This is another report of thrombolysis for stroke under oral anticoagulation with dabigatran without secondary intracerebral hemorrhage. For now, there are six case reports of thrombolysis in stroke under dabigatran treatment. In one additional case, the physicians abstained from thrombolysis because the last intake of 150 mg dabigatran was 2.5 h prior to stroke onset [6
]. One patient with several risk factors for hemorrhagic transformation (diabetes mellitus with hyperglycemia upon presentation and a large perfusion deficit on CT) who received thrombolysis suffered a fatal secondary intracerebral hemorrhage after thrombolysis despite normal coagulation parameters [7
]. Five other patients received rt-PA without intracranial hemorrhagic complications (table ), but one patient also developed skin ecchymoses [8
]. These cases indicate that thrombolysis might be safe if the aPTT is in the normal range, indicating that little dabigatran is present. Of course, general risk factors for thrombolysis-associated hemorrhage as hyperglycemia, severe strokes and large perfusion deficits or extensive early infarct signs have to be taken into consideration.
Synopsis of the seven published cases of stroke under dabigatran in the therapeutic time window
A stroke under anticoagulant therapy represents an ‘anticoagulation failure’. The most sensitive test to detect the presence of dabigatran is the thrombin time. In the case of our patient, the normal thrombin time clearly argues for the omission of at least one dose, because in the steady state a slight prolongation of the thrombin time should be expected even at trough level. Furthermore, the aPTT reagent used by our institution has been shown to be the most sensitive among three different commercially available aPTT reagents to detect dabigatran activity in a clinical trial of deep vein thrombosis prophylaxis after hip or knee surgery, still detecting a significant difference to trough concentrations at 12 h after 220 mg Pradaxa in a once daily dosing regime [13 and E. Lindhoff-Last, personal communication]. A normal aPTT measured with this reagent further supports that the patient has most probably missed at least one dose. So far, there has been very little information on medication adherence under NOA. Interestingly, there was a significantly greater discontinuation rate in both dabigatran arms in comparison to the warfarin arm (21% and 21% vs. 17% after 2 years, p < 0.001) in the RE-LY trial [1
]. The main reasons were ‘patient's decision’ and ‘gastrointestinal symptoms’. It can be assumed that these factors weigh even more profoundly on medication adherence in daily clinical practice than in a carefully selected study population with regular follow-up. Under warfarin treatment with regular coagulation monitoring, patients and physicians receive a regular feedback on medication adherence. We should establish similar ‘check-ups’ under NOA treatment to assure medication adherence and evaluate comedications and undesired drug reactions.
Interestingly, all cases of stroke under dabigatran reported so far do not show relevant alterations of the aPTT (table ), which is the second sensitive standard coagulation assay that is influenced by dabigatran. Inadequate dosing for stroke prevention or omission of at least one dose was reported in four of the seven cases [6
]. It would be very interesting to know the actual anticoagulant activity at the time of thrombolysis. Experimental studies in murine stroke models have shown that effective dabigatran anticoagulation with plasma levels up to 400 ng/ml does not lead to an increase in secondary intracerebral hemorrhage after rt-PA application [14
] or to an increase of spontaneous HT in case of a continued [15
] or early-initiated [16
] anticoagulation after experimental stroke. Of course, these data from animal studies cannot be translated into clinical practice, but they point towards the possibility that NOA might be safer than warfarin in terms of intracerebral hemorrhage, especially after a stroke. One possible consequence might be the opportunity to start early anticoagulation after a cardioembolic stroke. To further explore this, it would be of utmost interest to obtain the actual anticoagulant activity in patients who suffer a stroke under NOA.