Venous Thromboembolism Prophylaxis in Orthopedic Surgery

Venous Thromboembolism Prophylaxis
in Orthopedic Surgery
Prepared for:
Agency for Healthcare Research and Quality (AHRQ)
www.ahrq.gov
Outline of This Presentation
 The comparative effectiveness review (CER) process
 Overview of venous thromboembolism (VTE) and
orthopedic surgery
 VTE prophylaxis
 Results from the CER
 Summary of conclusions
 Gaps in knowledge
 What to discuss with your patients
Agency for Healthcare Research and Quality (AHRQ)
Comparative Effectiveness Review (CER) Development
 Topics are nominated through a public process, which includes
submissions from health care professionals, professional
organizations, the private sector, policymakers, the public, and
others.
 A systematic review of all relevant clinical studies is conducted by
independent researchers, funded by AHRQ, to synthesize the
evidence in a report summarizing what is known and not known
about the select clinical issue. The research questions and the
results of the report are subject to expert input, peer review, and
public comment.
 The results of these reviews are summarized into Clinician and
Consumer Research Summaries for use in decisionmaking and in
discussions with patients. The research reviews and the full report
are available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Rating the Strength of Evidence From the
Comparative Effectiveness Review
 The strength of evidence was classified into four broad
categories:
AHRQ. Methods Guide for Effectiveness and Comparative Effectiveness Reviews. April 2012. Available at www.effectivehealthcare.ahrq.gov/ehc/
products/60/318/MethodsGuide_Prepublication-Draft_20120409.pdf.
Thromboprophylaxis in Major Orthopedic Surgery
 Major orthopedic surgery including total hip replacement
(THR), total knee replacement (TKR), and hip fracture surgery
carries a risk for venous thromboembolism (VTE).
 Without prophylaxis, historic data suggest deep vein
thrombosis (DVT) occurs in 40–60 percent of cases in the 7–14
days following surgery.
 With routine use of thromboprophylaxis, symptomatic VTE in
patients within 3 months of surgery is approximately 1.3–10
percent.
 Prophylactic strategies may decrease the risk of VTE, DVT, and
pulmonary embolism.
 The main limitation of pharmacological VTE prophylaxis is the
risk of bleeding, which historically occurs in 1–3 percent of
THR and TKR surgeries.
American Academy of Orthopaedic Surgeons. Guideline on preventing venous thromboembolic disease in patients undergoing
elective hip and knee arthroplasty. Available at www.aaos.org/research/guidelines/VTE/VTE_guideline.asp .
Preventing Venous Thromboembolic Events in
Major Orthopedic Surgery
 A variety of strategies to prevent venous thromboembolism are
available:
 Pharmacological
 Oral antiplatelet agents
 Injectable low-molecular-weight heparins
 Injectable unfractionated heparin
 Injectable or oral factor Xa inhibitors
 Injectable or oral direct thrombin inhibitors
 Oral vitamin K antagonists
 Mechanical modalities
 Graduated compression
 Intermittent pneumatic compression
 Venous foot pump
 Combinations of these
Establishing the Need for a Systematic Review of
VTE Prophylaxis in Orthopedic Surgery
 The magnitude of benefit and harms in contemporary practice
and evaluation of pharmacological agents or devices available
within the United States amongst the orthopedic surgery
population is not well known.
 Additionally, the influence of these factors in contemporary
practice needs to be systematically evaluated:
 The impact of duration of prophylaxis on outcomes
 Whether dual prophylactic therapy is superior to single-modality
therapy
 The comparative effectiveness of different pharmacological or
mechanical modalities
 The risks of VTE, PE, and DVT and the causal link between DVT
and PE.
American Academy of Orthopaedic Surgeons. Guideline on preventing venous thromboembolic disease in patients undergoing
elective hip and knee arthroplasty. Available at www.aaos.org/research/guidelines/VTE/VTE_guideline.asp .
Baseline Postoperative Risk of Venous
Thromboembolism and Bleeding
Outcomes in Contemporary Practice
Baseline Postoperative Risks of VTE Outcomes in
the Absence of Pharmacological Prophylaxis
 Most of the literature evaluated total hip and total knee
replacement surgeries with very little evaluation of hip
fracture surgery. The baseline risk of venous
thromboembolism and bleeding outcomes in the absence
of pharmacological prophylaxis are as follows:
Outcome Total Hip Strength of Total Knee Strength of
Replacement Evidence Replacement Evidence
(THR) (TKR)
Pulmonary 6% Low 1% Low
embolism
Deep vein 39% Low 46% Low
thrombosis
Major bleeding 1% Moderate 3% Low
Minor bleeding 5% Low 5% Moderate
Comparative Effectiveness of
Pharmacological or Mechanical
Thromboprophylaxis Versus
No Thromboprophylaxis
Pharmacological versus no pharmacological prophylaxis
Mechanical versus no thromboprophylaxis
Comparative Effectiveness of Pharmacological
Prophylaxis Versus No Pharmacological Prophylaxis
Outcome Magnitude of Effect RR/OR (95% CI), Strength
NNT/NNH of Evidence
DVT Decreases risk by 44% RR 0.56 (0.47 to 0.68), Moderate
NNT 3 to 33
Proximal DVT Decreased risk by 47% RR 0.53 (0.39 to 0.74), High
NNT 4 to 213
Distal DVT Decreased risk by 41% RR 0.59 (0.42 to 0.82), High
NNT 8 to 35
Asymptomatic DVT Decreased risk by 48% RR 0.52 (0.40 to 0.69), Moderate
NNT 4 to 6
Symptomatic VTE NR
Major VTE Decreased risk by 79% RR 0.21 (0.05 to 0.95), Low
NNT 19 to 22
PE No difference OR 0.38 (0.13 to 1.07) Low
Abbreviations: 95% CI = 95-percent confidence interval; NNH = number needed to harm (the calculated range); NNT =
number needed to treat (the calculated range; NR = not reported or insufficient evidence to permit conclusions; OR = odds
ratio; RR = relative risk
Comparative Effectiveness of Pharmacological Prophylaxis
Versus No Pharmacological Prophylaxis: Adverse Effects
Outcome Magnitude of Effect RR/OR (95% CI), Strength

