Aspirin for Preventing the Recurrence of Venous

Thromboembolism

N Engl J Med. 2012;366:1959-67

VTE PrevalenceIncidence of DVT: 48 per 100,000Incidence of PE: 23 per 100,000Case-fatality rate

◦ Inpatient: 12%◦ 1-year: 19%; 3-year: 30%

Extrapolated data: 170K new cases/year of VTE in US diagnosed as inpatients, 99K recurrent hospitalizations

VTE PrevalencePrevalence of asymptomatic DVT

in patients not receiving prophylaxis (Geerts, Chest 2008)

◦Internal: 10-20%◦Stroke 20-50%, Critical care 10-80%◦General Surgery: 15-40%

VTE OutcomesDVT outcomes (Prandoni, Haematologica 1997)

◦ Mortality usually related to underlying illness

◦ Morbidity◦ 17% 2-year risk of recurrence (initial rx 3

months)◦ 25% 2-year risk of post-thrombotic

syndromePE outcomes (Goldhaber, Lancet 1999)

◦ Mortality: 17% at 3-monthsWorse in elderly patients (Kniffin, Arch Intern

Med 1994)

◦ 21% in-hospital & 39% 1-year mortality for PE

VTE CostsInpatient complications (Zhan, JAMA

2003)

◦3rd most common hospital complication, behind obstetrical trauma & decubitus ulcers

◦Excess LOS: 5.4 days◦Excess charges: $21,709◦Excess mortality: 6.5%

Virchow’s Triad

Stasis Trauma

Virchow RLK (1856). "Thrombose und Embolie. Gefässentzündung und septische Infektion". Gesammelte Abhandlungen zur wissenschaftlichen Medicin. Frankfurt am Main: Von Meidinger & Sohn. pp. 219–732. Translation in Matzdorff AC, Bell WR (1998). Thrombosis and embolie (1846-1856). Canton, Massachusetts: Science History Publications.

Hypercoaguability

Risk Factors for VTEAgePrior VTE Surgery, trauma ImmobilityPregnancy/postpartumMedical illness

◦ Cancer & cancer rx◦ Inflammatory Bowel Dz◦ Nephrotic Syndrome◦ Obesity

Meds◦ Hormone replacement◦ Tamoxifen, raloxifene◦ Cancer drugs◦ Erythropoetin

Thrombophilia◦ Inherited◦ Acquired

Risk Factors for VTEAgePrior VTE Surgery, trauma ImmobilityPregnancy/

postpartumMedical illness

◦ Cancer & cancer rx◦ Inflammatory Bowel

Dz◦ Nephrotic Syndrome◦ Obesity

Meds◦ Hormone replacement◦ Tamoxifen, raloxifene◦ Cancer drugs◦ Erythropoetin

Thrombophilia◦ Inherited◦ Acquired

Almost all inpatients have 1 RF

40% of inpatients have ≥3 RF

Risk StratificationRisk Categories

◦Low Risk (<10%)◦Moderate Risk (10-40%)◦High Risk (40-80%)

Risk Type Rx

LowMinor surgery & medical, mobile Early ambulation

ModerateMost general

surgery & medical patients

Medical +/- mechanical

HighOrtho & major

traumaMedical +/- mechanical

Bleeding RiskActive bleedingSevere trauma to head or SC with

hemorrhage within 4 weeks ICH within 1 yearCraniotomy within 2 weeks Intraocular surgery within 2 weeksGI/GU hemorrhage within last month

Post-op bleeding concernsThrombocytopenia (<50K)CoagulopathyEnd stage liver diseaseActive intracranial lesions/neoplasmHypertensive emergency

Other ConsiderationsHeparin-induced

thrombocytopenia (HIT)◦If hx, no LDUH or LMWH at any doses◦Fondaparinux OK

Epidural analgesia with indwelling catheter

Renal dysfunction◦Renally dose LMWH, consider

avoidance in pts with severely reduced CrCl

◦Avoid fondaparinux in pts with CrCl <30

VTE Prophylaxis

Prophylaxis ChoicesEarly & frequent ambulationMechanical

◦ Graduated compression stockings (GCS)◦ Intermittent pneumatic compression (IPC)

Medical◦ Aspirin◦ Low-dose Unfractionated Heparin (LDUH)◦ Low Molecular Weight Heparin (LMWH)◦ Fondaparinux (Arixtra©)◦ Warfarin (Coumadin©)

Mechanical ProphylaxisMultiple studies have shown benefit to

reduce risk of DVT (no studies large enough to show reduction in PE or mortality)

But, less evidence to support use and less effective than medical prophylaxis

Must be properly fitted, applied, and worn almost continuously

Reserve for use in patients with high bleeding risk (or as adjunctive therapy to medical prophylaxis in certain high risk patients) & reassess bleeding risk frequently

Minimal contraindications: severe PVD; amputees can use upper extremity IPCs

Low Dose Unfractionated Heparin5000 units SQ BID-TID

◦ TID dosing is more physiologic, but little head-to-head evidence it is better than BID

Reduced incidence of DVT, PE, fatal PEIncidence of major bleeding is low: 0.3

to 2 cases/1000 patient daysHIT is possible (3% risk of

thrombocytopenia), monitor platelets regularly

Low Molecular Weight HeparinMultiple choices: enoxaparin,

dalteparin, tinzaparin, nadroparin, rivaparin, certoparin

Enoxaparin: 40 mg SQ QD (or 30 mg SQ BID)

Renal dose adjustment: 30 mg QD (or avoid if CrCl <30)

