Impact of Bivalirudin and Paclitaxel -Eluting Stents on Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention of the Left Anterior Descending Artery




Patients with ST elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) of the left anterior descending artery (LAD) are at increased risk for cardiovascular events compared with patients undergoing non-LAD PCI. We assessed the impact of bivalirudin and paclitaxel-eluting stenting (PES) in patients with STEMI who underwent LAD PCI. In the HORIZONS-AMI trial, 1,445 patients had LAD PCI and 1,884 patients had non-LAD PCI. The 3-year composite rates of death, reinfarction, stroke, or ischemia-driven target vessel revascularization were significantly higher in patients who underwent LAD PCI compared with non-LAD PCI (24.0% vs 20.6%, hazard ratio [HR] 1.20, 95% confidence interval [CI] 1.04 to 1.39, p = 0.013), driven by a statistically significant increase in cardiac death (5.4% vs 2.7%, HR 2.00, 95% CI 1.40 to 2.86, p = 0.001). For patients who underwent LAD PCI, treatment with bivalirudin resulted in significantly lower rates of cardiac death (3.8% vs 6.8%, HR 0.55, 95% CI 0.34 to 0.89, p = 0.01), reinfarction (5.3% vs 9.5%, HR 0.55, 95% CI 0.37 to 0.83, p = 0.004), and major bleeding events (7.3% vs 11.8%, HR 0.60, 95% CI 0.43 to 0.86, p = 0.004) compared with unfractionated heparin plus glycoprotein IIb/IIIa inhibitor. Randomization to PES compared with bare-metal stenting resulted in a significant lower rate of target vessel revascularization (13.2% vs 19.8%, HR 0.64, 95% CI 0.47 to 0.86, p = 0.003) with no significant differences in stent thrombosis, reinfarction, or death. In conclusion, in patients with STEMI who underwent primary PCI of LAD, the use of bivalirudin was associated with a reduction in mortality and bleeding rates at 3 years. PES reduced revascularization rates in this population but did not have a significant impact on mortality.


Primary percutaneous coronary intervention (PCI) is the preferred reperfusion strategy in patients with ST elevation myocardial infarction (STEMI). Patients with acute anterior myocardial infarction undergoing primary PCI of the left anterior descending artery (LAD) experience worse outcomes including increased mortality, larger infarct size, left ventricular dysfunction, and impaired microvascular perfusion. Those patients may benefit most from new treatments strategies regarding anticoagulation, antiplatelet therapy, and stent implantation. In the Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) trial, patients with STEMI who underwent a primary PCI strategy did benefit from anticoagulation with bivalirudin and implantation of paclitaxel-eluting stents (PES). During long-term follow-up, the use of bivalirudin was associated with a significant reduction in bleeding events and cardiac mortality compared with administration of unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor. Moreover, patients who were randomized to PES implantation had significantly less target vessel revascularization (TVR) with no increase in the risk of stent thrombosis or mortality compared with bare-metal stent (BMS) implantation. Given the high risk of complications associated with primary PCI of LAD lesions, we sought to investigate the impact of bivalirudin and PES implantation on outcomes in this subgroup of the HORIZONS-AMI trial.


Methods


The design and primary outcomes of the HORIZONS-AMI trial have been previously reported. Briefly, HORIZONS-AMI was a prospective multicenter trial in which patients with STEMI undergoing primary PCI were randomized in 2 phases to (1) bivalirudin alone plus provisional use of glycoprotein IIb/IIIa inhibitors versus unfractionated heparin plus routine glycoprotein IIb/IIIa inhibitors and (2) the paclitaxel-eluting TAXUS Express stent versus an otherwise identical bare-metal Express stent (both Boston Scientific, Natick, Massachusetts). Patients presenting ≤12 hours of symptom onset with STEMI were considered for enrollment. Clinical exclusion criteria included contraindications to study medication or conditions that increase the risk of hemorrhage. After pharmacologic randomization, emergent angiography was performed followed by assessment for eligibility in the stent-randomized phase of the trial (lesions with reference vessel diameter of 2.25 to 4.0 mm and length <100 mm were eligible). Left main lesions, bifurcation lesions requiring planned dual stenting, and those with excessive tortuosity or severe calcification were excluded. Complete end point definitions have been reported. A blinded independent clinical events committee adjudicated all primary end point events using original source documents. Quantitative Coronary Angiography was performed at an independent core angiographic laboratory (Cardiovascular Research Foundation, New York, New York). Clinical follow-up was scheduled at 30 days, 6 months, 1, 2, and 3 years.


