What evidence is available for the use of aspirin alone for deep vein thrombosis (DVT) prophylaxis in orthopedic procedures (specifically hip and knee replacements)?

Comment by InpharmD Researcher

A comprehensive literature search did not identify a preferred duration of hours after total hip arthroplasty (THA) or total knee arthroplasty (TKA) for initiating aspirin for venous thromboembolism (VTE) prophylaxis. The timing of administration does not seem to be a focused clinical topic. One retrospective study reported patients received either 81 mg aspirin BID or 325 mg aspirin BID on the evening of or the next day after the procedure which concluded that low-dose 81-mg aspirin was non-inferior to high-dose 325-mg aspirin for preventing VTE. Additional studies reported aspirin being initiated on the night of the surgery or as early as 48 hours before the operation.

Background

American College of Chest Physicians (ACCP) guidelines for prevention of venous thromboembolism (VTE) in orthopedic surgery patients recommend anticoagulation with an agent such as aspirin for a minimum of 10 to 14 days in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA). For patients undergoing major orthopedic surgery (THA or TKA) and receiving low molecular weight heparin as thromboprophylaxis, it is recommended to start either 12 hours or more preoperatively or 12 hours or more postoperatively rather than within 4 hours or less preoperatively or 4 hours or less postoperatively. No recommendation is made concerning the timeline for initiating aspirin therapy. [1]

The European guidelines on perioperative VTE prophylaxis recommend the use of aspirin as an option for VTE prevention after THA or TKA, regardless of bleeding or VTE risk. However, the guidelines state no recommendation can be made regarding the dose and duration of aspirin treatment. [2]

A 2020 meta-analysis of 13 randomized controlled trials (N= 6060) assessed the safety and efficacy of aspirin for VTE prophylaxis after THA or TKA. However, the timing of aspirin initiation after surgery was not a focused discussion. When reviewing the included studies, the protocols for postoperative VTE prophylaxis greatly varied in both the timing and dosing strategy or were vague in citing when the dose was administered (i.e., postoperative day 1 to day 14). For example, a recent 2018 trial initiated aspirin 81 mg only when switching from 5 days of post-op rivaroxaban 10 mg. Because of the disparity and lack of focus on the timing of aspirin dosing, it is difficult to determine an optimal time to administer after surgery. The doses of aspirin ranged from 81 mg to up to 1200 mg daily dose (older studies typically employed higher doses). [3], [4]

While specific initiation for therapy for aspirin is not established, experts have observed the initiation of low-molecular-weight heparins for prophylaxis of venous thromboembolism within patients undergoing major orthopedic surgery. In Europe, traditionally, prophylaxis is started 12 hours before surgery, whereas in North America it is initiated 12 to 48 hours postoperatively. Perioperative prophylaxis begins either more than 12 hours before or 12 hours after surgery. [5]

References:

[1] Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e278S-e325S. doi:10.1378/chest.11-2404
[2] Afshari A, Ageno W, Ahmed A, et al. European Guidelines on perioperative venous thromboembolism prophylaxis: Executive summary. Eur J Anaesthesiol. 2018;35(2):77-83. doi:10.1097/EJA.0000000000000729
[3] Matharu GS, Kunutsor SK, Judge A, Blom AW, Whitehouse MR. Clinical effectiveness and safety of aspirin for venous thromboembolism prophylaxis after total hip and knee replacement: a systematic review and meta-analysis of randomized clinical trials. JAMA Intern Med. 2020;180(3):376.
[4] Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or Rivaroxaban for VTE Prophylaxis after Hip or Knee Arthroplasty. N Engl J Med. 2018;378(8):699-707. doi:10.1056/NEJMoa1712746
[5] Strebel N, Prins M, Agnelli G, Büller HR. Preoperative or Postoperative Start of Prophylaxis for Venous Thromboembolism With Low-Molecular-Weight Heparin in Elective Hip Surgery? Arch Intern Med. 2002;162(13):1451–1456. doi:10.1001/archinte.162.13.1451
Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

What evidence is available for the use of aspirin alone for deep vein thrombosis (DVT) prophylaxis in orthopedic procedures (specifically hip and knee replacements)?

Please see Tables 1-4 for your response.

