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2014- Efficacy and safety of novel antithrombotic strategies

Five interesting studies published or presented during ACC 2014

Since AHA 2013 five interesting studies have been published or presented during ACC 2014 on the efficacy and safety of novel antithrombotic strategies.
Venous Thromboembolism

Patients undergoing non-cardiac surgery face a risk on vascular ischemic complications, for the prevention of which perioperative aspirin may have a role for aspirin-naïve patients. Furthermore, the benefit or harm of aspirin interruption in non-cardiac surgery for patients on chronic aspirin has never been prospectively studied on a large scale.
In the POISE-2 trial 10,010 patients at risk for vascular complications and planned for non-cardiac surgery were randomized to aspirin (loading dose of 200 mg) or placebo given just before surgery. Patients taking aspirin the last 72 hours before surgery were excluded. Study drug was continued for 30 days in aspirin naïve patients (n = 5,628) and for 7 days in those with prior aspirin use (n = 4,382). Death or non-fatal myocardial infarction (MI) at 30 days (primary outcome) occurred in 7.0% in the aspirin group and 7.1% on placebo (HR 0.99, 95% CI 0.86 - 1.15, p = 0.92, fig 1). Major bleeding was seen more often on aspirin than with placebo (4.6% vs 3.8%, HR 1.23; 95% CI 1.01 - 1.49, p = 0.04). The outcomes were similar in the two aspirin strata. Life-threatening or major bleeding was an independent predictor of myocardial infarction (HR 1.82, 95% CI 1.40 - 2.36, p < 0.001).

Fig 1. Death or non-fatal myocardial infarction in the POISE-2 trial

Patients at high cardiovascular risk undergoing non-cardiac surgery do not benefit from aspirin prophylaxis, whether there were on or off aspirin prior to surgery. Aspirin interruption does not seem to cause MI in chronic aspirin users. Aspirin prophylaxis induces excess major bleeding which by itself is associated with MI. Possibly, perioperative aspirin prevents MI, but by the excess bleeding that it induces the final outcome of the strategy is neutral. Finally, chronic users in whom aspirin is stopped just before surgery may benefit for several days from the protective effects on one hand, but may also suffer excess bleeding on the other. In hindsight it would have been better to stop aspirin 5 to 7 days before surgery to come to conclusive results on benefit and harm in this subgroup. Anyway, the upcoming guidelines of ESC/ESA on non-cardiac surgery and its cardiovascular assessment and management (to be presented at ESC 2014) will probably scrutinize this important study and will come up with new advices on this topic.

An interesting study on anticoagulants in primary PCI for STEMI was scheduled as a Late-Breaking Clinical Trial at ACC 2014 and originates from a single interventional center in the United Kingdom. Dr. Rod Stables’ team from the Heart and Chest Hospital in Liverpool presented the data of the HEAT-PPCI
. During 22 months in 2012 and 2013 in total 1,829 patients with STEMI were randomized to a bolus of heparin (70U/kg) pre-procedure or a bolus of bivalirudin of 0.75 mg/kg followed by an infusion of 1.75mg/kg/h for the duration of the procedure. GPI use was allowed in both trial arms according to the ESC STEMI guidelines. Prasugrel or ticagrelor was used in 89% of patients. The primary endpoint was MACE (death, stroke, reinfarction or target lesion revascularization) at 30 days and occurred in 5.7% in the heparin group and 8.7% on bivalirudin (HR 1.52, 95% CI 1.10 - 2.10, p = 0.03, NNH = 33, fig 2). Stent thrombosis was 0.9% in the heparin group and 3.4% on bivalirudin (HR 3.91, 95% CI 1.60 - 9.50, p = 0.001,
NNH = 40). Mortality was 5.1 and 4.3% respectively. Unexpectedly, major bleeding was less common on heparin than with bivalirudin (3.1% vs 3.5%, HR 1.15; 95% CI 0.70 - 1.90, p = 0.59, NNH = 250).

Fig 2. MACE in the HEAT-PPCI trial

A similar study on anticoagulants in primary PCI for STEMI was presented at ACC 2014 and recently published.(3) The BRAVE-4 study was early terminated because of slow recruitment. In total 548 patients with STEMI were randomized to a loading dose of 60mg prasugrel followed by a daily dose of 10mg plus a
bolus of bivalirudin of 0.75 mg/kg followed by an infusion of 1.75mg/kg/h for the duration of the procedure, or to a loading dose of 600mg clopidogrel followed by a daily dose of 75mg plus a bolus of heparin (70-100U/kg) pre-procedure followed by an infusion with a target ACT of 200-250 sec. Bail-out GPI use was allowed in both trial arms in case of vessel occlusion or large thrombus burden. MACCE (death, myocardial infarction, stroke, unplanned infarct-artery revascularization, or stent thrombosis) at 30 days occurred in 13 (4.8%) patients in the prasugrel/bivalirudin group and 15 (5.5%) patients on
clopidogrel/heparin ( fig 3). Stent thrombosis was observed in 3 vs 4 patients, and death in 7 vs 7 patients.
TIMI major bleeding was seen in 7 vs 8 patients.

