Venous Thromboembolism In Orthopedics
Richard H. White, MD Internal Medicine Director, Anticoagulation Service UC Davis, Sacramento, CA
TOPICS
• • • • • • • • Anatomy and Definitions Epidemiology- Scope of the Problem History of VTE in Orthopedic surgery Risk Factors Efficacy of Prophylaxis Duration of Prophylaxis ACCP Recommendations Dosing Warfarin
ILEO-FEMORAL VEIN THROMBOSIS
Location of Venous Thrombosis:
DEFINITIONS
Proximal Clot: Popliteal vein or higher Distal: calf vein below trifurcation Superficial DVT: in vein just below the skin Idiopathic or “Unprovoked” : No clear, „reversible‟ or „transient‟ risk factor; ie surgery • Secondary: Associated with transient risk factor Surgery, pregnancy, trauma, • • • •
EPIDEMIOLOGY OF VTE
• Incidence Rate ~ 1.5/1000 per year
• • • • •
[After THR ~ 3/100 pts /90 days = 120/1000 pt-years!] Exponentially rise with age to 5/1000/year @ age >80 Women = Men Lower incidence in Asian/Pacific Islanders (RR=0.4) Increased 3-4 fold if thrombophilic disorder present. Strongly related to cancer, cajor surgery, trauma and immobilization.
SURGICAL PROCEDURE
NUMBER OF SURGERIES
91 Day Incidence of Thromboembolism N %VTE 95% CI % After Discharge
ORTHOPEDIC Total Hip Arthroplasty or Revision Partial Hip Arthroplasty ORIF of the Femur Total Knee Arthroplasty or Revision Internal Fixation-Femur without Reduction, or with Closed Reduction Shoulder Arthroplasty ORIFof the Tibia-Fibula ORIF of theHumerus 56720 1358 2.4 2.3-2.5 74
25023
38825
509
725
2.0
1.9
1.9-2.2
1.8-2.0
71
63
65745
9340 2034 31858 4267 100103 12795 11664
1147
127 11 161 19 283 29 20
1.7
1.4 0.5 0.5 0.5 0.3 0.2 0.2
1.7-1.8
1.2-1.6 0.3-0.8 0.4-0.6 0.3-0.6 0.3-0.3 0.2-0.3 0.1-0.2
44
67 55 77 42 63 69 80
Excision of Intervertebral Disc
Cruciate Ligament Repair Rotator Cuff Repair
Virchow’s Triad
Risk Factors for Venous Thrombosis-1
Circulatory Stasis
Anesthesia Stroke with paralysis Low flow: long car ride with „stiff legs‟; Obesity (esp TKR) Prolonged bed rest > 12 hrs for 2 or more days Age-immobility Pregnancy CHF, COPD
Risk Factors for Venous Thrombosis- 2
Hypercoaguable State
Thrombophilic disorders (genotype) idiopathic DVT/ prior DVT (phenotype) Cancer (adenocarcinomas esp.) Advanced age (stasis also increases) Hematologic disorders: P-vera, PNH etc.
Risk Factors for Venous Thrombosis- 3
Endothelial Injury
Direct trauma Surgery on lower extremity Fracture, lower extremity Intravenous catheter
What Are The Known 'Thrombophilic' Disorders
Factor V Leiden (FVL) Resistance to activated Protein C (without F-V Leiden) F-II mutation or “Prothrombin 20210A gene mutation” Protein C deficiency Protein S deficiency Anti-thrombin III (AT) deficiency High levels of VIIIc High homocysteine levels (not MTHFR gene) Lupus Anticoagulant- Anti-phosholipid Ab syndrome
Thromboprophylaxis: Historical Perspective
• 1916 Heparin Discovered • 1935 Heparin used Clinically • 1939 Dicumarol Isolated (sweet clover) • 1941 Dicumarol used Clinically • 1950‟s Development of venography and coagulation tests.
Thromboprophylaxis: Historical Perspective
• 1950‟s and early 60‟s. Diagnosis of DVT and PE largely clinical. • 1962-1968. Scope of the problem of PE after joint replacement began to be appreciated.