 

Low-Dose Aspirin Is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty

Design

Retrospective cohort study

N= 5,666

Objective

To compare 2 aspirin regimens with regard to the incidence of (1) symptomatic deep venous thrombosis (DVT), (2) pulmonary embolism (PE), (3) bleeding, and (4) mortality within 90 days after total knee arthroplasty (TKA)

Study Groups

325 mg aspirin (n= 4,339)

81 mg aspirin (n= 1,327)

Inclusion Criteria

Underwent elective, primary TKA; received 325 mg or 81 mg aspirin

Exclusion Criteria

Received other modalities of chemoprophylaxis (e.g., warfarin, enoxaparin) with or without aspirin on day of procedure

Methods

Electronic medical records were used to identify and collect data on patients. A manual chart review was conducted to identify patients who received only aspirin after TKA. All patients included in the study received either 81-mg aspirin twice daily (BID) or 325-mg aspirin BID on the evening of or the next day after the procedure for 4 to 6 weeks, per surgeons' preference. Complications occurring within 90 days postoperatively were collected via medical records. 

Duration

Underwent TKA between 2012 and 2016

Follow-up: 90 days

Outcome Measures

Incidence of symptomatic VTE (DVT and PE), bleeding, and mortality at 90 days post-operation

Baseline Characteristics

  

325 mg aspirin (n= 4,339)

81 mg aspirin (n= 1,327)

  

Age, years

 68 ± 10 68 ± 10  

Female

2,588 (59.7%) 787 (59.3%)  

BMI, kg/m2

 32.6 ± 6.7

32.6 ± 6.7

  

Age-adjusted CCI

 4.3 ± 2.2  4.5 ± 2.2  

BMI: body mass index, CCI: Charlson comorbidity index

Results

Endpoint

325 mg aspirin (n= 4,339)

81 mg aspirin (n= 1,327)

p-Value

VTE

 65 (1.5%)

9 (0.7%)

 0.02 

DVT

 61 (1.4%)

4 (0.3%)

 < 0.001 

PE

7 (0.2%)

5 (0.4%)

 0.13

Bleeding

7 (0.2%)

3 (0.2%)

 0.62

Mortality

6 (0.1%)

1 (0.1%)

 0.56

After adjusting for confounders, no correlation was found between aspirin dose and incidence of VTE (odds ratio [OR] 1.03, 95% confidence interval [CI] 0.45–2.36, p= 0.94) or DVT (OR 0.50, 95% CI 0.16–1.55, p= 0.20).

Adverse Events

 Please see results section above. 

Study Author Conclusions

Low-dose aspirin can be considered a safe and effective agent in the prevention of VTE since it was not inferior to high-dose aspirin for the prevention of VTE after TKA. With the overall low incidence of VTE, the role of chemoprophylaxis may be considered minimal in the periooperative prevention in low-risk patients.

InpharmD Researcher Critique

Unfortunately, specific details regarding the exact duration of time elapsed for when aspirin was started after TKA was not provided. Patient compliance with aspirin regimen upon discharge was not able to be assessed. 



References:

Faour M, Piuzzi NS, Brigati DP, et al. Low-Dose Aspirin Is Safe and Effective for Venous Thromboembolism Prophylaxis Following Total Knee Arthroplasty. J Arthroplasty. 2018;33(7S):S131-S135. doi:10.1016/j.arth.2018.03.001

 

Aspirin for Elective Hip and Knee Arthroplasty: A Multimodal Thromboprophylaxis Protocol 

Design

Retrospective study

N= 1,568

Objective

To determine the 90-day rate of venous thromboembolism (VTE), other complications, and mortality in patients who underwent primary elective hip and knee replacement surgery with multimodal thromboprophylaxis

Study Groups

Total hip arthroplasty (THA) (n= 887)

Total knee arthroplasty (TKA) (n= 645)

Unicompartmental knee arthroplasty (UKA) (n= 36)

Inclusion Criteria

Patients who underwent primary elective hip or knee arthroplasty by the senior author (AGDV) 

Exclusion Criteria

Not specified

Methods

Patients received chemoprophylaxis for six weeks after elective hip or knee surgery based on VTE risk stratification. Patients that were considered to have a low risk of VTE were given aspirin (started on the night of surgery; 325 mg orally twice a day). Patients at a high risk of VTE were given warfarin therapy and included those with a history of obesity, malignancy, VTE, active or recent cancer, known hypercoagulable disorder, debilitated patients who were expected to mobilize slowly after surgery, and those undergoing bilateral TKA. Patients with a history of non-life-threatening VTE [proximal deep vein thrombosis (DVT) or pulmonary embolism (PE)] were considered at very high risk and were treated with warfarin and LMWH until the international normalized ratio (INR) was therapeutic.  

