DVT Prophylaxis in Medical Patients

DVT Prophylaxis in Medical PatientsRog Kyle, MDMUSC6/5/12Review risks for developing DVT and bleeding from DVT prophylaxisReview current recommendations for inpatient DVT prophylaxis (AT9)Review different pharmacologic and mechanical methods for DVT prophylaxisExamine recent controversies in DVT prophylaxis

Risk for DVTHistorical baseline0.8% DVT0.4% PENot used by ACCP 2012Hospitalization in general associated with 8X VTE risk and 25% of all VTE50-75% of all in hospital VTE events are on medical servicesRisk for DVTImportant to remember that most RCTs looking at DVT prophylaxis used asymptomatic DVT detected by venography.Start as calf DVTReduction in asymptomatic parallels reduction in symptomatic DVTDoes not mean that the relative effects of asymptomatic and symptomatic events will be similar (particularly PE)Bleeding? - there are no published data addressing the relationship between wound or joint bleeding and either wound infection or long-term joint functionNet benefit (non-fatal) PE, DVT, GI bleed, periop bleed)Prevention complication Fatal events are rareRisk for DVTAT9Critically ill vs. non-criticalIn non-criticalRAMs (risk assessment model) suffer from prospective validation, among other problemsACCP 2012 guidelines utilize the Padua Prediction Score

Risk for DVTCritically ill vs. non-criticalIn non-criticalRAMs (risk assessment model) suffer from prospective validation, among other problemsACCP 2012 guidelines utilize the Padua Prediction ScoreHigh Risk 4

Padua Prediction ScoreJournal of Thrombosis and Haemostasis 2010; 8: 24502457Prospective cohort study, 1180 pts. (medical) followed to 90 days after d/cAssessedWhether pts could be assigned to high or low risk by a RAMWhether prophylaxis worked (TID heparin, LMWH, fondaparinux) in either groupRisk level was blinded to the treating MDUse of prophylaxis left up to the treating MDExcluded bleeding, plts < 100K, CrCl < 30Padua Prediction Score40 % high risk, 60% low risk40% of the high risk received DVT prophylaxis and 7.3% of the low riskOnly investigated symptomatic pts for DVT/PE

Padua Prediction Score40 % high risk, 60% low risk40% of the high risk received DVT prophylaxis and 7.3% of the low riskOnly investigated symptomatic pts for DVT/PEHighly significant (P < 0.001, HR 0.13)Of the 4 in the high risk/treated 3 occurred after d/c

Bleeding Risk from ProphylaxisACCP 2012 choose 0.4% major bleeding riskFrom the control arms of DVT prophylaxis trialsIMPROVE trial

Chest. 2011; 139(1):69-79Bleeding Risk from ProphylaxisACCP 2012 choose 0.4% major bleeding riskFrom the control arms of DVT prophylaxis trialsIMPROVE trial risk model too complex and not validatedAT9AT92.3. For acutely ill hospitalized medical patients at increased risk of thrombosis, we recommend anticoagulant thromboprophylaxis with low molecular- weight heparin [LMWH], low-dose unfractionated heparin (LDUH) bid, LDUH tid, or fondaparinux (Grade 1B) .AT92.4. For acutely ill hospitalized medical patients at low risk of thrombosis, we recommend against the use of pharmacologic prophylaxis or mechanical prophylaxis (Grade 1B) .DVT ProphylaxisLDUH vs. LMWHNo difference in DVT, PE, overall mortality or HIT (one trial)No cost differenceMinimally less major bleeds for LMWH (5/1000)BID vs. TID LDUHThe low quality evidence from these indirect comparisons provides no compelling evidence that LDUH TID dosing, compared with BID dosing, reduces VTE or causes more bleeding

Chest 2007;131;507-516BID heparin dosing causes fewer major bleeding episodes, while TID dosing appears to offer somewhat better efficacy in preventing clinically relevant VTE events

Chest 2011;140;374-381Moderate-quality evidence suggests that subcutaneous UFH bid and UFH tid do not differ in effect on DVT, PE, major bleeding, and mortalityGCS vs. IPCs vs. VFPsGCSConflicting data, thigh high probably better than knee high (CLOTS I, II trials)Surgical, stroke ptsMost studies screened for asymptomatic DVTIPC/VFPNo studies in hospitalized medical ptsLess DVT (sxc) but no mortality or PE benefit in surgical pts

GCS vs. IPCs vs. VFPsthe compelling evidence of a decrease in fatal PE that exists for anticoagulants and for aspirin does not exist for mechanical methodsMechanical Compression vs. HeparinNo studies in hospitalized medical ptsSurgical pts no difference in DVT, PE (except subgroup of LMWH vs. compression less DVT); less bleeding with compressionMechanical Compression + Heparinoids vs. Heparinoids AloneSurgical ptsIPCs + pharm trended better than pharm aloneGCS + pharm better than pharm alone but more skin complications

ButSurgical studies looking at IPC functioning found them working or applied properly in only 20 - 50% of pts.Extended Duration DVT ProphylaxisApproximately 70% of DVTs in medical pts occur in the out patient settingOver half of these pts had been hospitalized within the past 3 months, and 2/3s of these within 1 monthMEDENOX RTC - N Engl J Med 1999;341: 793-800RTC40/20 lovenox vs. placebo3 mos f/u

Extended Duration DVT ProphylaxisApproximately 70% of DVTs in medical pts occur in the out patient settingOver half of these pts had been hospitalized within the past 3 months, and 2/3s of these within 1 monthMEDENOX RTC - N Engl J Med 1999;341: 793-800EXCLAIM - Ann Intern Med. 2010;153:8-1840 lovenox for 28 days after initial therapy in hosp

