Aspirin for Venous Thromboembolism Prophylaxis in

Aspirin for Venous

Thromboembolism Prophylaxis

in Orthopedic Patients

Abigail Strate, PharmD PGY2 Family Medicine Pharmacy Resident and Clinical Instructor with

UTEP/UT Austin Cooperative Pharmacy Program

in collaboration with

Department of Family and Community Medicine,

Texas Tech Health Science Center, Paul L. Foster School of Medicine

October 10, 2014

Learning Objectives: 1. Compare the safety, efficacy, administration, and cost of aspirin with the alternative venous

thromboembolism (VTE) prophylaxis agents

2. Describe the current VTE prophylaxis standards of care for orthopedic patients

3. Analyze clinical trials examining the use of aspirin as VTE prophylaxis in orthopedic patients

4. Determine aspirin’s role for VTE prophylaxis in orthopedic patients

Jewish Currents. “February 27: who discovered aspirin?”. Activist Politics & Art. 2012.

Available at http://jewishcurrents.org/february-27-who-discovered-aspirin-9247.

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BACKGROUND

I. Definitions2-4

A. Venous thromboembolism (VTE): formation of blood clot in a vein

1. Deep venous thrombosis (DVT): formation of clot in deep vein – usually in the legs

2. Pulmonary embolism (PE): clot that has left deep veins and lodged in lungs

B. Arterial thrombus

1. Clot formation in atrial vessels

2. Cause of coronary heart disease and stroke

C. Orthopedic patients

1. Includes total knee arthroplasty (TKA), total hip arthroplasty (THA), and hip fracture

surgery (HFS)

2. Total hip arthroplasty

a. Same as total hip replacement

b. Socket and the ball (femoral head) are replaced

3. Hip fracture surgery

a. Encompasses any hip procedure other than THA

b. Common procedures: hemiarthroplasty, intramedullary (IM) nailing, open

reduction internal fixation (ORIF)

II. Epidemiology5-8

Table 1: Epidemiology of VTE and Hip Fracture

VTE Hip Fracture

Annual

Incidence Frequently clinically silent

1-2/1,000 of population

300,000-600,000 cases/year

Increases to 1 per 100 in those ≥ 80 years old

306,000 cases in 2010

84% of those ≥ 65 years old

Morbidity Increased risk for recurrence

Venous insufficiency

Pulmonary hypertension

Post-thrombotic syndrome

Complications from therapy

64% admitted to nursing home for first time

51% sustain long-term disability

Only 40% have full recovery

Mortality 10-30% within 30 days 1-year mortality of 20%

Annual $ $2-$10 billion $12.6 billion ($37,000/fracture)

III. VTE signs and symptoms9

Table 2: Signs and Symptoms of DVT and PE

DVT PE

Signs

Dilated superficial veins

Palpable cord

Homan’s sign (pain in

back of knee when foot

of affected leg is flexed

upward)

Symptoms

Complaints of leg:

Pain

Swelling

Warmth

Signs

Tachypnea

Tachycardia

Diaphoresis

Neck vein distention

Hypotension

Hypoxia

Symptoms

Cough

Chest pain

Chest tightness

Shortness of breath

Palpitations

Hemoptysis

Dizziness

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IV. DVT diagnosis9-10

A. Pretest probability: Wells Score for DVT

1. The Wells Score for DVT is the recommended first step in someone with a first time

suspected VTE but may be skipped in a patient with a history of VTE

2. Criteria for Wells Score

B. D-Dimer

1. A degradation product of cross-linked fibrin

2. Perform if pretest probability is low or moderate

3. Has a high sensitivity (>90%) and low specificity (~50%)

4. Potential causes for false positive d-dimer results: cancer, DIC, older age, infection,

pregnancy, surgery or trauma, inflammatory conditions, A. Fib., stroke

C. Venous Ultrasound

1. Perform first if pretest probability is high or to confirm an elevated d-dimer result

2. Optional to perform in lieu of the d-dimer for low-moderate pre-test probability results

D. CT Scan, venography, or magnetic resonance imaging

1. Alternative diagnostic agents if ultrasound reading is unclear

2. Not routinely used or recommended

V. PE Diagnosis11

A. Patients not suspected for a high-risk PE: perform Wells Score for PE

B. Criteria and interpretation of the Wells Score

C. Additional tests such as CT scan and electrocardiogram are more common in the diagnosis of PE

D. Diagnostic algorithms available in Appendix A

Table 3: Wells Score for DVT

Criteria Points

Active Cancer

Calf swelling > 3 cm compared to other calf

Collateral superficial veins

Pitting edema

Previous DVT

Swelling of entire leg

Localized pain along distribution of deep venous system

Paralysis, paresis, or recent cast immobilization of lower extremities

Recently bedridden > 3 days or major surgery in the past 4 wk

Alternative diagnosis at least as likely

+1

+1

+1

+1

+1

+1

+1

+1

+1

-2

≤ 1 point is “unlikely” a DVT

≥2 points is “likely” a DVT From: Bates SM, Jaeschke R, Stevens SM, et al. “Diagnosis of DVT”. CHEST. 2012;141(2S):e351S-e418S.

