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British Journal of Neurosurgery Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ibjn20

New oral anticoagulant and antiplatelet agents for neurosurgeons a

b

George Kimpton , Bassam Dabbous & Paul Leach a

b

Cardiff University School of Medicine, Heath Park, Cardiff, Wales, UK

b

Department of Neurosurgery, University Hospital of Wales, Cardiff, Wales, UK Published online: 12 Jun 2015.

To cite this article: George Kimpton, Bassam Dabbous & Paul Leach (2015): New oral anticoagulant and antiplatelet agents for neurosurgeons, British Journal of Neurosurgery To link to this article: http://dx.doi.org/10.3109/02688697.2015.1029433

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British Journal of Neurosurgery, 2015; Early Online: 1–8 © 2015 The Neurosurgical Foundation ISSN: 0268-8697 print / ISSN 1360-046X online DOI: 10.3109/02688697.2015.1029433

REVIEW ARTICLE

New oral anticoagulant and antiplatelet agents for neurosurgeons George Kimpton1, Bassam Dabbous2 & Paul Leach2 1Cardiff University School of Medicine, Heath Park, Cardiff, Wales, UK, and 2Department of Neurosurgery, University Hospital

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of Wales, Cardiff, Wales, UK

Abstract Until recently, warfarin, clopidogrel and aspirin have provided the mainstay for prevention of thrombotic disease in cardiac patients. However, new classes of drugs have recently emerged that promise better clinical outcomes and lower risks. Use of such agents has increased, but increased risk and severity of intra-cranial haemorrhage (ICH) still remain. These cases of intra-cranial bleeds present as emergencies to neurosurgical units. It is of paramount importance that neurosurgical practitioners are aware of those new drugs, useful monitoring tests and available emergency reversal options in case the patient needs emergency intervention. In this review we survey newly available agents in the UK at the time of publication. We look at the data provided by the manufacturers, related publications and international guidelines for their use and reversal. New anticoagulants offer a lower incidence of ICH compared with warfarin. Advanced and accurate monitoring tests are emerging, as are prospective data on reversal of anticoagulation in bleeding. Some standard coagulation tests may be of use, whilst reversal agents are available and being evaluated. The trial data shows that new antiplatelet agents have similar or increased incidence and severity of intra-cranial ICH compared with clopidogrel. There is currently limited data on monitoring or reversal. We suggest they may be managed similarly to clopidogrel by using platelet reactivity assays, optimising platelet count and using platelet transfusion with adjunctive agents.

non-vitamin-K-dependent oral anticoagulants include direct thrombin inhibitor dabigatran, and factor Xa inhibitors such as rivaroxaban and apixaban.1 The NAPTs include prasugrel and ticagrelor, both of which inhibit platelet aggregation by the same mechanism as clopidogrel, by inhibiting the ADP (P2Y12) receptor.2,3 All of these drugs offer advantages over their predecessors, but still carry a risk of intra-cranial haemorrhage (ICH).1,4–6 Presentation of patients with ICH taking these new drugs is challenging due to the lack of widespread understanding of their effects, and the paucity of evidence for their monitoring and management. Although the incidence of ICH is lower with NOACs, both the literature and conference proceedings are rife with reports of catastrophic bleeding following low-impact falls. Worryingly, there have been reports of increased patient morbidity and mortality during neurosurgery due to insufficient expertise in management of ICH in these patients. It is of utmost importance that neurosurgeons are aware of these drugs and their monitoring and management as their usage increases.

NOACs and NAPTs: Changes in bleeding risks NOACs were developed to replace warfarin due to its high risk of ICH, slow onset and offset of action and the need for frequent international normalised ratio (INR) monitoring. They have a fixed dose, do not require monitoring and have a much shorter half-life.7 The National Institute for Health and Care Excellence (NICE) primarily approved them for prevention of embolic stroke in AF, as in large Phase III trials all three (dabigatran, rivaroxaban and apixaban) showed equivalent or superior rates of embolic disease to warfarin.1 Additionally, all three decreased the incidence of ICH by 2–5 ICHs per 1000 patients per year compared with doseadjusted warfarin.8–10 However, dabigatran and rivaroxaban increased the incidence of gastrointestinal (GI) bleeding by 5–10 per 1000 patients per year, respectively. These drugs are also indicated by NICE in prevention of venous thromboembolism (VTE) after orthopaedic surgery.11 Additionally,

