Supervisor: Vs 余垣斌Presenter: CR 周益聖

INTRODUCTION

VTE vs. Warfarin• 2-3 per 1000 in the general population• Recurrence after discontinuation of anticoagulant– 1% per year for transient risk factor– 10% per year for unprovoked VTE

• Warfarin (INR 2.0-3.0) for the long-term treatment of VTE– Major bleeding 2% per year – VTE risk reduction > 90%

• Low-intensity warfarin regimen (INR 1.5-2.0) for extended treatment– Major bleeding 0.9% per year – VTE risk reduction around 75-80%

Becker, N Engl J Med 2012Linkins, Ann Intern Med. 2003Ridker, N Engl J Med 2003

Schulman et al., N Engl J Med 1995

The Duration of Anticoagulation I Trial

Schulman et al., N Engl J Med 1995

Schulman et al., N Engl J Med 1995

Schulman et al., N Engl J Med 1995

The Duration of Anticoagulation II Trial 6mos vs. indefinitely

Schulman et al., N Engl J Med 1997

Schulman et al., N Engl J Med 1997

Schulman et al., N Engl J Med 1997

Kearon et al., N Engl J Med 1999

Kearon et al., N Engl J Med 1999

Schulman et al., N Engl J Med 1997

ACCP guideline (9thedition)Antithrombotic Therapy for VTE

• VKA for 3 months– Proximal or isolated distal VTE provoked by surgery or

non surgical risk factor– First Unprovoked distal VTE– PE provoked by surgery or non surgical risk factor

• Extended VKA except high bleeding risk– First Unprovoked proximal VTE– Second unprovoked VTE– First unprovoked DVT in cancer pt’– First or second unprovoked PE

• Extended VKA no matter low or high bleeding risk– PE in active cancer

Kearon et al., CHEST 2012; 141:Suppl(2):e419S-e4194S

Pathogenesis of VTE

Becker, N Engl J Med 2012

WARFASA

The Warfarin and Aspirin Study

Becattini et al., N Engl J Med 2012

Aim

• Assess the clinical benefit of aspirin for the prevention of recurrence after a course of treatment with vitamin K antagonists in patients with unprovoked venous thromboembolism

WARFASA Design

Unprovoked VTE

s/p Vitamin K antagonist

RANDOMIZATION

1:1

n=205

n=197

Aspirin 100mg PO QD for 2 years

Placebo for 2 yearsn=403

• Assumption: 40% relative risk reduction with aspirin and expected event rate of 8.0% per year (Result:8.6%)• 70 events provide a power of 80%• Two sided α of 0.05

WARFASA Design•Multicenter, Investigator-initiated, Double-blind•Primary endpoint–recurrence of VTE

•Secondary endpoint–nonfatal myocardial infarction–unstable angina–Stroke–transient ischemic attack–acute ischemia of the lower limbs–death from any cause

•Principal safety outcome–major bleeding ( fatal, major organ, Hb↓ > 2g/dl, PRBC >2U)

Inclusion criteria

• older than 18 years of age• treated for 6 to 18 months with vitamin K

antagonists• unprovoked proximal deep-vein thrombosis

(DVT), pulmonary embolism (PE), or both– in the absence of any known risk factor

Exclusion criteria• Known cancer• Known major thrombophilia

– antiphospholipid antibodies– lupus anticoagulant– homozygous factor V Leiden– Prothrombin G21210A– deficiency of antithrombin, protein C or S– atrial fibrillation – prosthetic heart valve

• Atherosclerosis requiring treatment with aspirin or other anti-platelet agents• Active bleeding or high risk for bleeding or a bleeding episode which occurred

during the 6-18 months of anticoagulation• Pregnancy or breast-feeding• Women with venous thromboembolism associated with the use of estro-

progestin therapy

Result

Recurrent VTE

• Deep-vein thrombosis – 44 patients (ipsilateral in 51% of cases)

• Pulmonary embolism– 27 patients (fatal in 2 patients)

• Prior PE is at higher risk for recurrent PE compared to prior DVT– 12.7% vs. 3.2%– HR:5.52– 95% confidence interval : 2.29 to 13.30– P<0.001

Intention to treat analysis• 6.6% for aspirin vs. 11.2% for placebo per year– HR: 0.58– 95%CI:0.36-0.93– P=0.02

Post Hoc analysis

• Prior PE– 6.7% for aspirin vs. 13.5% for placebo per year– HR: 0.38– 95%CI:0.17-0.88– P=0.02

• Prior DVT– 6.5% for aspirin vs. 10.2% for placebo per year– HR: 0.65– 95%CI:0.65-1.20– P=0.17

Risk factors for recurrent VTE

• Age>65 years– HR: 2.26– 95%CI:1.16-4.41– P=0.02

• Male– HR: 2.02– 95%CI:1.16-3.49– P=0.01

• No association between anticoagulant > 6 months vs. longer

Hemorrhagic complications

• Major bleeding– 1 bowel angiodysplasia in ASA vs. 1 gastric ulcer in

placebo (0.3% per patient-year )• Non major bleeding– 1 gingival bleeding and 2 cutaneous hematoma in

ASA– 2 musculoskeletal bleeding and 1 hemorrhagic

gastritis in placebo

Secondary outcome

• Death– 6 in ASA (1.4% per year ) vs. 5 in placebo (1.3% per

year ) • Sudden death– 1 in each due to PE

• Arterial events– 8 in ASA (1.9% per year ) vs. 5 in placebo (1.3% per

year )

AE

• Gastric pain – 1 in ASA and 2 in placebo

• 1 cutaneous reaction in ASA• Renal failure in ASA• Antiplatelet – 5 in ASA and 3 in placebo

• Anticoagulant– 3 in ASA and 2 in placebo

Discussion

• Aspirin therapy, begun after 6 to 18 months of oral anticoagulant treatment, reduces the rate of recurrence by about 40%– no apparent increase in the risk of major bleeding

• Aspirin is a potential alternative to extended oral anticoagulant treatment for the long-term secondary prevention of venous thromboembolism

Limitation• Patients excluded – clinically significant thrombophilia– a bleeding event during the period of anticoagulant

treatment• Reduction in the risk of recurrence is lower with

aspirin than with these new oral agents (80% for dabigatran and rivaroxaban) or low dose warfarin (60%)

• Underpowered for showing effect of aspirin on the incidence of IHD or CVA

• The results may not apply to whom require aspirin for the prevention of arterial events

Strengths

• Randomized, placebo controlled, double blinded

• Treatment for 2 years• ITT analysis = On treatment analysis

Conclusion

• Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment

• With no apparent increase in the risk of major bleeding

Thanks for your attention!