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![Advantages LMW heparins vs heparin
• greater bioavailability than unfractionated heparin when given by subcutaneous injection.
• ●The duration of the anticoagulant effect is greater because of reduced binding to macrophages and
endothelial cells, permitting administration only once or twice daily.
• ●The anticoagulant response (anti-Xa activity) to LMW heparin is highly correlated with body weight,
permitting administration of a fixed dose. However, the dose may have to be adjusted for patients who are
extremely obese or have renal
• ●Laboratory monitoring is not necessary in nonpregnant patients; in fact, there is little correlation
between anti-Xa activity and either bleeding or recurrent thrombosis.
• ●They are much less likely to induce immune-mediated thrombocytopenia (ie, heparin-induced
thrombocytopenia) than unfractionated heparin:
• ●They do not increase osteoclast number and activity as much as unfractionated heparin, and may
therefore produce less bone loss.
• ●LMW heparin can be safely administered in the outpatient setting
• ●In patients with acute VTE, fixed-dose subcutaneous LMW heparin is more effective than adjusted-dose
unfractionated heparin for reducing the incidence of symptomatic recurrent VTE, major hemorrhage, and
all-cause mortality [79].
• ●Home management using LMW heparin is cost effective, and is likely to be preferred by patients and](https://image.slidesharecdn.com/teachinganticoagulantsinccuward-161030105130/75/Treatment-with-anticoagulation-35-2048.jpg)
![Advantages over heparin and warfarin
• Heparin and warfarin both have a relatively narrow therapeutic window and
more variable dose-response relationship that depends on a variety of factors;
these features lead to a requirement for frequent monitoring of clotting times
to optimize the therapeutic dose range and prevent bleeding [20,21]. Dose may
be affected by differing bioavailability, diet, and acute medical illnesses. In
contrast, the target-specific oral agents are generally used without a
requirement for monitoring of drug levels or coagulation (clotting) times. This
may be an advantage for patients for whom frequent monitoring is a greater
burden. It remains to be determined whether laboratory monitoring of any of
the target-specific oral agents can further improve their efficacy or safety
Laboratory
monitoring
• Warfarin pharmacokinetics is affected by the level of vitamin K intake and
production in the gastrointestinal tract, as well as induction of hepatic
cytochromes. Thus, warfarin effect can be altered by changes in diet,
administration of other medications, gastrointestinal disorders, and reduced
oral intake. Patients with difficulty controlling the prothrombin
time/international normalized ratio (PT/INR) may benefit from a target-specific
oral agent because these agents have less variability in drug effect for a given
dose than vitamin K antagonists. Affected patients may include those with
unavoidable drug-drug interactions (such as frequent need for antibiotics or a
large number of concomitant and variable medications) or unexplained poor
warfarin control. However, it is important to determine that the INR instability
with a vitamin K antagonist is not due to poor compliance, which may be easier
to monitor for vitamin K antagonists than for the target-specific agents.