HIT risk lower than LDUH (0.4%), but still monitor platelets

Warfarin Variable dosing, usually start at 5-10 mg daily; adjust per

INR Takes at least 48 hrs to have measurable effect on

coagulation, and may take 5-7 days to be clinically effective

Requires close monitoring No standard renal adjustment (although higher risk of

bleeding) Usually reserved for longer-term prophylaxis situations

(ortho procedures) Effective in patients already on for another indication (i.e.

don’t need to add a 2nd agent)

Long term anticoagulation (warfarin INR 2-3) is effective however… • causes major (fatal) bleeding

• inconvenient for patients (warfarin)

Aspirin so far…Main evidence for use

◦ Antiplatelet Trialists’ Collaboration (BMJ 1994): Metanalysis of >50 trials, many quite old & of questionable validity; Significant reduction in DVT rates with ASA

◦ PEP trial (Lancet, 2000): Significant reductions in VTE with 160 mg ASA QD in post-op ortho patients (NNT ~250 to prevent fatal PE, ~111 for any VTE event)

2008 ACCP guidelines recommend against ASA as primary form of VTE prophylaxis

Does aspirin reduce recurrence of venous thromboembolism (VTE) after a course of oral vitamin K

antagonist therapy in adults with a first-ever, unprovoked VTE?

MethodsDouble Blinded Randomized

placebo-controlled trial (Aspirin for the Prevention of Recurrent Venous Thromboembolism [Warfarin and Aspirin {WARFASA}] study)

Patients 403 patients >18 years of age (mean age 62 y,

64% men) who had a first-ever, objectively confirmed, symptomatic, unprovoked (without known risk factors), proximal deep venous thrombosis (DVT), pulmonary embolism (PE), or both.

Received oral vitamin K antagonists for 6 to 18 months (target interna-tional normalized ratio of 2.0 to 3.0), and were randomized within 2 weeks of anticoagulant withdrawal

Intervention : Aspirin, 100 mg once daily (n= 205), or placebo (n= 198) for 2 years.

Follow-up period : Median 25 months.Setting: 25 centers in Austria and Italy

OutcomesPrimary efficacy outcome was

symptomatic, objectively verified, recurrence of VTE (composite of DVT or PE).

Primary safety outcome was major bleeding (fatal, occurring in a critical site, ≥2.0-g/dL decrease in hemoglobin, or transfusion of ≥2 units of whole blood or red cells).

Secondary outcomes included DVT; PE; clinically relevant, non major bleeding; and mortality

Results

Results

Aspirin reduced recurrent VTE and DVT more than placebo

Groups did not differ for PE, bleeding, or mortality

ConclusionAfter discontinuation of anticoagulant therapy

for a first-ever, unprovoked venous thromboembolism, aspirin reduced recurrence.

Aspirin is an effective option for patients unable or who do not wish to continue anticoagulation beyond their initial therapy ◦Simple therapy◦Widely available◦Low cost◦Well tolerated with low risks bleeding◦Benefits not solely restricted to prevention of

recurrent VTE

CommentsPatients with an unprovoked VTE are

treated with oral anticoagulation for ≥3 months. The risk for recurrence of VTE is approximately 25% in 5 years.

Assessment of risk for recurrent VTE - The DASH Score - D-dimer, Age, Sex, Hormonal therapy –◦ An abnormal D-dimer measurement after

anticoagulation is stopped◦ <50 years of age◦ Male sex◦ VTE not associated with hormone therapy in

women

CommentsThis study needs to be assessed in the

context of the similar, but larger, ongoing ASPIRE study.

If the results are confirmed, there would be compelling data to support the use of aspirin, with its low cost and toxicity, to treat patients with low, and possibly intermediate, risk for VTE after ≥3 months of anticoagulation treatment.

Patients at high risk for recurrent VTE not at high risk for bleeding would benefit more from extended anticoagulation therapy given in the article

The Next level… ASPIRE Study

822 randomized

411 assigned placebo

411 assigned aspirin

411 received placebo

411 received aspirin

6 not qualifying DVT

10 revoked consent

4 lost to follow-up

6 not qualifying DVT

7 revoked consent

2 lost to follow-up

411 included in analysis

411 included in analysis

First patient enrolled May 2003, Last patient enrolled August 2011, Follow-up completed March 2012

Primary Outcome - Recurrent VTE

No. at risk 411

411

341

369

282

299

205

217

135

151

Years since randomization

Cum

ulati

ve ri

sk

Placebo

Aspirin

0 1 2 3 40

0.1

0.2

0.3

Aspirin

Placebo

HR = 0.74 (95% CI: 0.52-1.05), p=0.09

Major Vascular and Net Clinical Benefit

0 1 2 3 40

0.1

0.2

0.3

0 1 2 3 40

0.1

0.2

0.3

HR: 0.66 (0.48–0.92)p=0.01

HR: 0.67 (0.49–0.91)p=0.01

Aspirin

Placebo

Aspirin

Placebo

Cum

ulati

ve ri

sk

Years from randomisation

Meta-analysis ASPIRE & WARFASA

Pooled

WARFASA

ASPIRE 73/411

43/197

116/608

88/411

48/197

136/608

62/411

36/205

98/616

57/411

28/205

85/616

0.09

0.02

0.007

0.01

0.06

0.002

8/411

4/197

12/608

14/411

4/205

18/616

0.22

0.97

0.31

VTE

Major vascular events

Clinically relevant bleeds

Outcome & studyPlaceboevents/n

Aspirinevents/n Hazard Ratio (95% CI) P

Pooled

WARFASA

ASPIRE

Pooled

WARFASA

ASPIRE

0.74

0.58

0.68

0.66

0.67

0.66

Favors Aspirin Favors Placebo

1.72

0.98

1.47 0.2 0.5 1 2 5

Hazard Ratio

Thank You !!!