Treatment of Thromboembolism With Anticoagulants
Barritt DW, Jordan SC Lancet 1960; 1:1309-12
• Trial of treatment of patients with clinical PE. • 1.5 days of heparin followed by 2 weeks of phenindione: 0/16 treated patients had recurrent PE 12/19 untreated pts had PE (5 fatal)
Prevention of Thromboembolism after Lower Extremity Fracture
Sevitt, S and Gallagher, Lancet 1959;2: 981
• PE common among patient who die after: Fractured Hip -- 46% Fractured Femur -- 53% • Coumarin prophylaxis after hip fracture: 4/150 (2.7%) treated had DVT/PE 43/150 (27%) untreated had DVT/PE
Thromboembolism after Total Hip Arthroplasty
Johnson R, Green JR and Charnley J Clin Ortho 1977, 127: 123-132
• 7,959 THA‟s „62-‟73 1,174 given no prophylaxis • Unblinded observational data • PE diagnosed clinically (+ autopsy) • Incidence of fatal PE = 26/1174 (2.3%) • Incidence PE = 179/1174 (15%) in controls • Coumarin prophylaxis = 29/450 (6.5%) ; 0.8% fatal
Warfarin for Thromboembolism Prophylaxis after THA
Coventry MB, Nolan MB, Beckenbaugh RD JBJS 1973; 55-A: 1487-1492
• Warfarin started on the 5th day post-op • Unblinded clinical assessment • 2/58 (3.4%) with no Rx died of PE • 41/ 2,012 (2%) Rx‟d had PE, 2 (0.1%) died • 81 (4%) had major bleeding
1980’s: Epidemiology of Thromboembolism after THA
Based on placebo controlled trials:
Incidence of proximal DVT at 10-14 days
= 20-25%. (venography, I 125 scanning) Incidence of proximal plus calf DVT = 50-60%. Duration of risk unclear. Suggestion that post-hospitalization DVT was common.
Prophylaxis after Total Hip Replacement in the 1980’s
Use of warfarin and heparin not widespread Only sporadic use of pneumatic compression
Aspirin initially thought to be useful Increasing number of clinical trials were conducted:
- randomized trial design, blinded outcome - objective surrogate endpoint (venography) - larger sample size Some evidence that low-dose heparin ineffective
Efficacy of Low-Dose Heparin
Collins R, Scrimgeour A, Yusuf S, Peto R New Engl J Med 1988; 318:1162-1171
• Early meta-analysis.
• Low dose heparin as effective after orthopaedic surgery as in medical/urology pts • 68% reduction in DVT, 64% reduction in fatal PE. 15,000 IU better than 10,000 IU. • Bleeding increased 66% (absolute =2%)
Meta-analysis: Low Molecular Weight Heparin Prophylaxis
Nurmohamed MT, Rosendaal FR et al Lancet 1992; 340: 152-156
LMWH vrs UFH DVT PE Bleeding
N= 724 RR=0.75 (0.6-1.0) RR=0.76 (0.4-1.4 RR= 1.2 (0.4-4.0)
Enoxaparin vrs. UFH (7,500 bid)
Levine MN, Hirsh J et al. Ann Int Med 1991;114:545-551 2 Double blind randomized trials, venogram endpoint. Number c Venogram DVT Proximal DVT Number Total Proximal DVT LMWH UFH 258 263 19% 23% ns 5.4% 6.5% ns 333 332 4.8% 5.4%
Enoxaparin vrs. UFH (7,500 bid)
Levine MN, Hirsh J et al. Ann Int Med 1991;114:545-551 Double blind randomized trial, venogram endpoint. LMWH 333 11 (3.3%) 6 (1.8%) UFH 332 19 (5.7%) 12 (3.6%)
Number Major Bleeding Minor Bleeding
Enoxaparin vrs. UFH After Total Hip Arthroplasty
Colwell et al, JBJS 1994; 76-A 3-14
Randomized, open label clinical trial comparing Enox 30 mg bid, Enox 40 mg OD to heparin, 5,000 IU q 8 hr. N= 610, (~200 each group)
• LMWH
• UFH
9/194 (5%) DVT ; 4 (2%) prox 24/207 (12%) DVT ; 10 (5%) prox
Enoxaparin vrs. UFH Utility of Ultrasound
Colwell et al, JBJS 1994; 76-A 3-14
• Ultrasound done on POD 4 or 7.
• 387 (94%) normal but 12% of these had DVT on venogram day 7. NPV = 88% • 24 (6%) positive, but only 7 of 24 (29%) were confirmed by venogram. PPV = 29% • Conclusion: Screening US not accurate
Enoxaparin vrs.Warfarin After Total Hip Arthroplasty
Colwell et al, The Consortium Study JBJS-A. 2000 Sep;82(9):1362-3.