Keywords: antiplatelets; intra-cranial haemorrhage; neurosurgery; novel oral anticoagulants Advances in pharmacology in one area of medicine must be matched by an understanding of their benefits and risks by all clinicians. Whilst warfarin and clopidogrel revolutionised management of atrial fibrillation (AF) and acute coronary syndrome (ACS), respectively, new drugs with different risks profiles are gaining popularity. The novel drugs are classified into novel oral anticoagulants (NOACs) and the new antiplatelets (NAPTs). The

Correspondence: George Kimpton, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN, Wales, UK. E-mail: [email protected] Received for publication 4 November 2014; accepted 8 March 2015

1

2  G. Kimpton et al. NICE recommends dabigatran and rivaroxaban as possible treatments for deep vein thrombosis and pulmonary embolism, with a statement on apixaban due in June 2015.12–14

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NAPTs Clopidogrel vastly decreases the risks of stent thrombosis after percutaneous coronary intervention (PCI),15 but is known to increase the incidence and severity of ICH.16,17 This includes increased haematoma expansion, intra-ventricular haemorrhage and neurosurgical intervention, as well as lower functional outcomes.16,18 Additionally, clopidogrel shows significant variation in effect between patients, with some patients thought to be clopidogrel resistant.3 These patients have up to five times greater mortality after PCI.19 Prasugrel and ticagrelor were developed as more potent platelet inhibitors with lower inter-patient variability.3 Prasugrel increases rate of fatal bleeding, but offers incidence of ICH similar to that of clopidogrel.20 Ticagrelor shows no increase in fatal bleeding compared with clopidogrel, but increases both the rate and severity of ICH, with fatal ICH accounting for over half of all fatal bleeds in the largest trial of ticagrelor.21

Patients presenting with ICH: Challenges Both NOACs and NAPTs are relatively new drugs and hence do not have widespread use so far in the UK. This said, as use increases, the number of patients presenting with ICH whilst taking them will also increase.1 Neurosurgeons need to understand how to monitor and best manage these patients to improve outcomes.

Monitoring NOACs Monitoring coagulation in NOAC patients is notoriously difficult due to high variability of effects on standard coagulation tests.5,22 Importantly, INR is not recommended as it may give a false-negative result.23 This said, several routine coagulation tests may yield limited information in ICH. For dabigatran, activated partial thromboplastin time (APTT) is useful, provided that an accurate time of last administration is known. The European Heart Rhythm Association (EHRA) guidelines suggest that an APTT over two times the upper limit of normal suggests an excess bleeding risk, if taken 12–24 h after last ingestion.5,7,24 Additionally, thrombin time (TT) is extremely sensitive to any dabigatran concentration. A normal TT precludes the presence of therapeutic concentrations of dabigatran, whilst treatment drug levels will exceed the maximum detection values of the TT assay.25 The British Haematological Society guidelines suggest that a normal TT and APTT indicate a therapeutic concentration of dabigatran is unlikely.22 Prothrombin time (PT) shows a dose-dependent increase in rivaroxaban, meaning it may be prolonged if a patient is anticoagulated.7,26 At peak concentrations, 2–4 h after ingestion, PT is increased by 50–135%; however, at trough concentrations PT may increase as little as 6–19%.25 APTT is insensitive at low drug concentrations, meaning a normal APTT may not imply normal coagulation.25

