Anticoagulation in VTE The Haematologist s Perspective Dr. M.D. Maina FRCP Edin.
Disclosures None
The coagulation process that leads to haemostasis involves a complex set of reactions involving approximately 30 different proteins The net effect is the thrombin generation that cleaves fibrinogen to fibrin which together with platelets forms a stable thrombus
Extrinsic pathway illustrates generation of factor Xa The extrinsic pathway leads to the amplification of factor Xa generation
Role of Factor Xa thrombus in formation Factor Xa, with activated Factor V converts prothrombin to thrombin Factor Xa is a crucial site of amplification in the coagulation process i.e. One molecule Xa catalyzes formation of approximate 1000 thrombin molecules Factor Xa is therefore attractive target anticoagulant
Newer anticoagulants that have single targets Initiation TF VIIa Indirect Fondaparinux AT X IX Propagation Xa Ixa Inactive Factor Active Factor Transformation Catalysis Direct Rivaroxaban Apixaban Edoxaban Betrixaban Thrombin IIa II Prothrombin Direct Lepirudin Bivalirudin Argatroban Dabigatran TGN-167 Clot formation Fibrinogen Fibrin Adapted from: 1. Spyropoulos AC. Expert Opin Investig Drugs 2007;16:431 440
Thrombosis Bleeding PROBLEMS WITH VKAS NARROW THERAPEUTIC WINDOW Warfarin thrombosis Warfarin bleeding DIFFICULT TO KEEP WITHIN THERAPEUTIC RANGE FREQUENT INR MONITORING/ DOSE ADJUSTMENT Narrow therapeutic window MULTIPLE DRUG DRUG AND FOOD DRUG INTERACTIONS SLOW ONSET/OFFSET OF ACTION Dose INCREASED RISK OF BLEEDING 1. Ansell J et al, Chest 2004;126:204S 233S
RISK FACTORS FOR BLEEDING DURING VTE TREATMENT WITH VKA THERAPY HIGHER INR VALUES POOR INR CONTROL OR SUBOPTIMAL COAGULATION MONITORING PATIENT CHARACTERISTICS INCREASED AGE PREVIOUS GASTROINTESTINAL BLEEDING EVENT PREVIOUS HAEMORRHAGIC STROKE RENAL INSUFFICIENCY HEPATIC DISEASES DIABETES RECENT SURGERY CONCOMITANT USE OF DRUGS THAT INTERFERE WITH HAEMOSTASIS LENGTH OF THERAPY OTHER SERIOUS ACUTE OR CHRONIC ILLNESS 1. Schulman S et al, Chest 2008;133;257S 298S; 2. Torbicki A et al, Eur Heart J 2008;29:2276 2315
What are the properties of an ideal anticoagulant? Oral administration Wide therapeutic window Low risk of food and drug interactions Predictability No monitoring Fixed dose Convenient use both in and out of hospital Broad safety margin at a wide range of effective doses Ease of use regardless of concomitant medications and diet Safe and effective regulation of coagulation from the first dose and throughout therapy No need for routine laboratory monitoring: saves healthcare costs through fewer hospital/physician visits and has less impact on patients time Fixed doses for the majority of patients: no need for dose adjustment
Risk factors for fatal bleeding during VTE treatment Data from the RIETE registry found that the following risk factors were independently associated with fatal bleeding in the first 3 months of treatment of VTE: Age >75 years Metastatic cancer Immobility 4 days Major bleeding event within the past 30 days Abnormal prothrombin time Platelet count <100 10 9 /l Crcl <30 ml/min Anaemia 1. Nieto JA et al, J Thromb Haemost 2010;8:1216 1222
Major bleeding EINSTEIN DVT and PE: bleeding definitions Overt bleeding associated with: 2 g/dl fall in haemoglobin, or Transfusion of 2 units of packed red blood cells or whole blood, or Occurrence at a critical site,* or Death Non-major clinically relevant bleeding Overt bleeding not meeting the criteria for major bleeding, but associated with: Medical intervention, or Unscheduled contact (visit or telephone call) with a physician, or Temporary cessation of study treatment, or Discomfort such as pain, or impairment of activities of daily life *Intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retroperitoneal 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510; 2. EINSTEIN Integrated Protocol/Study number 11702/Version no 2.0/08Jun2009
Cumulative event rate (%) EINSTEIN DVT: PRIMARY EFFICACY OUTCOME TIME TO FIRST EVENT 4.0 Enoxaparin/VKA (n=1718) 3.0 Rivaroxaban (n=1731) 2.0 1.0 HR=0.68; p<0.001 (non-inferiority) RR=32% 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Number of patients at risk Rivaroxaban 1731 1668 1648 1621 1424 1412 1220 400 369 363 345 309 266 Enoxaparin/ VKA 1718 1616 1581 1553 1368 1358 1186 380 362 337 325 297 264 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510
