Cardiovascular Sciences Research Centre

During the ACC Scientific Sessions 2011 in Orlando, Florida, US, the first of the Late Breaking Sessions focused on antithrombotic therapy. The findings of these trials were certainly a mixed bag, with some negative results (TARGET), unexpected data (AIDA STEMI), and a degree of success (ATLAS). Nonetheless, each trial conclusion raised important and intriguing questions about the future of antithrombotic therapy.

Here we provide you with an overview of the late breaking clinical trials on the first day of the AHA Scientific Sessions 2011.

ADOPT

The Apixaban Dosing to Optimize Protection from Thrombosis (ADOPT) trial was presented by Samuel Z Goldhaber, MD from Brigham and Women’s Hospital, Harvard Medical School, US.

This randomized, double-blind, double-dummy trial tested the hypothesis that the extended use of apixaban would be more effective than the short term use of enoxaparin for venous thromboembolism (VTE) prophylasis in medically ill patients.

The outcome of the ADOPT trial revealed that 30-day prophylaxis with apixaban was not superior to 6-14 days of treatment with enoxaparin. Apixaban was also associated with an increase in major bleeding events compared to enoxaparin.

That the risk of VTE increases after hospital discharge is well-established; however the results of ADOPT do not provide justification for policy change in this treatment, although they do highlight the need to identify subgroups that would benefit from targeted extended prophylaxis.

TRACER

The TRACER trial provided an overview of the use of vorapaxar in the for treatment of acute coronary artery syndromes (ACS).

This large, multinational, double-blind, randomized trial compared vorapaxar with placebo in 12,994 patients with ACS without ST-segment-elevation. The primary endpoint was a composite of death from CV causes, MI or stroke. However, the TRACER trial was halted earlier this year after an increase in intercranial haemorrage was reported in patients with a history of stroke.

As the novel oral antithombotic agent had reached all primary and secondary end points, the researchers were able to present their findings at the AHA 2011.

There were no benefits in terms of primary end points, and vorapaxar significantly increased the risk of major bleeding, especially intercranial hemorrhage.

During the discussion, Dr Keith Fox from Edinburgh, UK noted that in the placebo population of the trail, patients had a 6.1% risk of death and a 12.1% risk of stroke at two years, and approximately half of these occurred at 4 months, stating that TRACER has “missed the sweet spot between efficacy and safety.”

ATLAS ACS2 TIMI 51

The results of the ATLAS ACS2 TIMI 51 trial was big news at the AHA Scientific Sessions 2011, showing that very low dose rivaroxaban (2.5 mg, and 5 mg, respectively) in combination with other antiplatelet therapies significantly lowers the effects of cardiac events in patients with symptoms across the ACS spectrum compared with the current standard of care.

The results of this trial were presented by C Michael Gibson, MD, Beth Isreal Deaconess Medicine Center, Boston, Mass. Us.

Rivaroxaban 5.0 mg produced a significant reduction in the primary end points, although the rates of CV death were not reduced. However, rivaroxaban 2.5 mg produced a 32% relative risk reduction in all cause mortality and a 34% risk reduction of CV death.

These benefits were consistent across all sub-groups, there was no evidence of rebound ischaemic events and no difference in the risk of fatal bleeding.

As Gibson stated during the presentation, the results of ATLAS ACS2 TIMI 51 represent “a new era in secondary prevention after acute coronary syndrome.” [1, 2]

References

1. Mega J, Braunwald E, Wiviott, et al., Rivaroxaban in patients with a recent acute coronary syndrome. NEJM 2011; November 13: 10.1056/NEJMoa1112277

2. Roe MT, Ohman EM. A new era in secondary prevention after coronary syndrome. NEJM 2011; November 13: 10.1056/NEJMe1112770

During the ACC Scientific Sessions 2011 in Orlando, Florida, US, the first of the Late Breaking Sessions focused on antithrombotic therapy. The findings of these trials were certainly a mixed bag, with some negative results (TARGET), unexpected data (AIDA STEMI), and a degree of success (ATLAS). Nonetheless, each trial conclusion raised important and intriguing questions about the future of antithrombotic therapy.

Here we provide you with an overview of the late breaking clinical trials on the first day of the AHA Scientific Sessions 2011.

AIDA STEMI

This trial, presented by Holger Thiele, MD, from Herzzentrum Leipzig, Leipzig, Germany, compared intracoronary (IC) and intravenous (IV) bolus abciximab during primary percutaneous coronary intervention (PCI) in STEMI patients.

This phase II, interventional, randomized efficacy study showed that the primary end point – a composite of death, new myocardial infacrction (MI) and new heart failure (HF) – was no different between the two groups. Therefore, although IC abciximab is safe, it does not add any further benefit when compared to standard IV abciximab bolus.

Furthermore, the event rate was less than anticipated in both groups – 7.0% IC and 7.6% IV (p=0.58) compared to the predicted event rate of 12%. These results were not expected, especially in the light of previous studies. However, as Thiele explained, many centres only included low-risk patients, which may have influenced these results.

The outcome of AIDA STEMI does not support a change in current clinical practice.

ISAR REACT4

Bivalirudin may be the preferable drug of choice when treating STEMI and NSTEMI patients undergoing PCI, according to the findings of the ISAR REACT 4 trial, presented by Adnan Kastrati, MD, Deutsches Herzzentrum, Munich, Germany. [1]

This randomized, double-blind, multicentre study involved 17,000 patients who were enrolled within 48 hours of presentation of NSTEMI acute coronary syndrome (ACS). All patients were treated with clopidogrel 600mg, before being randomized to an abciximab plus unfractionated heparin (UFH) infusion for 12 hours, or a bivalirudin bolus for the duration of PCI.

The primary end point was a composite of death, large MI or revascularization within 30 days of PCI.

Abciximab plus UFH did not reach this primary end point, and it increased the risk of bleeding in patients with NSTEMI undergoing PCI.

So is ISAR REACT 4 a ‘practice changing trial’?

During the presentation discussion, the consensus was that this may well be the case. Deepak L Bhatt MD, VA Boston Healthcare System, US, discussed the results, stating that in the light of results from trials such as ACUITY and HORIZON, “ISAR REACT 4 completes the puzzle of the role of bivalirudin in PCI.”

References

1. Kastrati A, Neumann FJ, Schulz S, et al., Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. NEJM 2011; November 13: 10.1056/NEJMoa1109596.