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Aims: The aim of this study was to compare the risk of stroke or systemic embolism (SE) and major bleeding in patients with atrial fibrillation (AF) using dabigatran, rivaroxaban, and apixaban in routine clinical practice., Methods and Results: Using nationwide registries in Norway from January 2013 to December 2017, we established a cohort of 52 476 new users of non-vitamin K antagonist oral anticoagulants (NOACs) with AF. Users of individual NOACs were matched 1:1 on the propensity score to create three pairwise-matched cohorts: dabigatran vs. rivaroxaban (20 504 patients), dabigatran vs. apixaban (20 826 patients), and rivaroxaban vs. apixaban (27 398 patients). Hazard ratios (HRs) for the risk of stroke or SE and major bleeding were estimated. In the propensity-matched comparisons of the risk of stroke or SE, the HRs were 0.88 [95% confidence interval (CI) 0.76-1.02] for dabigatran vs. rivaroxaban, 0.88 (95% CI 0.75-1.02) for dabigatran vs. apixaban, and 1.00 (95% CI 0.89-1.14) for apixaban vs. rivaroxaban. For the risk of major bleeding, the HRs were 0.75 (95% CI 0.64-0.88) for dabigatran vs. rivaroxaban, 1.03 (95% CI 0.85-1.24) for dabigatran vs. apixaban, and 0.79 (95% CI 0.68-0.91) for apixaban vs. rivaroxaban., Conclusion: In this nationwide study of patients with AF in Norway, we found no statistically significant differences in risk of stroke or SE in propensity-matched comparisons between dabigatran, rivaroxaban, and apixaban. However, dabigatran and apixaban were both associated with significantly lower risk of major bleeding compared with rivaroxaban., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The efficacy and safety of continued bivalirudin infusion after percutaneous coronary intervention (PCI) remains uncertain. We sought to investigate the association between post-PCI bivalirudin infusion and the risk of net adverse clinical events (NACE) at 30 days., Methods and Results: In the GLOBAL LEADERS study, all patients who received bivalirudin during PCI were categorized according to the use of bivalirudin infusion after the procedure. The primary endpoint of the present analysis was NACE [a composite of all-cause death, any stroke, any myocardial infarction, all revascularization, and bleeding assessed according to the Bleeding Academic Research Consortium (BARC) criteria Type 3 or 5] at 30 days. The key safety endpoint was BARC Type 3 or 5 bleeding and definite stent thrombosis. Of 15 968 patients, 13 870 underwent PCI with the use of bivalirudin. In total, 7148 patients received continued bivalirudin infusion after procedure, while 6722 patients received standard care. After propensity score covariate adjustment, the risk of NACE did not significantly differ between two treatments after PCI [continued bivalirudin infusion vs. no bivalirudin infusion: 3.2% vs. 3.1%, adjusted hazard ratio (aHR) 1.35, 95% confidence interval (CI) 0.99-1.84, P = 0.06] nor the BARC Type 3 or 5 bleeding (0.7% vs. 0.7%, aHR 0.89, 95% CI 0.44-1.79; P = 0.743) and definite stent thrombosis (0.5% vs. 0.3%, aHR 1.71, 95% CI 0.77-3.81, P = 0.189). However, continued bivalirudin infusion was associated with an increased risk of NACE and definite stent thrombosis in ST-elevation myocardial infarction (STEMI) patients., Conclusion: In an all-comers population undergoing PCI, there was no significant difference in the risk of NACE at 30 days between continued bivalirudin infusion vs. no bivalirudin infusion after procedure but continued bivalirudin infusion was associated with a higher risk of NACE in STEMI patients when compared with no infusion., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: Our aim was to study the impact of sex on anticoagulant treatment outcomes during percutaneous coronary intervention in acute myocardial infarction patients., Methods: This study was a prespecified analysis of the Bivalirudin versus Heparin in ST-Segment and Non ST-Segment Elevation Myocardial Infarction in Patients on Modern Antiplatelet Therapy in the Swedish Web System for Enhancement and Development of Evidence-based Care in Heart Disease Evaluated according to Recommended Therapies Registry Trial (VALIDATE-SWEDEHEART) trial, in which patients with myocardial infarction were randomised to bivalirudin or unfractionated heparin during percutaneous coronary intervention. The primary outcome was the composite of death, myocardial infarction or major bleeding at 180 days., Results: There was a lower risk of the primary outcome in women assigned to bivalirudin than to unfractionated heparin (13.6% vs 17.1%, hazard ratio 0.78, 95% confidence interval (0.60-1.00)) with no significant difference in men (11.8% vs 11.2%, hazard ratio 1.06 (0.89-1.26), p for interaction 0.05). The observed difference was primarily due to lower risk of major bleeding (Bleeding Academic Research Consortium definition 2, 3 or 5) associated with bivalirudin in women (8.9% vs 11.8%, hazard ratio 0.74 (0.54-1.01)) but not in men (8.5% vs 7.3%, hazard ratio 1.16 (0.94-1.43) in men, p for interaction 0.02). Conversely, no significant difference in the risk of Bleeding Academic Research Consortium 3 or 5 bleeding, associated with bivalirudin, was found in women 4.5% vs 5.4% (hazard ratio 0.84 (0.54-1.31)) or men 2.9% vs 2.1% (hazard ratio 1.36 (0.93-1.99)). Bleeding Academic Research Consortium 2 bleeding occurred significantly less often in women assigned to bivalirudin than to unfractionated heparin. The risk of death or myocardial infarction did not significantly differ between randomised treatments in men or women., Conclusion: In women, bivalirudin was associated with a lower risk of adverse outcomes, compared to unfractionated heparin, primarily due to a significant reduction in Bleeding Academic Research Consortium 2 bleeds.