• Multicenter, randomized, open-labeled study of
warfarin vrs enoxaparin (30 mg bid) for 6-9 days. • Endpoints: symptomatic DVT/PE (confirmed), death, and bleeding • Follow-up for 12 weeks • Enoxaparin: 1,516 pts Warfarin: 1,495 pts
Enoxaparin vrs.Warfarin After Total Hip Arthroplasty
Hospital DVT/PE Late DVT/PE Total DVT/PE Enoxaparin 4 (0.3%) 51 (3.4%) 55 (3.7%) Warfarin 17 (1.1%) 39 (2.6%) 56 (3.7%)
Symptomatic PE
Bleeding Deaths due to VTE Total Deaths
15 (1.0%)
18 (1.2%) 2 (0.13%) 9 (0.6%)
12 (0.8%)
8 (0.6%) 2 (0.13%) 10 (0.7%)
THROMBOEMBOLIC OUTCOMES AFTER THA OR TKA
White RH, Zhou H, Romano, PS, Bargar W,et al Arch Int Med 1998 158:1525-1531
Study of all patient undergoing THA and TKA In California between 1992-1994. Analysis of linked California Patient Discharge Data Set.
RESULTS:
OUTCOME
THA (19,586)
556 (2.8%) (1.8%) (1.1%) 133 (0.7%) 95 (0.5%) 329 (1.7%) 233 (1.2%) 57 (0.3%) 176 (0.9%)
TKA (24,059)
508 (2.1%) (1.4%) (0.8%) 268 (1.1%) 57 (0.2%) 183 (0.7%) 216 (0.9%) 60 (0.25%) 156 (0.6%)
DVT/PE DVT PE HOSP REHAB LATE DEATH HOSP LATE
Ortho Survey: 1997
• Respondents: performed ~ 16,700 THA or TKA
• Return Rate: 199/388 (51%) • Use of Prophylaxis After THA = TKA:
13% SC Heparin, 54% Warfarin (29% Home), 63% Pneumatic Compression in hospital 88% given one or methods. 23% ASA 75% TED 75%, 5% TED only
Enoxaparin for 7-10 Days Vrs Enoxaparin for 28-31 Days
Comp PC,. Enoxaparin Clinical Trial Group. J BJS Am. 2001 Mar;83-A(3):336-45.
• Extended enoxaparin dose = 40 mg/day
(not 30 mg q 12 h) • Venogram endpoint • Patients with hip (n= 435) and knee (n= 438) arthroplasty
Enoxaparin for 7-10 Days Vrs Enoxaparin for 28-31 Days
Group
TKA Total DVT Proximal DVT THA Total DVT Proximal DVT Extended (11-31 days) Prophylaxis Enoxaparin Placebo 38 (17%) 45 (21%) 9 (4.1%) 17 (7.7%) p= ns 17 (8%) 6 (2.7%) 50 (23%) 28 (13%) p<0.0001
Case Control Study: VTE after Hospital Discharge following THR
White RH, Neuman R, Romano P et al NEJM Dec 2000
21,178 Medicare patients were eligible for selection
as a case or control. Years 1995-1997. Performed a case-control (late VTE vrs no late VTE) study. 1,308 Medicare controls and 436 late + VTE case records. Obtained 98% of case records and 97% of control. Randomly selected 306 late VTE cases and 611 controls
Multivariate Model Odds Ratio 95% CI Age < 75 years 1.0 75-84 1.1 (0.8 - 1.5) > 85 years 2.1 (1.1 – 3.9) Female sex 1.4 (1.0 - 1.9) Non-white race 0.9 (0.4 – 2.2) Ambulating early 0.7 (0.5 – 0.9) History DVT/PE 3.4 (1.7 – 7.0) Rheumatoid arthritis 0.6 (0.2 - 1.8) BMI > 25 1.8 (1.1 - 2.9) Thromboprophylaxis: Regular heparin 1.5 (0.8 - 2.7) Enoxaparin 0.9 (0.6 - 1.4) Warfarin in-hospital 0.9 (0.6 - 1.4) Pneumatic Comp BMI < 25 0.3 (0.2 - 0.6) BMI 25 0.7 (0.5 - 1.1) Warfarin p discharge 0.6 (0.4 –1.0)
P Value 0.71 0.02 0.04 0.84 0.007 <0.001 0.38 0.03 0.23 0.70 0.57 < 0.001 0.16 0.04
The Future: Risk Stratification
We need prospective study to develop and then validate a risk stratification tool. However, it appears that HIGHER RISK ASSOCIATED WITH: • Older age • Increased BMI • Reduced Mobility • Prior VTE • No extended use of warfarin
Ultrasound Screening before Discharge after THA and TKA
Robinson et al Annals Int Med 1997; 127:439-445
• 1,024 pts randomized to US vrs Sham US
• All treated for ~7days with warfarin • Asymptomatic DVT detected in only 19 (3.7%) venography confirmed 8 of 19 cases • Outcome of DVT/PE in 4/505 US pts + 1 death 5/506 Sham US pts • Conclusion: Screening US does not help and misleads.
