DVT Prophylaxis in Medical Patients

Rog Kyle, MDMUSC6/5/12

• Review risks for developing DVT and bleeding from DVT prophylaxis

• Review current recommendations for inpatient DVT prophylaxis (AT9)

• Review different pharmacologic and mechanical methods for DVT prophylaxis

• Examine recent controversies in DVT prophylaxis

Risk for DVT

• Historical baseline– 0.8% DVT– 0.4% PE– Not used by ACCP 2012

• Hospitalization in general associated with 8X VTE risk and 25% of all VTE

• 50-75% of all in hospital VTE events are on medical services

Risk for DVT

• Important to remember that most RCT’s looking at DVT prophylaxis used asymptomatic DVT detected by venography.– Start as calf DVT– Reduction in asymptomatic parallels reduction in symptomatic DVT– Does 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 function

• Net benefit (non-fatal) – PE, DVT, GI bleed, periop bleed)– Prevention ≈ complication – Fatal events are rare

Risk for DVT

• AT9• Critically ill vs. non-critical• In non-critical– RAM’s (risk assessment model) suffer from

prospective validation, among other problems– ACCP 2012 guidelines utilize the “Padua Prediction

Score”

Risk for DVT

• Critically ill vs. non-critical• In non-critical– RAM’s (risk assessment model) suffer from

prospective validation, among other problems– ACCP 2012 guidelines utilize the “Padua Prediction

Score”– High Risk ≥ 4

Padua Prediction Score

• Journal of Thrombosis and Haemostasis 2010; 8: 2450–2457

• Prospective cohort study, 1180 pts. (medical) followed to 90 days after d/c

• Assessed– Whether pts could be assigned to high or low risk by a RAM– Whether prophylaxis worked (TID heparin, LMWH,

fondaparinux) in either group• Risk level was blinded to the treating MD• Use of prophylaxis left up to the treating MD

– Excluded bleeding, plts < 100K, CrCl < 30

Padua Prediction Score

• 40 % high risk, 60% low risk• 40% of the high risk received DVT prophylaxis

and 7.3% of the low risk• Only investigated symptomatic pts for DVT/PE

Padua Prediction Score

• 40 % high risk, 60% low risk• 40% of the high risk received DVT prophylaxis

and 7.3% of the low risk• Only investigated symptomatic pts for DVT/PE• Highly significant (P < 0.001, HR 0.13)• Of the 4 in the high risk/treated 3 occurred

after d/c

Bleeding Risk from Prophylaxis

• ACCP 2012 choose 0.4% major bleeding risk– From the control arms of DVT prophylaxis trials– IMPROVE trial

Chest. 2011; 139(1):69-79

Bleeding Risk from Prophylaxis

• ACCP 2012 choose 0.4% major bleeding risk– From the control arms of DVT prophylaxis trials– IMPROVE trial – risk model “too complex” and

“not validated”

AT9

AT9

• 2.3. 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) .

AT9

• 2.4. 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 Prophylaxis

LDUH vs. LMWH

• No difference in DVT, PE, overall mortality or HIT (one trial)

• No cost difference• Minimally less major bleeds for LMWH

(5/1000)

BID vs. TID LDUH

• The 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;507-516

“BID 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;374-381

“Moderate-quality evidence suggests that subcutaneous UFH bid and UFH tid do not differ

in effect on DVT, PE, major bleeding, and mortality”

GCS vs. IPC’s vs. VFP’s

• GCS– Conflicting data, thigh high probably better than

knee high (CLOTS I, II trials)– Surgical, stroke pts– Most studies screened for asymptomatic DVT

• IPC/VFP– No studies in hospitalized medical pts– Less DVT (sx’c) but no mortality or PE benefit in

surgical pts

GCS vs. IPC’s vs. VFP’s

• …the compelling evidence of a decrease in fatal PE that exists for anticoagulants and for aspirin does not exist for mechanical methods

Mechanical Compression vs. Heparin

• No studies in hospitalized medical pts• Surgical pts – no difference in DVT, PE (except

subgroup of LMWH vs. compression – less DVT); less bleeding with compression

Mechanical Compression + Heparinoids vs. Heparinoids Alone

• Surgical pts– IPC’s + pharm trended better than pharm alone– GCS + pharm better than pharm alone but more

skin complications

But…

• Surgical studies looking at IPC functioning found them working or applied properly in only 20 - 50% of pts.

