threatening bleeding, such as intracranial bleeding, • bleeding continues despite supportive measures or • urgent surgery.
- 49. PREGNANCY • As small molecules, the direct oral anticoagulants can all pass through the placenta. • Contraindicated in pregnancy • Women of childbearing potential - appropriate contraception is important. • The direct oral anticoagulants should be avoided in nursing mothers • Their safety in children has yet to be established.
- 50. Specific considerations: when to use each drug • Chronic Kidney Disease: • CrCl < 25 to 30ml/min: • recommend warfarin therapy • CrCl 30-49 ml/min: • Consider Rivaroxaban 15mg daily or • Apixaban 5mg twice daily • use the 2.5mg lower dose if two of the following are present: • age >80 years, • body weight < 60kg, • creatinine > 1.5mg/dl • CrCl > 50ml/min: • All choices are appropriate
- 51. • Patients with recurrent gastrointestinal (GI) bleed: • Dabigatran and rivaroxaban had higher rates of GI bleeding when compared to warfarin. • For apixaban, there was no difference in GI bleeding compared to Warfarin. • In patients who have difficulty with recurrent GI bleeding, • reasonable to consider apixaban until more data are available with the other agents.
- 52. Copyrights apply
- 56. References • Harrison’s_Principles_of_Internal_Medicine,_Twentieth_Edition_(Vol. 1_&_Vol.2 • Davidsons Principles and Practice of Medicine 23rd ed • UpToDate • CMDT • https://noacguide.com/
- 57. THANK YOU
Editor's Notes
- Disorders of coagulation can lead to an increased risk of bleeding (hemorrhage) or clotting (thrombosis)
- Specific coagulation factors (“a” indicates activated form) are responsible for the conversion of soluble plasma fibrinogen into insoluble fibrin. This process occurs via a series of linked reactions in which the enzymatically active product subsequently converts the downstream inactive protein into an active serine protease. In addition, the activation of thrombin leads to stimulation of platelets. HK, high-molecular-weight kininogen; PK, prekallikrein; TF, tissue factor.
- Vascular injury simultaneously triggers platelet activation and aggregation and activation of the coagulation system. Activation initiated - exposure of subendothelial collagen and von Willebrand factor (VWF), onto which platelets adhere. Adherent platelets become activated and release ADP and thromboxane A2. When platelets activated, glycoprotein IIb/ IIIa on their surface undergoes a conformational change that enables it to ligate fibrinogen and/or VWF and mediate platelet aggregation. Coagulation is triggered by tissue factor exposed at the site of injury. Which generates thrombin amplifies platelet recruitment to the site of injury. converts fibrinogen to fibrin, and the fibrin strands then weave the platelet aggregates together to form a platelet/fibrin thrombus.
- Most commercial heparin is derived from porcine intestinal mucosa and is a polymer of alternating d- glucuronic acid and N-acetyl-d-glucosamine residues. With a mean molecular weight of 15,000, and a range of 5000–30,000, almost all of the chains of unfractionated heparin are long enough to do so.
