Category Archives: Anticoagulation

Anticoagulant plus NSAID or aspirin use associated with increased bleeding risk

Clinical Question

For patients with acute venous thromboembolism, is the use of anticoagulants plus nonsteroidal anti-inflammatory drugs or aspirin associated with an increased risk of bleeding?

Bottom Line

For patients treated with anticoagulants for acute venous thromboembolism (VTE), the use of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin is associated with an increased risk of bleeding. This can occur in patients treated with rivaroxaban, as well as in those treated with enoxaparin plus a vitamin K antagonist (VKA). (LOE = 2b)Bottom Line


Davidson BL, Verheijen S, Lensing AW, et al. Bleeding risk of patients with acute venous thromboembolism taking nonsteroidal anti-inflammatory drugs or aspirin. JAMA Intern Med 2014;174(6):947-953.


The worldwide EINSTEIN DVT and EINSTEIN PE clinical trials compared rivaroxaban with enoxaparin plus a VKA for the treatment of acute VTE. These investigators used data from this cohort to examine the association between rivaroxaban or enoxaparin-VKA plus concomitant NSAID or aspirin use and the risk of clinically relevant and major bleeding. Clinically relevant bleeding was defined as nonmajor bleeding that resulted in either medical intervention, temporary cessation of study treatment, or patient discomfort. Major bleeding was that which resulted in death, occurred at a critical site, required transfusion of at least 2 units of red blood cells, or was associated with a 2 g/dL drop in hemoglobin. The cohort comprised 8246 patients, with half receiving rivaroxaban and half receiving enoxaparin-VKA. The NSAID analysis was adjusted for sex, as there were more women in the NSAID group. The aspirin analysis was adjusted for age and creatinine clearance, as patients in the aspirin group tended to be older with worse kidney function than the nonaspirin group. The NSAID or aspirin exposure period included 7 days after stopping the medication to reflect an ongoing risk. Clinically relevant bleeding was more likely to occur in the NSAID group as compared with the non-NSAID group (37.5 bleeding events per 100 patient-years vs 16.6 per 100 patient-years; hazard ratio [HR] = 1.77; 95% CI, 1.46-2.14). Findings were similar for both the NSAID-rivaroxaban-treated patients and NSAID-enoxaparin-VKA-treated patients. In the aspirin group, clinically relevant bleeding was also increased as compared with the nonaspirin group (36.6 bleeding events per 100 patient-years vs 16.9 per 100 patient-years; HR = 1.70; 1.38-2.11). For both the NSAID and the aspirin groups, the bleeding events were spread evenly over the duration of the use, suggesting that longer duration of use does not increase the risk of bleeding. Major bleeding increased 2.4-fold in the NSAID group and 1.5-fold in the aspirin group.

Nita Shrikant Kulkarni, MD
Assistant Professor in Hospital Medicine
Northwestern University
Chicago, IL

Secondary prevention of VTE: Are oral anticoagulant or antiplatelet drugs better?

OBJECTIVE: To summarise and compare the efficacy and safety of various oral anticoagulants (dabigatran, rivaroxaban, apixaban, and vitamin K antagonists) and antiplatelet agents (acetylsalicylic acid) for the secondary prevention of venous thromboembolism.
DESIGN: Systematic review and network meta-analysis.
DATA SOURCES: Literature search using Medline (1950 to present), Embase (1980 to present), and the Cochrane Register of Controlled Trials using the OVID interface. Publications from potentially relevant journals were also searched by hand. REVIEW
METHODS: Randomised controlled trials of patients receiving anticoagulants, antiplatelet drugs, or placebo or observation for secondary prevention of venous thromboembolism. Selected outcomes were rates of recurrent venous thromboembolism and major bleeding. Two reviewers independently extracted data onto standardised forms.
RESULTS: 12 articles met our inclusion criteria, with 11 999 patients evaluated for efficacy and 12 167 for safety. All treatments reduced the risk of recurrent venous thromboembolism. Compared with placebo or observation, vitamin K antagonists at a standard adjusted dose (target international normalised ratio 2.0-3.0) showed the highest risk difference (odds ratio 0.07; 95% credible interval 0.03 to 0.15) and acetylsalicylic acid showed the lowest risk difference (0.65; 0.39 to 1.03). Risk of major bleeding was higher with a standard adjusted dose of vitamin K antagonists (5.24; 1.78 to 18.25) than with placebo or observation. Fatal recurrent venous thromboembolism and fatal bleeding were rare. Detailed subgroup and individual patient level data were not available.
CONCLUSIONS: All oral anticoagulants and antiplatelet agents investigated in this analysis were associated with a reduced recurrence of venous thromboembolism compared with placebo or observation, although acetylsalicylic acid was associated with the lowest risk reduction. Vitamin K antagonists given at a standard adjusted dose was associated with the greatest risk reduction in recurrent venous thromboembolism, but also the greatest risk of major bleeding.
  • Most general practitioners know that newer drugs have lesser bleeding, but they do not know the smaller effect size of new anticoagulant drugs.
  • This review emphasizes something well know in clinical practice. It is important to have this meta-analysis but nothing new is learned.
Castellucci LA, Cameron C, Le Gal G, et al. Efficacy and safety outcomes of oral anticoagulants and antiplatelet drugs in the secondary prevention of venous thromboembolism: systematic review and network meta-analysis. BMJ. 2013 Aug 30;347:f5133. doi: 10.1136/bmj.f5133. (Review) PMID: 23996149