Aims: To describe heparin dosing requirements in patients who underwent catheter ablation of atrial fibrillation with uninterrupted anticoagulation using dabigatran etexilate (dabigatran) or warfarin to attain therapeutic activated clotting time (ACT) in the RE-CIRCUIT® study. The RE-CIRCUIT study showed significantly fewer major bleeding events in the dabigatran vs. warfarin treatment group. Unfractionated heparin was administered during the procedure to maintain ACT >300 s., Methods and Results: Patients were randomly assigned to dabigatran 150 mg bid or international normalized ratio-adjusted warfarin. Ablation was performed with uninterrupted anticoagulation and continued for 8 weeks after the procedure. Heparin was administered after placement of femoral sheaths before or immediately after transseptal puncture. Ablation was performed in 635 patients (dabigatran, 317; warfarin, 318); data were available from 396 patients administered heparin (dabigatran, 191; warfarin, 205). Most frequent time window from last dose of study drug to septal puncture was 0 to <4 h in the dabigatran (41.3%) and 16 to <24 h in the warfarin arms (44.7%). Overall mean (standard deviation) heparin dose was similar between the dabigatran and warfarin groups [12 402 (10 721) vs. 11 910 (8359) IU, respectively]. Heparin dosing requirement to reach therapeutic ACT was lowest when time from last dose of dabigatran to septal puncture was 0 to <4 h., Conclusion: Patients treated with dabigatran required a similar amount of unfractionated heparin as those treated with warfarin to achieve an ACT of >300 s during ablation. More heparin units were required when the time from the last dose of dabigatran to septal puncture increased., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Although a recent expert consensus statement has recommended periprocedural uninterrupted (UI) non-vitamin K antagonist oral anticoagulants (NOACs) during catheter ablation of atrial fibrillation (AF) as a Class I indication, there have been no clear randomized trials. We investigated the safety and efficacy of UI, procedure day single-dose skipped (SDS), and 24-hour skipped (24S) NOACs in patients undergoing AF ablation., Methods and Results: In this prospective, open-label, randomized multicentre trial, 326 patients (75% male, 58 ± 11 years old) scheduled for AF catheter ablation were randomly assigned in a 1:1:1 ratio to UI, SDS, and 24S at three tertiary hospitals. Bridging with low molecular weight heparin was carried out in the patients with persistent AF who were assigned to the 24S group. Dabigatran, rivaroxaban, and apixaban were assigned in order after randomization. The primary endpoint was the incidence of bleeding events within 1 month after ablation. The secondary endpoints included thrombo-embolic and other procedure-related complications. The intra-procedural heparin requirement was higher in the 24S group than others (P < 0.001), and the mean activated clotting time was comparable among the groups (P = 0.139). The incidence of major bleeding up to 1 month after ablation and a post-procedural reduction in the haemoglobin levels did not significantly differ among the treatment groups and different NOACs (P > 0.05). There were no fatal events or thrombo-embolic complications in all the three groups., Conclusion: In patients undergoing AF ablation, UI NOACs and SDS or double dose skipped NOACs had a comparable efficacy and safety, regardless of the type of NOAC., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Aims: We used the US Department of Defense Military Health System database to compare the safety and effectiveness of direct oral anticoagulants (DOACs) in patients with non-valvular atrial fibrillation (NVAF) initiating dabigatran vs. rivaroxaban or apixaban., Methods and Results: Two cohorts of adults with NVAF, newly initiated on standard-dose DOAC, were identified based on clinical approval dates: July 2011-June 2016 for dabigatran (150 mg b.i.d.) or rivaroxaban (20 mg QD) and January 2013-June 2016 for dabigatran (150 mg b.i.d.) or apixaban (5 mg b.i.d.). Propensity score matching (1:1) identified two well-balanced cohorts (dabigatran vs. rivaroxaban n = 12 763 per treatment group; dabigatran vs. apixaban n = 4802 per treatment group). In both cohorts, baseline characteristics and follow-up duration were similar between treatment groups. Patients newly initiating dabigatran had significantly lower risk of major bleeding vs. rivaroxaban [2.08% vs. 2.53%; hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.70-0.97; P = 0.018], while stroke risk was similar (0.60% vs. 0.78%; HR 0.77, 95% CI 0.57-1.04; P = 0.084). The dabigatran vs. apixaban cohort analysis found no differences in risk of major bleeding (1.60% vs. 1.21%; HR 1.37, 95% CI 0.97-1.94; P = 0.070) or stroke (0.44% vs. 0.35%; HR 1.26, 95% CI 0.66-2.39; P = 0.489)., Conclusion: Among NVAF patients newly initiated on standard-dose DOAC therapy in this study, dabigatran was associated with significantly lower major bleeding risk vs. rivaroxaban, and no significant difference in stroke risk. For dabigatran vs. apixaban, the reduced sample size limited the ability to draw definitive conclusions., (© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Effective anticoagulation in patients undergoing electrical cardioversion (ECV) for symptomatic atrial fibrillation is important to prevent adverse events. High medication adherence is a requirement. In patients with newly diagnosed atrial fibrillation (n = 169) who were intended to undergo ECV, the aim of this study was to measure self-reported short- and long-term adherence, evaluate whether dabigatran plasma concentrations reflect adherence, measure treatment satisfaction and assess whether adherence and treatment satisfaction are correlated., Methods and Results: Plasma concentrations (liquid-chromatography tandem mass spectrometry), the 8-point Morisky Medication Adherence Scale (MMAS-8) and the Anti-Clot Treatment Scale (ACTS) were measured after 3 weeks and 7 weeks of treatment. Combined mean peak (1-3 h after intake) and trough (10-16 h after intake) plasma concentrations were 175 (SD 109) ng/mL and 75 (SD 45) ng/mL, respectively. There was no relationship between short-term adherence (last 3 days) or long-term adherence (last 3-4 weeks) and plasma concentrations, unless the last intake was more than 48 h ago. After 7 weeks high, moderate, and low adherence, according to the MMAS-8, was seen in 74%, 21%, and 5% of patients, respectively. Treatment satisfaction was high (median ACTS score 68.5, range 46-75 points). Treatment satisfaction and adherence were not correlated., Conclusion: The percentage of patients in the high adherence group (74%) was lower than expected, which is a matter of concern. Dabigatran plasma concentrations could not detect short- or long-term non-adherence, unless the drug was last taken more than 48 h ago. Treatment satisfaction did not correlate with adherence., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Aims: This prospective, randomized, single-centre study aimed to directly compare the safety and efficacy of uninterrupted and interrupted periprocedural anticoagulation protocols with direct oral anticoagulants (DOACs) in patients undergoing catheter ablation of non-valvular atrial fibrillation (NVAF)., Methods and Results: We randomly assigned 846 NVAF patients receiving DOACs prior to ablation to uninterruption (n = 422) or interruption (n = 424) of the DOACs on the day of the procedure. The primary endpoint was a composite of symptomatic thromboembolisms and major bleeding events within 30 days after the ablation. Secondary endpoints included symptomatic and silent thromboembolisms and major and minor bleeding events. The primary endpoint occurred in 0.7% of the uninterrupted DOAC group [1 transient ischaemic attack (TIA) and 2 major bleeding events] and 1.2% of the interrupted DOAC group (1 TIA and 4 major bleeding events) (P = 0.480). The incidence of major and minor bleeding was comparable between the two groups (0.5% vs. 0.9%, P = 0.345; 5.9% vs. 5.4%, P = 0.753). Silent cerebral ischaemic lesions (SCILs) were observed in 138 (20.9%) of the 661 patients undergoing post-ablation magnetic resonance (MR) imaging. The uninterrupted and interrupted DOAC groups revealed a similar incidence of SCILs (19.8% vs. 22.0%, P = 0.484) and percentage of SCILs with disappearance on follow-up MR imaging (77.8% vs. 82.1%, P = 0.428)., Conclusion: Both the uninterrupted and interrupted DOAC protocols revealed a low risk of symptomatic thromboembolisms and major bleeding events and similar incidence of SCILs and minor bleeding events and may be feasible for periprocedural anticoagulation in NVAF patients undergoing catheter ablation.