Table 4: Wells Score for PE

Criteria Points

Clinical signs and symptoms of DVT

PE is primary diagnosis or equally likely

Heart rate > 100 beats per minute

Immobilization ≥ 3 days or surgery in last 4 weeks

Previous, objectively diagnosed PE or DVT

Hemoptysis

Malignancy with treatment within 6 months, or on palliative care

+3

+3

+1.5

+1.5

+1.5

+1

+1

≤ 2 points is “low risk” with a 1.3% chance of PE

2-6 points is “moderate risk” with a 16.2% chance of PE

≥6.5 points is “high risk” with a 40.6% chance of PE

Another interpretation:

≤4 “unlikely”

>4 “likely” From: Torbicki A, Perrier A, Konstantinides S, et al. “Guidelines on the diagnosis and management of

acute pulmonary embolism”. Eur Heart J. 2008.29(18):2276-2315.

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⊝ Warfarin

⊗ LMWH, UFH

⊘ Fondaparinux

⊕ Dabigatran

⊚ Rivaroxaban

⊛ Apixaban

PATHOPHYSIOLOGY

I. Relationship between VTE and hip fracture9, 12-13

A. Virchow’s Triad

1. Hypercoagulability

a. Increased age

b. Co-morbid conditions

2. Endothelial injury

a. Surgery

b. Trauma

c. Indwelling catheters

3. Venous stasis

a. Immobility

b. Co-morbid conditions

B. Translates into substantial risks for VTE (objective vs subjective)

1. Objectively confirmed DVT without prophylaxis: 40-60%

2. Only 1-14% progress to symptomatic DVT

3. Improved surgical techniques (in 2003) lead to lower modern numbers of subjective VTE

4. Estimated symptomatic VTE without prophylaxis currently estimated at 4.3%

II. Venous thromboembolism12, 14-15

A. Venous thrombosis occurs as a result of the activation of the clotting cascade

B. Anticoagulant medications: site of actions inhibit various points of the clotting cascade

C. Natural anticoagulants circulating to prevent over-production of thrombin

1. Antithrombin

2. Tissue factor pathway inhibitor

3. Heparin cofactor II

4. Plasminogen

5. Protein C and protein S

D. The stable clot that is formed is composed of fibrin, red blood cells, platelets, and leukocytes

Figure 1: Coagulation Cascade

Figure 1: Coagulation Cascade

Adapted from: Sander GE, Giles TD. “Ximelagatran: light at the end of the tunnel or the next tunnel”. Am J Geriatr Cardiol. 2004;13(4):221-224.

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III. Arterial embolism9, 15-16

A. Initiated differently than the venous thromboembolisms

B. Prevented with antiplatelet agents including aspirin, clopidogrel, ticagrelor, and others

*Via the expression of collagen, von Willebrand factor, fibronectin, and other proteins

**Via the expression of glycoproteins, adenosine diphosphate, thrombin, epinephrine, and thromboxane A2 Figure 2: Platelet Activation

IV. Comparison of venous and arterial embolism15

Table 5: Comparison of Venous and Arterial Embolism

Venous Arterial

Similarities Embolism formations depend on presence of platelets and activation of fibrinogen to fibrin

Formation shares similar risk factors of age, obesity, cigarette smoking, diabetes, hypertension,

hyperlipidemia, and metabolic syndrome

Differences Perpetuated by hypercoagulable state, protein

deficiencies, blood vessel abnormalities,

and/or blood flow abnormalities

Activity of coagulation cascade

Perpetuation more dependent on vessel wall,

platelet activity, and/or blood flow

abnormalities

Activity of platelet activation and

propagation

PHARMACOTHERAPY FOR VTE PROPHYLAXIS

I. Comparisons of VTE prophylaxis agents13, 17-27

A. Efficacy and safety of VTE prophylaxis agents when used after major orthopedic surgery in

comparison to enoxaparin

1. Enoxaparin RRR of 50-60%

2. Fondaparinux has ↑ efficacy and ↑ risk for bleed

3. LDUH and warfarin have ↓ efficacy and ↑ risk for bleed

4. New oral anticoagulant agents compared to enoxaparin trials

a. Apixaban: ADVANCE 1, ADVANCE 2, ADVANCE 3

b. Dabigatran: RE-MODEL, RE-MOBILIZE, RE-NOVATE, RE-NOVATE II

c. Rivaroxaban: RECORD 1, RECORD 2, RECORD 3, RECORD 4

Table 6: Comparative Efficacy and Safety of New Oral Anticoagulant Agents*

Outcome Apixaban (Eliquis®) Dabigatran (Pradaxa

®) Rivaroxaban (Xarelto

®)

THA - VTE and

Mortality Rates

Proved non-inferiority and

superiority

Proved non-inferiority and failed

to prove superiority**


superiority

TKA - VTE and

Mortality Rates

Failed to prove non-inferiority

(event rate lower than projected) Proved non-inferiority


superiority

THA – Bleeds Similar rates of major and non-

major bleeds

Similar rates of major and non-

major bleeds


major bleeds

TKA – Bleeds Similar rates of major bleeds

Fewer non-major bleeds


major bleeds


major bleeds

*For TKA, the comparison is made to the 30mg BID enoxaparin dosing (rather than 40mg Q Day)

**Based on primary outcome (VTE & mortality); Proved superiority for secondary outcome (major VTE & VTE mortality)

Damaged vessel wall attracts platelets*

Platelets adhere to vessel wall and

change to activated conformation

Active platelets attract more platelets

and fibrinogen**

Stable clot is formed of platelets,

collagen, and fibrin

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B. For full comparison of dosing and costs of VTE prophylaxis agents: See Appendix B

1. Cost

a. Highest cost: apixaban, dabigatran, rivaroxaban

b. Moderate cost: enoxaparin, fondaparinux

c. Lowest cost: LDUH, warfarin, aspirin

2. Routes

a. Oral: apixaban, dabigatran, rivaroxaban, warfarin, aspirin

b. Subcutaneous: enoxaparin, fondaparinux, LDUH

II. Aspirin mechanism of action28-30

A. For a brief history of aspirin see Appendix C

B. Irreversibly acetylates specific serine moieties of the cyclooxygenase enzymes (serine 530 of the

COX-1 and 516 of the COX-2)