Summary of Prophylaxis Data:
• Among patients undergoing THA and TKA, studies in
the early 1980s showed that absence of prophylaxis was associated with an unacceptably high incidence of asymptomatic DVT detected by venography. • Prophylaxis using LMWH, warfarin or UFH (7,500 IU bid) was associated with a low incidence of proximal DVT (~5%) 7-10 days later (venogram).
• Concurrent secular trends in management lowered VTE rates as well, especially early mobilization.
Summary of THR TKR Prophylaxis Data
• Extended prophylaxis appears to be warranted
among patients undergoing THA, to prevent symptomatic VTE. NNT= 65 • Routine use of screening US does not appear to be warranted.
Acceptable Prophylaxis Strategies
• THR, TKR, Hip Fracture: medical therapy with LMWH, anti-Xa (fondaparinux), or warfarin for at least 10 days. • Aspirin is NOT Recommended • US screening is NOT recommended • SCUDs or GCS if LMWH or anticoagulation not possible • No recommendations about bridging to warfarin • Trauma: LMWH unless risk of bleeding high, no IVC filter • Other orthopedic surgery: no rigorous recommendations
Frequency of Complications after THR and TKR: 1995-2001 in California
• N= 177319 operations • 539 Deaths in hospital (0.3%) Most were CAD, MI, CHF, Pneumonia, Stroke Complications within 3 mo: • 2237 DVT or PE (1.3% that had no prior Hx VTE) • 942 Prosthetic or peri prosthetic infections (0.5%, code 996.66 < 3 mo) • 132 Hematoma or seroma requiring drainage (0.07%)
Balancing the Risks:
• VTE is more common than infection (0.5%) and bleeding (0.07%).
• Unclear how many patients die of PE, but this appears to be quite rare (~0.1-0.2%) • However, 20%-30% of the cases with proximal VTE get post-phlebitic syndrome, 10% of these are quite severe ( overall =0.1%)
New Anticoagulants
• odiparcil • dibigitran
• Oral, no monitoring!
Warfarin Dosing
• It is more than giving warfarin! • Proper dosing is a must. • Frequent INR testing needed until stable. (documentation of adequate effect is a must!) • INR target 2.0-3.0. • Optimal Rx: coordination with an AC clinic.
Bayesian Forecasting:
Model of Theofanous and Barile:
Plasma concentration Cp(t) = Cpo X e-krt ; a one compartment open model after bolus;
PCA(t)= P0e-kdt – [mkd/(kd)2](1-e-kdt –kdt)-(m/kd)(1-e-kdt) ln(Cp0/CpMax) PCA(t)= P0e-kdt when Cp > Cpmax
where: PCA(t) = Prothrombin complex activity (can be converted to INR); Cp0 warfarin concentration at start of specified dosing interval M = variable relating warfarin concentration to clotting factor synthesis CpMax = warfarin level value when synthesis of clotting factors = 0. Kd = first order rate constant for warfarin elimination.
Web Version of WARFDOCS
Medical Legal Issues
• Unfortunately, with any bad outcome- you can be sued! Fatal PE, Post-phlebitic syndrome, Bleed and high INR
Rule for prophylaxis: use the right dose and duration, and monitor the patient closely . Outline and explain any adjustments in the chart. • Regarding post-operative anticoagulation:
– – – – start warfarin the night before or day of surgery start LMWH - fondaparinux 12 hours before/after surgery extended anticoagulation for ~ 4 weeks advised, esp THR monitor the INR closely, target INR 2.0-3.0