For thousands of years the bark and leaves of the willow tree have been used for alleviation of fever, aches and pains. The Ebers Papyrus, which dates from 1500 BC and is one of the oldest surviving medical texts, mentions the use of willow as an important component of Ancient Egyptian pharmacopeia. However, it wasn’t until the 19th century with the advent of modern organic chemistry that scientists were able to identify the active ingredient in willow as salicylic acid. Early formulations of the drug were impure or chemically unstable, but in 1897, Felix Hoffman working for Bayer Dye Company added an acetyl group to the compound to create acetylsalicylic acid, which was chemically pure and when given to patients had minimal side effects. Aspirin became a best-selling anti-inflammatory medication during the twentieth century but the molecular mechanism of action was not well characterized until the Nobel Prize winning pharmacologist John Vane discovered the inhibitory effects of aspirin on prostaglandins and platelet aggregation. This mechanistic understanding allowed scientists to propose novel uses of aspirin – for the prevention of vascular disease including stroke, coronary disease, and peripheral arterial and venous thrombosis.
Research published in the 1970s demonstrated a benefit to aspirin for the prevention of venous thromboembolism (VTE) in high-risk medical and surgical patients. However, the gold standard for treatment of VTE is anticoagulation either with anti-vitamin K therapy, heparin or its derivatives. Guidelines suggest that patients with unprovoked VTE consider lifelong anticoagulation because the risk of recurrent thrombosis in this group is 20% or more. Yet many patients prefer not to continue long-term anticoagulation because of inconvenience of long term monitoring of vitamin K antagonists and the increased risk of bleeding. Recently, the WARFASA trial, published in the NEJM in May, 2012, evaluated a strategy to continue long-term aspirin therapy in patients with unprovoked VTE who had undergone at least 6 months of anticoagulation but did not wish to continue such therapy indefinitely. The study results demonstrated a significant reduction in recurrent VTE among patients treated with aspirin 100mg daily as compared to placebo.
This week in NEJM we present a second study examining the effect of aspirin in secondary prevention of VTE. The Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) Trial randomized 822 patients with an unprovoked VTE who had completed at least three months of anticoagulation therapy to receive once daily either low-dose aspirin 100mg or placebo. The study showed a trend towards reduction in the primary outcome of recurrent symptomatic deep vein thrombosis (DVT) or pulmonary embolism (PE) in those assigned to aspirin therapy; however, these results were not statistically significant. The aspirin group did show a statistically significant reduction in the composite endpoint of VTE, stroke, myocardial infarction, or cardiovascular death. There was no significant difference between the two groups in relation to major bleeding events.
Why did this trial fail to show a benefit to aspirin in preventing recurrent VTE? Most likely this is because the study was underpowered to show a difference between the treatment and placebo groups. The study designers planned to recruit 3000 patients but only ended up with 822. However, the study authors anticipated this problem and also included a pre-planned pooled analysis of their data with the data from the 402 patients enrolled in the WARFASA Trial. This combined analysis does show both a clinically and statistically significant benefit to aspirin with a 32% reduction in rate of recurrent VTE. In summary, the authors conclude that for every 1000 patients treated for 1 year, aspirin can be expected to be associated with 17 fewer episodes of recurrent VTE and 28 fewer major thrombotic events, at the cost of 5 nonfatal bleeding episodes.
NEJM Deputy Editor Dan Longo believes that these trials will help change clinical practice. “Given the outcome of the ASPIRE and WARFASA studies, it appears that 100mg of aspirin a day significantly reduces the risk of recurrent thrombosis without an increase in bleeding risk in patients with an unprovoked thrombosis that has been appropriately treated with at least six months of warfarin.”
In 1966 a New York Times article called aspirin “The wonder drug that nobody understands.” Back then we did not realize that acetylsalicylic acid achieves its biological effect through prostaglandins which are vital mediators of both inflammation and platelet aggregation. Now, fifty years later, we have a much richer understanding of the biology of this remarkable drug that has been shown to be effective in preventing recurrent stroke, heart attack, and now venous thromboembolism.
For further commentary, see the editorial on ASPIRE from McMaster University’s Dr. Theodore Warkentin.