New research
Douketis et al. present the first randomised controlled trial of the benefits and risks of bridging anticoagulation (Douketis et al.
2015). Patients (
N = 1884) with AF had their warfarin stopped 5 days before surgery and received either twice daily dalteparin (100 units kg
−1) or placebo from 3 days until 1 day before surgery. Warfarin was restarted on the day of or the day after surgery. Dalteparin or placebo was restarted at 12–24 or 48–72 h after surgery for low or high bleeding risk procedures respectively and was continued until the INR was 2.0 or higher.
The primary efficacy outcome was the incidence of arterial thromboembolism (ATE) at 30 days (stroke, systemic embolism, transient ischaemic attack), and the primary safety outcome was major bleeding at 30 days. The authors performed a one-sided ‘non-inferiority’ test within a margin of 1 % of placebo to dalteparin comparing ATE rates. A two-sided ‘superiority’ test was performed to compare major haemorrhage rates. The study had 90 % power for the two primary end points.
Critique
Perioperative staff commonly face uncertainty as to the best management strategy for patients, presenting for surgery, who are taking warfarin for AF. This study addresses an important and common issue that has previously lacked high-quality research.
Some issues with the study design and conclusions have been raised (Duca et al.
2016). On closer examination of the study population, less than 3 % of patients had the highest CHADS
2 scores of 5 or 6. These patients have the highest annualised stroke risk (at 12–18 %) and would potentially benefit most from perioperative bridging anticoagulation (Gage et al.
2001). In addition, many surgical procedures associated with high rates of ATE were not represented at all, including carotid endarterectomy and major cancer surgery. Concluding that omission of bridging anticoagulation is non-inferior to use of bridging anticoagulation for all may cause disadvantage to these high-risk groups.
The diagnosis of ATE within the protocol required development and recognition of clinical symptoms. Silent ATE occurs more commonly than overt ATE and is associated with long-term complications (Sacco et al.
2013; Fanning et al.
2014). The results may therefore not reflect the true impact of omitting bridging anticoagulation.
The vast majority of procedures performed were associated with a low risk of bleeding, and almost 40 % of patients underwent minor gastrointestinal procedures including endoscopy. Preexisting guidelines state that such procedures may be performed without interruption of oral anticoagulation (Veitch et al.
2008). Without further information on the exact procedures carried out, and without subgroup analysis, it is difficult to know if the major conclusions apply to particular patient populations.
The study protocol randomised patients to receive high-dose dalteparin or placebo. In practice, if warfarin was withheld and high-dose dalteparin was not to be given, many hospital guidelines would advocate administration of lower dose low molecular weight heparin for venous thromboembolism prophylaxis (
www.guysandstthomas.nhs.uk/resources/our-services/acute-medicine-gi-surgery/elderly-care/periop-warfarin-adults.pdf) Accessed 2 Feb
2016). How the results of the BRIDGE study would affect these recommendations is unclear. Also, this study did not investigate newer anticoagulants, which are increasingly popular and have shorter half-lives (Baron et al.
2013). The ability to continue these agents closer to the time of surgery may reduce or eliminate the requirement for bridging anticoagulation therapy.
The authors understandably tested at a 1 % margin for a one-sided hypothesis of non-inferiority of placebo to dalteparin with regard to the incidence of ATE. However, their use of the term ‘superiority’ for the two-sided hypothesis for haemorrhage is a common misuse of the term, as ‘superiority’ is also a one-sided hypothesis. The two-sided hypothesis is simply the standard ‘inequality’ hypothesis when the usual null hypothesis is rejected (Columb and Lutz
2009). Another, not uncommon problem in RCTs that the authors had to deal with was the lower than expected event rates for ATE. However, an advantage with non-inferiority designs is that the study remained adequately powered as the non-inferiority margin of 1 % became proportionately larger with respect to the lower incidence rates.