NNT/NNH of Evidence
Major Bleeding No difference RR 0.74 (0.36 to 1.51) Moderate

Minor Bleeding Relative risk is RR 1.67 (1.18 to 2.38), High
higher for NNH 30 to 75
pharmacological
prophylaxis by 67%
Abbreviations: 95% CI = 95-percent confidence interval; NNH = number needed

to harm; NNT = number needed to treat; OR = odds ratio; RR = relative risk
Comparative Effectiveness of Mechanical
Prophylaxis Versus No Thromboprophylaxis
 Mechanical prophylaxis significantly decreased deep vein
thrombosis (DVT; results from one randomized controlled
trial; strength of evidence not rated).
 The risk for proximal or distal DVT was not significantly
different (results from one randomized controlled trial;
strength of evidence not rated).
 Data are not available to evaluate the comparative effect
of mechanical prophylaxis versus no prophylaxis on other
outcomes.
Comparative Effectiveness of
Pharmacological and Mechanical
Prophylaxis Agents
Prophylaxis Agents: LMWH Versus UFH
Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)
Comparators DVT Proximal Symptomati PE Major Minor Heparin-
DVT c Bleeding Bleeding induced
Thrombo-
VTE
cytopenia
LMWH Decreased Decreased NR Decreased Decreased No Decreased

