Prasugrel Plus Bivalirudin vs Clopidogrel Plus Heparin STEMI
Prasugrel Plus Bivalirudin vs Clopidogrel Plus Heparin STEMI
In this randomized trial of STEMI patients with planned primary PCI, we compared a regimen of prasugrel plus bivalirudin with a regimen of clopidogrel plus heparin. The main findings are the following: (i) we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus unfractionated heparin. (ii) Neither the composite of ischaemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with clopidogrel plus unfractionated heparin.
STEMI patients undergoing primary PCI have an increased risk of stent thrombosis. In two large STEMI trials with bivalirudin, an increased risk of acute stent thrombosis was observed with this drug. One goal of the BRAVE 4 trial was to improve the antithrombotic efficacy of adjunct pharmacotherapy during primary PCI by combining bivalirudin with prasugrel. In actual fact, there was no excess in the risk of the composite ischaemic endpoint or stent thrombosis with prasugrel added to bivalirudin. However, the trial was not powered to assess rare events like stent thrombosis. On the contrary, a positive effect of prasugrel is suggested by the lower rate of occluded vessels at initial angiography and numerically reduced use of GP IIb/IIIa inhibitors in this group. However, we cannot exclude that the higher use of GP IIbIIIa inhibitors in the control arm is related to the open-label design, as it might also have been the case in the previous EUROMAX trial. Moreover, recent pharmacodynamic data have shown that also for third-generation ADP receptor antagonists like prasugrel the time interval to achieve maximal platelet inhibition is significantly delayed in STEMI patients.
An additional goal of the BRAVE 4 trial was to provide patients with a therapy that is associated with a lower bleeding risk. Reduction in bleeding has been a consistent finding in contemporary trials comparing bivalirudin against a regimen of unfractionated heparin plus a GP IIb/IIIa inhibitor in ACS patients and also against heparin mono-therapy in troponin negative, coronary artery disease patients undergoing PCI. In compliance with recent trial results and current practice guidelines, GP IIb/IIIa inhibitors were only used as a bail-out in 4.6% of the patients in BRAVE 4.
The current trial shows, for the first time, that the reduction in bleeding with bivalirudin is abrogated with the concurrent administration of prasugrel. This was evident for bleeding defined by HORIZONS-AMI and by TIMI criteria.
The recent European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial assessed the role of pre-hospital use of bivalirudin compared with heparin in STEMI patients. In this trial, the use of bivalirudin was associated with a reduction in bleeding. In both groups, new ADP receptor antagonists, i.e. prasugrel or ticagrelor, were administered to ~50% of the patients. However, more than two-thirds of the patients in the heparin group compared with only 11.5% in the bivalirudin group also received GP IIb/IIIa inhibitors.
The most plausible explanation for the lack of reduction in bleeding with bivalirudin in BRAVE 4 is its combination with prasugrel. Prasugrel is characterized by a faster, more potent, and more consistent platelet inhibition compared with its predecessor clopidogrel. Yet, the enhanced antithrombotic efficacy with prasugrel occurred at the expense of an increased risk of bleeding in the overall acute coronary syndrome population. In addition, the reduction in bleeding by bivalirudin is mostly observed in trials in which the control group included the routine use of GP IIb/IIIa inhibitors, which was not the case in the present trial.
The primary endpoint was mainly driven by the occurrence of bleeding. The HORIZONS-AMI definition of bleeding used in the present study is well known and sometimes criticized for its sensitivity. The almost exclusive use of the femoral access might have contributed to the high overall bleeding rate. However, the incidence of bleeding according to the TIMI definition was comparable with the recent EUROMAX trial. Also the incidence of the ischaemic component of the primary endpoint (the composite of death, myocardial infarction, unplanned IRA revascularization, stent thrombosis, or stroke) was comparable with the incidences observed in previous STEMI trials.
The premature termination of the trial presents a major limitation. It reduced the actual power of the trial from 80 to 51%. On the basis of the two-sided Fisher's exact test, the CI does not exclude up to 30% reduction and up to 64% excess in the risk of the occurrence of the net clinical endpoint with prasugrel plus bivalirudin.
