5 million DVT s. Observational study of 1897 patients with VTE

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1 Thromboembolism epidemiology Venous Thromboembolism Arthur P. Wheeler, MD, FCCP Professor of Medicine Director, MICU Co-chair Pharmacy & Theraputics Division of Allergy, Pulmonary and Critical Care Medicine Vanderbilt Medical Center Conflicts: none million DVT s 9, PE s 29, fatalities Heit J. Blood. 2;16:91. VTE: a disease of hospitalized patients" VTE: a disease of previously hospitalized patients" Cases / 1, person years % received no prophylaxis in prior 3 days % in nursing homes or <9 days post-discharge Observational study of 1897 patients with VTE 74% of patients diagnosed as outpatients 6% hospitalized in the past 3 months 67% diagnosed within 1 month of discharge 7% received no anticoagulant prophylaxis 1 Hospitalized Community Heit Mayo Clin Proc 21; 76:112 Goldhaber Am J Cardiol 24; 93:29 Spencer FA, Arch Intern Med. 27;167:1471 DVT Incidence absent prophylaxis Cord Injury Stroke MICU General Surgery Acute MI General Medical Nicolaides 1997 Nicolaides 1997 Hirsch 199 Gallus 1994 Handley 1972 Mismetti 2 Geerts WH. Chest. 28;133:381S-43S Virchow s triad Advancing age Immobilization Cord injury Anesthesia Heart or lung failure Hyperviscosity Stroke Travel Cancer HIT Sepsis Oral contraceptives Corticosteroids Family history Hypercoagulable State Surgery Prior DVT Venous access Trauma Sepsis Vasculitis CVCs Protein C, S or AT III deficiency Activated protein C resistance (Leiden) Hyperhomocystenemia Antiphospholipid antibody Prothrombin 221 mutation Cirrhosis 1

2 Risk stratification in surgery Calf DVT % Proximal DVT % Clinical PE % Fatal PE % Very low <. Early walking +/- GCS/IPC (2C) Low < 2.4 GCS.2 +/-IPC (2C).2 Moderate 1-2 LMWH, 2-4 LDUH, 1-2 (2B) or GCS/IPC.1-.4 (2C) High 2-4 LMWH, LDUH q8h (1B), with GCS +/ IPC (2C) 4-1 Very High 4-8 LMWH, LDUH q8h, with GCS +/- IPC (1C) + extended for cancer (1B) Guyatt G. Chest. 212;141:7S Recommend no IVC filter or routine US Meta-analysisanalysis UFH Prophylaxis: q 12h vs q 8h Effect Size Weight q 12h Cade (1982) 3.6 (1.2, 8.3).7 Zawilska (1989).7 (.7, 2.) 1. Gardlund (1996) 2.7 (2.3, 3.3) 21.8 Bergmann (1996).9 (.1, 3.2) 14.7 Cade (1982) 3.1 (.6, 9.1) 4.4 Subtotal 234( (1.3, 33) 3.3) q 8h Harenberg (199) 4.1 (1.9, 17.9) 1.4 Gallus (1973) 2. (.6, 13.7) 1.9 Pitney (198) 2.7 (.7, 14.9) 1.6 Lechler (1996) 1.8 (.7, 3.9) 14.4 Harenberg (1996).6 (.2, 1.4) 21.2 Belch (1981). (.6, 17.9) 1.2 Kleber (23) 2. (.,.) 1.6 Subtotal.86 (.3, 1.4) Per 1 patient days King CS. Chest. 27;131:7 VTE Prophylaxis: LMWH vs UFH Meta-analysis of 36 trials of LMWH or UFH DVT Study Risk Ratio Weight, % (9% CI) Harenberg et al, ( ) 3.4 Turpie et al, (.1-.81) 11.2 Dumas et al, ( ) 14.4 Bergmann and Neuhart et al, ( ) 8.1 Harenberg et al, ( ).8 Lechler et al, ( ) 3.3 Hillborn et al, 22. ( ) 2. Kleber et al, ( ) 19.4 Diener et al, ( ) 18.9 Overall (9% CI).68 (.2-.88) Risk Ratio LMWH Better LMWH Worse Wein L. Arch Intern Med. 27;167: Mechanical devices in the ICU Arabi YM, Chest 213; 144:12 Ordered but often not used 74% of surgical patients ordered IPC s did not have them on. 39% device not in room! With intervention nonuse declined to 7% Gardiner D, Hospital Practice 213;41:4 DVT prophylaxis: Important, not perfect Rivaroxaban vs Enoxaparin: Orthopedics LMWH / FPX UFH tid $ 16-2 Use Critically in cancer, ill CHF or acutely or respiratory ill hospitalized failure or patients reduced at mobility increased & 1 other risk of risk thrombosis factor: 1A 1B $ 2-13 Total Hip Total Knee ICD Stockings ASA $ 1 $ 1 $ 1 Use if high Use bleeding high bleeding risk, until risk risk 1C abates or 2C Or as as adjunct to to anticoagulants 2A 2A No Should data in not medical be used : patients : 1A 1A DVT Relative Risk Reduction Geerts WH. Chest. 28;133:381S-43S. Kahn S, Chest 212 ; 141, supplement Eriksson B, NEJM 28; 38:276 Kakkar A, Lancet 28; 372:31 Lassen MR, NEJM 28; 38:2776 V Turpie AG, Lancet 29; 373:1673 2