EXCLAIMOnly RTC of extended DVT prophylaxis (LMWH) in medical pts (in-hospital and 28 days post-d/c)Reduced overall DVT (sym and asym)Level 1 mobility (bed rest)> 75 y.o.femaleNo difference fatal PENo difference in overall mortality and 4 ICBs (one fatal) in LMWH group (none in placebo)Overall, 5/1000 fewer sxc DVTs, 4/1000 major bleedsAT9 not recommendedASAStudies in medical pts 9 trials, 555 pts all antiplatelet drugs Small number of events (DVTs)Asymptomatic/symptomatic, proximal/distalUS/fibrinogen labeling/venographyUp to 8 wks of drug, bleeding events not reportedASAPooling 9 trials35% reduction in asymptomatic DVTNo effect on PE rateBleeding not reportedASAPEP Trial - Lancet 2000; 355: 129530213,000 + ortho pts (hip fx)160 mg ASA vs. placebo (+ any other thromboprophylaxis thought necessary) for 35 days35 days post hip fracture surg, THA, TKALess DVTs sym and asymLess PEs fatal and non-fatalNo overall mortality benefitNo difference in fatal bleeding (some increase in surg site bleeds)

ASAPEP Trial - Lancet 2000; 355: 129530213,000 + ortho pts (hip fx)160 mg ASA vs. placebo (+ any other thromboprophylaxis thought necessary) for 35 days35 days post hip fracture surg, THA, TKALess DVTs sym and asymLess PEs fatal and non-fatalNo overall mortality benefitNo difference in fatal bleeding (some increase in surg site bleeds)there is now good evidence for considering aspirin routinely in a wide range of surgical and medical groups at high risk of venous thromboembolism

AT9Based on the low quality of available evidenceno recommendation could be madeThere have been no studies of antiplatelet therapy compared with antithrombotic therapy (pharm or mech) to prevent VTE in acutely ill medical patients

Ann Intern Med. 2011;155:602-615Large meta-analysisRandomized trials including medical patients or strokesHeparin, LMWH, mechanical prophylaxis40 unique trials; 52,000 ptsMedical and stroke pts, no surg/trauma/OB

TrialsHeparin vs no heparin (1)LMWH vs no LMWH (2)LMWH vs UFH (3)Mechanical vs no mechanical (4)OutcomesDeath (primary); PE, major bleeding (secondary) (1, 2, 3)Death (4) Resultsno significant effect of prophylaxis on mortality (there was a trend in favor of heparin prophylaxis (P=0.056)Heparin vs no heparin3 less PEs, 9 more bleeds (4 major)/1000 ptsLMWH vs heparinNo difference in outcomesNo improved outcomes with mechanical prophylaxis in strokeConclusionReduced PE, no change total mortality, increased bleeding (heparin, LMWH) (stroke and medical pts)Therefore, no net clinical benefit

Raised numerous questionsWhich are the preferred outcomes (PE vs bleed)Use of surrogate outcomes asymptomatic DVT?Most PE not preceded by symptomatic DVTAsymptomatic PEs? No studies screen with CTEditorial commentsJCs recommendation for DVT proph only excludes children and pts hospitalized < 2 days

N Engl J Med 2011;365:2463-72N Engl J Med 2011;365:2463-72LMWH in Medical PatientsDouble blind, randomized, placebo controlledLMWH vs. placebo, all pts received elastic stockings with graduated compressionChina, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia8300+ ptsPrimary outcome death at 30 daysSecondary outcomes Death at 0-14 days, 0-90 days rate of cardiopulm death 14, 30, 90 days and sudden death or PE 14, 30, 90 days

Results

ConclusionNo reduction in the rate of death from any cause among hospitalized, acutely ill medical patients with the addition of lovenoxCounterintuitive?Pharm prophylaxis reduces DVT (including asympt DVT) in acutely ill medical pts by > 45%Assumed that DVTs in medical pts are the same as surgical distal to proximal progression (we know that proximal DVT in medical pts has higher risk of PE than distalReferencesKahn et al. Prevention of VTE in Nonsurgical Patients : Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141;e195S-e226SBarbar et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. Journal of Thrombosis and Haemostasis, 8: 24502457Decousus et al. Factors at Admission Associated With Bleeding Risk in Medical Patients. Chest. 2011; 139(1):69-79King et al. Twice vs Three Times Daily Heparin Dosing for Thromboembolism Prophylaxis in the General Medical Population. Chest 2007;131;507-516Phung et al. Dosing Frequency of Unfractionated Heparin Thromboprophylaxis. Chest 2011;140;374-381CLOTS Trial Collaboration. Thigh-Length Versus Below-Knee Stockings for Deep Venous Thrombosis Prophylaxis After Stroke. Ann Intern Med. 2010;153:553-562.Samama et al. A Comparison of Enoxaparin with Placebo for the Prevention of Venous Thromboembolism in Acutely Ill Medical Patients. N Engl J Med 1999;341:793-800.Hull et al. Extended-Duration Venous Thromboembolism Prophylaxis in Acutely Ill Medical Patients With Recently Reduced Mobility. Ann Intern Med. 2010;153:8-18.Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000; 355: 1295302Lederle et al. Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients and Those With Stroke: A Background Review for an American College of Physicians Clinical Practice Guideline. Ann Intern Med. 2011;155:602-615Kakkar et al. Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients. N Engl J Med 2011;365:2463-72.