Analyses were done by intention to treat. Data are summarized using descriptive statistics, presented as proportions (%, count/sample size), median (first, third quartiles), or mean ± SD. Continuous variables were compared using the Wilcoxon rank-sum text or t tests; differences in categorical variables were assessed by chi-square or Fisher’s exact test. Time-to-event data (with data censored at the time of a patient’s withdrawal from the study or at the last follow-up visit) are shown as Kaplan-Meier curves and compared with the log-rank test. Relative risks between the groups for time-to-event data are expressed as hazard ratios (HR) with 95% confidence intervals (CI) and as relative rates with 95% CI for categorical groups. Independent correlates of 3-year mortality in the LAD PCI group were determined by Cox proportional hazards regression. The potential baseline covariates considered for inclusion in the model were randomization to bivalirudin (vs unfractionated heparin plus glycoprotein IIb/IIIa inhibitor), age (per 10 year increase), presence of chronic total occlusion, proximal lesion location, diabetes mellitus, creatinine clearance <60, gender, and 600 mg clopidogrel loading dose. All analyses were performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina).




Results


In the HORIZONS-AMI study, 3,345 patients with STEMI underwent a primary PCI strategy, including 1,445 patients who had LAD PCI and 1,884 patients who had non-LAD PCI. There were 16 patients who could not be classified. Concomitant co-morbid risk factors were more frequent in patients who underwent LAD PCI compared with those who underwent non-LAD PCI, including advanced age, Killip class II to IV, severely decreased left ventricular function, and multivessel PCI ( Table 1 ). Patients with LAD lesions compared with patients with non-LAD lesions were less likely to have a history of smoking, previous myocardial infarction, previous coronary artery bypass grafting and were less likely to have Thrombolysis In Myocardial Infarction 0/1 flow or experience the use of aspiration catheters. Procedural use of unfractionated heparin plus glycoprotein IIb/IIIa inhibitors and bivalirudin were balanced between the patients in LAD group and in non-LAD PCI group, and there was no difference between the 2 groups in Thrombolysis In Myocardial Infarction 3 flow after procedure. The 3-year composite rates of death, reinfarction, stroke, or ischemia-driven TVR were significantly higher in patients who underwent LAD PCI compared with patients who underwent non-LAD PCI (HR 1.20, 95% CI 1.04 to 1.39), driven by statistically significant increases in cardiac death (HR 2.00, 95% CI 1.40 to 2.86), all-cause mortality (HR 1.62, 95% CI 1.24 to 2.13), and ischemic target lesion revascularization (TLR; Table 2 ). The risk of stroke or stent thrombosis did not differ. The risk of cardiac death was significantly greater in patients who underwent LAD PCI versus non-LAD PCI at every follow-up visit (in-hospital, 30 days, 1, 2, and 3 years).