Aims: To assess the incremental benefit of uninterrupted direct oral anticoagulants (DOACs) vs. uninterrupted vitamin K antagonists (VKA) for catheter ablation (CA) of non-valvular atrial fibrillation (NVAF) on three primary outcomes: major bleeding, thrombo-embolic events, and minor bleeding. A secondary outcome was post-procedural silent cerebral infarction (SCI) as detected by brain magnetic resonance imaging., Methods and Results: A systematic review of Medline, Cochrane, and Embase was done to find all randomized controlled trials (RCTs) in which uninterrupted DOACs were compared against uninterrupted VKA for CA of NVAF. A fixed-effect model was used, with the exception of the analysis regarding major bleeding events (I2 > 25), for which a random effects model was used. The benefit of uninterrupted DOACs over VKA was analysed from four RCTs that enrolled a total of 1716 patients (male: 71.2%) with NVAF. Of these, 1100 patients (64.1%) had paroxysmal atrial fibrillation. No significant benefit was seen in major bleeding events [risk ratio (RR) 0.54, 95% confidence interval (95% CI) 0.29-1.00; P = 0.05]. No significant differences were found in minor bleeding events (RR 1.11, 95% CI 0.82-1.52; P = 0.50), thrombo-embolic events (RR 0.74, 95% CI 0.26-2.11; P = 0.57), or post-procedural SCI (RR 1.06, 95% CI 0.74-1.53; P = 0.74)., Conclusion: An uninterrupted DOACs strategy for CA of NVAF appears to be as safe as uninterrupted VKA without a significantly increased risk of minor or major bleeding events. There was a trend favouring DOACs in terms of major bleeding. Given their ease of use, fewer drug interactions and a similar security and effectiveness profile, DOACs should be considered first line therapy in patients undergoing CA for NVAF.

Aims: To describe the prevalence and associated factors of inappropriate doses of direct oral anticoagulants (DOAC) in a national registry of patients of real clinical practice., Methods and Results: Five hundred and thirty outpatients with atrial fibrillation treated with DOAC were included in a prospective, national, multicentre study. The appropriateness of the doses of DOAC was defined according to the recommendations of the European Heart Rhythm Association. Mean age was 73 ± 9 years, with a 46% of women. Two hundred and sixty-seven patients were prescribed dabigatran, 190 rivaroxaban, and 73 apixaban. A total of 172 patients (32%) did not receive the appropriate dose: 93 patients received a lower dose (18%) and 79 patients a higher dose (15%). In the comparisons among the subgroups of inappropriately low, appropriate, and inappropriately high dose, we observed significant trends to older age (69 ± 8 years vs. 73 ± 10 years vs. 77 ± 6 years), more frequent female sex (37% vs. 46% vs. 59%), antiplatelet drugs (5% vs. 8% vs. 25%), rivaroxaban (14% vs. 38% vs. 53%), and apixaban use (5% vs. 15% vs. 19%), higher CHAD2DS2-VASc (3.00 ± 1.38 vs. 3.58 ± 1.67 vs. 4.59 ± 1.44) and HAS-BLED scores (1.83 ± 0.87 vs. 1.92 ± 1.07 vs. 2.47 ± 1.13), lower body mass index (30 ± 6 kg/m2 vs. 29 ± 4 kg/m2 vs. 28 ± 4 kg/m2) and glomerular filtration rate (74 ± 27 mL/min vs. 70 ± 22 mL/min vs. 63 ± 16 mL/min), and lower frequency of dabigatran use (81% vs. 47% vs. 28%) (all comparisons P ≤ 0.01)., Conclusion: In this real-life study, 32% of patients received an inappropriate dose of DOAC. Several clinical factors can identify patients at risk of this situation.

Aim: We tested the hypothesis that left ventricular hypertrophy (LVH) interferes with the antithrombotic effects of dabigatran and warfarin in patients with atrial fibrillation (AF)., Methods and Results: This is a post-hoc analysis of the Randomized Evaluation of Long-term anticoagulation therapY (RE-LY) Study. We defined LVH by electrocardiography (ECG) and included patients with AF on the ECG tracing at entry. Hazard ratios (HR) for each dabigatran dose vs. warfarin were calculated in relation to LVH. LVH was present in 2353 (22.7%) out of 10 372 patients. In patients without LVH, the rates of primary outcome were 1.59%/year with warfarin, 1.60% with dabigatran 110 mg (HR vs. warfarin 1.01, 95% confidence interval (CI) 0.75-1.36) and 1.08% with dabigatran 150 mg (HR vs. warfarin 0.68, 95% CI 0.49-0.95). In patients with LVH, the rates of primary outcome were 3.21%/year with warfarin, 1.69% with dabigatran 110 mg (HR vs. warfarin 0.52, 95% CI 0.32-0.84) and 1.55% with 150 mg (HR vs. warfarin 0.48, 95% CI 0.29-0.78). The interaction between LVH status and dabigatran 110 mg vs. warfarin was significant for the primary outcome (P = 0.021) and stroke (P = 0.016). LVH was associated with a higher event rate with warfarin, not with dabigatran. In the warfarin group, the time in therapeutic range was significantly lower in the presence than in the absence of LVH., Conclusions: LVH was associated with a lower antithrombotic efficacy of warfarin, but not of dabigatran, in patients with AF. Consequently, the relative benefit of the lower dose of dabigatran compared to warfarin was enhanced in patients with LVH. The higher dose of dabigatran was superior to warfarin regardless of LVH status., Clinical Trial Registration: http:www.clinicaltrials.gov. Unique identifier: NCT00262600., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We aim to determine the optimal dose of dabigatran in Korean patients with atrial fibrillation (AF)., Methods and Results: We analysed 1834 patients with non-valvular AF, classified into a warfarin group (n = 990), dabigatran 150 mg group (D150, n = 294), and 110 mg group (D110, n = 550). The D110 group was further classified into patients concordant (co-D110, n = 367) and patients discordant (di-D110, n = 183) with guidelines to dose reduction. Propensity-matched 1-year clinical outcomes were then compared. Efficacy outcomes were defined as thromboembolism composed of new-onset stroke or systemic embolism. Safety outcomes were major bleeding. Both D150 and D110 had comparable efficacies as warfarin. However, only D110 significantly lowered the risk of major bleeding [hazard ratio (HR) 0.19, 95% confidence interval (CI) 0.07-0.55, P = 0.002]. In a subgroup analysis according to guideline-concordant indications for dose reduction, both co-D110 and di-D110 displayed a comparable efficacy as warfarin. Both co-D110 (HR 0.22, 95% CI 0.06-0.76, P = 0.017) and di-D110 (HR 0.11, 95% CI 0.02-0.81, P = 0.030) significantly lowered incidences of major bleeding. There were no differences in the efficacy and safety between di-D110 and D150, and net clinical outcomes were similar., Conclusion: Although D150 and D110 had a comparable efficacy, only D110 lowered the risk of major bleeding in Korean AF patients compared with warfarin. Even the guideline-discordant use of dabigatran 110 mg demonstrated a similar efficacy and safety compared with D150. However, further prospective randomized trials are needed in order to comprehensively evaluate whether D150 or D110 is the optimal dosage in Asian patients with AF., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Heparin-induced thrombocytopenia (HIT) requires alternative anticoagulation strategies. We investigated outcomes in patients with HIT antibodies undergoing low-dose bivalirudin anticoagulation during left ventricular assist device implantation on an extracorporeal life support system (ECLS) and compared the results with non-HIT patients treated with heparin and receiving left ventricular assist device implantation with ECLS support., Methods: The institutional ventricular assist device database was searched for the period from March 2012 to March 2016. The primary end-point was the need for early (<7 days) surgical re-exploration due to persistent haemorrhage or cardiac tamponade postoperatively. The secondary clinical end-points were delayed chest closure, stroke, intracranial bleeding, re-thoracotomy >7 days and mortality up to 1 year. Unadjusted comparison was used for the entire groups. Because of non-random group assignment, propensity score matching was also performed to compare treatment effects., Results: Twenty-one patients were treated with bivalirudin and 36 patients with heparin. INTERMACS levels were lower, inotropic score was higher and the prevalence of mechanical ventilation and preoperative ECLS implants was also significantly higher in the heparin group than in the bivalirudin group (P-values <0.05). The primary end-point was reached by 19% in the bivalirudin group and 16.7% in the heparin group (bivalirudin group: odds ratio 1.18, 95% confidence interval 0.29-4.76; P = 0.820). The propensity score-matched groups also showed no difference in this regard (P = 0.455). All secondary clinical end-points were comparable between groups, both in the unadjusted analysis and in the propensity score-matched groups., Conclusions: In patients with HIT antibodies, low-dose bivalirudin anticoagulation on ECLS support appears to be a feasible option for left ventricular assist device implantation., (© The Author 2017. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Many sites routinely continue anticoagulation after primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction (STEMI), despite an unclear benefit-risk ratio. We evaluated the impact of this strategy on 30-day outcomes from a pooled patient-level database of two large primary percutaneous coronary intervention trials., Methods: EUROMAX and HORIZONS-AMI were both multicentre, international randomised trials comparing bivalirudin to heparin with or without glycoprotein IIb/IIIa inhibitors in patients with STEMI undergoing primary percutaneous coronary intervention. Outcomes at 30 days were analysed according to the use of post-procedural anticoagulation (unfractionated or low-molecular-weight heparins or fondaparinux) outside of the catheterisation laboratory., Results: Among 5239 patients undergoing primary percutaneous coronary intervention, 2153 (41.1%) received post-procedural anticoagulation. After adjusting for differences in baseline variables, there were no differences in the 30-day rates of adverse ischaemic events between patients without versus with post-procedural anticoagulation: adjusted odds ratio for major adverse cardiac events 0.80; 95% confidence interval 0.60-1.07; P=0.14; adjusted odds ratio for stent thrombosis 0.82; 95% confidence interval 0.55-1.24; P=0.35; adjusted odds ratio for death 1.07; 95% confidence interval 0.69-1.66; P=0.77. Conversely, protocol-defined major bleeding was decreased without post-procedural anticoagulation: adjusted odds ratio 0.74; 95% confidence interval 0.58-0.94; P=0.01. Similar results were observed for Thrombolysis In Myocardial Infarction major and minor bleeding., Conclusions: In this large STEMI database, a substantial proportion of primary percutaneous coronary intervention patients received post-procedural anticoagulation, which in turn was associated with higher bleeding rates without any reduction in ischaemic events. Therefore, routine post-procedural anticoagulation after primary percutaneous coronary intervention seems to have an unfavourable benefit-risk profile and should be avoided unless a well-established indication is present., Clinical Trial Registration: ClinicalTrials.gov , EUROMAX Identifier NCT01087723; HORIZONS Identifier NCT00433966.