- HEPARIN- MOA Heparin acts as an anticoagulant by activating antithrombin (previously known as antithrombin III) and accelerating the rate at which antithrombin inhibits clotting enzymes, particularly thrombin and factor Xa. Antithrombin, the obligatory plasma cofactor for heparin, is a member of the serine protease inhibitor (serpin) superfamily. Synthesized in the liver and circulating in plasma at a concentration of 2.6 ± 0.4 μM, antithrombin acts as a suicide substrate for its target enzymes. To activate antithrombin, heparin binds to the serpin via a unique pentasaccharide sequence that is found on one-third of the chains of commercial heparin (Fig. 114-5). Heparin chains without this pentasaccharide sequence have little or no anticoagulant activity. Once bound to antithrombin, heparin induces a conformational change in the reactive center loop of antithrombin that renders it more readily accessible to its target proteases. This conformational change enhances the rate at which antithrombin inhibits factor Xa by at least two orders of magnitude but has little effect on the rate of thrombin inhibition. To catalyze thrombin inhibition, heparin serves as a template that binds antithrombin and thrombin simultaneously. Formation of this ternary complex brings the enzyme in close apposition to the inhibitor, thereby promoting the formation of a stable covalent thrombin-antithrombin complex. Consequently, by definition, heparin has equal capacity to promote the inhibition of thrombin and factor Xa by antithrombin and is assigned an anti-factor Xa to anti-factor IIa (thrombin) ratio of 1:1. Heparin causes the release of tissue factor pathway inhibitor (TFPI) from the endothelium. A factor Xa–dependent inhibitor of tissue factor–bound factor VIIa, TFPI may contribute to the antithrombotic activity of heparin. Longer heparin chains induce the release of more TFPI than shorter ones. Fondaparinux synthetic analogue of the antithrombin-binding pentasaccharide sequence Licensed for thromboprophylaxis in general medical or surgical patients and in high-risk orthopedic patients and an alternative to heparin or LMWH for initial treatment of patients with established venous thromboembolism. Used in Europe as an alternative to heparin or LMWH in acute coronary syndrome, not licensed in United States. . PHARMACOLOGY Fondaparinux exhibits complete bioavailability after SC injection. With no binding to endothelial cells or plasma proteins, the clearance of fondaparinux is dose-independent and its plasma half-life is 17 h. The drug is given SC once daily. Because fondaparinux is cleared unchanged via the kidneys, it is contraindicated in patients with a creatinine clearance <30 mL/min and should be used with caution in those with a creatinine clearance <50 mL/min. False heparin resistant e L<whsp due to elevated factor VIII and fibrinogen(Acute phase reactants) Fondaparinux produces a predictable anticoagulant response after administration in fixed doses because it does not bind to plasma proteins. The drug is given at a dose of 2.5 mg once daily for prevention of venous thromboembolism. For initial treatment of established venous thromboembolism, fondaparinux is given at a dose of 7.5 mg once daily. When given in these doses, fondaparinux is as effective as heparin or LMWH for initial treatment of patients with DVT or PE and produces similar rates of bleeding. Fondaparinux is used at a dose of 2.5 mg once daily in patients with acute coronary syndromes. When this prophylactic dose of fondaparinux was compared with treatment doses of enoxaparin in patients with non-ST-segment elevation acute coronary syndrome, there was no difference in the rate of cardiovascular death, MI, or stroke at 9 days. However, the rate of major bleeding was 50% lower with fondaparinux than with enoxaparin, a difference that likely reflects the fact that the dose of fondaparinux was lower than that of enoxaparin. In acute coronary syndrome patients who require percutaneous coronary intervention, there is a risk of catheter thrombosis with fondaparinux unless adjunctive heparin is given. The dose can be reduced to 5 mg once daily for those weighing <50 kg and increased to 10 mg for those >100 kg. SIDE EFFECTS Does not cause HIT as doesnt bind to PF4. No cross-reactivity with HIT antibodies. Effective for treatment HIT patients although large clinical trials supporting its use are lacking. Major side effect - bleeding. No antidote. Protamine sulfate - no effect as it fails to bind to the drug. Recombinant activated factor VII reverses the anticoagulant effects of fondaparinux in volunteers, but it is unknown whether this agent controls fondaparinux-induced bleeding HEPARINS Activates antithrombin and acclerates the rate at which antithrombin inhibit factor Xa and thrombin Causes the release of tissue factor pathway inhibitor (TFPI) from the endothelium. Heparin binds to the endothelium and to plasma proteins other than antithrombin Effect of binding to endothelium At low doses, T1/2 of heparin is short as it binds rapidly to the endothelium. With higher doses of heparin, the half-life is longer because heparin is cleared more slowly once the