When we planned the trial, there was no precise evidence to substantiate the assumptions for sample size calculation. In the STEMI cohort of the TRITON-TIMI 38 trial, the relative risk reduction of the primary composite ischaemic endpoint of cardiovascular death, non-fatal myocardial infarction, or stroke was 21% with prasugrel compared with clopidogrel. Moreover, there was a 30% reduction in urgent target vessel revascularization and a 42% reduction in stent thrombosis with prasugrel. In the HORIZONS-AMI trial, the reduction in bleeding with bivalirudin was 40% compared with heparin plus GPIIbIIIa inhibitors. Assuming a synergistic effect of prasugrel plus bivalirudin, sample size calculation for the current trial was based on a 40% relative risk reduction with prasugrel plus bivalirudin compared with clopidogrel plus heparin.
The BRAVE 4 trial shares the limitation of an open-label design with previous trials of bivalirudin in STEMI patients. We tried to minimize the bias introduced by the open-label design by endpoint analysis according to the intention-to-treat principle, precise criteria for endpoint assessment, use of blinded core labs and blinded adjudication of endpoint events by specialized event adjudication committee members, based on original source data. Despite these measures, we cannot fully exclude an inherent bias of the open-label design.
In BRAVE-4, we enrolled STEMI patients up to 24 h after symptom onset. This is in line with the predecessor BRAVE-3 and the PLATO trial, but longer than in other bivalirudin trials. Whether differences in the time window from symptom onset to primary PCI affected the efficacy of the drugs under investigation in this trial remains unclear.
The door to balloon time in the current trial was rather long (median 89 min). This should be acknowledged as a limitation.
The prasugrel loading dose was reduced from 60 to 30 mg in clopidogrel preloaded patients. This reduction in the prasugrel loading dose was intended to prevent excess in bleeding. Recently, platelet function data have confirmed the adequacy of both, the 30 mg and the 60 mg prasugrel loading dose in patients that have already received 600 mg clopidogrel. However, safety data in this regard are still lacking.
Ticagrelor is a valuable addition to the adjunct therapy in patients with acute coronary syndrome. Since the BRAVE 4 trial was started before the approval of ticagrelor, it is unable to provide information on the value of the combination of ticagrelor with bivalirudin.
The long recruitment period, in which changes in clinical practice may have occurred, presents another limitation.
In this trial of STEMI patients presenting within 24 h of symptom onset and planned primary PCI, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus unfractionated heparin. Neither the composite of ischemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with a regimen of clopidogrel plus unfractionated heparin. However, the results must be interpreted in view of the premature termination of the trial.
Discussion
In this randomized trial of STEMI patients with planned primary PCI, we compared a regimen of prasugrel plus bivalirudin with a regimen of clopidogrel plus heparin. The main findings are the following: (i) we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus unfractionated heparin. (ii) Neither the composite of ischaemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with clopidogrel plus unfractionated heparin.
STEMI patients undergoing primary PCI have an increased risk of stent thrombosis. In two large STEMI trials with bivalirudin, an increased risk of acute stent thrombosis was observed with this drug. One goal of the BRAVE 4 trial was to improve the antithrombotic efficacy of adjunct pharmacotherapy during primary PCI by combining bivalirudin with prasugrel. In actual fact, there was no excess in the risk of the composite ischaemic endpoint or stent thrombosis with prasugrel added to bivalirudin. However, the trial was not powered to assess rare events like stent thrombosis. On the contrary, a positive effect of prasugrel is suggested by the lower rate of occluded vessels at initial angiography and numerically reduced use of GP IIb/IIIa inhibitors in this group. However, we cannot exclude that the higher use of GP IIbIIIa inhibitors in the control arm is related to the open-label design, as it might also have been the case in the previous EUROMAX trial. Moreover, recent pharmacodynamic data have shown that also for third-generation ADP receptor antagonists like prasugrel the time interval to achieve maximal platelet inhibition is significantly delayed in STEMI patients.
An additional goal of the BRAVE 4 trial was to provide patients with a therapy that is associated with a lower bleeding risk. Reduction in bleeding has been a consistent finding in contemporary trials comparing bivalirudin against a regimen of unfractionated heparin plus a GP IIb/IIIa inhibitor in ACS patients and also against heparin mono-therapy in troponin negative, coronary artery disease patients undergoing PCI. In compliance with recent trial results and current practice guidelines, GP IIb/IIIa inhibitors were only used as a bail-out in 4.6% of the patients in BRAVE 4.
The current trial shows, for the first time, that the reduction in bleeding with bivalirudin is abrogated with the concurrent administration of prasugrel. This was evident for bleeding defined by HORIZONS-AMI and by TIMI criteria.