Aims: Cardiac implantable electronic device (CIED) surgery is commonly performed in patients with atrial fibrillation (AF). The current analysis was undertaken to compare peri-operative anticoagulation management, bleeding, and thrombotic events in AF patients treated with dabigatran vs. warfarin., Methods and Results: This study included 611 patients treated with dabigatran vs. warfarin who underwent CIED surgery during the RE-LY trial. Among 201 warfarin-treated patients, warfarin was interrupted a median of 144 (inter-quartile range, IQR: 120-216) h, and 37 (18.4%) patients underwent heparin bridging. In dabigatran-treated patients (216 on 110 mg bid and 194 on 150 mg bid), the duration of dabigatran interruption was a median of 96 (IQR: 61-158) h. Pocket hematomas occurred in 9 (2.20%) patients on dabigatran and 8 (3.98%) patients on warfarin (P = 0.218). The occurrence of pocket hematomas was lower with dabigatran compared with warfarin with heparin bridging (RD: -8.62%, 95% CI: -24.15 to - 0.51%, P = 0.034) but not when compared with warfarin with no bridging (P = 0.880). Ischemic stroke occurred in 2 (0.3%) patients; one in the warfarin group (without bridging) and one in the dabigatran 150 mg bid group (P = 0.735)., Conclusion: In patients treated with dabigatran undergoing CIED surgery, interruption of dabigatran is associated with similar or lower incidence of pocket hematoma, when compared with warfarin interruption without or with heparin bridging, respectively. Whether uninterrupted dabigatran can reduce pocket hematoma or ischemic stroke remains to be evaluated., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.)

Aim: Post-procedural anticoagulation (AC) for routine prophylaxis may be administered after primary percutaneous coronary intervention (PCI) in ST-segment elevation myocardial infarction (STEMI), but the risks and benefits of this practice are uncertain. We therefore sought to assess the utility of routine post-procedural AC after primary PCI., Methods and Results: Patients undergoing primary PCI in the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial were grouped according to whether they received post-PCI AC for routine prophylaxis. Outcomes were assessed using propensity-adjusted multivariable analysis. Among 2932 patients in whom primary PCI for STEMI was performed, 869 (29.6%) received post-PCI AC for routine prophylaxis (median duration four days) and 2063 (70.4%) received no post-PCI AC. Time from PCI to ambulation was similar in both groups (median 0.9 vs 1.0 days, p=0.40), although hospitalization was prolonged in patients receiving AC for routine prophylaxis (median 6.0 vs 4.0 days, p<0.0001). After propensity-adjustment, patients who received and did not receive AC for routine prophylaxis after PCI experienced similar rates of 30-day adverse ischemic and major bleeding events. Deep venous thrombosis or pulmonary emboli developed rarely (0.3%) within 30 days, and were not significantly reduced by use of post-PCI AC for routine prophylaxis., Conclusions: In this large-scale prospective study, use of post-procedural AC for routine prophylaxis was relatively common, and was not associated with improved clinical outcomes, although the duration of hospitalization was prolonged. These data suggest that post-PCI AC for routine prophylaxis may not provide benefit after successful primary PCI in patients in whom early ambulation is likely.

Background: Myocardial reperfusion after primary percutaneous coronary intervention (PCI) can be assessed by the extent of post-procedural ST-segment resolution. The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial compared pre-hospital bivalirudin and pre-hospital heparin or enoxaparin with or without GPIIb/IIIa inhibitors (GPIs) in primary PCI. This nested substudy was performed in centres routinely using pre-hospital GPI in order to compare the impact of randomized treatments on ST-resolution after primary PCI., Methods: Residual cumulative ST-segment deviation on the single one hour post-procedure electrocardiogram (ECG) was assessed by an independent core laboratory and was the primary endpoint. It was calculated that 762 evaluable patients were needed to show non-inferiority (85% power, alpha 2.5%) between randomized treatments., Results: A total of 871 participated with electrocardiographic data available in 824 patients (95%). Residual ST-segment deviation one hour after PCI was 3.8±4.9 mm versus 3.9±5.2 mm for bivalirudin and heparin+GPI, respectively ( p=0.0019 for non-inferiority). Overall, there were no differences between randomized treatments in any measures of ST-segment resolution either before or after the index procedure., Conclusions: Pre-hospital treatment with bivalirudin is non-inferior to pre-hospital heparin + GPI with regard to residual ST-segment deviation or ST-segment resolution, reflecting comparable myocardial reperfusion with the two strategies.

