Aspirin for Preventing the Recurrence of Venous Thromboembolism N Engl J Med. 2012;366:

VTE Prevalence Incidence of DVT: 48 per 100,000 Incidence of PE: 23 per 100,000 Case-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 Prevalence Prevalence 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 Outcomes DVT 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 syndrome PE outcomes (Goldhaber, Lancet 1999) ◦ Mortality: 17% at 3-months Worse in elderly patients (Kniffin, Arch Intern Med 1994) ◦ 21% in-hospital & 39% 1-year mortality for PE

VTE Costs Inpatient complications (Zhan, JAMA 2003) ◦ 3 rd 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 ( ). Canton, Massachusetts: Science History Publications. Hypercoaguability

Risk Factors for VTE Age Prior VTE Surgery, trauma Immobility Pregnancy/postpartum Medical illness ◦ Cancer & cancer rx ◦ Inflammatory Bowel Dz ◦ Nephrotic Syndrome ◦ Obesity Meds ◦ Hormone replacement ◦ Tamoxifen, raloxifene ◦ Cancer drugs ◦ Erythropoetin Thrombophilia ◦ Inherited ◦ Acquired

Risk Factors for VTE Age Prior VTE Surgery, trauma Immobility Pregnancy/postpartum Medical 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 Stratification Risk Categories ◦ Low Risk (<10%) ◦ Moderate Risk (10-40%) ◦ High Risk (40-80%) RiskTypeRx Low Minor surgery & medical, mobile Early ambulation Moderate Most general surgery & medical patients Medical +/- mechanical High Ortho & major trauma Medical +/- mechanical

Bleeding Risk Active bleeding Severe trauma to head or SC with hemorrhage within 4 weeks ICH within 1 year Craniotomy within 2 weeks Intraocular surgery within 2 weeks GI/GU hemorrhage within last month Post-op bleeding concerns Thrombocytopenia (<50K) Coagulopathy End stage liver disease Active intracranial lesions/neoplasm Hypertensive emergency

Other Considerations Heparin-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 Choices Early & frequent ambulation Mechanical ◦ 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 Prophylaxis Multiple 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 Heparin 5000 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 PE Incidence of major bleeding is low: 0.3 to 2 cases/1000 patient days HIT is possible (3% risk of thrombocytopenia), monitor platelets regularly

Low Molecular Weight Heparin Multiple 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 2 nd 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?

Methods Double 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

Outcomes Primary 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

Conclusion After 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

Comments Patients 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

Comments This 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 6not qualifying DVT 10 revoked consent 4lost to follow-up 6not qualifying DVT 2revoked consent 2lost to follow-up 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 Years since randomization Cumulative risk Placebo Aspirin Aspirin Placebo HR = 0.74 (95% CI: ), p=0.09

Major Vascular and Net Clinical Benefit HR: 0.66 (0.48–0.92) p=0.01 HR: 0.67 (0.49–0.91) p=0.01 Aspirin Placebo Aspirin Placebo Cumulative risk Years from randomisation

Meta-analysis ASPIRE & WARFASA Pooled WARFASA ASPIRE 73/411 43/ /608 88/411 48/ /608 62/411 36/205 98/616 57/411 28/205 85/ /411 4/197 12/608 14/411 4/205 18/ VTE Major vascular events Clinically relevant bleeds Outcome & study Placebo events/n Aspirin events/n Hazard Ratio (95% CI)P Pooled WARFASA ASPIRE Pooled WARFASA ASPIRE Favors Aspirin Favors Placebo Hazard Ratio

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