Patients taking warfarin before surgery received warfarin after surgery regardless of their risk of VTE.  Patients with a recent history of a life-threatening PE (within 12 months), multiple PE or multiple proximal DVT were treated with a vena cava filter (VCF) inserted preoperatively and received warfarin and LMWH postoperatively.

Duration

Between January 2005 and October 2011

Outcome Measures

90-day complications

Baseline Characteristics

  

THA (n= 887)

TKA (n= 645)

 UKA (n= 36)

Age, years

 63 ± 13 66 ± 10 61 ± 10

Male

342 (38.6%) 212 (30.3%) 15 (37.5%)

Weight, kg

 81 ± 20 85 ± 19 81 ± 16

BMI, kg/m2

 29 ± 6.4 32 ± 6.5  30 ± 4.6

History of VTE

History of VTE

History of PE

History of DVT

Bilateral single-stage procedure

 

46 (5.2%)

9 (1%)

43 (4.8%)

42 (4.7 %)

 

24 (3.7%)

8 (1.2%)

20 (3.2%)

55 (8.5 %)

 

0

0

0

2 (5.6 %)

VTE Risk

Low risk

High risk

Very high risk

 

705 (79.5 %)

172 (19.4 %)

10 (1.1 %)

 

418 (64.8 %)

210 (32.6 %)

17 (2.6 %)

 

29 (80.6 %)

7 (19.4 %)

0 

Chemoprophylaxis

Aspirin

Warfarin

Enoxaparin to warfarin

Vene cava filter (VCF)

 

697 (79 %)

180 (20 %)

6 (0.7 %)

4 (0.5 %)

 

389 (60.3 %)

239 (37 %)

11 (1.7 %)

6 (0.9 %)

 

29 (80 %)

7 (20 %)

0

0

Results

Number of patients who developed 90-day complications, stratified by VTE risk
 

Low Risk

 High Risk Very High Risk

Complication

VTE

Tachycardia/arrhythmia

Myocardial infarction/angina

CHF

Endocarditis

Major organ/system bleeding

Cerebrovascular accident

Wound drainage requiring observation

Wound drainage requiring irrigation and debridement (I&D)

Superficial wound infection (SWI)

Deep wound infection (DWI)

Hypoxia/atelectasis

Pneumonia

Minor bleeding

Ileus

Reoperations

Periprosthetic fracture

Manipulations

 

13 (1.1%)

4 (0.3%)

2 (0.2%)

2 (0.2%)

1 (0.1%)

3 (0.3%)

1 (0.1%)

0

1 (0.1%)

3 (0.3%)

0

2 (0.2%)

3 (0.3%)

0

3 (0.3%)

1 (0.1%)

0

16 (3.8%) 

 

6 (1.5%)

12 (3.1%)

2 (0.5%)

1 (0.3%)

0

3 (0.8%)

0

2 (0.5%)

2 (0.5%)

11 (2.8%)

1 (0.3%)

1 (0.3%)

2 (0.5%)

4 (1%)

1 (0.3%)

1 (0.3%)

0

13 (6.2%)

 

0

1 (3.7%)

0

0

0

0

0

0

0

0

0

1 (3.7%)

1 (3.7%)

0

0

0

1 (3.7%)

0 

Total

 55 (4.8%) 62 (15.9%) 4 (14.8%)

The rate of VTE, PE, proximal DVT, and distal DVT was 1.2, 0.36, 0.45, and 0.36 %, respectively, in patients who received aspirin. The rates in those who received warfarin were 1.4, 0.9, 0.47, and 0.47 %, respectively. No VTE was observed in the 17 patients who received LMWH and warfarin, and in patients who had a VCF inserted preoperatively. The overall 90-day mortality rate was 0.2 %.

Adverse Events

See Results

Study Author Conclusions

Multimodal thromboprophylaxis in which aspirin is administered to low-risk patients is safe and effective following primary total joint replacement.