Figure 3- Aspirin Mechanism of Action

C. Aspirin is ~170 x more potent inhibitor of COX-1 than COX-2

D. COX-1

1. Enzymes are constitutively present in most cells

2. Inhibition remains throughout the life of the platelet (~10 days)

E. COX-2

1. Production is induced by inflammation

2. Once inhibited the cells can regenerate more COX-2

III. Aspirin pharmacokinetics26-27, 29-30

A. For a more complete review of aspirin pharmacokinetics, see Appendix D

B. Rapid absorption delayed with enteric coating

C. Large volume of distribution

D. Prodrug metabolized by ubiquitous esterases

E. Short duration of action but activity lasts for life of platelet (~10 days)

Membrane Phospholipid

Arachidonic Acid

Cyclooxygenase-1

Prostaglandins Thromboxane A2

Gastroprotection, platelet aggregation,

renal function

Cyclooxygenase-2

Prostaglandins

Pain, fever, renal function, reproduction,

development, antiplatelet

Phospholipase A2

Lipoxygenase Leukotrienes

ASPIRIN

(Doses<325mg)

ASPIRIN

(Doses≥325mg) ―

Adapted from: Eikelboom JW, Hirsh J, Spencer FA, et al. “Antiplatelet drugs”. CHEST.

2012;141(2S):e89S-e119S.

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IV. Dosing considerations with aspirin29-30

A. 100mg aspirin needed to achieve platelet inhibition with a single dose

B. Daily doses of 50-81 mg required to maintain platelet inhibition

C. Dosing evidence based on use in arterial embolism and pain/fever indications

D. Side effects are dose-dependent: gastrointestinal discomfort, bleeding, renal toxicity

E. Considerations with missed doses

1. COX activity recovers 10% per day that aspirin not taken

2. Only 20% COX activity required for clinically significant platelet coagulation to occur

CURRENT RECOMMENDATIONS

I. Guideline recommendations13, 31-33

A. American College of Chest Physicians (ACCP) guidelines

1. Release the “Prevention of VTE in Orthopedic Surgery Patients” guidelines

2. Current 9th edition released in 2012 available at:

http://journal.publications.chestnet.org/article.aspx?articleID=1159591

3. Grading scale used for recommendations

Table 7: ACCP Guideline Grading Scale

A B C

1 1A strong recommendation,

high quality of evidence

1B strong recommendation,

moderate quality of evidence

1C strong recommendation,

low quality of evidence

2 2A weak recommendation,

high quality of evidence

2B weak recommendation,

moderate quality of evidence

2C weak recommendation,

low quality of evidence

B. American Academy of Orthopaedic Surgeons (AAOS) guidelines

1. Release the “Preventing Venous Thromboembolic Disease in Patients Undergoing

Elective Hip and Knee Arthroplasty” guideline

2. Current guideline released in 2011 available at:

http://www.aaos.org/research/guidelines/VTE/VTE_guideline.asp

3. “Management of Hip Fracture Management in the Elderly”: no anticoagulation detail

4. Grading scale used for recommendations

Table 8: AAOS Guideline Grading Scale

Grade of Recommendation Interpretation Strong Recommendation

Moderate Suggestion

Limited The practitioner might

Inconclusive Unable to recommend for or against

Consensus The opinion of the work group (absence of reliable evidence)

C. Comparison of the current ACCP and AAOS recommendations

Table 9: Comparison of Recommendations for the ACCP and AAOS Guidelines

Parameter ACCP – 2012 Grade AAOS – 2011 Grade Who should

receive

prophylaxis

and with what

agents?

For THA and TKA, any

prophylaxis preferred over none

(including: LMWH,

fondaparinux, apixaban,

dabigatran, rivaroxaban, LDUH,

VKA, ASA*, IPCD)

1B for

pharmacologic

1C for IPCD

Pharmacologic or IPCD for all

elective THA and TKA if no

other bleeding or clotting risks

Moderate

For HFS, any prophylaxis

preferred over none (including:

LMWH, fondaparinux, LDUH,

VKA, ASA*, IPCD)

1B for

pharmacologic

1C for IPCD

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Table 9 continued: Comparison of Recommendations for the ACCP and AAOS Guidelines Parameter ACCP – 2012 Grade AAOS – 2011 Grade

What are the

preferred

prophylaxis

agents?

For THA, TKA and HFS,

LMWH is preferred agent with

remaining agents listed as

alternatives

2B for all

except VKA

and ASA are

2C

No recommendation for or

against specific strategies (options

included: apixaban, LMWH,

VKA, aspirin, dabigatran,

fondaparinux, rivaroxaban, IPCD,

GCS)

Inconclusive

Recommended to use

combination pharmacologic and

IPCD prophylaxis for all

orthopedic surgery patients

2C For patients with previous VTE,

pharmacologic preferred over

IPCD

Consensus

For patients at increased risk for

bleed, recommend using IPCD

rather than no prophylaxis

2C For patients with known bleeding

disorder or liver disease, IPCD or

GCS preferred over

pharmacologic

Consensus

For what

duration is

prophylaxis

indicated?