Purpose: The available clinical data on target-specific oral anticoagulant (TSOAC) reversal agents that are currently in development or have been approved by the Food and Drug Administration (FDA) are reviewed., Summary: The development of TSOACs such as dabigatran, rivaroxaban, edoxaban, and apixaban has presented benefits and new challenges. One of the main challenges associated with the use of TSOACs is the lack of suitable agent-specific reversal agents. Several treatment options for the management of life-threatening bleeding events associated with TSOAC use, such as fresh frozen plasma, prothrombin complex concentrates, and recombinant coagulation factor VIIa, have been used, with inconsistent results. Currently, two potential reversal agents for oral direct factor Xa inhibitors (andexanet alfa and ciraparantag) are at various stages of clinical development. Idarucizumab, a reversal agent for the oral direct thrombin inhibitor dabigatran, was approved by FDA in October 2015. Idarucizumab and andexanet alfa have been reported to produce anticoagulation reversal effects within minutes of administration. Ciraparantag was demonstrated to decrease whole blood clotting time to within 10% of baseline values in 10 minutes or less, with a return to baseline hemostasis in 10-30 minutes. TSOAC reversal agents have been generally well tolerated in clinical trials., Conclusion: Idarucizumab and other TSOAC reversal agents, such as andexanet alfa and ciraparantag, present the potential for consistent and effective treatment and management options when life-threatening or uncontrolled TSOAC-associated bleeding occurs or when emergency surgery is warranted in patients using TSOACs., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

The current treatment of thrombotic APS patients includes long-term anticoagulation with oral vitamin K antagonists (VKAs), with warfarin being the one most commonly used. However, the use of VKAs can be challenging, especially in patients with APS. VKAs monitoring in patients with aPL is complicated by the heterogeneous responsiveness to LAs of reagents used in the International Normalized Ratio test, potentially resulting in instability of anticoagulation. For decades, VKAs were the only available oral anticoagulants. However, non-VKA oral anticoagulants, including a direct thrombin inhibitor (dabigatran etexilate) and direct anti-Xa inhibitors (rivaroxaban, apixaban and edoxaban), are currently available. The use of these agents may represent a major step forward since, unlike VKAs, they have few reported drug interactions and they do not interact with food or alcohol intake, thereby resulting in more stable anticoagulant intensity. Most importantly, monitoring their anticoagulant intensity is not routinely required due to their predictable anticoagulant effects. In this review, we discuss the clinical and laboratory aspects of non-VKA oral anticoagulants, focusing on the available evidence regarding their use in patients with APS., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aims: The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial allowed patients who completed the trial receiving their assigned dabigatran 150 mg (D150) or 110 mg (D110) twice a day to continue into the Long-term Multicenter Extension of Dabigatran Treatment in Patients with Atrial Fibrillation (RELY-ABLE) trial. This permitted assessment of outcomes over a median of 4.6 and a maximum of 6.7 years, respectively., Methods and Results: The analysed population included only those patients who completed RE-LY on dabigatran and continued into RELY-ABLE without interruption of assigned dabigatran. Cumulative risk was expressed as Kaplan-Meier plots. Outcomes were compared using Cox proportional hazard modelling. Stroke or systemic embolization rates were 1.25 and 1.54% per year (D150 and D110, respectively); hazard ratio (HR) 0.81 [95% confidence interval (CI): 0.68-0.96] (P = 0.02). Ischaemic stroke was 1.03 (D150) and 1.29%/year (D110); HR 0.79 (95% CI: 0.66-0.95) (P = 0.01). Haemorrhagic stroke rates were 0.11 (D150) and 0.13%/year (D110); HR 0.91 (95% CI: 0.51-1.62) (P = 0.75). Rates of major haemorrhage were 3.34 (D150) and 2.76%/year (D110); HR 1.22 (95% CI: 1.08-1.37) (P = 0.0008). Intracranial haemorrhage rates were 0.32 (D150) and 0.23%/year (D110); HR 1.37 (95% CI: 0.93-2.01) (P = 0.11). Mortality was 3.43 (D150) and 3.55%/year (D110); HR 0.97 (95% CI: 0.87-1.08) (P = 0.54)., Conclusion: Annualized rates of all outcomes were constant with better efficacy of D150, less major bleeding with D110, and low intracerebral haemorrhage rates for both doses. There were no additional safety concerns. This is the longest continuous randomized experience of a novel anticoagulant., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.)

Background: Several new antithrombotic therapies have emerged for the treatment of acute coronary syndrome (ACS). We sought to assess contemporary patterns of antithrombotic therapies use in patients with ACS., Methods and Results: EYESHOT (EmploYEd antithrombotic therapies in patients with acute coronary Syndromes HOspitalized in iTalian cardiac care units) was a nationwide, prospective registry aimed to evaluate antithrombotic strategies employed in patients admitted to intensive cardiac care units (CCUs) for an ACS in Italy. Over a three-week period, 203 CCUs enrolled 2585 consecutive patients: 41.2% with ST-elevation myocardial infarction (STEMI) and 58.8% with non-ST elevation ACS (NSTE-ACS). During hospitalisation, low-molecular-weight heparins, aspirin, and clopidogrel were the most commonly used antithrombotic therapies. Among patients treated with percutaneous coronary intervention (PCI, n=1755), any crossover of heparin therapy occurred in 30.8% of cases, while switching from one P2Y12 inhibitor to another occurred in 3.6% of cases in the CathLab and in 14.2% before discharge. Of the 790 patients who did not receive revascularisation, switching of a P2Y12 inhibitor occurred in 5.7% of cases. At discharge, a new P2Y12 inhibitor (ticagrelor or prasugrel) in association with aspirin was prescribed in 59.5% of STEMI and 33.9% of NSTE-ACS patients: the most powerful predictor for prescription was PCI (odds ratio (OR) 6.18; 95% confidence interval (CI) 4.76-8.01; p<0.0001), whereas age ≥ 75 years was strongly associated with clopidogrel use (OR 0.28; 95% CI 0.22-0.36; p<0.0001)., Conclusions: The EYESHOT registry shows the current pattern of antithrombotic treatments for ACS patients admitted to Italian CCUs and provides insights which may help to improve the clinical care of such patients., (© The European Society of Cardiology 2014.)