Table 1

Baseline characteristics in patients who underwent left anterior descending (LAD) versus non-LAD percutaneous coronary intervention (PCI)


































































































































































































Variable LAD (n = 1,445) Non-LAD (n = 1,884) p
Age (yrs) 61.0 (53.0, 70.7) 59.5 (52.1, 68.8) 0.004
Women 22.1% (320/1,445) 23.4% (441/1,884) 0.39
Diabetes mellitus 17.3% (250/1,443) 15.5% (292/1,884) 0.16
Hypertension 52.1% (752/1,443) 52.8% (995/1,884) 0.69
Hyperlipidemia 41.4% (597/1,443) 44.0% (829/1,884) 0.13
Smoking 57.6% (829/1,440) 69.7% (1,305/1,872) <0.001
Body mass index (kg/m²) 27.0 (24.4, 30.1) 27.2 (24.7, 30.3) 0.09
Renal insufficiency 2.7% (39/1,443) 2.9% (54/1,883) 0.77
Previous myocardial infarction 8.1% (117/1,443) 12.3% (232/1,884) <0.001
Previous percutaneous intervention 9.0% (130/1,443) 11.6% (219/1,883) 0.015
Previous coronary artery bypass 1.3% (19/1,443) 3.5% (66/1,884) <0.001
Killip class II–IV 12.9% (185/1,440) 5.5% (104/1,884) <0.001
Symptom onset to balloon inflation (min) 221 (161, 340) 223 (160, 329) 0.83
Femoral access 93.6% (1,351/1,444) 93.8% (1,768/1,884) 0.74
Clopidogrel loading dose (mg)
300 35.9% (519/1,445) 33.8% (636/1,884) 0.19
600 63.9% (924/1,445) 66.1% (1,246/1,884) 0.19
Randomization to bivalirudin 48.4% (699/1,445) 51.4% (968/1,884) 0.09
Preprocedural heparin 64.9% (937/1,443) 66.1% (1,245/1,884) 0.49
Glycoprotein IIb/IIIa inhibitor 57.3% (826/1,441) 55.3% (1,040/1,882) 0.24
Given with bivalirudin 12.6% (88/697) 13.4% (129/966) 0.66
Giant thrombus 3.4% (24/697) 3.6% (35/966) 0.84
Sustained no reflow 4.7% (33/697) 4.6% (44/966) 0.86
Left ventricular ejection fraction <40% 27.2% (333/1,225) 5.2% (83/1,600) <0.001
2-Vessel coronary disease 33.5% (468/1,395) 35.9% (674/1,875) 0.15
3-Vessel coronary disease 20.4% (284/1,395) 22.4% (420/1,875) 0.16
Chronic total coronary occlusion 8.8% (121/1,381) 8.3% (154/1,867) 0.60
Number of stents implanted 1.5 ± 0.9 1.5 ± 0.8 0.59
Total stent length implanted (mm) 24 (16, 36) 24 (20, 36) 0.03
Any aspiration catheter 9.1% (131/1,432) 13.4% (250/1,864) <0.001
Multiple vessels treated 6.9% (98/1,417) 1.9% (35/1,846) <0.001
Number of vessels treated 1.1 ± 0.3 1.0 ± 0.1 <0.001
Any side branch lesion treated 9.3% (131/1,432) 3.9% (73/1,884) <0.001
TIMI flow 0/1 before PCI 60.8% 69.0% <0.001
TIMI flow 0/1 after PCI 2.1% 2.6% 0.34
TIMI flow 3 after PCI 90.8% 92.1% 0.17
Any CABG in-hospital 1.0% (14/1,445) 1.7% (32/1,884) 0.07

Data are presented as percentages (count/sample size), median (first, third quartiles), or mean ± SD.

CABG = coronary artery bypass grafting; TIMI = Thrombolysis In Myocardial Infarction.