How much coumadin should you start your patient on for a DVT?

Garcia P, Ruiz W, Loza Munarriz C. Warfarin initiation nomograms for venous thromboembolism. Cochrane Database Syst Rev. 2013 Jul 10;7:CD007699. (Review) PMID: 23839808

BACKGROUND: Venous thromboembolism (VTE) is a common condition in hospital patients. Considerable controversy is ongoing regarding optimal initial warfarin dosing for patients with acute deep venous thrombosis (DVT) and pulmonary embolism (PE). Achieving a therapeutic international normalized ratio (INR) with warfarin as soon as possible is important because this minimizes the duration of parenteral medication necessary to attain immediate anticoagulation, and it potentially decreases the cost and inconvenience of treatment. Although a 5-mg loading-dose nomogram tends to prevent excessive anticoagulation, a 10-mg loading-dose nomogram may achieve a therapeutic INR more quickly.
OBJECTIVES: To evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with VTE. SEARCH

METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Coordinator searched the Specialised Register (last searched January 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12). The review authors searched PubMed (last searched 10 April 2013) and LILACS (last searched 28 February 2013). In addition, the review authors contacted pharmaceutical companies.

SELECTION CRITERIA: Randomized controlled studies comparing warfarin initiation nomograms of 10 and 5 mg in patients with VTE.

DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. The review authors contacted study authors for additional information.

MAIN RESULTS: Four trials involving 494 participants were included. Three studies involving 383 participants provided data on the proportion of participants who had achieved a therapeutic INR by day five. Significant benefit of a 10-mg warfarin nomogram was observed (risk ratio [RR] 1.27, 95% confidence interval [CI] 1.05 to 1.54), although with substantial heterogeneity (I2 = 90%). The review authors analyzed each study separately because it was not possible to perform a subgroup analysis. One study showed significant benefit of a 10-mg warfarin nomogram for the proportion of outpatients with VTE who had achieved a therapeutic INR by day five (RR 1.78, 95% CI 1.41 to 2.25), with the number needed to treat for an additional beneficial outcome (NNTB = 3, 95% CI 2 to 4); another study showed significant benefit of a 5-mg warfarin nomogram in outpatients with VTE (RR 0.58, 95% CI 0.36 to 0.93) with NNTB = 5 (95% CI 3 to 28); a third study showed no difference (RR 1.08, 95% CI 0.65 to 1.80). No difference was observed in recurrent venous thromboembolism (RVTE) at 90 days when the warfarin nomogram of 10 mg was compared with the warfarin nomogram of 5 mg (RR 1.48, 95% CI 0.39 to 5.56); no difference was observed in major bleeding at 14 days (RR 1.69, 95% CI 0.22 to 13.04) and at 90 days (RR 0.62, 95% CI 0.10 to 3.78). No difference was observed in minor bleeding at 14 to 90 days (RR 0.32, 95% CI 0.15 to 1.83) or in length of hospital stay (mean difference [MD] -2.30 days, 95% CI -7.96 to 3.36).

AUTHORS’ CONCLUSIONS: In patients with acute thromboembolism (DVT or PE) aged 18 years or older, considerable uncertainty surrounds the use of a 10-mg or a 5-mg loading dose for initiation of warfarin to achieve an INR of 2.0 to 3.0 on the fifth day of therapy. Heterogeneity among analyzed studies limits certainty surrounding optimal warfarin initiation nomograms.


  • General Internal Medicine-Primary Care(US):  Although most of the data are known, a systematic review emphasizes the evidence based treatment.
  • General Practice(GP)/Family Practice(FP):  In Russia, it is not up to primary care to do this; I believe in places where practice is more advanced the review will be of interest.