3 Apixaban vs Enoxaparin: Orthopedics Total Knee Total Hip 6 RCT n=811 Rivaroxaban 1 mg/d PO x 3 days 4 vs. 3 Enoxaparin 4 mg/d sq x 2 1 +/- 4 days 1 ate (%) Event ra Rivaroxaban Enoxaparin VTE Bleeding VTE death Cohen A, NEJM 213; 368: 13 Lassen MR. NEJM 29; 361:94 Lassen MR. Lancet 21; 37:87 Lassen MR. NEJM 21; 363:2487 Dabigtran vs Enoxaparin: Orthopedics Total Knee Total Hip VTE Prophylaxis Use Among Patients Recommended to Receive it xis Rates (%) Prophylax US Non-US N=1,16 Total LMWH UFH IPC Stockings ASA Eriksson B, Thromb Haemos 27;:2178 Eriksson B, Lancet 27; 37:949 Ginsberg J, J Arthroplasty 29; 24:1 Eriksson B, Thromb Haemost 211;1:721 Tapson V. Chest 27;132:936 CURVE: 16% prophylaxis Thromb Res 27 ENDORSE: 4% prophylaxis Lancet 28 Physician response to prompts & overall prophylaxis rate % 4% Total Prophylaxis Rate 3% 2% 1% % Control Neutral Educational Risk Conner Chest 118: 162S, 2 3

4 Prophylaxis following consistent reminders Computerized prophylaxis prompts Now > 94% Percent Prophylaxis rates Control Prompted Δ 41 % VTE indicence Kucher N NEJM 2; 32:969 63% had risk score >4 Long term post discharge medical prophylaxis (EXCLAIM) Apixaban extended prophylaxis in immobile medical patients (ADOPT) End points Extended prophylaxis n=213 (%) Placebo n=227 (%) RR P value reduction (%) VTE events Symptomatic No symptoms NNT = 46 patients to avoid one VTE event. NNT = 224 to result in one major bleeding event. RCT N=628 (449 evaluable) Mandatory ultrasound 3 days of oral (2. mg BID) apixaban vs. enoxaparin (4 mg) x 6-14 d Hull RD Ann Intern Med 21; 13:8-18 Goldhaber S, NEJM 211;36:2167 Potential pharmacological strategies VTE prevention UFH sq q8h q12h (renal) Enoxaparin sq 4 mg qd 3 mg qd (renal) 3 mg q12h (TKR) Rivaroxaban po/tube 1 mg qd Apixaban po/tube 2. mg bid Dabigatran po 1 or 22 mg qd Fondaparinux sq 2. mg qd Venous thromboembolism 9% ~% ~% 63-7% of fatal PE s unsuspected during life Stein Chest 199; 11:978 Sandler J R Soc Med 1989; 82:23-3%? ~1% 4