35 days prophylaxis preferred

over the minimum duration of 10-

14 days

2B Should be discussed between

patients and physicians

Consensus

THA: total hip arthroplasty; TKA: total knee arthroplasty; HFS: hip fracture surgery; IPCD: intermittent pneumatic compression device;

GCS: graduated compression stockings; ASA: aspirin; VKA: vitamin K antagonist; LDUH: low-dose unfractionated heparin

* Cite the Antiplatelet Trialists’ Collaboration Meta-Analysis as being poor evidence. Cite the PEP trial as evidence why aspirin should be

used rather than no prophylaxis at all.

D. Recommendations from the ACCP 2008 guidelines (available at:

http://journal.publications.chestnet.org/article.aspx?articleID=1085923)

1. For elective THA or TKA

a. Recommend LMWH, fondaparinux, or warfarin

b. Recommend against aspirin, dextran, LDUH, GCS, or venous foot pump solely

2. Hip fracture surgery

a. Recommend fondaparinux, LMWH, warfarin, or LDUH

b. Recommend against aspirin solely

3. Recommendations against aspirin use

a. Cite the weaknesses of the Antiplatelet Trialists’ Collaboration meta-analysis

b. Cite the PEP trial as showing benefit with aspirin and as showing no significant

benefit with aspirin

c. Cite both the above trials as proving increased risk of bleeding with aspirin

E. International guideline recommendations

Table 10: Comparison of International Guideline Recommendations for the Use of Aspirin for VTE Prophylaxis in Ortho Surgery Patients

Australia NICE ICS France Brazil S. Africa Japan Germany SIGN

THA

TKA

HFS NICE: National Institute for Health and Care Excellence- UK; ICS: Cardiovascular Disease Educational and Research Trust- Europe;

SIGN: Scottish Intercollegiate Guidelines Network

From: Struijk-Mulder MC, Ettema HB, Verheyen CC, et al. “Comparing consensus guidelines on thromboprophylaxis in orthopedic

surgery”. J Thromb Haemost. 2010;8:678-683.

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II. FDA indications26

Table 11: Comparison of FDA Indications for VTE Prophylaxis Agents

LMWH Heparin Warfarin Fondaparinux Apixaban Rivaroxaban Dabigatran Aspirin

THA

TKA

HFS

III. The Joint Commission’s Surgical Care Improvement Project (SCIP) measures34

A. Joint document between the Joint Commission and Centers for Medicare & Medicaid Services

B. Specifies surgical criteria that have to be met for accreditation and reimbursement including

pharmacotherapy issues

1. Timing of anticoagulants pre- and post-operatively

2. Acceptable agents for VTE prophylaxis

3. Duration of antimicrobial use

4. Appropriate documentation

C. 2014 recommendations based on the ACCP 2012 guidelines

D. Performance measure description: “surgery patients who received appropriate VTE prophylaxis

within 24 hours prior to anesthesia start time to 24 hours after anesthesia end time”

E. Aspirin added to the list of acceptable VTE prophylaxis in TKA and THA in the July 1, 2013

update for SCIP measures

IV. Healthy People 2020 “Blood Disorders and Blood Safety” objectives

35

A. Objective 13.2: “reduce VTE among adult surgical patients”

B. Objective 12: “reduce the number of persons who develop venous thromboembolism”

LITERATURE REVIEW

I. Selection of trials

A. 100’s of articles on this topic dating back to 1950s

B. Many underpowered to detect a difference

C. Inclusion criteria

1. Landmark trials

2. Trials comparing aspirin to placebo or LMWH in orthopedic patients

3. Evaluating rates of VTE (subjective or objective)

4. Newer trials due to the change in practices in 2003

D. Exclusion criteria

1. Negative trials underpowered to show a difference

2. Trials evaluating arterial embolism and not VTE

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II. Antiplatelet Trialists’ Collaboration. “Collaborative overview of randomised trials of antiplatelet

therapy-III: reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis

among surgical and medical patients”. BMJ. 1994;308:235-248.36-37

Trial 1

Study Design Meta-analysis of all antiplatelet trials published by March 1990 that assessed DVT

Objectives Assess whether antiplatelets prevent DVT and PE or death from PE in high risk medical, post op, and post

orthopedic surgery patients. Also reviewed serious bleeding complications when possible.

Trials Inclusion Criteria: Randomized trials which assessed antiplatelet vs. placebo OR antiplatelet vs.

antiplatelet. Trial available by March 1990 which systematically monitored DVT.

Exclusion Criteria: Trials comparing antiplatelets to anticoagulants (unless one anticoagulant group

included antiplatelet therapy too). Trials for patients with subarachnoid hemorrhage or for prevention of

eclampsia or migraine.

Methods Trials identified by computer literature searches (Medline and Current Contents), manual journal searches,

review of reference lists of similar articles, review of abstracts and meeting proceedings, collaboration with

the trials register of the International Committee on Thrombosis and Haemostasis, inquiry of colleagues, and

by inquiry of manufacturers of antiplatelet drugs

Statistics Power Analysis: Numbers needed for 80% power

High Risk (orthopedic surgery)

DVT 400

PE 4,000

PE Death 10,000

ITT (for trials that all patient data was not published, information was sought out)

Completed separate analysis for placebo-controlled trials

For uneven treatment allocations, sample sizes were adjusted

Proportional and absolute reductions were calculated

Results Baseline characteristics of patients not published

Average duration of prophylaxis in orthopedic patients ~2 weeks

Efficacy Outcome Traumatic ortho pts adjusted % odds

reduction (unadjusted p value) n=964

Elective ortho pts adjusted % odds

reduction (unadjusted p value) n=1154

DVT 31% (=0.02) 49% (<0.0001)

PE 60% (<0.005) 51% (=0.04)