Pharmacokinetics](https://image.slidesharecdn.com/teachinganticoagulantsinccuward-161030105130/75/Treatment-with-anticoagulation-40-2048.jpg)
More Related Content
Similar to Treatment with anticoagulation
Treatment with anticoagulation
- 1. Treatment with anticoagulation BySomayyeh Nasiripour Pharm.D Board of clinical pharmacy Assistant professor at IUMS
- 2. • Antithrombotic agent– include both antiplatelet agents (eg, aspirin, clopidogrel) as well as anticoagulants. • ●Anticoagulant – include a variety of agents that inhibit one or more steps in the coagulation cascade. Their mechanisms vary, including direct enzymatic inhibition, indirect inhibition by binding to antithrombin, and antagonism of vitamin K-dependent factors by preventing their synthesis in the liver and/or modification of their calcium-binding properties
- 4. Warfarin racemic mixture ofS and R enantiomers The more potent S form of the drug is metabolized primarily by the CYP2C9 hepatic microsomal enzyme system. This enzyme system is inducible by many drugs and has a number of genetic variants Warfarin is strongly protein-bound, primarily to albumin; only the non-protein- bound fraction is biologically active Warfarin is rapidly absorbed from the gastrointestinal tract after oral administration, with a bioavailability of 100%, and its peak absorption is usually seen within 60 to 90 minutes. T ½ ….. 44 hr
- 5. Mechanism of action throughinhibition of the vitamin K-dependent gamma-carboxylation of coagulation factors II, VII, IX, and X Warfarin also inhibits the vitamin K-dependent gamma-carboxylation of proteins C and S Because of these competing effects, vitamin K antagonists, such as warfarin, create a biochemical paradox by producing an anticoagulant effect due to the inhibition of procoagulants (factors II, VII, IX, and X) and a potentially thrombogenic effect by impairing the synthesis of naturally occurring inhibitors of coagulation (proteins C and S) The ultimate anticoagulant effect of warfarin is delayed until the normal clotting factors, especially prothrombin, are cleared from the circulation. The peak effect does not occur until 36 to 72 hours after drug administration (factor II (prothrombin) is t ½ three days) For this reason, parenteral anticoagulants and warfarin should overlap by four to five days when warfarin is initiated in patients with acute thrombotic disease
- 7.
- 8. Genetic interactions Polymorphisms inthe genes for enzymes involved in warfarin clearance and the synthesis of vitamin K-dependent coagulation factors have been associated ( It was estimated from this study that genetic alterations in CYP2C9 and VKORC1 accounted for 6 to 10 percent and 21 to 25 percent of the variance in warfarin dose, respectively) polymorphisms in these two enzymes can account for up to 60 percent of interindividual variability in response to treatment with warfarin CYP2C9 is involved in the metabolic clearance of warfarin(wild-type CYP2C9*1 and variants CYP2C9*2 and CYP2C9*3) The dose was highest in the *1/*1 genotype (5.2 mg/day), intermediate *1/*2 or *1/*3 genotype (4.2 mg/day) and lowest with the *2/*2, *3/*3, or *2/*3 genotypes (3.4 mg/day). Vitamin K epoxide reductase complex 1 (VKORC1) recycles vitamin K and is required for gamma carboxylation of vitamin K-dependent coagulation factors. The dose was highest in those with the non-A/non-A genotype (5.7 mg/day), intermediate in those with the non-A/A genotype (4.4 mg/day) and lowest in those with the A/A genotype (3.7 mg/day). A reduced starting dose may be considered in patients with A haplotypes, in Asian-Americans, age >65, liver disease, malnourished, or taking a medication that potentiates warfarin
- 9. drug interactions Altered plateletfunction (eg, aspirin, clopidogrel Gastrointestinal injury (eg, NSAIDs) COX-2 lead to fewer bleeding, NSAID use for >1 month more bleeding ) Altered vitamin K synthesis in the GI tract (eg, antibiotics) ●Alterations in warfarin metabolism (eg,PPI (esomeprazole), amiodarone, rifampin, simvastatin, gemfibrozil) ●Interference with vitamin K metabolism (eg, acetaminophen patients must be warned against taking any new drugs, including herbal products, over-the-counter medications, and even cutaneous application of large amounts of potentially interfering drugs (eg, topical azoles) The risk of over-anticoagulation was most strongly increased by amoxicillin, clarithromycin, norfloxacin, and trimethoprim- sulfamethoxazole, often within the first three days of antibiotic usage.
