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Impact of Diabetes Mellitus on the Safety and Effectiveness of Bivalirudin in Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty
JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 4, NO. 7, 2011
© 2011 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 1936-8798/$36.00 DOI: 10.1016/j.jcin.2011.04.008
CLINICAL RESEARCH
Impact of Diabetes Mellitus on the Safety and Effectiveness of Bivalirudin in Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty Analysis From the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) Trial Bernhard Witzenbichler, MD,* Roxana Mehran, MD,# Giulio Guagliumi, MD,† Dariusz Dudek, MD,‡ Kurt Huber, MD,§ Ran Kornowski, MD,储 Thomas D. Stuckey, MD,¶ Martin Fahy, SCD,# Helen Parise, SCD,# Gregg W. Stone, MD# Berlin, Germany; Bergamo, Italy; Krakow, Poland; Vienna, Austria; Petach Tikva, Israel; Greensboro, North Carolina; and New York, New York Objectives We sought to evaluate the safety and efficacy of bivalirudin compared with glycoprotein IIb/IIIa inhibitors (GPI) in diabetic patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Background Prior studies have demonstrated that GPI are especially beneficial in patients with diabetes with acute coronary syndromes and/or those undergoing PCI. Methods In the multicenter, prospective HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI were randomized to bivalirudin or unfractionated heparin plus a GPI. Clinical outcomes were analyzed at 30 days and 1 year in patients with diabetes. Results Diabetes mellitus was present in 593 patients (16.5%). The rates of cardiac death were significantly lower in diabetic patients treated with bivalirudin compared with heparin plus GPI (30 days: 2.1% vs. 5.5%, p ⫽ 0.04; 1 year: 2.5% vs. 7.1%, p ⫽ 0.01), and bivalirudin resulted in lower 30-day rates of stroke (0% vs. 2%, p ⫽ 0.02). There were no significant differences among diabetic patients randomized to bivalirudin versus heparin plus GPI in the 1-year rates of major adverse cardiac events (14.2% vs. 16.2%, p ⫽ 0.44), major bleeding (8.7% vs. 10.7%, p ⫽ 0.42), or stent thrombosis (4.2% vs. 3.8%, p ⫽ 0.85). By interaction testing, the relative effects of bivalirudin compared with heparin plus GPI were not significantly different in patients with and without diabetes. Conclusions In patients with diabetes mellitus presenting with STEMI undergoing primary PCI, anticoagulant therapy with bivalirudin compared with heparin plus GPI is safe and effective and might reduce cardiac mortality at 30 days and 1 year. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966) (J Am Coll Cardiol Intv 2011;4:760 – 8) © 2011 by the American College of Cardiology Foundation
From the *Department of Cardiology and Pneumology, Charité Campus Benjamin Franklin, Berlin, Germany; †Ospedali Riuniti di, Bergamo, Bergamo, Italy; ‡Jagiellonian University, Krakow, Poland; §Wilhelminenhospital, Vienna, Austria; 储Rabin Medical Center, Petach Tikva, Israel; ¶LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, North Carolina; and the #Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York. This work was sponsored by the Cardiovascular Research Foundation (New York, New York) with grant support from Boston Scientific and The Medicines Company. Dr. Witzenbichler has received lecture fees from Boston Scientific, Abbott Vascular, and The Medicines Company. Dr. Mehran serves on advisory boards for/consultant to Abbott Vascular, AstraZeneca, OrthoMcNeil,
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 4, NO. 7, 2011 JULY 2011:760 – 8
Patients with diabetes mellitus and acute coronary syndromes— both non–ST-segment elevation acute myocardial infarction (NSTEMI) (1) and ST-segment elevation acute myocardial infarction (STEMI) (2)—are at greater risk of death and myocardial infarction compared with patients without diabetes mellitus. Previous studies have suggested that glycoprotein IIb/IIIa inhibitors (GPI) improve the prognosis in diabetic patients, including those undergoing percutaneous coronary intervention (PCI) for stable ischemic heart disease (3,4), for NSTEMI (1,5) and STEMI (6). However, most of the evidence favoring GPI in STEMI patients undergoing primary PCI was established in the era before thienopyridines (7). A recent study demonstrated that the GPI abciximab does not reduce infarct size or improve clinical outcomes in STEMI patients within 24 h of symptom onset treated with dual antiplatelet therapy, whether diabetic or not (8). Bivalirudin is a direct thrombin inhibitor with antiischemic properties and favorable bleeding event rates when used in elective PCI (9), in acute coronary syndromes patients (10) and STEMI patients treated with primary PCI (11). However, the impact of bivalirudin in high-risk patients with diabetes and STEMI undergoing PCI has not been reported. Therefore, we evaluated the safety and efficacy of bivalirudin in comparison with treatment with heparin plus GPI in diabetic patients with STEMI undergoing primary PCI from the randomized, prospective multicenter HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial.