The recent European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) trial assessed the role of pre-hospital use of bivalirudin compared with heparin in STEMI patients. In this trial, the use of bivalirudin was associated with a reduction in bleeding. In both groups, new ADP receptor antagonists, i.e. prasugrel or ticagrelor, were administered to ~50% of the patients. However, more than two-thirds of the patients in the heparin group compared with only 11.5% in the bivalirudin group also received GP IIb/IIIa inhibitors.
The most plausible explanation for the lack of reduction in bleeding with bivalirudin in BRAVE 4 is its combination with prasugrel. Prasugrel is characterized by a faster, more potent, and more consistent platelet inhibition compared with its predecessor clopidogrel. Yet, the enhanced antithrombotic efficacy with prasugrel occurred at the expense of an increased risk of bleeding in the overall acute coronary syndrome population. In addition, the reduction in bleeding by bivalirudin is mostly observed in trials in which the control group included the routine use of GP IIb/IIIa inhibitors, which was not the case in the present trial.
The primary endpoint was mainly driven by the occurrence of bleeding. The HORIZONS-AMI definition of bleeding used in the present study is well known and sometimes criticized for its sensitivity. The almost exclusive use of the femoral access might have contributed to the high overall bleeding rate. However, the incidence of bleeding according to the TIMI definition was comparable with the recent EUROMAX trial. Also the incidence of the ischaemic component of the primary endpoint (the composite of death, myocardial infarction, unplanned IRA revascularization, stent thrombosis, or stroke) was comparable with the incidences observed in previous STEMI trials.
Limitations
The premature termination of the trial presents a major limitation. It reduced the actual power of the trial from 80 to 51%. On the basis of the two-sided Fisher's exact test, the CI does not exclude up to 30% reduction and up to 64% excess in the risk of the occurrence of the net clinical endpoint with prasugrel plus bivalirudin.
When we planned the trial, there was no precise evidence to substantiate the assumptions for sample size calculation. In the STEMI cohort of the TRITON-TIMI 38 trial, the relative risk reduction of the primary composite ischaemic endpoint of cardiovascular death, non-fatal myocardial infarction, or stroke was 21% with prasugrel compared with clopidogrel. Moreover, there was a 30% reduction in urgent target vessel revascularization and a 42% reduction in stent thrombosis with prasugrel. In the HORIZONS-AMI trial, the reduction in bleeding with bivalirudin was 40% compared with heparin plus GPIIbIIIa inhibitors. Assuming a synergistic effect of prasugrel plus bivalirudin, sample size calculation for the current trial was based on a 40% relative risk reduction with prasugrel plus bivalirudin compared with clopidogrel plus heparin.
The BRAVE 4 trial shares the limitation of an open-label design with previous trials of bivalirudin in STEMI patients. We tried to minimize the bias introduced by the open-label design by endpoint analysis according to the intention-to-treat principle, precise criteria for endpoint assessment, use of blinded core labs and blinded adjudication of endpoint events by specialized event adjudication committee members, based on original source data. Despite these measures, we cannot fully exclude an inherent bias of the open-label design.
In BRAVE-4, we enrolled STEMI patients up to 24 h after symptom onset. This is in line with the predecessor BRAVE-3 and the PLATO trial, but longer than in other bivalirudin trials. Whether differences in the time window from symptom onset to primary PCI affected the efficacy of the drugs under investigation in this trial remains unclear.
The door to balloon time in the current trial was rather long (median 89 min). This should be acknowledged as a limitation.
The prasugrel loading dose was reduced from 60 to 30 mg in clopidogrel preloaded patients. This reduction in the prasugrel loading dose was intended to prevent excess in bleeding. Recently, platelet function data have confirmed the adequacy of both, the 30 mg and the 60 mg prasugrel loading dose in patients that have already received 600 mg clopidogrel. However, safety data in this regard are still lacking.
Ticagrelor is a valuable addition to the adjunct therapy in patients with acute coronary syndrome. Since the BRAVE 4 trial was started before the approval of ticagrelor, it is unable to provide information on the value of the combination of ticagrelor with bivalirudin.
The long recruitment period, in which changes in clinical practice may have occurred, presents another limitation.
Summary and Conclusion
In this trial of STEMI patients presenting within 24 h of symptom onset and planned primary PCI, we were unable to demonstrate significant differences in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus unfractionated heparin. Neither the composite of ischemic complications nor bleeding were favourably affected by prasugrel plus bivalirudin compared with a regimen of clopidogrel plus unfractionated heparin. However, the results must be interpreted in view of the premature termination of the trial.
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