By Will Boggs MD
NEW YORK (Reuters Health) - 9/7/2019
Bridging with low-molecular-weight heparin (LMWH) is associated with worse outcomes after stroke in patients with nonvalvular atrial fibrillation (AF), according to results from the RAF and RAF-NOACs studies.
"The most important result of this RAF analysis is that bridging anticoagulation with LMWH not only does not reduce ischemic recurrence in stroke patients with AF, but it is also associated with a worse global outcome due to an increased risk of hemorrhagic transformation," Dr. Riccardo Altavilla of the University of Perugia, Italy, told Reuters Health by email.
Acute heparin treatment is used as bridging therapy until the therapeutic range of oral anticoagulants, the treatment of choice for secondary prevention of stroke in patients with nonvalvular AF, is achieved. Whether this common approach is beneficial or harmful remains unclear.
Dr. Altavilla and colleagues used data from 1,810 patients enrolled in the prospective RAF and RAF-NOACs studies to compare outcomes according to whether or not they received bridging therapy and according to the type of oral anticoagulant initiated.
One in five patients underwent bridging therapy with LMWH. Oral anticoagulant therapy was initiated with warfarin in 32% of patients and with non-vitamin-K-antagonist oral anticoagulants (NOACs) in the remaining 68%, the researchers report in Stroke, online June 21.
Twice as many patients in the bridging group (11.3%) as in the non-bridged group (5.1%) experienced the combined outcome of stroke, transient ischemic attack (TIA), systemic embolism, symptomatic cerebral bleeding and major extracerebral bleeding (P=0.0001).
In multivariable analysis, bridging therapy was associated with 2.3-fold increased odds of the combined outcome, 2.2-fold increased odds of an ischemic event, and 2.4-fold increased odds of a hemorrhagic event, compared with non-bridging - all significant results.
In a propensity score-matched analysis of 323 pairs of patients, bridging therapy was associated with 3.08-fold increased risk of the combined outcome, 4.50-fold increased risk of ischemic event, and 2.71-fold increased risk of hemorrhagic event, also significant increases.
The analysis by anticoagulant type revealed a significantly lower rate of ischemic outcome in patients treated with NOACs (2.9%) than in patients treated with warfarin (6.8%), whereas the anticoagulant groups did not differ significantly in hemorrhagic events.
"These findings are clearly against bridging therapy," Dr. Altavilla said. "There is no space left for bridging therapy in stroke patients with cardioembolic stroke due to AF."
"Bridging therapy is still overused in clinical practice despite that all international guidelines advise against it," he said. "Probably, there are unconscious biases that can sway clinician decisions on the use of bridging therapy due to the perception that heparin may be safer compared to direct anticoagulation with direct-acting oral anticoagulants (DOACs)."
Dr. Altavilla added, "The timing of anticoagulation after cardioembolic stroke is still controversial, but two randomized controlled trials (RCTs) are ongoing to explore this issue: the Swedish 'Timing of Oral
Anticoagulant Therapy in Acute Ischemic Stroke with Atrial Fibrillation' study and the international, multicenter 'Early Versus Late Initiation of Direct Oral Anticoagulants in Post-Ischemic Stroke Patients with Atrial fibrillation (ELAN)' study. These RCTs will strengthen the results from observational studies and support physicians in their therapeutic decisions."
Dr. Bruce C. V. Campbell from Royal Melbourne Hospital, University of Melbourne, in Parkville, Australia, who wrote an accompanying editorial, told Reuters Health by email, "There is very little data to support the continued use of bridging when commencing anticoagulation after stroke. The rationale for bridging is to protect against recurrent ischemic events while oral anticoagulation is taking effect. However, this doesn't apply to DOACs, which are active within a couple of hours of the first dose, and these data showed no reduction in ischemic events when bridging was used during warfarin titration."
"When using DOACs there is probably no indication to use bridging anticoagulation," he said. "Bridging also seems not to benefit patients commencing warfarin after stroke. The use of perioperative bridging anticoagulation in warfarin-treated patients is a slightly different question - a randomized trial of perioperative bridging did not show benefit, although high-risk AF patients were under-represented."
Dr. Candice L. Garwood of Eugene Appelbaum College of Pharmacy and Health Sciences, Wayne State University, in Detroit, who recently reviewed anticoagulation bridge therapy in patients with AF, told Reuters Health by email, "It is interesting that early ischemic risk is increased in those who were bridged. The practice of bridging assumes potential for increased bleeding in order to prevent stroke recurrence. Now there is mounting evidence that suggests thrombosis risk is not mitigated by bridging."
"Bridging with LMWH is not benign and, in fact, is likely harmful in terms of ischemic and hemorrhagic risk," said Dr. Garwood, who was not involved in the study. "Optimal timing of oral anticoagulant therapy, without LMWH bridging, is still an important question to consider."
Dr. Matt A. Pappas from Cleveland Clinic, in Ohio, who has also researched bridging anticoagulation and its cost-effectiveness, told Reuters Health by email, "Theory and data suggest that bridging increases the risk of hemorrhage. It's surprising that in this cohort bridging also seemed to increase the risk of recurrent ischemic stroke, but if that finding is true, it would be hard to justify bridging in any cases."
"A patient with a CHA2DS2-Vasc score of 3 has a daily risk of stroke of less than 1 in 1,000," he said. "In the long term, anticoagulation is clearly helpful for preventing stroke and disability. But even small short-lived risks can tip the scales towards harm, and so physicians should feel comfortable withholding anticoagulation when clinical situations demand it." Dr. Pappas also was not involved in the study.