endothelium is saturated. Clearance is mainly extrarenal by macrophages.. Because of its dose-dependent clearance mechanism, the plasma half-life of heparin ranges from 30 to 60 min with bolus IV doses of 25 and 100 U/kg, respectively Effect of binding to plasma protein Reduces anticoagulant activity Some of the heparin-binding proteins found in plasma are acute-phase reactants whose levels are elevated in ill patients Activated platelets also release platelet factor 4 (PF4),that binds heparin with high affinity. The large amounts of PF4 found in the vicinity of platelet-rich arterial thrombi can neutralize the anticoagulant activity of heparin. This phenomenon may attenuate heparin's capacity to suppress thrombus growth. As heparin-binding proteins in plasma vary from person to person, the anticoagulant response to fixed or weight-adjusted doses of heparin is unpredictable. Coagulation monitoring is essential to ensure that a therapeutic response is obtained. Especially in the cases of treatment and to prevent bleeding >35000units/d are needed to maintain therapeutic aptt range.------------------HEPARIN RESISTANCE
- Approximately 25% of Caucasians have at least one variant allele of CYP2C9*2 or CYP2C9*3, whereas those variant alleles are less common in African Americans and Asians (Table 114-8). Heterozygosity for CYP2C9*2 or CYP2C9*3 decreases the warfarin dose requirement by 20–30% relative to that required in subjects with the wild-type CYP2C9*1/*1 alleles, whereas homozygosity for the CYP2C9*2 or CYP2C9*3 alleles reduces the warfarin dose requirement by 50–70%. Consistent with their decreased warfarin dose requirement, subjects with at least one CYP2C9 variant allele are at increased risk for bleeding. Several genetic variations of VKORC1 are in strong linkage disequilibrium and have been designated as non-A haplotypes. CYP2C9 mediates oxidative metabolism of the more active S isomer. Two relatively common variants, CYP2C9*2 and CYP2C9*3, encode an enzyme with reduced activity. Patients with these variants require lower maintenance doses of warfarin. the relative risks for warfarin-associated bleeding in CYP2C9*2 or CYP2C9*3 carriers are 1.9 and 1.8, respectively. Polymorphisms in VKORC1 also can influence the anticoagulant response to warfarin. VKORC1 variants are more prevalent than variants of CYP2C9. Asians have the highest prevalence of VKORC1 variants, followed by Caucasians and African Americans Compared with VKORC1 non-A/non-A homozygotes, the warfarin dose requirement decreases by 25 and 50% in A haplotype heterozygotes and homozygotes, respectively.
- Because warfarin has a narrow therapeutic window, frequent coagulation monitoring is essential to ensure that a therapeutic anticoagulant response is maintained. Even patients with stable warfarin dose requirements should have their INR determined every 3–4 weeks
- Warfarin therapy is most often monitored using the prothrombin time, sensitive to reductions in the levels of prothrombin, factor VII, and factor X. The test is performed by adding thromboplastin, a reagent that contains tissue factor, phospholipid, and calcium, to citrated plasma and determining the time to clot formation. Although the INR has helped to standardize anticoagulant practice, problems persist. The precision of INR determination varies depending on reagent-coagulometer combinations. complicating INR determination is unreliable reporting of the ISI by thromboplastin manufacturers. every laboratory must establish the mean normal prothrombin time with each new batch of thromboplastin reagent. Thromboplastins vary in their sensitivity to reductions in the levels of the vitamin K–dependent clotting factors. Thus, less sensitive thromboplastins will trigger the administration of higher doses of warfarin to achieve a target prothrombin time. To accomplish this, the prothrombin time must be measured in fresh plasma samples from at least 20 healthy volunteers using the same coagulometer that is used for patient samples. For most indications, warfarin is administered in doses that produce a target INR of 2.0–3.0. An exception is patients with mechanical heart valves, particularly those in the mitral position or older ball and cage valves in the aortic position, where a target INR of 2.5–3.5 is recommended.
- Although these processes are often described separately, there are multiple points of overlap and crosstalk between platelets, procoagulant factors, endogenous anticoagulant and fibrinolytic factors, and the endothelium, to promote an appropriate level of hemostasis and limit clot formation to sites of vessel injury. The active site and "exosite I," a positively charged region of the thrombin molecule that is physically separated from the active site (divalent DTIs) . Exosite I is also the site of interaction of many physiologic thrombin substrates, including fibrinogen, factor V, protein C, thrombomodulin (a thrombin receptor on endothelial cells), and thrombin receptors (PAR1 and PAR4) on platelets . The active site of the thrombin enzyme is buried deep in a groove on one side of the molecule ; this deep groove and surrounding amino acids enhance the specificity of the enzyme .
