Upload
baldric-webb
View
223
Download
3
Tags:
Embed Size (px)
Citation preview
Venous Thromboembolism Prophylaxis in Orthopedic
SurgeryPrepared for:
Agency for Healthcare Research and Quality (AHRQ)
www.ahrq.gov
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
Outline of This Presentation
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.
Agency for Healthcare Research and Quality (AHRQ) Comparative Effectiveness Review (CER) Development
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
The strength of evidence was classified into four broad categories:
Rating the Strength of Evidence From the Comparative Effectiveness Review
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.Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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.
Thromboprophylaxis in Major Orthopedic Surgery
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 .
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
Preventing Venous Thromboembolic Events in Major Orthopedic Surgery
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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.
Establishing the Need for a Systematic Review of VTE Prophylaxis in Orthopedic Surgery
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
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Baseline Postoperative Risks of VTE Outcomes in the Absence of Pharmacological Prophylaxis
Outcome Total Hip Replacement
Strength of Evidence(THR)
Total Knee
Replacement
Strength of Evidence(TKR)
Pulmonary embolism
6% Low 1% Low
Deep vein thrombosis
39% Low 46% Low
Major bleeding 1% Moderate 3% Low
Minor bleeding 5% Low 5% Moderate
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:
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Comparative Effectiveness of Pharmacological or Mechanical
Thromboprophylaxis Versus No Thromboprophylaxis
Pharmacological versus no pharmacological prophylaxis
Mechanical versus no thromboprophylaxis
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Comparative Effectiveness of Pharmacological Prophylaxis Versus No Pharmacological Prophylaxis
Outcome Magnitude of Effect
RR/OR (95% CI), NNT/NNH
Strength of Evidence
DVT Decreases risk by 44%
RR 0.56 (0.47 to 0.68), NNT 3 to 33
Moderate
Proximal DVT Decreased risk by 47%
RR 0.53 (0.39 to 0.74), NNT 4 to 213
High
Distal DVT Decreased risk by 41%
RR 0.59 (0.42 to 0.82),NNT 8 to 35
High
Asymptomatic DVT
Decreased risk by 48%
RR 0.52 (0.40 to 0.69),NNT 4 to 6
Moderate
Symptomatic VTE NR
Major VTE Decreased risk by 79%
RR 0.21 (0.05 to 0.95),NNT 19 to 22
Low
PE No difference OR 0.38 (0.13 to 1.07)
Low
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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),
NNT/NNH
Strength of Evidence
Major Bleeding No difference RR 0.74 (0.36 to 1.51)
Moderate
Minor Bleeding Relative risk is higher for pharmacological prophylaxis by 67%
RR 1.67 (1.18 to 2.38),NNH 30 to 75
High
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Abbreviations: 95% CI = 95-percent confidence interval; NNH = number neededto harm; NNT = number needed to treat; OR = odds ratio; RR = relative risk
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 Mechanical Prophylaxis Versus No Thromboprophylaxis
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Comparative Effectiveness of Pharmacological and Mechanical
Prophylaxis Agents
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Comparative Effectiveness of Pharmacological Prophylaxis Agents: LMWH Versus UFH
Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)
Comparators
DVT Proximal DVT
Symptomatic VTE
PE Major Bleeding
Minor Bleedin
g
Heparin-induced Thromb
o-cytopeni
a
LMWH vs. UFH
Decreased risk by 20%; RR 0.80 (0.65 to 0.99), NNT 12 to 100 (SOE = Moderate)
Decreased risk by 40%; RR 0.60 (0.38 to 0.93), NNT 14 to 50 (SOE = High)
NR Decreased odds by 52%; OR 0.48 (0.24 to 0.95), NNT 8(SOE = Moderate)
Decreased odds by 35%;
OR 0.57 (0.37 to 0.88), NNT 41(SOE = High)
No difference;RR 0.90 (0.63 to 1.28) (SOE = Moderate)
Decreased odds by 88%; OR 0.12 (0.03 to 0.43), NNT 34 to 202(SOE = Moderate)
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
Comparative Effectiveness of Pharmacological Prophylaxis Agents: Enoxaparin Versus Fondaparinux
Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)
Comparators
DVT Proximal
DVT
Symptomatic VTE
PE Major Bleeding
Minor Bleeding
Enoxaparinvs. fondaparinux
Relative risk is higher for enoxaparinby 99%;RR 1.99 (1.57 to 2.51), NNH 13 to 26(SOE = Moderate)
Odds are higher for enoxaparin by 219%;OR 2.19(1.52 to 3.16), NNH 44 to 122 (SOE = Low)
No difference; OR 0.70(0.48 to 1.02) (SOE = Low)
No difference; OR 3.34 (0.58 to 19.32) (Not rated)