5 Evolution of DVT-PE treatment Nothing Inpatient, intermittent IV bolus UFH Inpatient, bolus + continuous infusion UFH x 7-14 days Weight based protocols Duration reduced to -7 days Inpatient, sq LMWH Outpatient sq LMWH Oral Xa and IIa inhibitors Nothing? Immobilization as part of DVT/PE treatment? Characteristic Walk after day 2 Bed rest 8 days Proximal DVT n= 63 9 Baseline VQ defect 62% 71% New VQ defect day % 17% New symptomatic PE 1.7% Fatal PE All patients treated with LMWH, leg bandages or stockings Schellong SM Thromb Heamost 1999; 82:127 UFH recommendations Effectiveness of non-protocolized unfractionated heparin Begin empiric therapy if safe Bolus 8-1 U/kg Infusion > 18 U/kg/hr PTT 6 hr post-bolus Achieve PTT ratio > 1. within 24 hours Start warfarin early Use a protocol 1 8 Percent 6 PTT's > 1. x control Days after Starting Heparin Wheeler Arch Int Med 1988; 148:1321 Challenges to effective UFH use 311 patients with thrombosis at MGH Average: bolus 7 U/kg, infusion 1 U/kg/hr Therapeutic success: 8% on first PTT. 71% in first day 7% for 4 consecutive days. > ½ the patients had or more PTT s per day Hylek EM. Arch Int Med 23; 163:621 PTT for Patients Receiving IV Heparin aptt for Patients Receiving IV Heparin Cleveland Clinic Foundation Inpatients, October-December 24 cy Frequen aptt Includes all values from 24 hours after drip was ordered until drip was discontinued; 48% within therapeutic ranges; manual chart review for validation has not yet occurred. Snow V. Ann Intern Med. 27;146:24.

6 Impact of failing to promptly anticoagulate Low molecular weight heparins Relative Risk of Recurrence Basu NEJM 1972 Hull NEJM 1986 Depolymerized unfractionated heparin Preferential anti-xa activity Lower MW high bioavailability (>9%) Little endothelial or plasma protein binding longer half-life Do not predictably alter PTT Renal clearance like all heparins Incidence of recurrent of VTE Incidence of major bleeding Adapted from: Dolovich Arch Intern Med 2 Adapted from Dolovich Arch Intern Med 2 Outcomes after first DVT DVT 3 Pts LMWH or UFH + Warfarin Percent 2 recurrence months Warfarin 78 Recurrences 4% ipsilateral 36% contralateral 19% PE (9 fatal) 8 years Prandoni P Ann Intern Med.1996;12:1 Months after diagnosis Coagulation Activity and Dosing ctivity (%) Coagulation Factor A Loading, then Maintenance Dose VII IX Observation Time (days) Snow V, Ann Intern Med. 27;146:24. X II 6

7 Duration of warfarin patients with second DVT, 2 randomized to 1 warfarin for: 1 6 months or indefinitely 4 year follow-up Schulman NEJM 1997; 336:393. cidence Percent In Recurrence Hemorrhage 6 month Permanent Death Non-inferiority RCT n=264 Proximal DVT or PE UFH or LMWH (median 9 d) then: Dabigatran 1 mg q12 unmonitored vs. INR adjusted warfarin x 6 mos Schulman S. NEJM 29; 361: 2342 Rivaroxaban in DVT: Einstein DVT D V T R Day 1 Rivaroxaban 1 mg/q12h n=1731 Day -1 (median 8) Enoxaparin 1 mg/kg q12h + VKA n=1718 Day 21 VKA Rivaroxaban 2 mg/qd 6-12 mos Rivaroxaban 2 mg/qd n=62 Placebo n= mos n= 3449 Safety endpoints Primary endpoint Early: Major bleeding + Recurrent thromboembolism clinically relevant non-major + bleeding Confirmed or suspected PE Continuation: Major bleeding related death EINSTEIN investigators, NEJM 21; epub:1 P E Rivaroxaban DVT- efficacy 3.% 2.1% 7.1% 1.3% Major Bleeding: rivaroxaban.7% placebo % EINSTEIN investigators, NEJM 21; epub:1 RCT n=4832 symptomatic PE +/- in DVT Rivaroxaban1 mg PO bid x 21 d then 2 mg /d. Enoxaparin 1 mg/kg BID then warfarin INR 2-3 x 3,6,12 mos Efficacy Major Bleeding RCT n=244 in DVT (6%) or PE (2%) Apixaban 1 mg PO bid x 7 d vs mg qd x 6 months vs. Enoxaparin 1 mg/kg BID then warfarin INR 2-3 x 6 months 7

