CardioExchange Archive

In the recent WARFASA study, published in the New England Journal of Medicine, Dr. Cecelia Becattini et al found that aspirin treatment in patients with first-time unprovoked VTE resulted in a significant reduction in subsequent VTE but did not increase the risk for bleeding, compared with placebo:

• VTE recurrence: 6.6% per year with aspirin versus 11.2% with placebo
• Major bleeding occurred in one patient in each treatment group.

In this study, patients received 6 to 18 months of oral anticoagulation followed by 100 mg of ASA or placebo daily for 2 years. CardioExchange’s John Ryan had the opportunity to interview Becattini of the University of Perugia in Italy.

Ryan: Dr. Becattini, congratulations on a wonderful study and thank you for taking the time to join us today. In your study, patients with unprovoked DVT/PE were treated with warfarin for anywhere between 6 and 18 months. What, in your view, is the optimum duration of warfarin therapy after DVT/PE, and how do your findings change that, if at all?

Becattini: As we shown in previous studies (WODIT DVT and WODIT PE) extending warfarin treatment for an additional 3 or 9 month period beyond the initial 3 months is not associated with a reduced risk for recurrent VTE after warfarin is discontinued. Thus, I believe that warfarin given for 3 months is probably enough to treat a first episode of unprovoked venous thromboembolism in the majority of patients.  The results of the WARFASA study support the possibility of a long term secondary prevention of recurrent venous thromboembolism with aspirin after the initial anticoagulant treatment. If our results are confirmed by an ongoing study with a similar design, aspirin could be included among the options for extended treatment of venous thromboembolism.

Ryan: In the recent EINSTEIN-Extension study, DVT/PE recurrence was decreased ~80% by rivaroxaban therapy. With the introduction of novel anticoagulants, how does one decide between ASA and agents such as rivaroxaban and dabigatran and what does the evidence tell us?

Becattini: The new oral anticoagulants, including rivaroxaban and dabigatran, have the potential to change the current practice related to the treatment of venous thromboembolism. The risk reduction observed in the WARFASA study is only about 40%.

However, data on indefinite anticoagulation with the new drugs are not currently available and some concern remain after that placebo controlled trials showed an increase, although limited, in bleeding complications with these agents. These points should be taken into account when deciding on the agent to be used in the extended anticoagulant treatment.

Ryan: On the same line, in ROCKET  AF, there were increased thromboembolic events noted when patients had their rivaroxaban discontinued. Did you observe any increased DVT/PE when the ASA was discontinued? If yes, why do you think so and if not, why not?

Becattini: We did not explore for this specific issue. However, this point could be assessed in a further data analysis.

Ryan: Almost all the patients in WARFASA were white (99%). How does that effect the application of your study to US population with the large number of African-American patients, many of whom have comorbidities?

Becattini: The WARFASA study is the first observation on the role of aspirin for secondary prevention of venous thromboembolism. Unfortunately, no data are currently available specifically for African-Americans. However, concerning the comorbidities, our study population is probably representative of the population with unprovoked venous thromboembolism.

Ryan: There were remarkably low rates of bleeding in WARFASA. How do you reconcile that with the recent findings published in JAMA by Giorgia De Berardis and colleagues from Puglia, also in Italy, who compared 186,425 people taking low-dose aspirin with the same number of matched controls not taking aspirin and found rates of major bleeding requiring hospitalization of 5.58 per 1000 person-years in patients taking aspirin compared to 3.60 per 1000 person-years in patients not on aspirin.

Becattini: The WARFASA study is not sized to show a difference of incidences of 3 to 5 per thousand. However, our results show that benefits probably overweigh harms in case aspirin is used in a definite population at a fixed 100 mg dose.

Ryan: The WARFASA study concentrated on unprovoked DVT/PE. How do you expect your findings would differ in a population with provoked DVT/PE and how do you feel the treatment options differ?

Becattini: Indeed, no data is currently available concerning the efficacy and safety of aspirin in patients with provoked DVT/PE. The main difference is that the risk for recurrence after venous thromboembolism associated with a transient risk factor is lower than after unprovoked venous thromboembolism. Thus, the benefit/risk balance could be different in this setting.

Ryan: I have a 62 year-old lady in clinic with an unprovoked DVT who has recently finished 6 months of warfarin therapy. What do you suggest I offer her now in the way of treatment?  

Becattini: I suggest discussing with the patient risks and benefits of prolonging anticoagulant treatment and also the results of a recent study showing the possibility of a risk reduction lower than that obtained with oral anticoagulants but with lower bleeding risks and lower inconvenience for monitoring by shifting from warfarin to aspirin for extended secondary prevention of recurrence.

Ryan: What about young patients? How does your study impact the care of a 33-year-old female with unprovoked DVT/PE?

Becattini: In this case, the patient has about 60 years of treatment to be balanced with an active life to maintained. I believe this is the class of patients who can actually take an advantage from secondary prevention with aspirin in terms of every-day life (sports, pregnancy, etc.).  Again I will discuss with the patient all the options above.

Ryan: Dr. Becattini, congratulations again on this landmark paper. Thank you for answering our questions today.

• How does WARFASA impact your practice?
• Do you have any questions for Dr. Becattini?