Prasugrel Plus Bivalirudin vs Clopidogrel Plus Heparin STEMI
Prasugrel Plus Bivalirudin vs Clopidogrel Plus Heparin STEMI
The trial was stopped for slow recruitment. The main reason for this was the lack of extramural funding. Neither interims analysis was performed, nor was the trial stopped for safety reasons.
From September 2009 until December 2013 a total of 548 patients were enrolled and randomly assigned to either therapeutic strategy: prasugrel plus bivalirudin (n = 271) or clopidogrel plus heparin (n = 277).
Prior to randomization, a clopidogrel loading dose was administered to 63 patients (23.2%) in the prasugrel plus bivalirudin group and 65 patients (23.5%) in the clopidogrel plus heparin group. Moreover, 221 patients (81.5%) in the prasugrel plus bivalirudin group and 221 patients (79.8%) in the clopidogrel plus heparin group received unfractionated heparin before randomization.
Baseline clinical and demographic characteristics of the patients are shown in Table 1. Among all randomized patients, 249 patients (91.9%) in the prasugrel plus bivalirudin group and 260 patients (93.9%) in the clopidogrel plus heparin group were discharged with the diagnosis of myocardial infarction. More than 40% of these patients presented with anterior wall myocardial infarction and 79% were classified as Killip class I on admission.
Median time interval from symptom onset to admission was 184 [90–460] min and median door to balloon time was 89 [67–112] min. Other time intervals are displayed in Table 2.
Table 3 summarizes the angiographic and procedural characteristics. Access site was the femoral artery in all but one patient. Patients in the prasugrel plus bivalirudin group had a better blood flow according to TIMI grade before PCI [TIMI 0 flow: 120 patients (48.2%) vs. 159 patients (61.2%); P = 0.023]. GP IIb/IIIa inhibitors were administered to 4.6% of the patients, 8 patients (3.0%) in the prasugrel plus bivalirudin group and 17 patients (6.1%) in the clopidogrel plus heparin group (P = 0.074). Among patients randomized to the clopidogrel plus heparin group, 249 patients (89.9%) received unfractionated heparin after randomization until the end of catheterization. The median dose of unfractionated heparin in the clopidogrel plus heparin group given after randomization was 5000 [IQR 4000–7000] IU. Drug-eluting stent implantation was the dominant PCI technique in both groups. Final TIMI blood flow grade was comparable in both groups and more than 90% had TIMI flow grade 3 after PCI. Medication at discharge is summarized in Table 4.
Follow-up was complete in all but four patients, two patients in the prasugrel plus bivalirudin group, and two patients in the clopidogrel plus heparin group. Their follow-up length ranged between 2 and 17 days and none of them incurred a clinical event during this observation period.
At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin (relative risk, 1.09; one-sided 97.5% CI, 0–1.79), P = 0.680, Figure 1). The two-sided Fisher's exact test yielded a relative risk of 1.07 (95% CI 0.70–1.64). The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stroke, or stent thrombosis occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI, 0.40–1.96; P = 0.894, Figure 2). Bleeding was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI, 0.74–1.88; P = 0.543, Figure 3). Six patients (2.2%) in the prasugrel plus bivalirudin group and five patients (1.8%) in the clopidogrel plus heparin group died from cardiac cause (relative risk, 1.23; 95% CI, 0.32–5.03; P = 0.970). The individual components of the primary endpoint are displayed in Table 5. Definite stent thrombosis was observed in three patients of the prasugrel plus bivalirudin group (1.1%) and four patients (1.5%) of the clopidogrel plus heparin group (relative risk, 0.77; 95% CI, 0.11–4.49; P = 0.976). Major or minor bleeding according to the TIMI definition were also comparable between study groups [32 patients (11.9%) in the prasugrel plus bivalirudin group and 28 patients (10.2%) in the clopidogrel plus heparin group (relative risk, 1.17; 95% CI, 0.70–1.96; P = 0.616)].
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Figure 1.
Primary composite endpoint. Kaplan–Meier curves of the primary endpoint—the composite of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, stroke, or major bleeding in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days. Statistical comparison for the primary endpoint was performed by using a one-sided 2.5% significance level. [A two-sided Fisher's exact test with a 5% significance level yielded a relative risk of 1.07 (95% confidence interval 0.70–1.64).]
(Enlarge Image)
Figure 2.