No standard laboratory assays reliably measure anticoagulation by apixaban. APTT may be unchanged at therapeutic drug concentrations. Data on PT is unclear, but shows poor correlation with drug levels and may be insensitive to apixaban within the lower part of the therapeutic range. Several assays show sensitive linear quantification of drug levels. These include diluted thrombin time (dTT), (commercially available as Hemoclot®: Hyphen Biomed, NeuvillesurOise, France) and ecarin-based assays (chromogenic and clotting time) for dabigatran. Ecarin-based assays are criticized for their lack of standardisation and variability between reagents.25,27 For both rivaroxaban and apixaban, chromogenic factor Xa assays are considered the most sensitive and accurate assay to determine the presence and concentration of anti-Xa agents. Some centres already use anti-Xa assays calibrated for lowmolecular-weight heparins (LMWHs). A normal result using these tests suggests that the patient is not anticoagulated due to rivaroxaban or apixaban.25 Meanwhile, new calibration agents specific for these drugs allow accurate quantitative measurement of drug concentrations and may give an indication of the degree of anticoagulation, as well as drug excretion. Currently, there are no data relating the results from these assays to timing of surgery or clinical outcomes in ICH. However, if available, accurate measurement of drug blood concentration could be used to help monitor resolution of normal coagulation.7 This is especially useful in those with reduced renal function, as NOACs are cleared more slowly in such patients than in the general population. This can be used as an adjunct to recommended times before surgery as given in Table II. However, it should be noted that the infrequent use of these assays makes it unlikely that they will be available outside of working hours. Neurosurgical units should communicate with clinical scientists in order to establish what tests are available and establish a protocol for their use. This can then be added into our example protocol for investigation and management of these patients (Figure 1).

NAPTs Platelet count may change outcomes in ICH for those taking antiplatelets. Patients on aspirin and clopidogrel with a platelet count under 135 000/mL are significantly more likely to have progression on radiology and require neurosurgical intervention.28 This suggests that below this level there may be increased benefit from platelet transfusion. Evidence in clopidogrel-related ICH suggests that reduced platelet reactivity indicates increased likelihood of early haemorrhage expansion and poorer outcomes at 3 months.29 Several laboratory and near-patient systems have been developed and validated for measuring platelet reactivity; however, these are mostly outside of routine practice and are institution dependent. Large-scale data from trials of antiplatelet agents in PCI has led to development of cut-off values to predict risk of bleeding for four assays. VerifyNow (Accumetrics, California, USA) and Multiplate analyser (Roche Diagnostics, Mannheim, Germany) systems are near-patient systems, whilst laboratory tests include the vasodilator-stimulated phosphoprotein (VASP) assay and thromboelastography platelet mapping

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NOACs and NAPTs for neurosurgeons  3

Fig. 1. Protocol for management of ICH in a patient taking NOACs, in addition to standard care. Based on references 7, 22, 25, 55. NOAC, novel oral anticoagulant; ICH, intra-cranial haemorrhage; FBC, full blood count; eGFR, estimated glomerular filtration rate; APTT, activated partial thromboplastin time; TT, thrombin time; dTT, diluted thrombin time; PT, prothrombin time; OD, once daily; BD, twice daily; IV, intra-venous; Hb, haemoglobin; X h, X hours; PCC, prothrombin complex concentrates (Factors II, XI and X  VII); aPCC, activated PCC (Factors II, XI, X and activated Factor VII, Feiba®).

(TEG: Haemoscope Corporation, Illinois, USA). These cut-off values can be used before PCI to predict bleeding risk,30,31 although it is not clear whether they are applicable for noncardiac surgery on patients taking NAPTs after PCI. The American Society of Thoracic surgeons now recommends that timing of surgery is based on platelet function testing as opposed to arbitrary 5- or 7-day cut-offs, due to the high

negative predictive value of these tests;26,30,31 however, they acknowledge that no validated, absolute levels have been established to predict operative bleeding. This said, TEG has been validated for prognostic use in cardiothoracic surgery. TEG-measured platelet reactivity has been successfully used to time CABG surgery, and was found to reduce bleeding outcomes and transfusion

4  G. Kimpton et al. requirements.31,32 A larger trial (BIANCA) now seeks to compare platelet reactivity measures before surgery.31 In neurosurgery, a small study was conducted in patients using TEG. It found that hypocoagulable patients were more likely to drop their Glasgow Coma Scale (GCS) scores after 24 h, and that these patients had higher 30-day mortality. Only 25% of these patients were hypocoagulable on PT or INR tests. However, this was an observational study with no description of use of antiplatelet therapy (APT) in these patients.33 Overall in neurosurgery, none of the assay cut-off values have been validated to change management of patients with ICH. In the meantime, available assays are used to measure changes in patient platelet reactivity and to check excretion of NAPTs.

