DVT Prophylaxis in Medical
Patients
Rog Kyle, MD
MUSC
6/5/12
• 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 molecularweight 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
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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.