Objective: To evaluate the safety, effectiveness, and dosing of off-label bivalirudin to argatroban and lepirudin in patients with heparin-induced thrombocytopenia (HIT) using a new pharmacist driven protocol., Methods: Retrospective cohort study of forty eight patients treated with lepirudin, argatroban, or bivalirudin from November 2010 to February 2012 for suspected HIT. Patients were excluded if the bivalirudin therapy was being used for acute coronary syndrome or if the treatment duration was less than 24 hours. The primary endpoint was time to therapeutic activated partial thromboplastin time (aPTT 50-90 seconds for argatroban and bivalirudin and 50-85 seconds for lepirudin). The secondary endpoints were elevation in international normalized ratio (INR), bleeding episodes, and percent time in aPTT target range., Results: Patients receiving bivalirudin reached a therapeutic aPTT more quickly than those receiving argatroban and lepirudin (3.7 hours vs. 14.2 hours vs. 14.7 hours, p <0.001). The INR was increased more in patients treated with argatroban than lepirudin and bivalirudin (1.3 vs. 0.3 vs. 0.4, p = 0.4). Clinically significant bleeding in patients treated with bivalirudin was significantly lower than that observed with argatroban or lepirudin (7% vs. 22% vs. 56%, p = 0.02). The average percentage of therapeutic aPTTs drawn was higher for patients treated with bivalirudin than those patients treated with argatroban and lepirudin (90% vs. 66% vs. 67%, p = 0.2)., Conclusion: A pharmacist-driven protocol for bivalirudin provided a significantly shorter time to therapeutic aPTT and lower bleeding rate for patients being treated for HIT when compared to lepirudin and argatroban. A larger study should be considered to confirm the results of this single center study., (Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Direct oral anticoagulants (DOACs) specifically target factor IIa or Xa and represent a major step forward in the treatment of acute- and long-term prevention of venous thrombo-embolism (VTE). They are at least as effective and as safe as conventional therapy (heparins and vitamin-K inhibitors) and have practical advantages, such as fixed dosing and no need for laboratory monitoring. These antithrombotic agents introduce a new paradigm for the day-to-day management of VTE. Direct oral anticoagulants should streamline the management of most patients with VTE and will facilitate care in the outpatient setting. Nevertheless, it remains uncertain how to select specific DOACs for particular profiles of patients, and the optimal management of bleeding complications is evolving., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.)

Purpose: Currently available clinical data and optimal strategies for reversing oral anticoagulants in patients who are bleeding or need an urgent invasive procedure or operation are reviewed., Summary: Bleeding from oral anticoagulants, including new target-specific oral agents (TSOAs), is a common cause of morbidity and mortality, especially in elderly patients. Limited clinical data are available to guide the reversal of warfarin or TSOAs in patients who are bleeding or need an urgent invasive procedure or operation. A panel of five experts with diverse backgrounds in anticoagulation therapy, cardiology, critical care, and emergency medicine and with experience in managing complications of anticoagulation therapy was convened to develop practical strategies for managing patients receiving oral anticoagulants who are bleeding or have an urgent need for an invasive procedure. The strategies were designed to guide clinicians in the acute care setting by providing efficient and potentially effective management concepts to avoid delays in initiating treatment that could adversely affect patient outcomes. The consensus of this expert panel is summarized herein. Recommendations are based on currently available evidence from a comprehensive review of the literature and other pertinent data, along with the experience and expert opinion of the panelists., Conclusion: Bleeding is a serious complication of the use of oral anticoagulants, and limited information is available to guide the reversal of warfarin or TSOAs in patients who are bleeding or are in need of an urgent invasive procedure. Use of a systematic approach to assessing and treating these patients based on available evidence and expert opinion can help avoid delays that could adversely affect patient outcomes.

Purpose: The results of a study to determine whether pharmacist monitoring in the crucial first months of dabigatran therapy in patients with atrial fibrillation or flutter can help optimize adherence and stroke-prevention outcomes are presented., Methods: A retrospective preimplementation-postimplementation study was conducted at a Veterans Affairs (VA) hospital to evaluate dabigatran adherence and treatment outcomes in a group of patients whose therapy was monitored by anticoagulation clinic (ACC) pharmacists (n = 20) and a historical comparison group (n = 48) that received usual care (UC). The primary endpoint was the medication possession ratio (MPR) averaged across each group over three months (acceptable adherence was defined as an MPR of ≥80%); three secondary endpoints (dabigatran-related bleeding and incident stroke and venous thromboembolism) were evaluated., Results: Relative to the UC group, ACC-monitored patients were significantly more likely to have undergone recommended baseline laboratory tests before dabigatran initiation (p = 0.02). ACC patients were also more likely to have MPR values of ≥80% at the end of the three-month follow-up period (25% of patients versus 10% of patients), although the difference was not statistically significant; the mean MPR values in the ACC-monitored and UC groups were 93.1% and 88.3%, respectively. Aside from one episode of major gastrointestinal bleeding, none of the evaluated adverse outcomes occurred in either group., Conclusion: VA patients treated with dabigatran for nonvalvular atrial fibrillation or flutter and followed by a pharmacist-managed ACC did not differ significantly from similar patients receiving UC in the proportion adherent with dabigatran therapy or in the frequency of minor or major bleeding episodes. Thromboembolic events and strokes were absent in both groups.

Novel oral anticoagulants that directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban, apixaban) are currently available for prevention of venous thromboembolism (VTE) after orthopaedic surgery, treatment of acute VTE, and prevention of arterial thromboembolism in non-valvular atrial fibrillation. These agents offer advantages over VKAs, including rapid onset, shorter half-lives, fewer drug interactions, and lack of need for routine monitoring. However, there are no established agents to reverse their anticoagulant effect. We review the risk of bleeding with the novel oral anticoagulants and the limitations of conventional coagulation assays for measuring anticoagulant effect. We provide an approach to the management of patients with bleeding complications with evidence for various interventions for reversal, where available.

Purpose: Available evidence on laboratory monitoring of coagulation assays and reversal strategies for the management of hemorrhagic events associated with the newer anticoagulants is reviewed., Summary: While there are no published studies with dabigatran and prothrombinase-induced clotting time (PiCT) and no chromogenic assays available to measure the anticoagulant effects, thrombin time and activated partial thromboplastin time (aPTT ) may be used to detect the presence of dabigatran. Although ecarin clotting time is sensitive to elevated concentrations of dabigatran, only a small fraction of institutions have access to this assay. Rivaroxaban and apixaban prolong prothrombin time, dilute prothrombin time, aPTT, Heptest results, and PiCT to varying degrees, having the most- pronounced effects at higher concentrations. In contrast, the chromogenic antifactor Xa assay proved to be sensitive to lower amounts of rivaroxaban and apixaban with less variability. Despite the expectations with these newer anticoagulants, the associated risk of bleeding is significant, and there are insufficient data depicting treatment options in emergency situations. Until four-factor prothrombin complex concentrates (PCCs) become available in the United States, the obtainable options are activated PCC, three-factor PCCs, and recombinant factor VIIa., Conclusion: Although there is currently no gold standard of measurement for any of the newer anticoagulants, the published literature enables practitioners to evaluate the efficacy and sensitivity of a majority of these assays. Prohemostatic agents can be used in instances of severe, life-threatening hemorrhagic complications.