- Direct factor Xa inhibitors bind to the active site of factor Xa and inhibit factor Xa activity without a requirement for cofactors.
- INDICATIONS The direct oral anticoagulants have been compared with warfarin for stroke prevention in patients with nonvalvular atrial fibrillation in four randomized trials that enrolled 71,683 patients. A meta-analysis of these data demonstrates that compared with warfarin, the higher doses of the direct oral anticoagulants significantly reduce stroke or systemic embolism by 19% (p = 0.001), primarily driven by a 51% reduction in hemorrhagic stroke (p <0.0001), and are associated with a 10% reduction in mortality (p <0.0001). The direct oral anticoagulants reduce intracranial hemorrhage by 52% compared with warfarin (p <0.0001), but increase gastrointestinal bleeding by about 24% (p = 0.04). Based on these findings, dabigatran, rivaroxaban, apixaban, and edoxaban are licensed as alternatives to warfarin for stroke prevention in nonvalvular atrial fibrillation, which is defined as atrial fibrillation occurring in patients without mechanical heart valves or severe rheumatic valvular disease, particularly mitral stenosis and/or regurgitation. The direct oral anticoagulants were compared with conventional anticoagulation therapy in 27,023 patients with acute venous thromboembolism. The primary efficacy endpoint in these trials - recurrent venous thromboembolism, The primary safety outcome - either major bleeding or the composite of major and clinically relevant non-major bleeding. Recurrent fatal and non-fatal venous thromboembolism 2.0% of those given direct oral anticoagulants compared with 2.2% of those given a vitamin K antagonist (relative risk [RR] 0.90, 95% confidence interval [CI]: 0.77–1.06). Major bleeding direct oral anticoagulants were associated with a 39% reduction in the risk of major bleeding (RR 0.61, 95% CI: 0.45–0.83), a 63% reduction in intracranial bleeding (RR 0.37, 95% CI: 0.21–0.68), and a 64% reduction in fatal bleeding (RR 0.36, 95% CI: 0.15–0.84). clinically relevant non-major bleeding was reduced by 27% with the direct oral anticoagulants compared with vitamin K antagonists (RR 0.73, 95% CI: 0.58–0.93). Overall, the direct oral anticoagulants demonstrate a favorable benefit-to-risk profile compared with warfarin, and their relative efficacy and safety are maintained across a wide spectrum of atrial fibrillation patients, including those over the age of 75 years and those with a prior history of stroke.
- The direct oral anticoagulants are non-inferior to well-managed vitamin K antagonist therapy for treatment of venous thromboembolism, but are associated with significantly less bleeding. Dabigatran and edoxaban were started after a minimum of a 5-day course of parenteral anticoagulant therapy, rivaroxaban and apixaban were administered in all-oral regimens starting with a higher dose for 21 days and 7 days, respectively. When used in this all-oral fashion, both agents were non-inferior to conventional therapy and were associated with significantly less major bleeding.
- The effect of the drugs on tests of coagulation varies depending on the time that the blood is drawn relative to the timing of the last dose of the drug and the reagents used to perform the tests. Chromogenic anti-factor Xa assays and a diluted thrombin clotting time with appropriate calibrators provide quantitative assays to measure the plasma levels of the factor Xa inhibitors and dabigatran, respectively.
- Increased risk of intracranial bleeding with warfarin likely reflects the reduction in functional levels of factor VII, which precludes efficient thrombin generation at sites of microvascular bleeding in the brain.
- Coagulation testing will determine the extent of anticoagulation and renal function should be assessed so that the half-life of the drug can be calculated.
- ANTIDOTE Idarucizumab is a specific reversal agent for dabigatran. A monoclonal antibody fragment, idarucizumab binds dabigatran with high affinity to form a 1:1 complex that is then cleared by the kidneys. an intravenous bolus of 5 g. Andexanet alfa and Ciraparantag under development for reversal of rivaroxaban, apixaban, and edoxaban but neither is approved. Prothrombin complex concentrate considered for reversal of the oral factor Xa inhibitors in patients with life-threatening or ongoing bleeding.