risk by 20%; risk by 40%; odds by odds by 35%; difference; odds by
vs. UFH RR 0.80 (0.65 52%; OR 0.57 (0.37 RR 0.90 88%; OR
to 0.99), RR 0.60 OR 0.48 to 0.88), (0.63 to 0.12 (0.03
NNT 12 to (0.38 to (0.24 to NNT 41 1.28) to 0.43),
100 0.93), 0.95), (SOE = High) (SOE = NNT 34 to
(SOE = NNT 14 to NNT 8 Moderate) 202
Moderate) 50 (SOE = (SOE =
(SOE = Moderate) Moderate)
High)
Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; major
bleeding = for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical
site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the
calculated range); NNT = number needed to treat (the calculated range); NR = not reported or insufficient evidence to permit
conclusions; OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; UFH = unfractionated
heparin; VTE = venous thromboembolism
Prophylaxis Agents: Enoxaparin Versus Fondaparinux
Comparators DVT Proximal Symptomatic PE Major Minor
DVT Bleeding Bleeding
VTE
Enoxaparin Relative Odds are No difference; No Decreased Decreased
vs. risk is higher for OR 0.70 difference; odds by odds by
fondaparinux higher for enoxaparin (0.48 to 1.02) 35%; 43%;
enoxaparin by 219%; (SOE = Low) OR 3.34 OR 0.65 OR 0.57 (0.35
by 99%; OR 2.19 (0.58 to (0.48 to 0.89), to 0.94),
RR 1.99 (1.52 to 3.16), 19.32) NNT 74 to NNT 31 to
(1.57 to (Not 145 60
2.51), NNH 44 to rated) (SOE = (SOE = Low)
NNH 13 to 122 Moderate)
26 (SOE = Low)
(SOE =
Moderate)
Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; major bleeding = for example, bleeding leading to
greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection,
or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to
treat (the calculated range); OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; VTE =
venous thromboembolism
Prophylaxis Agents: LMWH Versus Warfarin

DVT VTE Bleeding Bleeding
LMWH Decreased No No No difference; Odds are Relative risk is

vs. warfarin risk difference; difference; OR 1.11 higher for higher for
by 34%; RR 0.63 OR 1.00 (0.57 to 2.19) LMWH LMWH
RR 0.66 (0.39 to (0.69 to 1.46) (SOE = by 92%; by 23%;
(0.55 to 0.79), 1.00) (SOE = Low) Moderate) OR 1.92 RR 1.23
NNT 6 to 13 (SOE = (1.27 to 2.91), (1.06 to 1.43),
(SOE = Low) Low) NNH 57 to NNH 18 to 218
220 (SOE =
(SOE = High) Moderate)
Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; major bleeding
= for example, bleeding leading to greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding,
bleeding leading to infection, or bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range);
NNT = number needed to treat (the calculated range); OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of
evidence rating; VTE = venous thromboembolism
Prophylaxis Agents: UFH Versus Desirudin

DVT VTE Bleeding Bleeding
UFH Relative risk is Odds are NR No difference; NR NR
vs. higher for UFH higher for OR 3.23
desirudin by 231%; UFH by (0.56 to 18.98)
RR 2.31 477%; (SOE = Low)
(1.34 to 4.00), OR 4.74
NNH 5 to 11 (2.99 to 7.49),
(SOE = Moderate)
NNH 11
(SOE =
Moderate)
Abbreviations: 95% CI = 95-percent confidence interval; DVT = deep vein thrombosis; major bleeding = for example, bleeding leading to
greater transfusion requirements and/or reoperation; minor bleeding = for example, surgical site bleeding, bleeding leading to infection, or
bleeding leading to transfusion but not reoperation; NNH = number needed to harm (the calculated range); NR = not reported or insufficient
evidence to permit conclusions; OR = odds ratio; PE = pulmonary embolism; RR = relative risk; SOE = strength of evidence rating; UFH =
unfractionated heparin; VTE = venous thromboembolism
and Mechanical Prophylaxis
 Warfarin decreased the risk of proximal deep vein
thrombosis (DVT) by 63 percent when compared with
mechanical prophylaxis.
 Strength of Evidence = Moderate
 Patients on aspirin had higher rates of DVT when
compared with those using only mechanical prophylaxis.
 Pharmacological plus mechanical prophylaxis reduced the
risk of DVT by 52 percent when compared with
pharmacological prophylaxis alone.
Comparative Effectiveness of Prolonged
(≥28 Days) Versus Standard (7–10 Days)
Pharmacological Prophylaxis
Prolonged (≥28 Days) Versus Standard (7–10 Days)
Pharmacological Prophylaxis: Clinical Outcomes
Prolonged Versus Magnitude of Effect Risk/Odds (95% CI) NNT/NNH Strength
Standard-Duration of
Prophylaxis Evidence
Symptomatic VTE Decreased RR 0.38 NNT 8 to 54 Moderate
risk by 62% (0.19 to 0.77)
PE Decreased OR 0.13 NNT 24 to High
odds by 87% (0.04 to 0.47) 232
Nonfatal PE Decreased odds by OR 0.13 (0.03 to 0.54) NNT 58 Moderate
87%
DVT Decreased risk by 63% RR 0.37 (0.21 to 0.64) NNT 5 to 32 Moderate
Asymptomatic Decreased risk by 52% RR 0.48 (0.31 to 0.75) NNT 8 to 65 High