The availability of automated anti-Xa heparin assays provides the opportunity to manage patient unfractionated heparin levels directly, rather than by the activated partial thromboplastin time. Because critically ill patients can acquire an antithrombin deficiency, we compared the performance of 3 anti-Xa heparin assays, 1 with and 2 without antithrombin supplementation, by analyzing in vitro aliquots of plasma with defined antithrombin levels and specimens from intensive care patients receiving intravenous heparin therapy. Heparin concentration recovery, in vitro, was dependent on the plasma antithrombin concentration for all 3 assays. The antithrombin-supplemented assay demonstrated improved heparin recovery in direct correlation to the heparin concentration in the plasma. The greatest effect of antithrombin supplementation occurred when the antithrombin level dropped below 40%, a level present in only 5% of the patient specimens. Analysis of patient specimens demonstrated significant correlation among the 3 assays. Classification of the clinical adequacy of patient heparin levels showed agreement of 80% or more between the antithrombin-supplemented and nonsupplemented assays. The antithrombin-supplemented assay did not significantly improve clinical usefulness.

Appropriate management, as well as efficacy and safety, of heparin-induced thrombocytopenia (HIT) and prevention of severe consequences with argatroban and lepirudin are discussed. Heparin-induced thrombocytopenia, a serious immune-mediated drug reaction, can occur as an isolated incident (isolated HIT) or with acute thrombosis sometimes referred to as HIT and associated thrombosis syndrome (HITTS). Due to the severe consequences associated with HIT, appropriate management is critical. Argatroban and lepirudin, two direct thrombin inhibitors (DTIs), are currently FDA approved for use in patients with HIT. The clinical experience with these agents is critically examined in this article. The safety and efficacy of argatroban in management of HIT were the subject of a single published clinical trial. The study was designed to reflect conventional clinical practice, whereby treatment of patients with HIT was initiated upon clinical suspicion. In several of these patients, HIT antibodies could not be demonstrated. Compared to historical controls, argatroban demonstrated efficacy in patients with isolated HIT; however, no differences were observed in HIT patients with acute thrombosis. Rates of bleeding episodes did not differ between argatroban and control. The clinical efficacy and safety of lepirudin have been the subject of three clinical trials and one large drug monitoring program. Lepirudin has demonstrated benefit in HIT patients with or without existing thromboembolism. Bleeding rates were higher than in the historical control. However, bleedings requiring transfusion did not differ. Although no direct head-to-head comparison trials of argatroban and lepirudin have been conducted, parallels can be drawn between the agents based on careful review of published clinical trials. Consistently, rates of new thrombosis, limb amputation, and death appear to be lower in patients treated with lepirudin as compared with those treated with argatroban, whereas the risk for major bleeding per patient day seems to be similar with both DTIs.

Aim: Unstable coronary artery disease (CAD) is a multifactorial disease involving both thrombotic and inflammatory processes. We have assessed the time-course and the influence of thrombin inhibitors on changes in fibrinogen and C-reactive protein levels, and their relation to myocardial ischaemia in unstable CAD., Methods and Results: Three hundred and twenty patients were randomized to 72 h infusion with three different doses of inogatran, a direct thrombin inhibitor, or unfractionated heparin. There were no significant differences between the treatment groups in fibrinogen or C-reactive protein levels. Overall, the fibrinogen levels were significantly increased in the first 24-96 h and still elevated at 30 days. The C-reactive protein levels showed a more pronounced increase during the first 24-96 h, but then markedly decreased over 30 days. Troponin-positive compared to troponin-negative patients had higher fibrinogen and C-reactive protein levels up to 96 h, although there was an increase compared to pre-treatment levels in both groups. A high fibrinogen level (pre-treatment top tertile) was associated with an increased rate of death or myocardial (re-)infarction at 30 days, 13% vs 5.6%, P=0.03, and increased long-term mortality. A high C-reactive protein level was related to increased 30-day mortality, 4% vs 0%, P=0.01., Conclusion: Myocardial cell injury was related to a high degree of inflammation, only some of which is an acutephase response due to tissue damage. The rise in fibrinogen was sustained, which might reflect low grade inflammation with long-term risk of thrombosis. The transient elevation of C-reactive protein levels might indicate a propensity to a pronounced inflammatory response and is associated with increased mortality.

Aims: To compare effects of heparin and hirudin on biochemical markers of coagulation., Methods and Results: Patients (n=395) with unstable angina or myocardial infarction without ST elevation were randomized to a 72-h infusion of one of three regimens: unfractionated heparin (bolus of 5000 IU followed by an infusion of 1200 IU. h(-1)), low-dose hirudin (HBW 023; 0.2 mg. kg(-1)bolus followed by 0.10 mg. kg(-1). h(-1)) or medium-dose hirudin (0.4 mg. kg(-1)bolus followed by 0.15 mg. kg(-1). h(-1)). Infusions were adjusted to maintain an activated partial thromboplastin time of between 60-100 s. Activated partial thromboplastin time, prothrombin fragment 1.2 (F1.2), thrombin antithrombin III complex and D-dimer were measured before, during and after the infusion. Median activated partial thromboplastin time was similar in the two groups early on, but was significantly lower in the heparin group than in the combined hirudin group 48 h after starting the infusion (53 s and 75 s, respectively;P<0.001), and 6 h after stopping (31 s and 46 s, respectively;P<0.001). Median F1.2 levels were not significantly different between the groups during the infusion. Median thrombin antithrombin III levels in the heparin and hirudin groups were 2.8 microg. l(-1)and 2.3 microg. l(-1), respectively, at 6 h (P<0.001), and 3.0 microg. l(-1)and 2.3 microg. l(-1), respectively, at 48 h (P<0.001). Median D-dimer levels were 320 ng. ml(-1)and 260 ng. ml(-1)48 h after starting the infusion in the heparin and hirudin groups, respectively (P<0.001), and 415 ng. ml(-1)and 280 ng. ml(-1), respectively (P<0.001) 6 h after stopping. D-dimer levels were significantly elevated above baseline values in both groups 24-48 h after stopping the infusions., Conclusions: The greater reduction of thrombin antithrombin III and D-dimer during the hirudin infusion supports the hypothesis that hirudin is a more potent antithrombin agent than heparin. Increased D-dimer levels after stopping heparin or hirudin suggest that there is an ongoing pro-coagulant state. These results point to the greater efficacy of hirudin in preventing early clinical events (death, myocardial infarction and refractory ischaemia) compared with heparin that have been observed in large randomized trials. Persistent activation of coagulation afterstopping infusions in our study suggests that a longer course of antithrombotic treatment may be needed to pacify the thrombus., (Copyright 2000 The European Society of Cardiology.)

Unlabelled: Aims Direct thrombin inhibitors have failed to prove superiority over unfractionated heparin in several clinical trials of unstable coronary artery disease. We have investigated the relationship between activated partial thromboplastin time levels and adverse clinical events, i.e. death, myocardial (re-)infarction or refractory angina. Methods and Results One thousand two hundred and nine patients with unstable coronary artery disease were randomized to 72 h infusion with inogatran, a low molecular mass direct thrombin inhibitor, or unfractionated heparin. During 30 days follow-up there was no significant difference between inogatran and unfractionated heparin treatment as regards clinical outcome. 11.6% of the 464 inogatran treated patients with activated partial thromboplastin time above the median at 6 h (44 s) had a clinical event in 7 days, and 6.6% of the 423 patients with activated partial thromboplastin time below the median (P=0.01). After 30 days the event rate was still 41% higher in the inogatran patients with activated partial thromboplastin time above the median (P=0.06). Activated partial thromboplastin time in quartiles indicated a direct relationship between higher activated partial thromboplastin time and worse outcome. In contrast, during heparin infusion there was a trend for improved clinical outcome with activated partial thromboplastin time above the median, but this benefit was lost after cessation of treatment., Conclusions: Higher activated partial thromboplastin time levels during inogatran treatment are related to increased risk of death, myocardial infarction or refractory angina. This might, at least in part, be explained by differences in anticoagulant mechanisms between direct thrombin inhibitors and heparin, and further emphasizes the poorly defined optimal activated partial thromboplastin time range during treatment with direct thrombin inhibitors in unstable coronary artery disease., (Copyright 1999 The European Society of Cardiology.)