8 214 RCT n=8292 in DVT (6%) or PE (4%) Enoxaparin x > d then Edoxaban 3-6 mg PO/d x 3-6 months vs. Warfarin INR 2-3x months NOACs efficacy vs warfarin NOACs safety vs warfarin But I can reverse heparin warfarin No difference in clinical outcomes Sarode R, Circulation 213; 128: 1234 Thrombolytic therapy for DVT ent Perce >% Clot lysis All Complications Forster Chest 21; 119:72 Review of randomized studies TPA Heparin Major Bleeding N=363 Intracranial Bleeding Propensity matched 3649 patients with catheter directed thrombolysis vs 9,618 treated with anticoagulation Characteristic Catheter directed Anticoagulated p Hospital mortality 1.2%.9%.1 Pulmonary embolism 17.9% 11.4% <.1 Intracranial hemorrhage.9%.3%.3 IVC filter placement 34.8% 1.6% <.1 LOS 7.2 d. d <.1 Charges $8,94 $2,164 <.1 Bashier R, JAMA Intern Med 214; epub 7/1/14 Enden T, Lancet 211; epub 12/13/11 8

9 Circulation 24; 11: 744 Risk of Recurrence or Death PE with RV dilation and elevated troponin Tenteplase + Heparin Placebo+ Heparin p Number Death or hemodynamic decompensation 13 (2.6%) 28 (.6%).2 Death to day 7 6 (1.2%) 9 (1.8%).42 Death to day 3 12 (2.4%) 16 (3.2%).42 Extra-cranial bleeding 32 (6.3%) 6 (1.2%) <.1 Stroke 12 (2.4%) 1 (.2%).3 Meyer G. NEJM 214; 37: 142 Facts about thrombolysis for PE Images and PA pressures are reliably improved faster with lytics. No study has ever shown a survival benefit of thrombolysis over anticoagulation for PE of any severity. Major bleeding occurs in 1/1 recipients and in 2/1 it is intracranial hemorrhage. Thrombolysis is used rarely: 2.4% of 1,116 consecutive PE patients in PA. Ibrahim SA, Arch Intern Med 28; 168:2183 Who should get thrombolytics? Run of the mill DVT or PE: NO Sub-massive: Probably NO use risk stratification? ECHO BNP Troponin Combination? Massive PE: absent bleeding: probably YES Venacaval filters Venacaval filters 4 patients with proximal DVT +/- PE Anticoagulated > 3 months (% at 8 yr) Randomized: +/- filter Non-blinded 8 year follow up 7% had PTS Decousus NEJM 1998; 338:49 PREPIC study group Circ 2 112;. 416 Decousus NEJM 1998; 338:49 PREPIC study group Circ 2 112;

10 Potential pharmacological strategies VTE prevention Rivaroxaban po/tube 1 mg qd Apixaban po/tube 2. mg bid Dabigatran po 1 or 22 mg qd Enoxaparin sq 4 mg qd 3 mg qd (renal) 3 mg q12h (TKR) Fondaparinux sq 2. mg qd UFH sq q8h q12h (renal) Acute treatment UFH iv bolus + aptt monitored infusion Enoxaparin sq: 1. mg/kg qd 1 mg/kg q12 h 1 mg/kg qd (renal) Apixaban po/tube -1 mg bid Dabigatran po 1 mg q12 Fondaparinux sq -1 mg Rivaroxaban po/tube 1 mg q12h : 2 qd Sq UFH q8h IV tpa.9 mg/kg Chronic treatment INR adjusted warfarin Enoxaparin sq: 1. mg/kg qd 1 mg/kg q12 h 1 mg/kg qd (renal) Apixaban po/tube -1 mg bid Dabigatran po 1 mg q12 Fondaparinux sq -1 mg Rivaroxaban po/tube 2 mg qd PTT adjusted sq UFH q8h Quality of Life after VTE Post-thrombotic syndrome develops in 2-4% of DVTs. DVT recurs in ~3% after anticoagulation stopped Permanent disability for 1 million Americans Cohen JM. CHEST 212; 141:38 Socks trial RCT 18 patients Anticoagulation x 3 months +/- below knee fitted elastic stockings x 2 years First proximal DVT Endpoint: PTS at years Conclusions VTE is common. VTE s seeds are sown among inpatients for an outpatient harvest (diagnosis). Effective chemical prophylaxis dramatically reduces risk. Doctors usually omit prophylaxis. Ignorance? Denial? Fear? Prandoni P, Ann Intern Med 24; 141:249 Conclusions Achieving early anticoagulation is important. Traditional practice of UFH followed by warfarin is cumbersome, expensive and dangerous. Most VTE can be treated with outpatient LMWH. p Dabigatran, rivaroxaban, apixaban, and edoxaban should replace heparin / warfarin treatment. Thrombolytics improve physiology and images but not mortality and are rarely used. Caval filters do not change mortality. 1