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A randomized controlled trial of the new agent M118 in elective percutaneous coronary intervention.

ESC Working Group on Thrombosis

Since the last American Heart Association meeting in November 2010 some interesting new studies have been published or presented.
Venous Thromboembolism


The first trial is EMINENCE: a randomized controlled trial of the new agent M118 in elective percutaneous coronary intervention.1 M118 is a low molecular weight heparin with an almost equal anti-Xa and anti-IIa ratio, which can be given intravenously and subsequently subcutaneously. The plasma half-life is approximately 1 hour after intravenous injection, and 2 to 3 hours after subcutaneous administration. The substance does not activate platelets and the antithrombin activity can be monitored by standard techniques like ACT and aPTT. Finally, it can be reversed by protamine sulphate.
In 503 patients undergoing elective coronary intervention M118 was tested in a phase-2 design: 50 IU/kg iv, 75 IU/g iv and 100 IU/kg iv against UFH with a dose of 70 U/kg. The primary outcome (composite of death, MI, repeat PCI, stroke, thrombocytopenia, catheter thrombus, bailout use of II/IIIa blockers and bleeding through 30 days) occurred in 22.7%, 28.3% and 30.1% of patients randomized to the high, intermediate and low dose of M118, compared to 31.1 % in the UFH patients.

 intermediate and low dose of M118, compared to 31.1 % in the UFH patient

Bleeding was similar between the arms leading to the conclusion that the novel low molecular weight heparin M118 is well tolerated in patients undergoing elective coronary intervention. Larger trials with M118 are warranted.

Three important trials were presented at the American College of Cardiology meeting in April 2011 in New Orleans.

The first was the RADAR trial testing an anti-IXa substance against UFH in ACS in a phase 2B design.
Factor IX is activated by tissue factor/FVIIa in the cell-bound initiation phase of blood coagulation cascade before the beginning of the final common pathway. A PEG factor IXa inhibitor (pegnivacogin) has been developed together with a controlling agent that reverses the activity of PEG anti-IXa called anivamersen. The combination of these substances is called REG1.
The objective of the RADAR study was to verify if a single dose of pegnivacogin would be effective in blocking factor IX activity and also to determine if  reversal would be possible with anivamersen.
In total 800 patients with a planned catheterisation received either UFH (n = 200) or the new REG1 treatment (1mg/kg pegnivacogin, n= 600 combined with anivamersen): one arm with 25% reversal, one with 50%, one with 75% and with 100% reversal using anivamersen. The primary outcome (ACUITY bleeding at 30 days) was seen in 65% with the lowest reversal vs. 30% with highest reversal, the last being similar to UFH. Ischemic events seemed lower with pegnivacogin (3.0% without a dose response of anivamersen) compared to UFH (5.7%, figure).

Ischemic events


In 3 patients given pegnivacogin allergic reactions occurred.
Thus, the RADAR study shows that factor IXa inhibition results in significant bleeding over UFH, but can be reversed. On the other hand, total reversal did not result in lower bleeding compared with UFH. Overall, the new treatment seemed to reduce recurrent ischemic events. These findings warrant a larger study with this interesting new anticoagulant with an effective reversal agent in patients undergoing catheterisation, or even PCI.

The second study was the MAGELLAN trial, in which over 8,100 hospitalized medical patients were randomized to the oral direct Xa blocker rivaroxaban 10mg daily or to enoxaparin 40 mg once daily. The oral drug was given for 35 days, whereas enoxaparin was given for 4 days followed by placebo for the rest of the time. The primary outpoint was a composite of asymptomatic proximal deep vein thrombosis detected by mandatory ultrasonography, symptomatic deep vein thrombosis, symptomatic non-fatal pulmonary embolism, or deep vein thrombosis-related death. The primary endpoint at day 10 per protocol occurred in 2.7% of the rivaroxaban patients and 2.7% in the enoxaparin patients (p for non-inferiority 0.003, figure).

 primary endpoint at day 10

 The second pre-specified primary outcome was collected at 35 days. As expected rivaroxaban was superior to enoxaparin/placebo in preventing the primary efficacy endpoint: 4.4 % with rivaroxaban and 5.7 % with enoxaparin/placebo (relative risk reduction 23%, 95% CI 4% - 38%, p = 0.02).
Clinically relevant bleeding, however, occurred in 2.8% in the rivaroxaban patients vs. 1.2% in enoxaparin patients (RR2.3, p < 0.001) in the first 10 days with major bleeding seen in 0.6% of the rivaroxaban patients vs. 0.3% in the enoxaparin patients (RR 2.2, p = 0.03). Overall, at 35 days clinical relevant bleeding occurred in the 4.1% in the rivaroxaban patients vs. 1.7% in the enoxaparin /placebo patients (RR 2.5, p <  0.001) and major bleeding in 1.1% of the rivaroxaban patients vs. 0.4% of the enoxaparin /placebo patients (RR 2.9,  p = 0.004).
In conclusion, rivaroxaban is as effective as enoxaparin in the prevention of deep vein thrombosis- related events in critically ill hospitalized medical patients during hospitalization, but at the price of a doubling of clinically relevant and major bleeding. After hospital discharge rivaroxaban was superior over placebo, but again at a significant triple increase in bleeding. Therefore, rivaroxaban in a dose of 10mg daily cannot be advised in the protection of medical patients against deep vein thrombosis and venous embolism during hospital stay or in the month thereafter. Possibly, lower doses of rivaroxaban would have been safer, but likely at the cost of efficacy during the hospital phase.

The third trial presented at ACC 2011 was the EXCELLENT study carried out in South Korea. In 1,443 patients undergoing PCI with DES almost exclusively for non-STE ACS (45%) and elective procedures (50%) clopidogrel was given in a randomized way for 6 months vs. 12 months. The patients were followed for more than a year. In the patients randomized to 6 months clopidogrel the primary outcome (target vessel failure) was seen in 4.7% versus 4.4% in patients randomized to 12 months (HR1.17, 95% CI 0.73 - 1.89, p = 0.51, figure) at one year.

Target Vessels Failure


Landmark analysis at 6 months and 12 months did not show an increase of target vessel failure in the patients who stopped their clopidogrel at 6 months. Cardiac death, MI, stent thrombosis or major bleeding were not different between both groups. Important to mention is that 26% of patients randomized to 6 months continued the treatment, but also 30% in the patients who were randomized to stop at 12 months of clopidogrel. There was also a sub-randomization to everolimus eluting and sirolimus eluting stents, which showed complete similarity of both clopidogrel regimens for the everolimus and a tendency towards more target vessel failure in the patients randomized to sirolimus eluting stents.

 

Conclusion:

In conclusion, in this relatively small study with few ischemic endpoints and low bleeding complications 6 months of clopidogrel seems as effective as 12 months clopidogrel in elective stent implantation for relatively low risk PCI. Possibly, the newer stent designs make clopidogrel exposure longer than 6 months unnecessary. Results of much larger 6 versus 12 months clopidogrel trials after DES like ISAR-SAFE are eagerly awaited.

References


  1. Rao SV, Melloni C, Myles-DiMauro S, et al. Evaluation of a new heparin agent in percutaneous coronary intervention: results of the phase 2 evaluation of M118 in percutaneous coronary intervention (EMINENCE) trial. Circulation 2010;121:1713-1721

Notes to editor


Freek W.A. Verheugt, Onze Lieve Vrouwe Gasthuis, 9 Oosterpark, NL-1091-AC Amsterdam, The Netherlands
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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