- 12. Influence of diet Profoundweek-to-week differences in the dietary content of vitamin K are known to alter the stability of anticoagulation control with warfarin recommended dietary allowance for vitamin K is in the range of 65 to 80 mcg/day The effect of increased dietary vitamin K intake can be overcome by a higher warfarin dose . since there is evidence that a low intake of vitamin K may be associated with a higher risk of unstable warfarin control , high vitamin K intake reduces the risk of a low INR by lessening the influence of incidental consumption of vitamin K-rich food on the INR The patients with unstable warfarin control had a significantly lower intake of dietary vitamin K (29 versus 76 mcg/day). We suggest that, in patients with unexplained unstable warfarin control, a trial of supplementation with low-dose oral vitamin K (eg, 100 to 200 mcg orally per day) be instituted, along with close monitoring of the INR, in order to improve such contro
- 13. • cause significant interactionwith warfarin by increasing warfarin clearance, requiring a 12 percent (95% CI 7-17) increase in warfarin dosage compared with nonsmokers smoking
- 15.
- 16. Warfarin resistance • inabilityto prolong PT or INR into the therapeutic range when the drug is given at normally prescribed doses. • Patients who need more than 15 mg/day • Warfarin resistance is different than warfarin failure, defined as a new thrombotic event despite a therapeutic prothrombin time and INR. • This situation is commonly seen in patients with malignant diseases • important characteristic of warfarin resistance is that patients need much smaller doses of vitamin K to reverse the effect of warfarin
- 17. CAUSES WARFARIN RESISTANCE •Pharmacokinetic resistance • Pharmacodynamic resistance •Poor patient compliance (the most common •• High consumption of vitamin K •• Decreased absorption of warfarin •• Increased clearance by P450 •• Drug interactions Acquired Hereditary
- 18. Genetic factors Hyperalbuminemia Hypoalbuminemia Hyperlipidemia Diuretics Pharmacokinetic resistance Increasedaffinity VKOR for vitamin K Production of clotting factors that is not dependent on vitamin K Decreased VKOR sensitivity to warfarin Pharmacodynamic resistance
- 19. Plasma warfarin levels •therapeutic total plasma warfarin level lies between 0.5 μg/mL and 3.0 • Subtherapeuti c should raise suspicion of intestinal malabsorptio or poor compliance • Clotting assays of factors II, VII, IX, and X may be a more precise way to assess the pharmacodynami cs of warfarin • Measured turnaround time of 2 to 7 days, as oppose to 24 hours for factor II and X activity
- 21. Heparin • an indirectthrombin inhibitor that complexes with antithrombin (AT, formerly known as AT III), converting this circulating cofactor from a slow to a rapid inactivator of thrombin, factor Xa, and to a lesser extent, factors XIIa, XIa, and IXa • The binding of heparin to the heparin binding site on AT produces a conformational change in AT, accelerating the inactivating function of AT 1000- to 4000-fold • Inactivation of thrombin, but not factor Xa, requires the formation of a ternary complex in which heparin binds both to AT and to a binding site on thrombin containing chains at least 18 saccharide units long; such long units are present in most chains of unfractionated heparin, are less commonly present in the low molecular weight (LMW) heparins
- 22. Heparin mechanism ofaction Heparin Antithrombin III Thrombin
- 23. 5/98 MedSlides.com 23 AT UnfractionatedHeparin Differential inhibitory activity against factor Xa and IIa activity Thrombin (IIa) HF S C AT LMWH Thrombin (IIa) HF S C By binding to AT, most UH and LMWH can inhibit Xa activity. Fewer than half the chains of LMWH are of sufficient length to also bind factor IIa, therefore has decreased anti-IIa activity.