InpharmD Researcher Critique

It is a retrospective study which lacks a control group. Only symptomatic VTE was recorded, potentially underestimating the total prevalence of VTE. The low-risk group was given aspirin (325 mg PO BID) which was started on the night of surgery. 



References:

Vulcano E, Gesell M, Esposito A, et al. Aspirin for elective hip and knee arthroplasty: a multimodal thromboprophylaxis protocol. Int Orthop. 2012;36(10):1995-2002.

 

Prophylaxis for Deep Vein Thrombosis with Aspirin or Low Molecular Weight Dextran in Korean Patients Undergoing Total Hip Replacement. A Randomized Controlled Trial

Design

Randomized controlled trial

N= 150

Objective

To establish the incidence of deep venous thrombosis (DVT) in patients undergoing uncemented hip replacement without prophylaxis and to evaluate the efficacy of low molecular weight dextran and aspirin in preventing DVT

Study Groups

Aspirin (n= 50)

Low molecular weight dextran (n= 50)

Control (n= 50)

Inclusion Criteria

Aged greater than 18 years, undergoing primary uncemented total hip replacement, informed consent 

Exclusion Criteria

History of aspirin intolerance, consumption of aspirin-containing compounds or other antiplatelet agents within 14 days prior to surgery

Methods

Aspirin, 1.2 g daily in three divided doses, was supplied as 100 mg buffered or enteric-coated tablets, starting 48 hours before the operation and finishing 14 days after.  Low molecular weight dextran was infused intravenously at a rate of 50 cc/hour perioperatively and continued during the following two days.

Duration

From December 1990 to July 1994

Outcome Measures

Incidence of DVT

Baseline Characteristics

  

Control (n= 50)

Low molecular weight dextran (n= 50)

 Aspirin (n= 50)

Age, years

21-30

31-40

41-50

51-60

61-70

71-80

> 81

 

3 (6%)

4 (8%)

9 (18%)

18 (36%)

13 (26%)

2 (4%)

1 (2%)

 

1 (2%)

6 (12%)

10 (20%)

15 (30%)

15 (30%)

2 (4%)

1 (2%) 

 

3 (6%)

8 (16%)

7 (14%)

16 (32%)

12 (24%)

3 (6%)

1 (2%)

Male

41 (82) 38 (76) 40 (80)

Preoperative diagnosis

Avascular necrosis

Sequelae of hip fracture

Osteoarthritis

Dysplastic hip

Sequelae of hip dislocation

Quiescent tuberculosis

 

37 (74%)

7 (14%)

2 (4%)

2 (4%)

1 (2%)

1 (2%)

 

34 (68%)

9 (18%)

3 (6%)

1 (2%)

2 (4%)

1 (2%)

 

35 (70%)

9 (18%)

2 (4%)

1 (2%)

1 (2%)

2 (4%)

Results

Endpoint

Control (n= 50)

Aspirin (n= 50)

Low molecular weight dextran (n= 50)

Positive venogram

 10 (20%) 6 (12%) 3 (6%)

Negative venogram

 40 44 47

Overall incidence

 10/50 (20%) 6/50 (12%) 3/50 (6%)

Significance

 - 0.055 < p < 0.1 p< 0.05

Obesity (p< 0.05) and long-term administration of steroids (p< 0.05) were risk factors for DVT which reached statistical significance in the control group. 

Adverse Events

Common Adverse Events: wound hematoma (2% control, 0% aspirin, 4% dextran)

Serious Adverse Events: N/A

Percentage that Discontinued due to Adverse Events: N/A

Study Author Conclusions

Low molecular weight dextran significantly reduce the incidence of deep venous thrombosis and aspirin, though less effective, had a similar effect.

InpharmD Researcher Critique

Aspirin, 1.2 g daily in three divided doses, was initiated 48 hours before the operation; however, a perhaps outdated study utilized a relatively higher dosage of aspirin compared to more recent literature. The 12% incidence of DVT in the aspirin group did not reach statistical significance.



References:

Kim YH, Choi IY, Park MR, et al. Prophylaxis for deep vein thrombosis with aspirin or low molecular weight dextran in Korean patients undergoing total hip replacement. A randomized controlled trial. Int Orthop. 1998;22(1):6-10.