Decreased odds by 35%;OR 0.65 (0.48 to 0.89),NNT 74 to 145 (SOE = Moderate)
Decreased odds by 43%; OR 0.57 (0.35 to 0.94), NNT 31 to 60 (SOE = Low)
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
Comparative Effectiveness of Pharmacological Prophylaxis Agents: LMWH Versus Warfarin
Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)Comparat
orsDVT Proximal
DVT
Symptomatic
VTE
PE Major Bleeding
Minor Bleeding
LMWH vs. warfarin
Decreased risk by 34%;RR 0.66(0.55 to 0.79), NNT 6 to 13 (SOE = Low)
No difference; RR 0.63(0.39 to 1.00)(SOE = Low)
No difference; OR 1.00 (0.69 to 1.46) (SOE = Low)
No difference;OR 1.11 (0.57 to 2.19)
(SOE = Moderate)
Odds are higher for LMWH by 92%;OR 1.92(1.27 to 2.91), NNH 57 to 220(SOE = High)
Relative risk is higher for LMWHby 23%; RR 1.23(1.06 to 1.43), NNH 18 to 218 (SOE = Moderate)
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
Comparative Effectiveness of Pharmacological Prophylaxis Agents: UFH Versus Desirudin
Magnitude of Effect; Risk/Odds (95% CI), NNT/NNH (SOE)
Comparators
DVT Proximal DVT
Symptomatic
VTE
PE Major Bleedin
g
Minor Bleedin
g
UFH vs. desirudin
Relative risk is higher for UFH
by 231%;RR 2.31 (1.34 to 4.00), NNH 5 to 11 (SOE = Moderate)
Odds are higher for UFH by 477%; OR 4.74 (2.99 to 7.49), NNH 11 (SOE = Moderate)
NR No difference; OR 3.23(0.56 to 18.98)(SOE = Low)
NR NR
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
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. Strength of Evidence = Moderate
Pharmacological plus mechanical prophylaxis reduced the risk of DVT by 52 percent when compared with pharmacological prophylaxis alone. Strength of Evidence = Moderate
Comparative Effectiveness of Pharmacological and Mechanical Prophylaxis
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Comparative Effectiveness of Prolonged (≥28 Days) Versus
Standard (7–10 Days) Pharmacological Prophylaxis
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Prolonged (≥28 Days) Versus Standard (7–10 Days) Pharmacological Prophylaxis: Clinical Outcomes
Prolonged Versus Standard-Duration Prophylaxis
Magnitude of Effect
Risk/Odds (95% CI)
NNT/NNH Strength of Evidence
Symptomatic VTE
Decreasedrisk by 62%
RR 0.38(0.19 to 0.77)
NNT 8 to 54
Moderate
PE Decreasedodds by 87%
OR 0.13(0.04 to 0.47)
NNT 24 to 232
High
Nonfatal PE Decreased odds by 87%
OR 0.13 (0.03 to 0.54)
NNT 58 Moderate
DVT Decreased risk by 63%
RR 0.37 (0.21 to 0.64)
NNT 5 to 32
Moderate
Asymptomatic DVT
Decreased risk by 52%
RR 0.48 (0.31 to 0.75)
NNT 8 to 65
High
Symptomatic DVT
Decreased odds by 64%
OR 0.36 (0.16 to 0.81)
NNT 27 to 79
High
Proximal DVT Decreasedrisk by 71%
RR 0.29(0.16 to 0.52)
NNT 9 to 71
HighSobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
Prolonged (≥28 Days) Versus Standard (7–10 Days) Pharmacological Prophylaxis: Adverse Effects
Prolonged Versus Standard-DurationProphylaxis
Magnitude of Effect
Risk/Odds (95% CI)
NNT/NNH Strength of Evidence
Major Bleeding No difference OR 2.18(0.73 to 6.51)
Low
Minor Bleeding Odds are higher for prolonged prophylaxis by 244%
OR 2.44(1.41 to 4.20)
NNH 11 to 118
High
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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 ofVenous Thromboembolism
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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. Strength of Evidence = Moderate
Characteristics That May Affect Risk of Venous Thromboembolism: Results
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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 the RECORD Trials
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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).
RECORD 2: The primary efficacy outcome occurred in 2.0 percent of patients given rivaroxaban and 9.3 percent of patients given enoxaparin (ARR = 7.3%; 95% CI, 5.2 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. RECORD 3: The primary efficacy outcome occurred in 9.6 percent of
patients given rivaroxaban and 18.9 percent of patients given enoxaparin (ARR = 9.2%; 95% CI, 5.9 to 12.4; P < 0.001).
RECORD 4: The primary efficacy outcome occurred in 6.9 percent of patients given 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 Outcomes From the RECORD Trials
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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.
Summary of Conclusions
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
Gaps in Knowledge
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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
What To Discuss With Your Patients
Sobieraj DM, Coleman CI, Tongbram V, et al. Comparative Effectiveness Review No. 49. Available at www.effectivehealthcare.ahrq.gov/thrombo.cfm.
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