Thrombolysis in anticoagulated patients
Patients who experience AIS should be considered for urgent thrombolytic therapy to restore perfusion and function of the ischemic brain. However, effective anticoagulation present at the time of reperfusion is a contraindication for thrombolysis [11, 12] because of the possibility of increased risk of symptomatic hemorrhage . Therefore, current guidelines recommend against using the intravenous recombinant tissue-type plasminogen activator alteplase in patients with AIS who have an international normalized ratio (INR) > 1·7  or whose prothrombin time (PT) is >15 s .
However, INR or PT are not adequate to assess the coagulation status and risk of bleeding in patients who are on a NOAC. The challenge for clinicians evaluating and considering treatment options for patients with AIS who are taking NOACs is to determine reliably and rapidly the anticoagulant effect of these agents and to estimate the potential increased risk of symptomatic hemorrhage with reperfusion (to weigh against the potential benefits of early reperfusion). Given the potential impact of antiplatelet agents, especially acetylsalicylic acid (ASA) , their use in conjunction with anticoagulation should also be carefully considered.
Laboratory testing of the anticoagulant effects of the NOACs
Traditional tests of coagulation, such as the PT/INR and activated partial thromboplastin time (aPTT), are not reliable for measuring the anticoagulant effects of dabigatran, rivaroxaban, and apixaban. There are a number of reasons for this.
Plasma concentrations of dabigatran that cause a significant anticoagulant effect may not cause an alteration in the PT/INR, and, although the aPTT is altered by therapeutic plasma concentrations of dabigatran, the correlation between dabigatran plasma concentrations and aPTT results is nonlinear. Therefore, the aPTT provides only a qualitative, and not a quantitative, indication of the presence of dabigatran . In contrast, thrombin time (TT) and the ecarin clotting time (ECT) are sensitive indicators of the presence of dabigatran activity. The TT and ECT both show a linear correlation with dabigatran; a normal TT and a normal ECT both exclude the possibility of a substantial effect of a direct thrombin inhibitor [18, 19]. Unlike TT, the ECT is not influenced by the use of other anticoagulants . However, the ECT is not as readily available as TT , and where thrombolytic therapy is necessary, it is not appropriate to delay thrombolysis for several hours to receive ECT results. The Hemoclot thrombin inhibitor assay (a diluted TT assay from Hyphen BioMed, Neuville-sur-Oise, France) is less sensitive than the TT and correlates linearly with plasma concentrations of dabigatran; however, it is not widely available yet.
Although the PT and aPTT may be prolonged by the direct Factor Xa inhibitors rivaroxaban and apixaban, neither assay is reliable for quantifying the anticoagulant effects of these agents . Like the aPTT for dabigatran, the PT provides only a qualitative indication of the presence of rivaroxaban or apixaban [21, 22], and is able to do so only when it is used with specific thromboplastin reagents that are known to be sensitive to the effects of rivaroxaban [such as Néoplastine® CI Plus (Diagnostica Stago, Asnières sur Seine, France) or RecombiPlasTin 2G (Instrumentation Laboratory, Bedford, MA, USA)] [21, 22]. Additionally, the PT for the patient must be known to be normal at baseline if a calibrated PT assay is used to estimate rivaroxaban concentration . Direct Factor Xa activity assays do correlate with plasma concentrations of rivaroxaban and apixaban, but these tests must be calibrated individually for each type of therapy being assessed (e.g. rivaroxaban or apixaban). Furthermore, they are not yet readily and rapidly available worldwide [24, 25].
If the TT, ECT, Hemoclot, and anti-Factor Xa assay are available, a clinically relevant anticoagulant effect can be excluded in patients taking NOACs by detecting either a normal TT, ECT, or Hemoclot thrombin inhibitor assay ≥four-hours after the final dose has been administered to patients taking dabigatran, or a normal anti-Factor Xa assay ≥five-hours after the final dose has been administered to patients taking rivaroxaban or apixaban [15, 24, 26-29]. The timing of these assessments reflects the peak levels of these agents, ensuring that the assays are performed at or after peak levels of the drugs have occurred .
Although the coagulation measurements discussed can facilitate the clinical decision concerning thrombolysis, more research is needed to better define ‘cut-off’ points for such assays that correlate accurately with risk of thrombosis and bleeding, to provide reliable and fast point-of-care tests, and to develop appropriate recommendations for their use.
Clinical assessment of the anticoagulant effects of the NOACs
Until a simple, fast, and reliable quantitative laboratory measure of the degree of anticoagulation in patients taking direct thrombin inhibitors or direct Factor Xa inhibitors is established, clinical assessment is also required to determine the anticoagulant effects of the NOACs, based on the time since the last dose was taken, the patient's renal function as measured by the creatinine clearance, and the concurrent intake of any medications that may interact with P–glycoprotein or cytochrome P450 3A4.
A patient taking one of the NOACs who experiences an AIS should not be considered a candidate for thrombolysis unless his/her clinical history and the results of laboratory tests reliably indicate the absence of an anticoagulant effect, or until at least two half-lives have elapsed since the most recent dose in patients with normal renal function (which is approximately 24 h for the NOACs) , and coagulation tests are normal [1-3, 15, 24, 30]. However, this is an arbitrary recommendation that has yet to be tested in clinical practice, and other authorities have recommended that 48 h (approximately four half-lives) should elapse prior to thrombolysis . For patients with renal impairment, this period should be extended even further and absence of anticoagulation confirmed by appropriate laboratory testing.