 

Aspirin for Thromboprophylaxis after Primary Lower Limb Arthroplasty: Early Thromboembolic Events and 90 Day Mortality in 11,459 Patients

Design

Prospectively collected, retrospective analysis 

N= 11,459

Objective

To present the outcomes of a single surgeon series of patients who underwent total hip (THA), total knee (TKA) or unicompartmental knee arthroplasty (UKA) with aspirin as the primary agent for post-operative thromboprophylaxis

Study Groups

Total hip arthroplasty (THA) (n= 5,941)

Total knee arthroplasty (TKA) (n= 5,028)

Unicompartmental knee arthroplasty (UKA) (n= 490)

Inclusion Criteria

Patients who underwent primary lower limb arthroplasty with aspirin as the primary agent for post-operative thromboprophylaxis

Exclusion Criteria

Not specified

Methods

Aspirin 150 mg was given once daily for six weeks from the first post-operative day. Patients with a previous history of proximal DVT or PE were given warfarin. Low molecular weight heparin (LMWH) was used initially until the INR reached the therapeutic range of 2 to 2.5. All patients were reviewed at six weeks after THA and UKA and three months after TKA.

Duration

Between November 2002 to April 2014

Outcome Measures

90-day all-cause mortality, incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE)

Baseline Characteristics

  

THA (n= 5,941)

TKA (n= 5,028)

 UKA (n= 490)      

Age, years

 68.5 ± 10.3 70.4 ± 9.0 66.9 ± 9.1      

Male

2,640 1,888 247       

Results

Endpoint

THA

TKA

 UKA

Operations, n

 90-day mortality, n (%) Operations, n 90-day mortality, n (%) Operations, n 90-day mortality, n (%)
2002 73 0 (0%) 64 0 (0%) 0 0 (0)
2003 358 2 (0.56%) 307  2 (0.65%) 0  0 (0) 
2004 454 6 (1.32%) 387  5 (1.29%) 0  0 (0) 
2005 383 3 (0.78%) 481  1 (0.21%) 0  0 (0) 
2006 556 3 (0.54%) 570  2 (0.35%) 0  0 (0) 
2007 693 2 (0.29%) 509  1 (0.20%) 0  0 (0) 
2008 671 0 (0%) 558  3 (0.54%) 49 0 (0) 
2009 693 3 (0.43%) 466  4 (0.86%) 92  0 (0) 
2010 583 1 (0.17%) 415  1 (0.24%) 148  0 (0) 
2011 573 2 (0.35%) 468  2 (0.43%) 68  0 (0) 
2012 477 0 (0%) 401  0 (0%) 64  0 (0) 
2013 310 0 (0%) 286  0 (0%) 54  0 (0) 
2014 117 1 (0.85%) 116  1 (0.86%) 15  0 (0) 
Total 5,941 23 (0.39%) 5,028  22 (0.44%) 490  0 (0) 

Causes of death      

 N
Cardiac (ischemic heart disease ) 17   
Respiratory failure 6
Pulmonary embolism 7
Cancer 5
Cerebrovasuclar accident 3
Ruptured aortic aneurysm 2
Gastrointestinal bleed 2
Cause not given 1
Total 45
Early post-operative complications

Complications within 90 days

THA

 TKA/UKA
Infection 18 20
Haematoma 2  5 
Wound dehiscence 4  4 
Total (%) 24 (0.40%)  29 (0.53%) 

The incidence of PE was 0.57% after THA, 1.47%, after TKA and 1.22% after UKA between 2002 and 2014. The incidence and annual distribution of imaging-confirmed symptomatic proximal DVT shows an overall mean incidence of < 0.5% per year for each of the three procedures over the 12-year period.

Adverse Events

See Results

Study Author Conclusions

With individualised risk assessment and as part of a multimodal approach, Aspirin is safe to use as the main thromboprophylactic agent in primary arthroplasty. It is not associated with an increased incidence of symptomatic DVT, PE, or death.

InpharmD Researcher Critique

Though the data were prospectively collected, the study is subject to the limitations inherent to an observational, retrospective analysis. Once-daily aspirin 150 mg was initiated for six weeks from the first post-operative day. The use of aspirin for thromboprophylaxis did not increase 90-day mortality or thromboembolic complications. 



References:

Ogonda L, Hill J, Doran E, et al. Aspirin for thromboprophylaxis after primary lower limb arthroplasty: early thromboembolic events and 90 day mortality in 11,459 patients. Bone Joint J. 2016;98-B(3):341-348.