- 24. 5/98 MedSlides.com 24 Mechanismof Action • Summary – Catalyzes ATIII – Specific for fluid-phase thrombin – Prolongs aPTT by inactivating thrombin and blocking Xa generation
- 25. Limitations • narrow therapeuticwindow of adequate anticoagulation without bleeding • a highly variable dose-response relation requiring laboratory monitoring. • The variable anticoagulant response is due in part to differences in bioavailability of subcutaneous heparin and to competitive occupation of binding sites by plasma proteins (other than AT and coagulation factors), by proteins secreted by platelets (platelet factor 4), and by endothelial cells • Some of these heparin-binding proteins are acute phase reactants, thus reducing the effectiveness of heparin in acutely ill patients. • Another limitation to the use of heparin is a reduced ability to inactivate thrombin bound to fibrin as well as factor Xa bound to activated platelets within a thrombus .As a result, a thrombus may continue to grow during heparin therapy or clotting may be reactivated after heparin has been discontinued. • — The presence of a prolonged baseline aPTT makes this test unreliable for monitoring therapy with unfractionated heparin
- 26. Heparin-induced thrombocytopenia (HIT) • alife-threatening complication of exposure to heparin (ie, unfractionated heparin, LMWH) that occurs in up to 5%, regardless of the dose, schedule, or route of administration • HIT results from an autoantibody directed against platelet factor 4 (PF4) in complex with heparin • HIT antibodies activate platelets and can cause catastrophic arterial and venous thrombosis, with a mortality rate as high as 20 percent, although with improved recognition and early intervention, mortality rates below 2 percent have been reported. • definitive laboratory data (ie, immunoassay and/or functional assay for HIT antibodies) may not be available for several days. Thus, we make a presumptive diagnosis of HIT based on clinical findings and immediately available laboratory data. • The 4 T's score :(, degree of Thrombocytopenia, Timing, Thrombotic events or sequelae, alternative causes of thrombocytopenia)
- 27. Calculator: Pretest probabilityof heparin-induced thrombocytopenia (4-T's score) • • • Thrombocytopenia • Platelet count fall >50 percent AND nadir ≥20,000/microL (2 points) • Platelet count fall 30 to 50 percent OR nadir 10,000 to 19,000/microL (1 point) • Platelet count fall <30 percent OR nadir <10,000/microL (0 points) • Timing of platelet count fall • Clear onset between days 5 and 10 of heparin exposure, OR platelet count fall at ≤1 day if prior heparin exposure within the last 30 days (2 points) • Consistent with fall in platelet count at 5 to 10 days, but unclear (eg, missing platelet counts), OR onset after day 10, OR fall ≤1 day with prior heparin exposure within 30 to 100 days (1 point) • Platelet count fall at <4 days without recent heparin exposure (0 points) • Thrombosis or other sequelae • Confirmed new thrombosis, skin necrosis, or acute systemic reaction after intravenous unfractionated heparin bolus (2 points) • Progressive or recurrent thrombosis, non-necrotizing (erythematous) skin lesions, or suspected thrombosis that has not been proven (1 point) • None (0 points) • Other causes for thrombocytopenia present • None apparent (2 points) • Possible (1 point) • Definite (0 points)
- 29. The importance ofthe HIT diagnosis and its implications (eg, lifetime avoidance of all forms of heparin) should be emphasized to the patient and all individuals caring for the patient, and recorded in the medical record. Sources of heparin include unfractionated heparin, LMW heparin, heparin flushes, heparin- bonded catheters, and heparin-containing medications (eg, some prothrombin complex concentrates) Heparin cessation alone is often not sufficient since patients with HIT remain at risk for subsequent thrombosis, especially during the period when the HIT antibody continues to activate platelets immediate anticoagulation with a non-heparin anticoagulant (eg, argatroban, danaparoid, fondaparinux, bivalirudin) rather than discontinuation of heparin alone, unless there is a strong contraindication (eg, bleeding, high bleeding risk).
- 30. We treat patientswith renal insufficiency with argatroban at therapeutic doses since argatroban is metabolized hepatically and does not require dose adjustment in this setting. after discontinuation, the aPTT returns to normal within two hours ●We treat patients with hepatic impairment with fondaparinux at therapeutic doses. ●We treat patients with renal and hepatic impairment with argatroban or bivalirudin at reduced doses.