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Elective surgery Stopping anticoagulation carries the increased risk of thrombotic events, which is further aggravated by surgery. This is especially true with NOACs, as their half-lives are shorter than those of warfarin, meaning total offset of anticoagulation is much faster (Table I).1,7 Hence, bridging therapy – the use of agents with shorter half-lives (i.e. LMWHs) that can be stopped shortly before surgery to reduce thrombotic risk – is thought to have little role in patients taking NOACs.1 There is currently no high-quality data on the subject, and it may be that those who are at high thrombosis risk (high CHADS2 score and previous thrombotic event) may benefit from bridging, requiring multidisciplinary discussion. The EHRA-recommended time between the last dose of each NOAC and surgical incision is discussed in Table II. This is segregated by glomerular filtration rate (GFR) for rivaroxaban due to its 80% renal clearance, with additional 24 h for each reduction of 30 ml/min of creatinine clearance. For rivaroxaban and apixaban in neurosurgery, this is greater than or equal to 48 h regardless of clearance (renal clearance 35% and 27%, respectively).

Restarting NOACs is also difficult after surgery due to the much faster onset of action than warfarin (within 2 h), which has the potential to precipitate haemorrhage. Hence, in patients with AF, intermediate use of LMWH for 48–72 h before restarting NOACs is recommended by the EHRA.7 NAPTs are more complicated to manage in elective surgery. Forty-five days after stent placement, stopping dual APT increases the risk of a major acute coronary event by 2–12.5 times compared with those 2 years after PCI.31 Accordingly, in those with the highest risk (myocardial infarction [MI] in the last 6 weeks, bare metal stent in the last 6 weeks or drug-eluting stents in the last 12 months) bridging therapy is recommended.2,3 Bridging involves stopping ticagrelor or prasugrel for 5 and 7 days, respectively. Expert reviews then recommend maintaining platelet inhibition using antiplatelet agent tirofiban by infusion. The short half-life of this drug means that it can be stopped 4–8 h before surgery to allow rapid recovery of platelet function, and recommenced after adequate haemostasis until restarting of an antiplatelet agent.3 Additionally, neurosurgical patients should stop their aspirin intake preoperatively. It is recommended that therapy is interrupted for no more than 3–5 days.3

Emergency reversal strategies NOACs have short half-lives which means that coagulation improves within 12–24 h.1,34 Hence, delaying surgery as long as possible will reduce bleeding risks.7 Analysis of nonneurosurgical bleeding patients showed improved surgical outcomes with interventions after 24 and 48 h.34 Hence, the EHRA suggests that delaying surgery by over 12 h, or even 24 h, may improve outcomes. Additionally, NOACs’ half-life is largely dependent on renal clearance, and hence may be reduced in low GFR or large bleeds affecting renal perfusion.5 In these patients the above-described monitoring strategies may be useful.

Table I. Comparative pharmacology of NOACs and NAPTs. NICE-indicated NOACs Dabigatran Mechanism

Rivaroxaban

Direct thrombin inhibitor

NICE-indicated NAPTs Apixaban

Prasugrel

Factor Xa inhibitor

Ticagrelor

P2Y12 receptor inhibitor

NICE Indications

Prevention of VTE after orthopaedic surgery (TA157, 2008), Non-valvular AF (TA249, 2012),

Prevention of VTE after orthopaedic surgery (TA170, 2009), Non-valvular AF (TA256, 2012), Treatment of DVT and prevention of recurrent VTE (TA261, 2012), Treating PE and preventing recurrent VTE (TA287, 2013)

Prevention of VTE after orthopaedic surgery (TA245, 2012), Non-valvular AF (TA275, 2013)

Anti-thrombosis after PCI (TA317, 2014)

Management of ACS (TA236, 2011)

Time to effect Half-life Renally excreted proportion Recommended time before surgery (CrCl 80 ml/min) Monitoring

1–2 h 12–17 h 80%

2–4 h 5–9 h young, 11–13 h elderly 35%

3–4 h 8–15 h 27%

1–2 h 7h 60%

2h 8–9 h Negligible

7d

5d

All fixed cavity surgery:  48 h Other surgeries with low risk of bleeding  24 h APTT (Quantitative), TT (Qualitative)

PT (Qualitative, low sensitivity at low therapeutic levels)