Laboratory assays should be used only to confirm the absence of a coagulation effect with the NOACs. There are no known assay values (i.e. analogous to the INR cutoff of 1·7 with warfarin) below which thrombolysis can be performed safely in a patient experiencing AIS while being treated with a NOAC.
Using these criteria, it is unlikely that patients taking a NOAC who experience an acute stroke would be suitable for thrombolysis, unless they have missed their daily (or twice-daily) dose(s) of the NOAC on the day of the stroke. Specific and accurate tests to evaluate the plasma concentrations and anticoagulant effects of the NOACs are in development. In Europe, approved commercial assays for the newer agents, such as BIOPHEN DiXal (Aniara, West Chester, OH, USA) [32, 33] and TECHNOVIEW Rivaroxaban CAL Set (Stago BNL, Leiden, the Netherlands) [34-36], are now becoming available.
Theoretically, reversing the effect of a NOAC before thrombolysis is appealing. However, this is not recommended, because reversing any anticoagulation therapy (e.g. with prothrombin complex concentrates) before initiating thrombolytic therapy is untested, and there are concerns that it might result in prothrombotic risks that are more substantial than the increased risk of hemorrhagic transformation of the brain infarct related to any residual anticoagulation . Furthermore, no specific reversal agents for the NOACs are currently available, although several are in development [24, 38, 39].
Currently, endovascular therapy encompasses a range of approaches, including endovascular pharmacological thrombolysis, mechanical and aspiration thrombectomy, the use of a guidewire or microcatheter to manipulate the clot, and stent retriever technology. Three recently published randomized trials have reported no benefit or harm associated with endovascular therapy compared with current best medical therapy with intravenous tissue plasminogen activator in a total of 1145 patients with AIS [40-42]. Subgroup analyses have suggested that patients with severe ischemic stroke caused by major intracranial artery occlusion who are treated early (within six-hours of symptom onset) may benefit from thrombectomy . It must be noted that in all three trials, first-generation recanalization devices were used. These are inferior in efficacy when compared with the newer endovascular devices (e.g. stent retrievers) [43, 44]. Trials to test the superiority of the new devices are under way. Theoretically, the presence of a NOAC should not interfere with the efficacy and safety of endovascular thrombectomy.
Restarting anticoagulation after AIS
Another challenge faced by clinicians is determining when to restart anticoagulation therapy after AIS. In a systematic review of 24 randomized controlled trials involving 23 748 patients with AIS, anticoagulant treatment within the first few days after the stroke reduced the incidence of recurrent ischemic stroke but increased the rate of symptomatic ICH, compared with no anticoagulant treatment. Hence, there was no net benefit in terms of a reduction of any type of recurrent stroke over the course of the subsequent few weeks, or in terms of mortality and disability at the end of the follow-up period (which lasted from 12 days to one-year) [45, 46].
Similar results were suggested by a meta-analysis of seven trials of anticoagulation with unfractionated heparin, low molecular weight heparin, or heparinoids compared with other treatments (ASA or placebo), started within 48 h of cardioembolic ischemic stroke . Therefore, some guidelines recommend that after AIS in patients with nonvalvular AF, oral anticoagulation should be started (or restarted) one to two-weeks after stroke onset, by which time the risk of hemorrhagic transformation of the fresh brain infarct is likely to have subsided [31, 48]. Consequently, the pivotal trials of the NOACs (ROCKET AF, RE-LY, and ARISTOTLE) only permitted the inclusion and, therefore, the oral anticoagulation treatment of patients who had experienced an ischemic stroke if at least 7–14 days had elapsed between the stroke and the initiation of anticoagulant treatment [6-8].
When to reinstitute anticoagulation after an ischemic event is a frequent clinical challenge, for which, unfortunately, no prospective data are available, hence personal opinion generally shapes the decision. Some clinicians adopt a cautious approach and suggest waiting at least 2 weeks before anticoagulation is resumed. However, a recent practice guideline by the European Heart Rhythm Association  gives a more personalized recommendation, to quote:
Continuation of NOACs after ischaemic stroke depends on the infarct size. If the infarct size is not expected to relevantly increase the risk of early secondary intracerebral bleeding, administration of NOACs should be continued by analogy to VKAs. Clinical study data regarding re-institution of anticoagulation are missing. Some advocate as a rule of thumb the 1–3–6–12 day rule, with re-institution of anticoagulation in patients with a transient ischaemic attack (TIA) after 1 day, with small, non-disabling infarct after 3 days, with a moderate stroke after 6 days, while large infarcts involving large parts of the arterial territory will be treated not before 2 (or even 3) weeks. (Heidbuchel et al., Paragraph 14.2.2)
Although relevant clinical data are not available, in our opinion this is a reasonable recommendation. Additionally, exceptionally high thromboembolic risk (e.g. prosthetic valve) may also need to be considered.
The optimal time at which the risk of recurrent thromboembolism exceeds the risk of hemorrhagic transformation of the acute brain infarct with anticoagulation is likely to vary among individual patients – this can be from 3 to 21 days after the stroke, depending on the size of the infarct [49, 50] and the individual patient's risk factors for these events [49-51]. Patients with small (vs. large) ischemic lesions, controlled blood pressure (systolic < 140 mmHg), and normal blood glucose and platelet counts are likely to be at a lower risk of hemorrhagic transformation of the brain infarct and might be considered for earlier initiation of anticoagulant therapy if they are deemed to be at high risk of recurrent stroke [49-51]. Patients with transient ischemic attacks or minor ischemic stroke but without a visualized ischemic abnormality on magnetic resonance imaging (or on a computed tomography scan performed after a few days have elapsed) should be able to safely start anticoagulation without further delay.