Table 2

Three-year clinical outcomes in patients who underwent left anterior descending (LAD) and non-LAD percutaneous coronary intervention

























































































Variable LAD (n = 1,445) Non-LAD (n = 1,884) p
MACE 24.0 (340) 20.6 (377) 0.013
Death or reinfarction 14.4 (205) 11.5 (210) 0.09
Death 8.3 (118) 5.3 (96) 0.001
Cardiac 5.4 (76) 2.7 (50) 0.001
Noncardiac 3.1 (42) 2.6 (46) 0.37
Reinfarction 7.4 (101) 7.2 (128) 0.74
Q-wave 3.1 (42) 4.1 (73) 0.15
Non–Q-wave 4.7 (63) 3.6 (63) 0.11
Stroke 1.6 (22) 1.6 (29) 0.99
Ischemic TVR 14.8 (200) 13.2 (236) 0.19
Ischemic TLR 12.4 (167) 10.1 (180) 0.004
Ischemic TVR, non-TLR 4.4 (59) 5.4 (95) 0.24
Ischemic non-TVR 9.5 (129) 10.8 (193) 0.28
Stent thrombosis
Definite 4.2 (56) 4.6 (80) 0.56
Definite/probable 4.8 (64) 5.3 (92) 0.51

Data are presented as percentages (counts).

MACE = major adverse cardiovascular events.

Composite of death, reinfarction, stroke, or ischemic TVR.


Ischemic TVR defined as any ischemia-driven repeat percutaneous intervention or bypass surgery of the target vessel. The target vessel consists of the target lesions plus any additional lesions in the main epicardial coronary artery or branches containing the target lesion.


Academic Research Consortium definite or probable.



First randomization in the patients in the LAD PCI group resulted in a treatment strategy with bivalirudin (n = 699) or unfractionated heparin plus glycoprotein IIb/IIIa inhibitor (n = 746). Baseline characteristics did not differ between the groups except for a history of smoking ( Table 3 ). Treatment with bivalirudin resulted in significantly lower rates of cardiac death (HR 0.55, 95% CI 0.34 to 0.89), reinfarction (HR 0.55, 95% CI 0.37 to 0.83), and bleeding events (HR 0.60, 95% CI 0.43 to 0.86) compared with treatment with unfractionated heparin plus glycoprotein IIb/IIIa inhibitor ( Table 4 and Figure 1 ). The risk of stroke, ischemic TVR, and stent thrombosis within 3 years was not different between the 2 groups. However, in patients who underwent LAD PCI, subacute, late, and very late stent thrombosis occurred significantly less often with bivalirudin (3.6% vs 6.6%, HR 0.53, 95% CI 0.32 to 0.88, p = 0.01). There were no significant interactions for stent type and type of anticoagulation with respect to total mortality, cardiac death, myocardial infarction, and major adverse cardiovascular events. For both, patients with proximal and with nonproximal LAD PCI, the randomization to bivalirudin versus unfractionated heparin plus glycoprotein IIb/IIIa inhibitor resulted in lower rates of major bleeding (proximal 8.1% vs 10.6%, p = 0.21; nonproximal 6.2% vs 14.0%, p = 0.004) and cardiac death (proximal 4.3% vs 6.0%, p = 0.28; nonproximal 3.0% vs 7.0%, p = 0.04). In patients randomized to unfractionated heparin plus glycoprotein IIb/IIIa inhibitor, bleeding risk and occurrence of events did not differ between abciximab and eptifibatide.



Table 3

Baseline characteristics in patients who underwent left anterior descending percutaneous coronary intervention





















































































































