Aspirin overall adjusted % odds reduction = 39%

Safety Outcome Antiplatelet Group % Control Group % p value

Fatal PE 1% 2.7% =0.0001

Other fatalities not published not published NS

Bleed requiring transfusion 0.7% 0.4% =0.04

Reoperation, hematoma,

infection due to bleed 7.8% 5.6% =0.003

Author’s

Conclusions Use of antiplatelets for 1-3 weeks in high risk medical, general surgery, and orthopedic surgery patients

significantly ↓ the rates of DVT and PE without imposing a significant bleeding risk

ASA is the most familiar and affordable antiplatelet and its use is more practical than SQ prophylaxis

agents upon hospital discharge

The authors recommend further evaluation of ASA vs. ASA plus dipyridamole

Limitations Meta-analysis (potential for uncontrolled bias’, publication bias, journal selection bias, unaccounted for

confounding variables)

Average daily ASA dose from all trials was 1,248 mg/patient/day

Raw data not reported for individual groups, only adjusted controls

~ ¼ of trials were active-controlled trials (no placebo)

Specific statistical tests used were not disclosed

Strengths Large sample size with very thorough search method for trials

Contacted authors for study clarifications or more data

Reviewer’s

Conclusions

With the above limitations in mind, I could not recommend ASA in orthopedic patients. However, the data

is compelling if combined with the results of multiple other well-powered and well-designed trials.

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III. Pulmonary Embolism Prevention (PEP) Trial Collaborative Group. “Prevention of pulmonary

embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP)

trial”. The Lancet. 2000;355:1295-1302.38

Trial 2

Study Design Prospective, randomized, double-blind, parallel groups, multi-center, placebo-controlled

Objectives To confirm or refute the results of the 1994 meta-analysis results as well as assess effects of antiplatelet

prophylaxis therapy on perioperative bleeding

Subjects Inclusion Criteria: Patients with femoral neck fracture or other proximal femur fractures (plus THA and

TKA for those patients in New Zealand)

Exclusion Criteria: Exclusion was left to the discretion of the physician. Likely included patients with

other clear indication for ASA (e.g. MI), those with clear contraindication to ASA (e.g. PUD).

Methods Patients randomized to either ASA 160mg daily or placebo daily

Started preoperatively (first dose chewed or broken) and continued for 35 days

Patients also received any thromboprophylaxis deemed necessary by their physician

Non-study ASA and other NSAIDs were discouraged, but not prohibited for study inclusion

Non-fatal events (DVT, PE, bleeds) were followed-up for duration of hospital stay

Fatal events were followed-up for full duration of study (35 days)

Statistics Determined a trial of 13,000-14,000 would be required to achieve a power of 90% at p=0.05 to detect a

risk reduction of at least ⅓ with ASA

All analysis were intention to treat completed with Cox’s proportional hazards model

Results

Baseline characteristics were similar (mean age = 79 and 79% of patients were female)

Efficacy Outcome ASA (n=6679) Placebo (n=6677) Relative Risk Reduction% (p value)

Any DVT 69 (1.0%) 97 (1.5%) 29% (=0.03)

Any PE 46 (0.7%) 81 (1.2%) 43% (=0.002)

Any VTE 105 (1.6%) 165 (2.5%) 36% (=0.0003)

In the subgroup of patients on LMWH, statistical significance was lost (a total of 5856 patients were on

either LMWH or UFH in addition to either ASA or placebo)

In the group of THA and TKA, statistical significance was not reached for any outcomes (including DVT,

PE, total VTE, PE mortality, and total mortality)

Safety Outcome ASA (n=6679) Placebo (n=6677) p value

Bleeding w/ transfusion 23 17 0.3

Bleeding w/o transfusion 182 122 0.0005

Wound bleed w/ transfusion 31 21 0.2

Wound bleed w/o transfusion 171 141 0.09

All-cause mortality: 447 in ASA group and 461 in placebo group HR of 0.97 (94% CI, 0.85-1.10)

Author’s

Conclusions

When the results of the PEP trial are combined with the previous meta-analysis, it is expected that the use of

ASA should reduce incidence of VTE by at least ⅓ in surgical patients

Limitations Use of additional ASA, NSAIDs, or heparins was allowed

44% of patients were also on LMWH or UFH

Primary outcomes were pre-specified as vascular death and major non-fatal vascular events, but results

focus on the secondary outcomes of DVT, PE, and VTE

No adjustments made for over-testing (tested for DVT, PE, VTE, non-fatal (5) and fatal (5) vascular

events, all deaths, 10 points on bleeding age, sex, fracture site, NSAID use, time to dose, heparin use,

TEDs use, surgical procedures, use of anesthesia, time to follow-up)

Bleeding endpoints were diluted into subgroups without an overall comparison

No assessment of aspirin ADRs (dyspepsia, heartburn)

Non-fatal events were only assessed during hospital stay (mean length of stay was 16 days)

Strengths Use of intention to treat analysis (10% of those analyzed never started therapy and 20% didn’t complete it)

Mean age of population reflects that of many clinical situations with HFS

Able to replicate given calculations for RRR

Reviewer’s

Conclusions

The limitations of this trial are frustrating and suspicious. It is also important to note that statistical

significance was only met in HFS patients not on LMWH therapy. However, RRR in this trial were similar

to those seen in the Antiplatelet Trialists’ Collaboration meta-analysis. This trial strengthens the results of

the previous meta-analysis but still leaves many unanswered questions and weak recommendations.