None sufficiently sensitive

Platelet function tests if available

NOAC, Novel oral anticoagulant; NAPT, New antiplatelet; NICE, National Institute for Health and Care Excellence (UK); AF, atrial fibrillation; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; PCI, percutaneous coronary intervention; ACS, acute coronary syndrome; X h, X hours; X d, X days; APTT, activated partial thromboplastin time; TT, thrombin time; PT, prothrombin time; TA, NICE Technology Appraisal (Number). These are comprehensively researched recommendations on the use of medicines by the National Health Service (NHS) in Britain. For more information, see http://www.nice.org.uk/guidance/

NOACs and NAPTs for neurosurgeons  5 Table II. Recommended time before elective surgery with a high risk of bleeding. Time delay before high-risk surgery (hours) Renal clearance (CrCl, ml/min)  80 50–80 30–50 15–30 15

Dabigatran

Rivaroxaban

Apixaban

 48  72  96 Not indicated Not indicated

 48  48  48  48 Not indicated

 48  48  48  48 Not indicated

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Kindly reproduced from Heidbuchel et al. 2013: EHRA: Practical guide to NOACs.7 CrCl, Creatinine clearance, ml/min, millilitre per minute.

In some situations, patients may require immediate surgery. These patients require a strategy for reversing anticoagulation. Established therapies in warfarin such as fresh-frozen plasma (FFP) or vitamin K do not affect anticoagulation by NOACs.1,5,55 In patients who present after taking dabigatran, haemodialysis can remove 45–60% of plasma dabigatran in 4 h or up to 80% over longer time periods,35,36 but not rivaroxaban or apixaban. Equally, in case of recent ingestion of dabigatran (within 2 h), oral activated charcoal will attenuate further drug absorption.22 However, in patients requiring immediate or urgent surgery we recognise that logistically these strategies are difficult to implement. No specific reversal agents of dabigatran are yet been licenced. Neurosurgeons need to be aware of the RE-VERSE AD Phase III trial of an antibody fragment designed to quickly reverse the effect of dabigatran, detailed below. Patients with major bleeding who require reversal agents or those in need of urgent surgery are eligible, meaning ICH cases should be proposed for enrolment. Eleven UK centres are involved, most of which have neurosurgical units. As of March 2015, Basingstoke, Cardiff, Liverpool, two London centres, Manchester, Plymouth, Salisbury and Taunton are recruiting, with Bristol and Southampton beginning enrolment in the future. Leicester appears to no longer be involved in the trial. More information and trial protocol can be found at http://clinicaltrials.gov/show/NCT02104947. Currently suggested therapies for reversal of NOAC anticoagulation include non-specific coagulation support. Guidelines are awaiting prospective data for evaluating prothrombin complex concentrates (PCCs: Factors II, XI and X  VII, 25 U/kg, possible to repeat once) and activated PCC (APCC: Factors II, XI, X and activated Factor VII, Feiba 50IE/kg, max 200IE/kg/day).7 These have animal and laboratory data, but are not proved in bleeding or ICH patients, or patients carrying the risk of thrombosis.5,37,38,55 Consultation with experts in haemostasis is advised before their use. Managing patients with NOAC associated ICH is complicated, and we have summarised available evidence in a suggested protocol (Figure 1).

NAPTs In ICH, European Society of Cardiology guidelines recommend stopping and neutralising APT despite thrombosis risk.15 For antiplatelet agents, data from platelet transfusion in ICH is not conclusive, although a randomised controlled trial (RCT) is underway.39 Observational data suggests a

benefit in non-traumatic haemorrhage.40 Expert reviews suggest transfusion of 10–12.5 units of platelets on admission with the suggestion of further transfusions for 48 h.41,42 Currently, there is no prospective data on NAPTs or clopidogrel, although one RCT in patients taking aspirin suggested benefit in spontaneous ICH.44 Some authors suggest the addition of desmopressin: 0.3 mg/kg or tranexamic acid: 2 g.41,43,56 We have summarised available evidence and expert reviews into an example protocol for the treatment of ICH in patients taking NAPTs (Figure 2).