Fig 3. MACE in the BRAVE-4 trial

In both HEAT-PPCI and BRAVE-4 bivalirudin in primary PCI for STEMI was not better than heparin in ischemic and bleeding outcomes. The short duration of bivalirudin infusion may be responsible for the increase in stent thrombosis in HEAT-PPCI, which was also seen in HORIZONS-AMI and Euromax with the same magnitude. The longer action of unfractionated heparin may be protective against stent thrombosis. Yet, bleeding was numerically less with heparin, for which there is no explanation.

Edoxaban is an oral direct factor Xa blocker and proved to be non-inferior in efficacy and safety to warfarin in stroke prevention in atrial fibrillation (3). The 21,105 patients in ENGAGE-AF TIMI 48 were randomized to warfarin (INR 2-3), high exposure edoxaban 60mg qd, or low exposure edoxaban 30mg qd. Both doses could be halved in case of anticipated high drug exposure due to in diminished kidney function, body weight < 60 kg or drug interactions leading to increased bleeding risk (quinidine, verapamil, dronedarone). Anti-factor Xa was measured and found to be correlated with outcomes (fig 4)(4).

Fig 4. Anti-Xa activity in 4 doses of edoxaban and outcomes in ENGAGE-AF TIMI 48

Dose reduction resulted in a gradient of anti-FXa activity. Nevertheless, high dose edoxaban remained more efficacious than low dose. Dose reduction was associated with even less bleeding with low dose edoxaban. Thus, a gradient of anti-FXa activity across a 15 to 60 mg dose of edoxaban suggests the therapeutic window is narrower for bleeding than for thromboembolism.


Unlike with dabigatran and rivaroxaban (5) , there has been no experience in reversing the anti-Xa activity of edoxaban. In a phase 1 single-dose placebo-controlled, 2-arm, 3-way crossover, study 24 healthy subjects (age 18-45 y) were randomized to either edoxaban 60 mg qd (cohort 1) or edoxaban 180 mg qd (cohort 2).(5) Within each cohort subjects were randomized to 1 of 6 treatment (Tx) sequences with: A (edoxaban + prothrombin complex concentrate (PCC) placebo), B (edoxaban + PCC 25 IU/kg) or C (edoxaban + PCC 50 IU/kg). For all treatments edoxaban was followed 1 h post-dose with a 1-2 h i.v. infusion of PCC or placebo.
All treatments were well tolerated. Mean percent reductions from baseline in endogenous thrombin potential (ETP) were -39.5, -30.4, and -33.4% for treatments A, B and C, respectively, in cohort 1 and -49.9, -37.8 and -58.9% for treatments A, B and C, respectively, in cohort 2. Mean ETP returned to baseline with PCC administration within 3.5 h (cohort 2, treatment B) or 3 h (all other PCC treatments). With treatment A the ETP had not returned to baseline at 72 h (both cohorts). PCC treatment led to an a maximum increase in ETP from baseline compared with placebo (21.6 and 32.9% for treatments B and C, respectively, vs 3.1% for treatment A in cohort 1; 18.4 and 32.4% for treatments B and C vs -1.0% for treatment A in cohort 2. Similar trends were observed for thrombin generation (TG) peak and velocity. There were no changes in TG lag or time to peak. High variability was observed in the TG data for all parameters assessed. Effects on prothrombin time were not reversed.

Thus, both doses of PCC 25 and 50 IU/kg reversed edoxaban-induced TG inhibition as measured by ETP. However, the results should be interpreted with caution due to the high variability observed for TG. Co-administration of PCC with edoxaban seemed safe.


1. Devereaux PJ, Mrkobrada M, Sessler DJ, et al. Aspirin in patients undergoing noncardiac surgery. N Engl J Med 2014; 370:1494-503
2. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093-2104
3. Schulz S, Richardt G, Laugwitz KL, et al. Prasugrel and bivalirudin vs clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J 2014; doi:10.1093/eurheartj/ehu182
4. Ruff CT, Giugliano RP, Braunwald E, et al. Relationship between dose, antifactor Xa activity, and outcomes in patients randomized to edoxaban in the ENGAGE AF-TIMI 48 trial. J Am Coll Cardiol 2014;63:suppl 1:A329
5. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011;124:1573-1579
6. Brown K, Wickremasingha P, Parasrampuria D, Kochan J, Dishy V, S Minggao. The impact of prothrombin complex concentrate on the anticoagulatory effects of edoxaban. J Am Coll Cardiol 2014;63:suppl 1:A2095
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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