Rationale

Venous thromboembolism (VTE) is a common cause of morbidity and mortality.(1) The annual VTE event rate is approximately 142 per 100,000 persons.(2) Moreover, patients with VTE are susceptible to the development of long-term complications such as recurrent VTE, post-thrombotic syndromes or cardiopulmonary dysfunction and/or reduced exercise tolerance.(2) The effectiveness of warfarin in preventing and reducing the occurrence of thromboembolic events is well established.(3-6) Despite its effectiveness, warfarin has many drug-drug interactions. Of them, warfarin and acetylsalicylic acid (aspirin) is one of the most important due to the widespread use and prolonged effect of aspirin.(6)

Not all salicylates pose the same risk. Methylsalicylate, an active ingredient in many topical analgesic preparations, is used for pain reduction for musculoskeletal disorders.(7) When used in therapeutic doses, it is not expected to interact with warfarin due the lack of antiplatelet effects.(8) However, when used in extremely high amounts, serum concentrations of methylsalicylate may increase INR.(7, 9-14)

Algorithm

Explanation

Warfarin is a vitamin K antagonist, which competitively inhibits a series of coagulation factors, as well as proteins C and S.(15) These factors are biologically activated by the addition of carboxyl groups depending on vitamin K.(15) Warfarin competitively inhibits this chemical reaction, thus depleting functional vitamin K reserves reducing the synthesis of active coagulation factors.(15)

Aspirin irreversibly inhibited prostaglandin G/H synthase through acetylation of Ser529 of the enzyme in the platelets, consequently prevented thromboxane A2 and prostacyclin formation.(16) Thromboxane A2 is a platelet agonist,(16, 17) whereas prostacyclin stimulates production vascular endothelium.(16) Aspirin’s antiplatelet action does not appear to be dose-dependent;(8, 18) and the low dose (75-100 mg) of aspirin appeared to effectively inhibit the production of thromboxane while preserving prostacyclin production.(8, 16, 19, 20) However, the risk of gastrointestinal irritation and hemorrhage associated with aspirin seemed to be dosed dependent. (21) Therefore, there is probably no additional antithrombotic benefit, but an increased risk of bleeding when using aspirin doses higher than 75-100 mg.

Warfarin and aspirin independently increase the risk of bleeding. The use of warfarin monotherapy and low-dose aspirin monotherapy increased the risk for gastrointestinal bleeding by 4.3,(22) and 3.1-fold, respectively, compared to placebo.(23) The risk of major bleeding for warfarin plus aspirin was 2.5-fold greater than aspirin alone.(24) A prospective cohort study showed that gastrointestinal bleeding occurred more frequently in patients who used low-dose aspirin plus warfarin compared to placebo with an odds ratio of 3.6 (95% CI, 1.7 to 8.9, p=0.0021) after adjusting for age, sex, and use of non-steroidal anti-inflammatory drugs (NSAIDs). (25) Another retrospective case-control study found the risk of gastrointestinal bleeding was significantly greater in patients taking warfarin plus aspirin compared to patients taking no medication with an odds ratio of 6.7 (95% CI 4.3 to 9.9).(26)

Aspirin may increase the bleeding risk when combined with warfarin.(25) Nonetheless, warfarin and aspirin are used intentionally in many patients for their additive anticoagulant effects.(27, 28) Dual use is common in high-risk populations such as patients with heart-valve replacement who have experienced a major systemic embolism (about 2-3% per year) despite using anticoagulants.(19) The American College of Cardiology/American Heart Association (ACC/ AHA) guidelines recommended a combination of low dose aspirin (75-100 mg) and warfarin in patients with a mechanical prosthesis valve, a bioprosthetic aortic or mitral valve.(29) There is also robust evidence demonstrated the significantly greater reduction in major systemic embolism and mortality in mechanical heart valves patients who were treated with the combination of low dose aspirin and warfarin compared to patients treated with warfarin monotherapy.(19, 30, 31) Combination therapy for this population is appropriate because the benefits appear to outweigh risk of bleeding.(19, 30, 31)

For patients without significant history of embolism, the use of the combination of aspirin and warfarin is controversial. The ACC/AHA guideline do not provide guidance on the combination of warfarin and aspirin therapy in patients with chronic atrial fibrillation (AF), CAD, or those at high risk for stroke.(29) Multiple studies have demonstrated that warfarin plus aspirin reduced the risk of cardiovascular events (i.e., myocardial infarction, stroke, or death).(32-36) Some experts also suggested that adding aspirin to warfarin might be useful because patients receiving oral anticoagulation therapy frequently have concomitant coronary artery disease (CAD) or are at high risk for stroke.(28). However, some experts do not recommend using aspirin in addition to anticoagulant therapy for primary prevention of CAD, including patients with diabetes.(5) They point to other studies that suggest adding aspirin to warfarin did not reduce the risk of recurrent coronary events or thromboembolism in patients with atrial fibrillation and stable CAD,(37) nor prevent reinfarction, stroke, or cardiovascular death.(38, 39)

Non-acetylated salicylates would not be expected to affect the risk of bleeding because these compounds do not have antiplatelet effects.(8) However, high serum concentrations of salicylates may increase INR. Case studies reported concurrently use of warfarin and topical salicylate in an excessive amount resulted in increased INR and bleeding.(7, 9-14)

Precautions

  • Consider using acetaminophen rather than aspirin because aspirin increases the risk of GI hemorrhage in patients on warfarin.(22) Although acetaminophen does not have anti-inflammatory property, it has antipyretic and analgesic properties similar to aspirin.(40) However acetaminophen can increase the anticoagulant effect on warfarin, so monitor the INR if acetaminophen is used in doses over 2 g/day for a multiple days.(41)
  • Factors such as GI bleeding within 14 days, recent stroke (within 4 weeks), recent surgery (within 2 weeks), platelets < 75,000/L, and uncontrolled HTN (systolic BP >180 mmHg, diastolic BP >110 mmHg) are considered to significantly increase the risk of bleeding.(1)

Artifacts for implementers

Drug interaction algorithm implementation survey

Supporting documentation

References

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Creation and Revision Dates
Created: 11/1/2019
Last revision: 11/1/2019