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IV. Jameson SS, Charman SC, Gregg PJ, et al. “The effect of aspirin and low-molecular-weight

heparin on venous thromboembolism after hip replacement”. J Bone Joint Surg Br. 2011;93-

B(11):1465-1470.39

Trial 3

Study Design A retrospective review of the National Joint Registry (NJR) in England and Wales, the Hospital Episode

Statistics (HES), and the English National Health Service (NHS) from 2003-2008

Objectives Compare rates of VTE, major hemorrhage, and death after THA in patients that received either ASA or

LMWH VTE prophylaxis

Subjects Inclusion Criteria: Patient having undergone a THA (with that listed as the primary diagnosis) with data

logged in the HES and pharmacologic data logged in the NJR and with data for at least a 90-day follow up

Exclusion Criteria: Patients receiving more than one pharmacological prophylaxis agent

Methods Patients were identified with inclusion and exclusion criteria through the databases

Comorbid conditions were sought through the Royal College of Surgeons Charlson Score

HES data used to assess VTE, death within 90 days, major hemorrhage, and wound complications

requiring reoperation within 30 days

Statistics Multivariable logistic regression and propensity score matching done to adjust for differences in baseline

risk due to bias inherent with non-randomization

Unadjusted and adjusted (for differences in baseline risk factors) OR were calculated (OR <1 indicates

that rates were lower with the LMWH group than with ASA)

p value < 0.05 statistically significant

Results Groups similar (age, gender, # comorbid conditions, surgery indication, anesthesia use, prosthesis type)

ASA group had more patients also on mechanical prophylaxis (82% vs 72%) and had more patients

undergo a posterior rather than an anterior approach (54% vs 40%)

Outcome ASA (n=22940) LMWH (n=85642) Adjusted OR (95% CI) p value

PE 0.68% 0.68% 0.97 (0.81-1.17) 0.78

DVT 0.99% 0.94% 0.91 (0.79-1.06) 0.23

Death 0.65% 0.61% 0.84 (0.69-1.01) 0.06

CVA/GI

Hemorrhage 0.77% 0.72% 0.92 (0.77-1.09) 0.34

Return to OR 0.31% 0.36% 1.15 (0.88-1.50) 0.29

Outcomes based on propensity score matching

Outcome ASA (n=22940) LMWH (n=22940) Adjusted OR (95% CI) p value

PE 0.68% 0.64% 0.94 (0.75-1.17) 0.56

DVT 0.99% 0.84% 0.84 (0.70-1.03) 0.1

Death 0.65% 0.51% 0.77 (0.61-0.98) 0.04

CVA/GI

Hemorrhage 0.77% 0.73% 0.95 (0.77-1.17) 0.63

Return to OR 0.31% 0.33% 1.17 (0.76-1.46) 0.74

Author’s

Conclusions

This study provides further evidence that LMWH should be used rather than ASA as the VTE prophylaxis

agent of choice due to its ↓ risk of mortality following THA

Limitations Retrospective (non-randomized) risks for bias in group allocation

ASA was at ↓ risk for bleeding due to more receiving the posterior approach and at ↓ risk for clotting due

to more receiving additional mechanical prophylaxis

Unable to assess compliance, minor ADRs (minor bleeding), or some risk factors (smoking, obesity)

Potential that event rates were under accounted for due to miscoding

Only 54% of identified THA patients were linked with NJR

Strengths Large sample size

Relevant outcomes assessed

Adjustments made for potential bias and uneven baseline characteristics

Reviewer’s

Conclusions

Results from this trial showed a favorable trend towards LMWH with statistical significant results on

mortality compared to ASA. The mortality results have not been replicated in previous ASA trials. Though,

it is likely that previous trials were underpowered to do so. The cause of decreased mortality with the use of

LMWH is unknown so these results cannot be clinically applied to select patients with specific risks.

However, the overall results should be considered when selecting a VTE prophylaxis regimen.

Strate 13 of 19

V. Anderson DR, Dunbar MJ, Bohm ER, et al. “Aspirin versus low-molecular-weight heparin for

extended venous thromboembolism prophylaxis after total hip arthroplasty (EPCAT)”. Ann Intern

Med. 2013;158:800-806.40

Trial 4

Study Design Prospective, randomized, double-blind, multi-center (in Canada), active controlled

Objectives Compare extended prophylaxis with ASA and dalteparin for preventing symptomatic VTE after THA

Subjects Inclusion Criteria: Patients undergoing elective, unilateral THA at 1 of 12 participating institutions

Exclusion Criteria: Hip fracture in past 3 months, metastatic cancer, life expectancy < 6 months, current

bleeding on anticoagulation, ASA allergy, HIT or heparin allergy, CrCl<30mL/min, plt<100 x 109/L, on

long-term anticoagulation for other indication, development of VTE after fracture but prior to

randomization

Methods The morning after surgery, patient received 5000 units dalteparin SQ Q day x 10 days

Then randomized to receive 5000 units dalteparin SQ Q day + ASA placebo OR dalteparin placebo +

ASA 81mg PO Q day x 28 days (total duration = 38 days)

Randomization was stratified based on center and need for additional ASA therapy

Patients were followed for 90 days post randomization

Note: patients previously on ASA therapy were initially excluded from trial, but protocol was modified to

include these patients due to difficulty with recruitment

Statistics For 95% power, need N=1100 with a p value of <0.05 reaching statistical significance

Fisher exact test used to determine difference between ASA and dalteparin group

ITT used for primary outcome and safety outcomes

Composite analysis performed to determine the net benefit of ASA

Results Trial was stopped early due to difficulty recruiting after the release of rivaroxaban in Canada