Variable Bivalirudin (n = 699) UFH + GP IIb/IIIa (n = 746) p
Age (yrs) 60.7 (52.4, 70.8) 61.1 (53.4, 70.7) 0.40
Women 22.6% (158/699) 21.7% (162/746) 0.68
Diabetes mellitus 16.2% (113/699) 18.4% (137/744) 0.26
Hypertension 51.1% (357/699) 53.1% (395/744) 0.44
Hyperlipidemia 42.5% (297/699) 40.3% (300/744) 0.40
Smoking 61.0% (425/697) 54.4% (404/743) 0.01
Body mass index (kg/m²) 27.2 (24.4, 30.4) 26.8 (24.4, 29.7) 0.37
Renal insufficiency 2.9% (20/699) 2.6% (19/744) 0.72
Previous myocardial infarction 8.3% (58/699) 7.9% (59/744) 0.80
Previous percutaneous intervention 9.6% (67/699) 8.5% (63/744) 0.46
Previous coronary artery bypass 1.6% (11/699) 1.1% (8/744) 0.41
Killip class II–IV 12.9% (90/697) 12.8% (95/743) 0.94
Femoral access 93.3% (652/699) 93.8% (699/745) 0.67
Clopidogrel loading dose (mg)
300 35.3% (243/688) 36.6% (266/726) 0.61
600 63.2% (435/688) 62.0% (450/726) 0.63
Prerandomization heparin 66.8% (467/699) 63.2% (470/744) 0.15
Left ventricular ejection fraction <40% 25.9% (151/582) 28.3% (182/643) 0.35
Number of stents implanted 1.5 ± 0.8 1.5 ± 0.9 0.97
Total stent length implanted (mm) 24 (18, 36) 24 (16, 36) 0.51
Any aspiration catheter 9.5% (66/693) 8.8% (65/739) 0.63
Multiple vessels treated 7.1% (49/687) 6.7% (49/730) 0.76
Number of vessels treated 1.1 ± 0.3 1.1 ± 0.3 0.76
Any side branch lesion treated 9.3% (65/699) 9.3% (69/745) 0.98
TIMI flow 0/1 before PCI 60.6% 61.1% 0.82
TIMI flow 0/1 after PCI 2.3% 1.9% 0.62
TIMI flow 3 after PCI 90.3% 91.3% 0.51
Any CABG in-hospital 0.7% (5/699) 1.2% (9/746) 0.34

Data are presented as percentages (count/sample size), median (first, third quartiles), or mean ± SD.

CABG = coronary artery bypass grafting; GP = glycoprotein; TIMI = Thrombolysis In Myocardial Infarction; UFH = unfractionated heparin.


Table 4

Impact of bivalirudin on three-year clinical outcomes in patients who underwent left anterior descending percutaneous coronary intervention






























































































Variable Bivalirudin (n = 699) UFH + GP IIb/IIIa (n = 746) p
MACE 22.8 (157) 25.0 (183) 0.38
Death or reinfarction 11.8 (81) 16.9 (124) 0.007
Death 7.1 (49) 9.4 (69) 0.12
Cardiac 3.8 (26) 6.8 (50) 0.01
Noncardiac 3.5 (23) 2.8 (19) 0.44
Reinfarction 5.3 (35) 9.5 (66) 0.004
Q-wave 2.4 (16) 3.7 (26) 0.17
Non–Q-wave 3.2 (21) 6.1 (42) 0.01
Stroke 1.5 (10) 1.7 (12) 0.76
Ischemic TVR 15.0 (99) 14.6 (101) 0.77
Bleeding
Major (non-CABG related) 7.3 (50) 11.8 (86) 0.004
TIMI major or minor 6.4 (44) 10.7 (78) 0.005
GUSTO 8.2 (56) 12.8 (93) 0.005
Stent thrombosis §
Definite 4.0 (26) 4.4 (30) 0.74
Definite/probable 4.1 (27) 5.4 (37) 0.30

CABG = coronary artery bypass grafting; GP = glycoprotein; GUSTO = Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries scales; MACE = major adverse cardiovascular events; TIMI = Thrombolysis In Myocardial Infarction; UFH = unfractionated heparin.

PES and BMS combined.


Composite of death, reinfarction, stroke, or ischemic TVR.


Ischemic TVR defined as any ischemia-driven repeat percutaneous intervention or bypass surgery of the target vessel. The target vessel consists of the target lesions plus any additional lesions in the main epicardial coronary artery or branches containing the target lesion.


§ Academic Research Consortium definite or probable.


Dec 5, 2016 | Posted by in CARDIOLOGY | Comments Off on Impact of Bivalirudin and Paclitaxel -Eluting Stents on Outcomes in Patients Undergoing Primary Percutaneous Coronary Intervention of the Left Anterior Descending Artery

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