Secondary composite ischaemic endpoint. Kaplan–Meier curves of the secondary composite ischaemic endpoint of death, myocardial infarction, revascularization of the infarct-related artery, stent thrombosis, or stroke in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days.
(Enlarge Image)
Figure 3.
Secondary endpoint of bleeding. Kaplan–Meier curves of the secondary endpoint of bleeding (non-CABG related, HORIZONS-AMI definition) in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days.
The results for the primary and secondary endpoints observed in the overall population were consistent with the results observed in the 93% of the patients with confirmed myocardial infarction.
Treatment effect was homogeneous across pre-specified subgroups defined by age, gender, presence of diabetes mellitus, body mass index, use of unfractionated heparin prior to randomization, use of clopidogrel loading prior to randomization, or time interval from symptom onset to primary PCI. (Figures 4–6). In patients receiving <5000 IU of unfractionated heparin after randomization, the primary endpoint was observed in 11 of 75 patients (14.7%) compared with 29 of 200 patients (14.5%) in those patients receiving 5000 IU or more of unfractionated heparin [relative risk, 1.01 (95% CI, 0.48–1.96); P = 0.902].
(Enlarge Image)
Figure 4.
Subgroup analysis for the primary endpoint. Thirty-day incidence and relative risk of the primary endpoint in pre-specified subgroups (two-sided tests).
(Enlarge Image)
Figure 5.
Subgroup analysis for the secondary composite ischaemic endpoint. Thirty-day incidence and relative risk of the secondary composite ischaemic endpoint (composite of death, myocardial infarction, unplanned infarct related artery-revascularization, stent thrombosis, or stroke) in pre-specified subgroups.
(Enlarge Image)
Figure 6.
Subgroup analysis for the secondary bleeding endpoint. Thirty-day incidence and relative risk of the secondary bleeding endpoint in pre-specified subgroups.
Results
Patients and Procedures
The trial was stopped for slow recruitment. The main reason for this was the lack of extramural funding. Neither interims analysis was performed, nor was the trial stopped for safety reasons.
From September 2009 until December 2013 a total of 548 patients were enrolled and randomly assigned to either therapeutic strategy: prasugrel plus bivalirudin (n = 271) or clopidogrel plus heparin (n = 277).
Prior to randomization, a clopidogrel loading dose was administered to 63 patients (23.2%) in the prasugrel plus bivalirudin group and 65 patients (23.5%) in the clopidogrel plus heparin group. Moreover, 221 patients (81.5%) in the prasugrel plus bivalirudin group and 221 patients (79.8%) in the clopidogrel plus heparin group received unfractionated heparin before randomization.
Baseline clinical and demographic characteristics of the patients are shown in Table 1. Among all randomized patients, 249 patients (91.9%) in the prasugrel plus bivalirudin group and 260 patients (93.9%) in the clopidogrel plus heparin group were discharged with the diagnosis of myocardial infarction. More than 40% of these patients presented with anterior wall myocardial infarction and 79% were classified as Killip class I on admission.
Median time interval from symptom onset to admission was 184 [90–460] min and median door to balloon time was 89 [67–112] min. Other time intervals are displayed in Table 2.
Table 3 summarizes the angiographic and procedural characteristics. Access site was the femoral artery in all but one patient. Patients in the prasugrel plus bivalirudin group had a better blood flow according to TIMI grade before PCI [TIMI 0 flow: 120 patients (48.2%) vs. 159 patients (61.2%); P = 0.023]. GP IIb/IIIa inhibitors were administered to 4.6% of the patients, 8 patients (3.0%) in the prasugrel plus bivalirudin group and 17 patients (6.1%) in the clopidogrel plus heparin group (P = 0.074). Among patients randomized to the clopidogrel plus heparin group, 249 patients (89.9%) received unfractionated heparin after randomization until the end of catheterization. The median dose of unfractionated heparin in the clopidogrel plus heparin group given after randomization was 5000 [IQR 4000–7000] IU. Drug-eluting stent implantation was the dominant PCI technique in both groups. Final TIMI blood flow grade was comparable in both groups and more than 90% had TIMI flow grade 3 after PCI. Medication at discharge is summarized in Table 4.
Clinical Outcomes
Follow-up was complete in all but four patients, two patients in the prasugrel plus bivalirudin group, and two patients in the clopidogrel plus heparin group. Their follow-up length ranged between 2 and 17 days and none of them incurred a clinical event during this observation period.