- 31. Platelet count monitoring –Patients who have received unfractionated heparin in the past 100 days and who are starting treatment with unfractionated heparin or LMW heparin are at risk for developing accelerated thrombocytopenia. For these patients, a baseline platelet count and a repeat platelet count within 24 hours is recommended. Subsequent monitoring depends on the clinical setting and heparin product, as outlined in the following points – Postoperative patients receiving unfractionated heparin have the greatest risk of HIT, which may be >1 percent. For these patients, platelet count monitoring every other day from day 4 to day 14 or until heparin is stopped, whichever occurs first, is suggested. prophylactic dose unfractionated heparin, or LMW heparin following unfractionated heparin – Medical and obstetrical patients receiving prophylactic dose unfractionated heparin, or medical/obstetrical patients receiving LMW heparin following treatment with unfractionated heparin, have a risk of HIT of approximately 0.1 to 1 percent. For these patients, platelet count monitoring every two to three days from day 4 to day 14 or until heparin is stopped, whichever occurs first, is suggested. Medical/obstetrical patients who are receiving only LMW heparin orheparin as vascular catheter flushes have a risk of HIT of <0.1 percent. For these patients, routine monitoring is not necessary.
- 32. Prevention of VTE •usual dose is 5000 U SC two hours preoperatively BD /TDS • Enoxaparin : 40 mg / day SC
- 34. Subcutaneous heparin • unfractionatedheparin (initial dose 333 units/kg SQ followed by a fixed dose of 250 units/kg SQ every 12 hours) • the use of twice-daily unmonitored subcutaneous weight-adjusted unfractionated heparin was as effective and safe as twice- daily subcutaneous LMW heparin, and less expensive.
- 35. Advantages LMW heparinsvs heparin • greater bioavailability than unfractionated heparin when given by subcutaneous injection. • ●The duration of the anticoagulant effect is greater because of reduced binding to macrophages and endothelial cells, permitting administration only once or twice daily. • ●The anticoagulant response (anti-Xa activity) to LMW heparin is highly correlated with body weight, permitting administration of a fixed dose. However, the dose may have to be adjusted for patients who are extremely obese or have renal • ●Laboratory monitoring is not necessary in nonpregnant patients; in fact, there is little correlation between anti-Xa activity and either bleeding or recurrent thrombosis. • ●They are much less likely to induce immune-mediated thrombocytopenia (ie, heparin-induced thrombocytopenia) than unfractionated heparin: • ●They do not increase osteoclast number and activity as much as unfractionated heparin, and may therefore produce less bone loss. • ●LMW heparin can be safely administered in the outpatient setting • ●In patients with acute VTE, fixed-dose subcutaneous LMW heparin is more effective than adjusted-dose unfractionated heparin for reducing the incidence of symptomatic recurrent VTE, major hemorrhage, and all-cause mortality [79]. • ●Home management using LMW heparin is cost effective, and is likely to be preferred by patients and
- 36. Direct thrombin inhibitor Theybind to thrombin directly, rather than by enhancing the activity of antithrombin, as is done by heparin. Parenteral DTIs include bivalirudin ,argatroban ,desirudin •The only oral DTI available for clinical use is dabigatran etexilate (Pradaxa); another oral agent, ximelagatran (Exanta), was withdrawn from the market in 2006 due to hepatotoxicity and cardiovascular events
- 37. Direct factor Xainhibitor They bind directly to factor Xa, rather than enhancing the activity of antithrombin III, as is done by heparin. •There are no parenteral direct factor Xa inhibitors in clinical use. •Several oral agents are available, including rivaroxaban ,apixaban and edoxaban Of note, the generic names for these agents all end in "Xa-ban" (eg, rivaroxaban, apixaban, edoxaban).