An unscheduled interim analysis was done and determined that non-inferiority was met and superiority

was unlikely to be met

All baseline characteristics were similar (mean age ~ 57)

Primary outcome: development of symptomatic objectively confirmed DVT or PE during the 90 day follow-up

Outcome LMWH (n=398) ASA (n=380) p value for Non-

inferiority

p value for

Superiority

Total 5 (1.3%) 1 (0.3%) <0.001 0.22

PE 3 (0.8) 0 - -

Proximal DVT 2 (0.5) 1 (0.3) - -

Secondary outcomes: No statistically significant differences between the two groups (wound infection,

MI, death, stroke or TIA, thrombocytopenia)

Safety outcomes: no statistically significant differences between the two groups on major or minor bleeds

Author’s

Conclusions

ASA may be a reasonable VTE prophylaxis option in THA patients that have already received 10 days of

LMWH therapy

Limitations The study was stopped early and power was not met

ASA use protocol changed mid-way through study

Adherence monitoring not specified but suspected it may have been low in the LMWH group

ASA was not used as a sole agent at the start of therapy

This trial assessed for thrombocytopenia (rare side effect) but did not assess for dyspepsia

The mean age of these patients was very low (57.9 in LMWH group and 57.6 in the ASA group)

Strengths Trial has a strong design (randomization, blinding, prospective)

Patients were treated for an adequate time frame

Appropriate dalteparin doses were used

Reviewer’s

Conclusions

The design of this trial resulted in many patients using additional non-study ASA which means the

appropriate dose of ASA is still hard to determine. Also, the average age of the patients in this study is much

younger than that seen in hip fracture patients in clinical practice which weakens the applicability of the

results. However, the results of this trial do match those found in previously well powered trials and the use

of ASA following LMWH bridging may make many more clinicians more comfortable with the use of ASA

for VTE prophylaxis following THA.

Strate 14 of 19

ADDITIONAL CONSIDERATIONS

I. Selecting an aspirin dose37-38, 40-42

A. From orthopedic patient trials

1. Antiplatelet Trialists’ Collaborative: ~1,242 mg

2. PEP trial: 160 mg

3. EPCAT trial: 81 mg (after LMWH bridging)

B. Consider mechanism of action

C. Other trials of aspirin for VTE prophylaxis: WARFASA and ASPIRE

1. Similar study designs

2. Methods: patients experiencing their first unprovoked VTE having completed warfarin

therapy were randomized to placebo or aspirin 100mg daily and followed up for 2-4 years

3. Pooled results

a. Recurrent VTE: aspirin RRR of 32% (p=0.007)

b. Vascular events: aspirin RRR of 34% (p=0.002)

c. Major and nonmajor bleeding: no statistically significant difference

D. Consider need to load versus bridge

II. Adherence

A. Oral therapy compliance versus injectable therapy

B. Other oral therapy options available now

C. Risks associated with missed doses

III. Cost and accessibility43-45

A. Individual costs can be high for some agents

1. Frequently accessible through programs

2. See Appendix E for information on patient assistance programs

B. Cost Effective Analysis from 2010

1. The incremental cost effectiveness ratio (ICER) was $1300-$7200 per VTE avoided for 4

weeks of LMWH compared to aspirin

2. Fondaparinux was more cost effective than LMWH

3. No conclusions drawn on new oral anticoagulants although some small studies showing

both dabigatran and rivaroxaban are more cost effective than LMWH

C. Patient assistance programs (more information in Appendix E)

IV. Patient factors

A. Past medical history

1. Peptic ulcer disease

2. Conditions already requiring the use of aspirin (limited evidence)

B. Drug interactions

1. ASA + NSAIDs

2. Concurrent use of warfarin

C. Renal function (see Appendix B)

Strate 15 of 19

CONCLUSION

I. LMWH versus aspirin13, 37-38, 41-42

A. LMWH is still the first-line agent for VTE prophylaxis in orthopedic patients

B. LMWH provides ~ 50-60% RRR compared to placebo for VTE

C. Aspirin provides ~ 30% RRR compared to placebo for VTE

D. Aspirin has proven non-inferiority to LMWH in certain patient population groups

II. Legal considerations13, 31, 34

A. The use of aspirin is supported by current guidelines

B. SCIP protocols now include aspirin as an option

III. Aspirin is a good VTE prophylaxis option if the clinician is faced with no alternative (due to

compliance, financial, formulary, or other reasons)

APPENDICES

Appendix A: PE Diagnositic Algorithms11

From: Torbicki A, Perrier A, Konstantinides S, et al.

“Guidelines on the diagnosis

and management of acute

pulmonary embolism”. Eur

Heart J. 2008.29(18):2276-

2315.

Suspected High-Risk PE

ie: with shock or hypotension

Suspected Non-High Risk PE

ie: without shock or hypotension

Strate 16 of 19

400 BC

•Hippocrates gave willow bark (contains salicylic acid) for childbirth pains

1853

•French scientists make salicylic acid from salicin

•In this form it was irritating to the gut and caused vomitting

1893 •German scientists make acetyl salicylic acid which reduces gut irritation

1897 •Scientists at Bayer (in Germany) patent acetyl salicylic acid and start clinical trials

1899 •Clinical trials are completed and Bayer begins marketing aspirin

1930's •Bayer's patent on aspirin expires and the drug is marketed as a generic

1974 •First evidence released about aspirin's benefit in preventing heart attacks

1982 •Two Swedish and one English scientist win the Nobel Prize for the discovery of aspirins mechanism of action