Future therapies: NOAC inhibitors At the time of publication, several inhibitors of NOAC activity are in Phase III trials. For dabigatran, a humanised antibody fragment (Fab) idarucizumab (Boehringer Ingelheim, Germany) has been developed with structural property similar to thrombin and with 350 times greater affinity for dabigatran, but without enzymatic activity.45 In Phase I/II trials, idarucizumab resulted in complete and sustained reversal of anticoagulation on coagulation assays.46 A Phase III trial (RE-VERSE AD, clinicaltrials.gov identifier: NCT02104947) is ongoing, enrolling patients taking dabigatran with overt major bleeding or need of urgent surgery. There is no comparator arm, and the trial will mostly analyse laboratory endpoints. Hard clinical endpoints will be time to cessation of bleeding (A) and occurrence of major bleeding (B). Enrolment is estimated to be completed in April 2017.47 For factor Xa inhibitors, a truncated version of factor Xa has been developed as a decoy for rivaroxaban and apixaban. This protein lacks a catalytic site or membrane-binding domains, but inhibits activity of rivaroxaban and apixaban in addition to that of some LMWHs.48 In Phase II trials, subjects who were given the decoy protein, andexanet alfa (Portola Pharmaceuticals, San Francisco, USA) after rivaroxaban showed an immediate reduction in inhibition of Factor Xa. Inhibition was comparable with placebo after 2 h.49 Andexanet alfa was granted the ‘breakthrough therapy’ designation by the Food and Drug Administration (FDA) in November 2013.50 Two placebo-controlled Phase III trials are registered for rivaroxaban and apixaban: ANNEXA-R (clinicaltrials.gov identifier: NCT02220725)51 and ANNEXA-A (clinicaltrials.gov identifier: NCT02207725),52 respectively. These trials enrol ‘reasonably healthy’ volunteers between 50 and 75 years to evaluate laboratory anticoagulation parameters against placebo. No clinical endpoints will be evaluated and those with active bleeding are excluded. In October 2014, a press statement was released by andexanet alfa’s manufacturer stating the completion of the initial phase of ANNEXA-A trial. This trial found that bolus injection ‘immediately and significantly reversed the anticoagulation’ of apixaban. It was said that results were to be published in November 2014 with results of further trials expected in early 2015.50 Although these have been published as press releases, the authors have been unable to locate formal reports of these in the literature. In addition, a third trial was announced in December 2014 (NCT02329327). This will evaluate andexanet alfa in a

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6  G. Kimpton et al.

Fig. 2. Protocol for management of ICH in a patient taking new oral antiplatelets, in addition to standard care. This is based mostly on evidence from clopidogrel, meaning it is also applicable to these patients. Based on references 2, 3, 26, 28, 31, 41, 43 and 56. NAPT, New oral antiplatelet (prasugrel and ticagrelor); ICH, intra-cranial haemorrhage; MI, myocardial infarction; FBC, full blood count; eGFR, estimated glomerular filtration rate; IV, intra-venous.

single-arm observational study of 270 patients with acute major bleeding, and the number of patients with cessation of bleeding within 24 h. There is no control group and patients are excluded if they are expected to undergo surgery

or receive PCC, FFP or rFVIIa within 24 h of andexanet alfa administration. The trial will include patients with ICH confirmed by computed tomography, but excludes those with GCS under seven, haematoma volume above 30 cm3

NOACs and NAPTs for neurosurgeons  7 or ‘ICH characteristics defined in more detail in the protocol’. Recruitment has now opened at a single US centre and is estimated to close in 2022.53 According to the manufacturer’s press release, this is a ‘Phase four’ study intended to underpin a Biologics Licence Application from the FDA by the end of 2015.54 For neurosurgery, these inhibitors may provide a vital tool in ICH, depending on trial results. Use of fast-acting intra-venous reversal agents may allow earlier neurosurgical intervention than NOAC metabolism. However, further trials of these agents should evaluate hard clinical endpoints in bleeding patients. Analysis should include mortality, bleeding complications and safety outcomes such as thrombotic events.

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Conclusion Neither NOACs nor NAPTs have a clear strategy for management of ICH in patients taking these medications. Further prospective data is required to give useful cut-off values for emerging monitoring assays and effective protocols for reversal of these drug-induced coagulopathies. Current suggestions include delaying surgery as long as possible in NOACs, with PCCs as a possible reversal strategy. In NAPTs, platelet transfusion may offer benefits, especially in spontaneous ICH.­ Declaration of interest:  The authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.­

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New oral anticoagulant and antiplatelet agents for neurosurgeons.

Until recently, warfarin, clopidogrel and aspirin have provided the mainstay for prevention of thrombotic disease in cardiac patients. However, new cl...
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