At 30 days, the primary composite endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stent thrombosis, stroke, or bleeding was observed in 42 patients (15.6%) randomized to prasugrel plus bivalirudin and 40 patients (14.5%) randomized to clopidogrel plus heparin (relative risk, 1.09; one-sided 97.5% CI, 0–1.79), P = 0.680, Figure 1). The two-sided Fisher's exact test yielded a relative risk of 1.07 (95% CI 0.70–1.64). The composite ischaemic endpoint of death, myocardial infarction, unplanned revascularization of the infarct related artery, stroke, or stent thrombosis occurred in 13 patients (4.8%) in the prasugrel plus bivalirudin group and 15 patients (5.5%) in the clopidogrel plus heparin group (relative risk, 0.89; 95% CI, 0.40–1.96; P = 0.894, Figure 2). Bleeding was observed in 38 patients (14.1%) in the prasugrel plus bivalirudin group and 33 patients (12.0%) in the clopidogrel plus heparin group (relative risk, 1.18; 95% CI, 0.74–1.88; P = 0.543, Figure 3). Six patients (2.2%) in the prasugrel plus bivalirudin group and five patients (1.8%) in the clopidogrel plus heparin group died from cardiac cause (relative risk, 1.23; 95% CI, 0.32–5.03; P = 0.970). The individual components of the primary endpoint are displayed in Table 5. Definite stent thrombosis was observed in three patients of the prasugrel plus bivalirudin group (1.1%) and four patients (1.5%) of the clopidogrel plus heparin group (relative risk, 0.77; 95% CI, 0.11–4.49; P = 0.976). Major or minor bleeding according to the TIMI definition were also comparable between study groups [32 patients (11.9%) in the prasugrel plus bivalirudin group and 28 patients (10.2%) in the clopidogrel plus heparin group (relative risk, 1.17; 95% CI, 0.70–1.96; P = 0.616)].
(Enlarge Image)
Figure 1.
Primary composite endpoint. Kaplan–Meier curves of the primary endpoint—the composite of death, myocardial infarction, unplanned revascularization of the infarct-related artery, stent thrombosis, stroke, or major bleeding in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days. Statistical comparison for the primary endpoint was performed by using a one-sided 2.5% significance level. [A two-sided Fisher's exact test with a 5% significance level yielded a relative risk of 1.07 (95% confidence interval 0.70–1.64).]
(Enlarge Image)
Figure 2.
Secondary composite ischaemic endpoint. Kaplan–Meier curves of the secondary composite ischaemic endpoint of death, myocardial infarction, revascularization of the infarct-related artery, stent thrombosis, or stroke in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days.
(Enlarge Image)
Figure 3.
Secondary endpoint of bleeding. Kaplan–Meier curves of the secondary endpoint of bleeding (non-CABG related, HORIZONS-AMI definition) in the prasugrel plus bivalirudin and the clopidogrel plus heparin group at 30 days.
The results for the primary and secondary endpoints observed in the overall population were consistent with the results observed in the 93% of the patients with confirmed myocardial infarction.
Treatment effect was homogeneous across pre-specified subgroups defined by age, gender, presence of diabetes mellitus, body mass index, use of unfractionated heparin prior to randomization, use of clopidogrel loading prior to randomization, or time interval from symptom onset to primary PCI. (Figures 4–6). In patients receiving <5000 IU of unfractionated heparin after randomization, the primary endpoint was observed in 11 of 75 patients (14.7%) compared with 29 of 200 patients (14.5%) in those patients receiving 5000 IU or more of unfractionated heparin [relative risk, 1.01 (95% CI, 0.48–1.96); P = 0.902].
(Enlarge Image)
Figure 4.
Subgroup analysis for the primary endpoint. Thirty-day incidence and relative risk of the primary endpoint in pre-specified subgroups (two-sided tests).
(Enlarge Image)
Figure 5.
Subgroup analysis for the secondary composite ischaemic endpoint. Thirty-day incidence and relative risk of the secondary composite ischaemic endpoint (composite of death, myocardial infarction, unplanned infarct related artery-revascularization, stent thrombosis, or stroke) in pre-specified subgroups.
(Enlarge Image)
Figure 6.
Subgroup analysis for the secondary bleeding endpoint. Thirty-day incidence and relative risk of the secondary bleeding endpoint in pre-specified subgroups.
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