Aims: Thrombin plays a key role in the clinical syndrome of unstable angina. We investigated the safety and efficacy of five dose levels of efegatran sulphate, a direct thrombin inhibitor, compared to heparin in patients with unstable angina., Methods: Four hundred and thirty-two patients with unstable angina were enrolled. Five dose levels of efegatran were studied sequentially, ranging from 0.105 mg. kg(-1). h(-1)to 1.2 mg. kg(-1). h(-1)over 48 h. Safety was assessed clinically, with reference to bleeding and by measuring clinical laboratory parameters. Efficacy was assessed by the number of patients experiencing any episode of recurrent ischaemia as measured by computer-assisted continuous ECG ischaemia monitoring. Clinical end-points were: episodes of recurrent angina, myocardial infarction, coronary intervention (PTCA or CABG), and death., Results: Efegatran demonstrated dose dependent ex-vivo anticoagulant activity with the highest dose level of 1.2 mg. kg(-1). h(-1)resulting in steady state mean activated partial thromboplastin time values of approximately three times baseline. Thrombin time was also increased. Neither of the efegatran doses studied were able to suppress myocardial ischaemia during continuous ECG ischaemia monitoring to a greater extent than that seen with heparin. There were no statistically significant differences in clinical outcome or major bleeding between the efegatran and heparin groups. Minor bleeding and thrombophlebitis occurred more frequently in the efegatran treated patients., Conclusion: Administration of efegatran sulphate at levels of at least 0.63 mg. kg(-1). h(-1)provided an anti-thrombotic effect which is at least comparable to an activated partial thromboplastin time adjusted heparin infusion. There was no excess of major bleeding. The level of thrombin inhibition by efegatran, as measured by activated partial thromboplastin time, appeared to be more stable than with heparin. Thus, like other thrombin inhibitors, efegatran sulphate is easier to administer than heparin. However, no clinical benefits of efegatran over heparin were apparent., (Copyright 1999 The European Society of Cardiology.)

Aim: This study evaluated a novel specific thrombin inhibitor, inogatran, in comparison with unfractionated heparin, with regard to markers for coagulation activity in patients with unstable coronary artery disease., Methods and Results: In the Thrombin Inhibition In Myocardial Ischaemia (TRIM) study patients were randomized to one of three different doses of inogatran or to unfractionated heparin, given intravenously over 72 h. In a subpopulation of 320 patients, markers for coagulation activity were measured at baseline, during and after the study infusion. Prothrombin fragment 1 + 2, indicating thrombin generation, decreased in the low, medium and high dose inogatran groups and in the heparin group during the first 6 h of treatment by 12%, 15%, 21% and 26%, respectively. From 6 h to 72 h after the start of infusion the levels changed by -7%, -6%, -4% and +34%, respectively. The increase in the heparin group continued after the infusion was stopped. Thrombin-antithrombin complex, also indicating thrombin generation, decreased by 0%, 2%, 18% and 22%, respectively, during the first 6 h of treatment. During the same period soluble fibrin, an intermediate in fibrin formation, increased both in the low and medium inogatran group by 9%, while a decrease by 4% and 18%, respectively, was seen in the high dose inogatran group and in the heparin group. Fibrin dissolution, as measured by fibrin D-dimer, decreased during the first 24 h of treatment by 20%, 18%, 18% and 20%, respectively. The first 24 h after discontinuation of infusion, fibrin D-dimer increased by 6%, 23%, 25% and 44%, respectively. After 72 h, at the end of infusion, patients treated with inogatran, to a larger extent than those given heparin, had suffered from death, myocardial infarction or refractory angina pectoris. After 7 days this trend was less marked., Conclusion: The more pronounced decrease in thrombin generation and fibrin turnover during the first 6 h of infusion, and the later increase in thrombin generation and fibrin turnover, in the heparin group, as compared to the inogatran groups, may be related to the lower clinical event rate during infusion with heparin compared with inogatran and the recurrence of ischaemic events, early after cessation of heparin infusion.

Background: Unstable coronary artery disease, i.e. unstable angina or non-Q wave myocardial infarction, is caused by rupture of atheromatous plaques initiating thrombus formation. Thrombin is thought to be pivotal in platelet activation and thrombus growth. The aim of the present study was to compare the effect of three different doses of a novel, low molecular weight, selective thrombin inhibitor (inogatran) with that of heparin in unstable coronary artery disease. The composite primary end-point was death, incidence of myocardial infarction, refractory angina or recurrent angina after 7 days. Secondary end-points were the same after 3 and 30 days, as were death and myocardial infarction with or without refractory angina on all three occasions., Methods: Patients (n = 1209) admitted with suspected unstable angina, or non-Q wave myocardial infarction, were randomly assigned to double-blind treatment with inogatran or heparin bolus doses. This was followed by a 3 day infusion with a low (LDI), medium (MDI), or high (HDI) dose of inogatran, aiming at plasma concentrations of 0.15, 0.4 or 0.8 micromol.l-1, or heparin initiated at 1200 U.h-1., Findings: Treatment with inogatran resulted in median activated partial thromboplastin times after 24 h of 36, 44 and 53 s in the low, medium and high dose inogatran groups, respectively, as compared to 54 s in the heparin group (ns). At the end of the infusion, after 3 days, heparin-treated patients had fewer composite events (29.5%) than inogatran-treated patients (LDI = 39.4%, MDI = 37.6%, HDI = 36.1%; P = 0.01). The event rate after 7 days with respect to the primary end-point, however, did not differ between the groups (heparin = 41.0%, LDI = 45.7% MDI = 45.9%, HDI = 45.5%; ns). Death and myocardial infarction occurred less frequently in the heparin group (0.7%) than in the three inogatran groups (LDI = 3.6%, MDI = 2.0%, HDI = 4.0%; P < 0.05) after 3 days. After 7 days, this difference was attenuated (heparin = 2.6% vs LDI = 4.0%, MDI = 4.3%, HDI = 6.7%; P = 0.10). After 30 days there were no significant differences in event rates between the four groups. Major bleeding occurred in 1.1% of the patients within 7 days, with no differences between the groups., Conclusions: During study drug infusion the event rate was very low in the heparin group, and none of the inogatran dosages were better than heparin in preventing ischaemic events. Furthermore, there was no relationship between event rate and inogatran dosage. Thus, this study does not indicate that the efficacy of inogatran would improve with higher doses, despite a clear dose-effect as regards the prolongation of activated partial thromboplastin time. After cessation of heparin or inogatran there was an increase in event rates, suggestive of a rebound phenomenon.