DVT
Symptomatic DVT Decreased odds by OR 0.36 (0.16 to 0.81) NNT 27 to 79 High
64%
Proximal DVT Decreased RR 0.29 NNT 9 to 71 High
risk by 71% (0.16 to 0.52)
Prolonged (≥28 Days) Versus Standard (7–10 Days)
Pharmacological Prophylaxis: Adverse Effects
Prolonged Versus Magnitude of Risk/Odds NNT/NNH Strength of
Standard-Duration Effect (95% CI) Evidence
Prophylaxis
Major Bleeding No difference OR 2.18 Low

(0.73 to 6.51)
Minor Bleeding Odds are OR 2.44 NNH 11 to 118 High

higher for (1.41 to 4.20)
prolonged
prophylaxis by
244%
Abbreviations: 95% CI = 95-percent confidence interval; major bleeding = for example, bleeding
leading to greater transfusion requirements and/or reoperation; minor bleeding = for example,
surgical site bleeding, bleeding leading to infection, or bleeding leading to transfusion but not
reoperation; NNH = number needed to harm (the calculated range); NNT = number needed to
treat (the calculated range); OR = odds ratio
Patient or Surgical Characteristics That
May Affect the Risk of
Venous Thromboembolism
Characteristics That May Affect Risk of Venous
Thromboembolism: Results
 Patients who receive general anesthesia may have a higher risk
of deep vein thrombosis (DVT) than those who receive regional
anesthesia; however, there were no differences in proximal or
symptomatic DVT.
 Strength of Evidence = Low
 No difference in risk of DVT or proximal DVT was found among
patients receiving cemented versus noncemented arthroplasty.
 Strength of Evidence = Low
 Observational data suggest that patients with congestive heart
failure were at an increased risk for symptomatic, objectively
confirmed venous thromboembolism when compared with
those without it.
Summary of the RECORD Trials
 The oral direct factor Xa inhibitor, rivaroxaban, was approved
by the FDA for preventing DVT, which may be associated with
PE, in patients undergoing THR or TKR surgery.
 This decision was based, in part, on the findings of four phase
III trials known as the Regulation of Coagulation in Orthopedic
Surgery to Prevent Deep Venous Thrombosis and Pulmonary
Embolism (RECORD) trials: RECORD 1, RECORD 2, RECORD 3,
and RECORD 4.
 They compared various regimens of rivaroxaban and enoxaparin
in THR or TKR surgery.
 The primary efficacy outcome was composite DVT, nonfatal PE,
or all-cause mortality.
 The primary safety outcome was major bleeding.
Summary of Outcomes From the RECORD Trials
 RECORD 1 and 2 trials (THR):
 There was reduced risk of the primary efficacy outcome with prolonged rivaroxaban
(started 6–8 hours postoperatively, for 35 ± 4 days) when compared with enoxaparin
given as either prolonged (started evening before surgery, for 36 ± 4 days) or standard-
duration (started evening before surgery, for 13 ± 2 days) prophylaxis.
 RECORD 1: The primary efficacy outcome occurred in 1.1 percent of patients given
rivaroxaban and 3.7 percent of patients given enoxaparin (ARR = 2.6%; 95% CI, 1.5
to 3.7; P < 0.001).
to 9.4; P < 0.0001).
 RECORD 3 and 4 trials (TKR):
 Rivaroxaban decreased the risk of the primary efficacy outcome when compared with
enoxaparin.
to 12.4; P < 0.001).
rivaroxaban and in 10.1 percent of patients given enoxaparin (ARR = 3.19%, 95% CI,
0.71 to 5.67; P = 0.0118).
 In all four trials, there were no significant differences in the risk for the primary safety
outcome of major bleeding or for the risks of mortality or minor bleeding outcomes.