Appendix B: Comparative Dosing of Anticoagulant Agents for VTE Prophylaxis26-27

Dosing for VTE Prophylaxis After

THA/TKA/HFS

Renal Adjustments for VTE

Prophylaxis Route

Estimated

Cost

Enoxaparin 30 mg q12hr (THA or TKA)

40 mg q24hr (THA)

CrCl < 30 mL/min: 30 mg Q Day SQ $$

Fondaparinux 2.5 mg Q Day CrCl 20-50 mL/min: 1.5 mg Q Day SQ $$

Apixaban 2.5 mg BID None for prophylaxis dosing PO $$$

Dabigatran 220 mg Q Day CrCl 30-50 mL/min: 150 mg Q Day PO $$$

Rivaroxaban 10 mg Q Day CrCl <30 mL/min: avoid use PO $$$

UFH 5000 units q8-12 hrs None for prophylaxis dosing PO $

Warfarin Adjusted to INR 2-3 Adjusted to INR 2-3 PO $

Aspirin Debated CrCl <10 mL/min: avoid use PO $

Appendix C: A Brief History of Aspirin28

Appendix D: Aspirin Pharmacokinetics26-27, 29-30

Absorption

Rapid, though delayed with enteric coating

Peaks at 1-2 hours (3-4 hours with enteric coated tablets)

>24 hours of dosing required for maximal COX inhibition

Distribution Bioavailability of 40-50%

Lower bioavailability with enteric coated or sustained release formulations

Metabolism

Hydrolyzed to the active form (salicylate) by esterases (found in GI, RBCs, and

synovial fluid)

Salicylate is hepatically conjugated

Half-life

o Parent drug: 20 minutes

o Salicylate: dose-dependent, 3 hours for doses <600mg

Excretion

Renal: 10% (salicylic acid), 75% (salicyluric acid), 10% (phenolic glucuronide), 5%

(acyl glucuronide)

Dialyzable via hemodialysis and peritoneal dialysis

Adapted from: Aspirin Foundation. “Aspirin timeline”. What is Aspirin? Available at

http://www.aspirin-foundation.com/what/timeline.html. Accessed September 22, 2014.

Strate 17 of 19

Appendix E: Patient Assistance Programs43-44

Medication Requirements Additional Details

Enoxaparin

Be a US resident with SSN

At or below 250% of FPL

Have no private or public prescription coverage

Delivered in 2-4 business days

English and Spanish applications available

Medicare Part D patients are ineligible

http://www.needymeds.org/generic_list.taf?_fu

nction=name&name=enoxaparin%20sodium

Fondaparinux

Be a US resident

At or below 250% of FPL

Have no prescription coverage for medication

Delivered to physician’s office

https://www.rxhope.com/PAP/info/PAPList.asp

x?drugid=4334&fieldType=drugid

Have Medicare Part D

At or below 250% FPL

Delivered to patients home

https://www.rxhope.com/PAP/info/PAPList.asp

x?drugid=4334&fieldType=drugid

Rivaroxaban

Have no prescription coverage for medication

Income details not provided online

Application must be completed by hospital

http://www.needymeds.org/drug_list.taf?_functi

on=name&name=Xarelto&gname=rivroxaban

&coupon=1

Apixaban

Have no prescription coverage

At or below 250% FPL

For outpatient use only

Reside in US, Puerto Rico, or USVI

Delivered in 5-7 business days

English and Spanish applications available


nction=name&name=apixaban

May have insurance

No income limits

Must be US resident

Delivered in 10 days

Delivered to physician’s office or patient home


nction=name&name=apixaban

Appendix F: List of Abbreviations

A. Fib.: Atrial Fibrillation

AAOS: American Academy of Orthopaedic Surgeons

ACCP: American College of Chest Physicians

ADRs: adverse drug reactions

ASA: aspirin

ATC: Antiplatelet Trialists’ Collaboration

BID: twice daily

COX: cyclooxygenase

CrCl: creatinine clearance

DIC: disseminated intravascular coagulation

DVT: deep vein thrombosis

FDA: Food and Drug Administration

FPL: Federal Poverty Line

GCS: graduated compression stockings

HES: Hospital Episode Statistics

HFS: hip fracture surgery

HIT: heparin-induced thrombocytopenia

ICER: incremental cost effectiveness ratio

ICS: Cardiovascular Disease Educational and Research

Trust

IM nailing: intramedullary nailing

INR: international normalized ratio

IPCD: intermittent pneumatic compression device

LDUH: low-dose unfractionated heparin

LMWH: low-molecular-weight heparin

MI: myocardial infarction

N: number

NHS: National Health Service

NICE: National Institute for Health and Care

Excellence

NJR: National Joint Registry

OR: odds ratio

ORIF: open reduction internal fixation

PE: pulmonary embolism

PEP: pulmonary embolism prevention

Plts: platelets

PO: oral

Pts: patients

PUD: peptic ulcer disease

Q day: daily

RRR: relative risk reduction

SCIP: Surgical Care Improvement Project

SIGN: Scottish Intercollegiate Guidelines Network

SQ: subcutaneous

SSN: Social Security number

THA: total hip arthroplasty

TKA: total knee arthroplasty

UFH: unfractionated heparin

USVI: United States Virgin Islands

VKA: vitamin K antagonist

vs: versus

VTE: venous thromboembolism

ACKNOWLEDGMENTS

Valerie Valencia, PharmD

Nathan D. Pope, PharmD, FACA

Amanda Loya, PharmD

Margie Padilla, PharmD, CDE, BCACP

Jeri Sias, PharmD, MPH

Francisco Roman, PharmD

Samantha Strong, PharmD

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Documents

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