Extended Duration DVT Prophylaxis

• Approximately 70% of DVT’s in medical pts occur in the out patient setting

• Over half of these pts had been hospitalized within the past 3 months, and 2/3’s of these within 1 month

• MEDENOX RTC - N Engl J Med 1999;341: 793-800– RTC– 40/20 lovenox vs. placebo– 3 mos f/u

Extended Duration DVT Prophylaxis

• Approximately 70% of DVT’s in medical pts occur in the out patient setting

• Over half of these pts had been hospitalized within the past 3 months, and 2/3’s of these within 1 month

• MEDENOX RTC - N Engl J Med 1999;341: 793-800

• EXCLAIM - Ann Intern Med. 2010;153:8-18– 40 lovenox for 28 days after initial therapy in hosp

EXCLAIM

• Only 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.• female

– No difference fatal PE– No difference in overall mortality and 4 ICB’s (one fatal) in LMWH

group (none in placebo)– Overall, 5/1000 fewer sx’c DVT’s, 4/1000 major bleeds

• AT9 – not recommended

ASA

• Studies in medical pts – 9 trials, 555 pts – all antiplatelet drugs

• Small number of events (DVT’s)• Asymptomatic/symptomatic, proximal/distal• US/fibrinogen labeling/venography• Up to 8 wks of drug, bleeding events not

reported

ASA

• Pooling 9 trials– 35% reduction in asymptomatic DVT– No effect on PE rate– Bleeding not reported

ASA

• PEP Trial - Lancet 2000; 355: 1295–302– 13,000 + ortho pts (hip fx)– 160 mg ASA vs. placebo (+ “any other

thromboprophylaxis thought necessary”) for 35 days– 35 days post hip fracture surg, THA, TKA

• Less DVT’s – sym and asym• Less PE’s – fatal and non-fatal• No overall mortality benefit• No difference in fatal bleeding (some increase in surg site

bleeds)

ASA

• PEP Trial - Lancet 2000; 355: 1295–302– 13,000 + ortho pts (hip fx)– 160 mg ASA vs. placebo (+ “any other thromboprophylaxis

thought necessary”) for 35 days– 35 days post hip fracture surg, THA, TKA

• Less DVT’s – sym and asym• Less PE’s – fatal and non-fatal• No overall mortality benefit• No 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”

AT9

• “Based on the low quality of available evidence…no recommendation could be made”

• There 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;155:602-615

• Large meta-analysis• Randomized trials including medical patients

or strokes• Heparin, LMWH, mechanical prophylaxis• 40 unique trials; 52,000 pts• Medical and stroke pts, no surg/trauma/OB

• Trials– Heparin vs no heparin (1)– LMWH vs no LMWH (2)– LMWH vs UFH (3)– Mechanical vs no mechanical (4)

• Outcomes– Death (primary); PE, major bleeding (secondary)

(1, 2, 3)– Death (4)

• Results– no significant effect of prophylaxis on mortality (there was a trend in

favor of heparin prophylaxis (P=0.056)– Heparin vs no heparin

• 3 less PE’s, 9 more bleeds (4 major)/1000 pts– LMWH vs heparin

• No difference in outcomes– No improved outcomes with mechanical prophylaxis in stroke

• Conclusion– Reduced PE, no change total mortality, increased bleeding (heparin,

LMWH) (stroke and medical pts)– Therefore, no net clinical benefit

• Raised numerous questions– Which are the preferred outcomes (PE vs bleed)– Use of surrogate outcomes – asymptomatic DVT?• Most PE not preceded by symptomatic DVT• Asymptomatic PE’s? No studies screen with CT

– Editorial comments• JC’s recommendation for DVT proph only excludes

children and pts hospitalized < 2 days

N Engl J Med 2011;365:2463-72

N Engl J Med 2011;365:2463-72

LMWH in Medical Patients

• Double blind, randomized, placebo controlled• LMWH vs. placebo, all pts received elastic stockings with

graduated compression– China, India, Korea, Malaysia, Mexico, the Philippines, and

Tunisia• 8300+ pts• Primary outcome – death at 30 days• Secondary 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

• Conclusion– No reduction in the rate of death from any cause among

hospitalized, acutely ill medical patients with the addition of lovenox

• Counterintuitive?– Pharm prophylaxis reduces DVT (including asympt DVT) in

acutely ill medical pts by > 45%– Assumed that DVT’s 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 distal

References• Kahn 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-e226S• Barbar 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: 2450–2457

• Decousus et al. Factors at Admission Associated With Bleeding Risk in Medical Patients. Chest. 2011; 139(1):69-79• King et al. Twice vs Three Times Daily Heparin Dosing for Thromboembolism Prophylaxis in the General

Medical Population. Chest 2007;131;507-516• Phung et al. Dosing Frequency of Unfractionated Heparin Thromboprophylaxis. Chest 2011;140;374-381• CLOTS 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: 1295–302

• Lederle 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;155:602-615

• Kakkar et al. Low-Molecular-Weight Heparin and Mortality in Acutely Ill Medical Patients. N Engl J Med 2011;365:2463-72.