- 38. COMPARISON WITH HEPARINAND WARFARIN • similar to warfarinAdherence • All anticoagulants increase bleeding risk • Overall, the bleeding risks of the target- specific oral agents are comparable to warfarin, with a significant decrease in central nervous system (CNS) bleeding Bleeding risk
- 40. Advantages over heparinand warfarin • Heparin and warfarin both have a relatively narrow therapeutic window and more variable dose-response relationship that depends on a variety of factors; these features lead to a requirement for frequent monitoring of clotting times to optimize the therapeutic dose range and prevent bleeding [20,21]. Dose may be affected by differing bioavailability, diet, and acute medical illnesses. In contrast, the target-specific oral agents are generally used without a requirement for monitoring of drug levels or coagulation (clotting) times. This may be an advantage for patients for whom frequent monitoring is a greater burden. It remains to be determined whether laboratory monitoring of any of the target-specific oral agents can further improve their efficacy or safety Laboratory monitoring • Warfarin pharmacokinetics is affected by the level of vitamin K intake and production in the gastrointestinal tract, as well as induction of hepatic cytochromes. Thus, warfarin effect can be altered by changes in diet, administration of other medications, gastrointestinal disorders, and reduced oral intake. Patients with difficulty controlling the prothrombin time/international normalized ratio (PT/INR) may benefit from a target-specific oral agent because these agents have less variability in drug effect for a given dose than vitamin K antagonists. Affected patients may include those with unavoidable drug-drug interactions (such as frequent need for antibiotics or a large number of concomitant and variable medications) or unexplained poor warfarin control. However, it is important to determine that the INR instability with a vitamin K antagonist is not due to poor compliance, which may be easier to monitor for vitamin K antagonists than for the target-specific agents. Pharmacokinetics
- 41. Settings in whicha heparin or vitamin K antagonist may be preferable • The direct thrombin inhibitors and direct factor Xa inhibitors are not used in patients with prosthetic heart valves, due to greater risk of valve thrombosis, which may be fatal Prosthetic heart valves • Direct thrombin inhibitors and direct factor Xa inhibitors are not used during pregnancyPregnancy • Renal insufficiency is a common setting in which heparin or warfarin may be preferable to the target-specific agentsRenal impairment Dosing convenience Gastrointestinal disease
- 42. INDICATIONS Venous thromboembolism prophylaxis– ●Venous thromboembolism management – ●Atrial fibrillation ●Unstable angina, myocardial infarction, coronary stenting ●Heparin-induced thrombocytopenia
- 43. Dabigatran(Pradax: 75 mg,110 mg, 150 mg) • Dabigatran etexilate (Pradaxa) is an orally administered prodrug that is converted in the liver to dabigatran, • The half-life is approximately 12 to 17 hours in individuals with normal renal function. • Absorption is unaffected by food • capsules should only be dispensed and stored in the original bottle or blister package in which they came, due to the potential for product breakdown from moisture and resulting loss of potency • Once the bottle is opened, the pills inside must be used within four months • The capsules should not be crushed or opened before administration, as removal of the capsule shell results in dramatic increases in oral bioavailability FDA Study Shows Dabigatran Lowers Risk for Stroke and Death, Increases GI Bleeding Compared With Warfarin May 2014
- 44. Dosing (dabigatran) • Dabigatranis generally given at a fixed dose without monitoring. Maximum anticoagulant effects are achieved within two to three hours of ingestio Venous thromboembolism (VTE) prophylaxis in surgical patients: 110 mg one to four hours after surgery, followed by 220 mg once daily for 28 to 35 days (hip replacement) or 10 days (knee replacement). ●Treatment and secondary prevention of VTE: 150 mg orally twice daily (CrCl >30 mL/min). ●Stroke prevention in atrial fibrillation (AF): 150 mg orally twice daily (CrCl >30 mL/min); or 75 mg orally twice daily (CrCl 15 to 30 mL/min).
- 45. Laboratory testing andmonitoring (dabigatran) • Laboratory testing prior to initiating dabigatran should include platelet count, prothrombin time (PT), and activated partial thromboplastin time (aPTT), to assess and document coagulation status before anticoagulation; and measurement of serum creatinine, as a baseline and for potential dose adjustment in the event of renal insufficiency. • Routine monitoring of coagulation is not required for patients taking dabigatran, because drug levels are relatively predictable for a given dose. Settings in which coagulation testing for dabigatran effect may be helpful include the following: ●Bleeding in a patient receiving dabigatran, or with suspected dabigatran overdose – ●Need for emergent or urgent surgery in a patient receiving dabigatran –