Cumulative event rate (%) EINSTEIN DVT: PRINCIPAL SAFETY OUTCOME (COMPOSITE OF MAJOR OR NON-MAJOR CLINICALLY RELEVANT BLEEDING) 14 12 Enoxaparin/VKA (n=1711) 10 8 Rivaroxaban (n=1718) Number of patients at risk Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140 Enoxaparin/ VKA 6 4 2 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510
Cumulative event rate (%) EINSTEIN DVT: principal safety outcome (composite of major or non-major clinically relevant bleeding) 14 12 10 8 6 4 2 Enoxaparin/VKA (n=1711) Rivaroxaban (n=1718) Number of patients at risk Rivaroxaban 1718 1585 1538 1382 1317 1297 715 355 338 304 278 265 140 Enoxaparin/ VKA 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 1711 1554 1503 1340 1263 1238 619 338 321 287 268 249 118 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510
EINSTEIN DVT: principal safety outcome analysis Rivaroxaban (n=1718) Enoxaparin/VKA (n=1711) HR (95% CI) n (%) n (%) p-value First major or non-major clinically relevant bleeding 139 (8.1) 138 (8.1) 0.97 (0.76 1.22) p=0.77 Major bleeding 14 (0.8) 20 (1.2) 0.65 (0.33 1.30) p=0.21 Contributing to death 1 (<0.1) 5 (0.3) In a critical site 3 (0.2) 3 (0.2) Associated with fall in haemoglobin 2 g/dl and/or transfusion of 2 units 10 (0.6) 12 (0.7) Non-major clinically relevant bleeding 126 (7.3) 119 (7.0) Safety population 1. The EINSTEIN Investigators. N Engl J Med 2010;363:2499 2510
Monitoring and reversal NOACS Dabigatran (direct thrombin inhibition) Rivaroxaban, apixaban and edoxaban (direct Factor Xa inhibitors) Approved for Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation Treatment of and secondary prevention of venous thromboembolism after major orthopedic surgery
In one large phase iii trial unmonitored treatment with NOACS was shown to be non-inferior and in some cases superior to dose adjusted warfarin for prevention of VTE. NOACS reduced major bleeding by 28% and fatal bleeds by 50% Many clinicians are reluctant to prescribe NOACS mainly due to lack of evidence to answer real world questions i.e. How and when should the effect of NOACS be measured? How should NOACS be administered before and after invasive procedures?
Monitoring NOACS do not require routine lab monitoring and dose adjustment. Measurement may be necessary in those which below on-therapy or above on-therapy levels are suspected
Rivaroxaban, epixaban, edoxaban anti Xa: this is not available in most laboratories Pt/inr Rivaroxaban and edoxaban prolong pt. Only mildly increased and may remain normal in typical trough levels Aptt A normal apt doesn t exclude on-therapy drug levels
Dabigatran Thrombin time is inordinately sensitive to dabigatran i.e. A concentration as little as 90mg/ml can make tt unmeasurable hence not usable Normal tt excludes clinically relevant blood levels Prothrombin time/inr May be normal in the presence of on-therapeutic and even above on-therapy levels In a study in ex vivo samples from patients with af inr 1.2 achieved only when dabigatran concentrations > 400(mg/ml)
Reversal non-specific Prothrombin complex concentrate (pcc) Plasma derived product containing vit k dependent factors II, VII, IX, X (4 Factor pcc) developed for reversal of vit k agonist Recombinant Factor VII Corrected rivaroxaban induced prolonged pt Reduced bleeding in rats but not primates
Specific Idarucizumab Humanized monoclonal antibody with high affinity to dabigatran Corrects dabigatran induced prolonged clotting time A recent interim analysis reported results of 51 patients with serious bleeding and 39 requiring urgent procedure. Administration of 5gm of iv idarucizumab resulted in: Haemostasis achieved at a median of 11.4 hr Normal intraoperative haemostasis was achieved in 92% of patients in urgent procedure group Rapid normalization of tta (dilute)
Andexanet alfa Recombinant Factor Xa with capacity to bind Factor Xa inhibitor In vitro studies showed dose dependent correction of anti Xa activity induced by rivaroxaban, apixaban, betrixaban and edoxaban
Management strategy for NOACS-associated bleeding Minor bleeding (i.e. Ecchymosis epistaxis menorrhagia) Drug discontinuation moderate bleeding (G.I. Bleeding) Packed cells Plasma Platelet those on antiplatelets Severe/life threatening bleeding Non-specific reversal therapy (PCC 50 iu/kg) Haemodialysis may be used to remove dabigatran Antifibrinolytic therapies (tranexamic acid may be considered) Specific reversal
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