Summary of Conclusions
 Estimated native (i.e., without pharmacological prophylaxis)
incidence of DVT after THR and TKR surgery was 39 percent and 46
percent, respectively.
 Pharmacological prophylaxis decreases the risk of DVT with some
increased risk of minor bleeding when compared with no
pharmacological prophylaxis.
 LMWH may decrease the risk for DVT when compared with warfarin
at the expense of increases in major and minor bleeding.
 LMWH provides greater protection against DVT and PE when
compared with unfractionated heparin while reducing the risk of
bleeding and heparin-induced thrombocytopenia.
 LMWH was not as effective in protecting against the risk of DVT
when compared with an injectable factor Xa inhibitor, although the
odds of bleeding were reduced.
 Prolonged prophylaxis decreased the risk of thromboembolism at the
risk of increased minor bleeding when compared with standard-
duration prophylaxis.
Gaps in Knowledge
 Inadequate data did not permit conclusions about the
comparative benefits and adverse effects associated with VTE
prophylaxis in non–joint–replacement surgery.
 More information is needed on the following aspects of VTE
prophylaxis in the setting of major orthopedic surgery:
 Clinically important outcomes including symptomatic venous
thromboembolism, post-thrombotic syndrome, clinically relevant
bleeding, prosthetic infection, reoperation, and mortality and
whether intermediate outcomes predict health outcomes
 Surgical, postsurgical, or patient factors that predict outcomes
 The optimal followup period needed to determine longer term
outcomes
 Optimal duration of thromboprophylaxis
 The role of combined pharmacological and mechanical
prophylaxis
What To Discuss With Your Patients
 General background information on the risk of
thromboembolic disease
 That thromboembolic disease is a major risk after joint–
replacement surgery and why some form of prophylactic
treatment is indicated
 Options for prophylaxis
 Bleeding as the major risk of pharmacological prophylaxis
Resource for Patients
 Preventing Blood Clots After Hip
or Knee Replacement Surgery or
Surgery for a Broken Hip, A
Review of the Research for Adults
is a free resource for patients. It
can help patients talk with their
health care professionals about
the many options for treatment.
It provides information about:
 Pharmacological options for
preventing venous
thromboembolism (VTE)
 Nonpharmacological options for
preventing VTE
 Current evidence of effectiveness
and harms associated with VTE-
prevention methods
 Questions for patients to ask their
doctor

Venous Thromboembolism Prophylaxis in Orthopedic Surgery

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Venous Thromboembolism Prophylaxis

Outcome Magnitude of Effect RR/OR (95% CI), Strength

Major Bleeding No difference RR 0.74 (0.36 to 1.51) Moderate

Abbreviations: 95% CI = 95-percent confidence interval; NNH = number needed

LMWH Decreased Decreased NR Decreased Decreased No Decreased

Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)

LMWH Decreased No No No difference; Odds are Relative risk is

Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)

Asymptomatic Decreased risk by 52% RR 0.48 (0.31 to 0.75) NNT 8 to 65 High

Major Bleeding No difference OR 2.18 Low

Minor Bleeding Odds are OR 2.44 NNH 11 to 118 High

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