Methods Patient population and study protocol. The HORIZONS-
AMI study design has been previously described in detail (11,12). In summary, the HORIZONS-AMI trial was a prospective, open-label, randomized, multicenter trial in which 3,602 patients with STEMI presenting within 12 h of symptom onset and undergoing a primary PCI management strategy were randomized 1:1 to bivalirudin alone versus unfractionated heparin plus a GPI (the control group). After angiography, eligible patients were randomized again in a 3:1 ratio to either TAXUS Express paclitaxel-eluting stents or otherwise identical uncoated Express bare-metal stents (Boston Scientific, Natick, Massachusetts). The study was approved by the institutional and Regado Sciences, and has received research support from Bristol-Myers Squibb/ sanofi-aventis. Dr. Guagliumi serves as a consultant for Boston Scientific, Volcano, and Cordis, and has received research grant support from Medtronic, Boston Scientific, LightLab Imaging, and Abbott Vascular. Dr. Dudek has received research grants or served as consultant/advisory board member for Abbott, Adamed, Biotronik, Balton, Bayer, BBraun, BioMatrix, Boston Scientific, Boehringer, Ingelheim, Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, GlaxoSmithKline, Invatec, Medtronic, The Medicines Company, Merck Sharp & Dohme,
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review board or ethics committee at each participating center, and all patients signed informed consent. Patient eligibility criteria has also been described previously (11–13). In summary, consecutive patients ⱖ18 years of age with symptom onset within 12 h of duration and ST-segment elevation of ⱖ1 mm in ⱖ2 contiguous leads, new left bundle branch block, or true posterior myocardial infarction were considered for enrollment. Principal exclusion criteria included contraindications to any of the study medications; prior administration of fibrinolytic therapy, bivalirudin, GPI, low molecular weight heparin, or fondaparinux for the present admission (prior unfractionated heparin was allowed); current use of coumadin; history of bleeding diathesis, conditions predisposing to hemorrhagic risk, or refusal to receive blood transfusions; stroke or transient ischemic attack within 6 months or any permanent neurological deficit; recent or known platelet count ⬍100,000 cells/mm3 or hemoglobin ⬍10 g/dl; planned elective surgical proAbbreviations cedure that would necessitate inand Acronyms terruption of thienopyridines GPI ⴝ glycoprotein IIb/IIIa during the first 6 months after inhibitor enrollment; coronary stent imMACE ⴝ major adverse plantation within 30 days; and cardiovascular event(s) noncardiac comorbid conditions NACE ⴝ net adverse clinical with life expectancy ⬍1 year or event(s) that might result in protocol nonNSTEMI ⴝ non–ST-segment compliance. elevation acute myocardial Endpoints and statistical analysis.
infarction
The 2 primary endpoints of the PCI ⴝ percutaneous coronary intervention HORIZONS-AMI trial were major bleeding (not related to STEMI ⴝ ST-segment elevation acute myocardial coronary artery bypass grafting) infarction and net adverse clinical events TIMI ⴝ Thrombolysis in (NACE), defined as the combiMyocardial Infarction nation of major bleeding or major adverse cardiovascular events (MACE). Major adverse cardiovascular events comprised death, reinfarction, target vessel revascularization for ischemia, or stroke. The endpoint definitions have been detailed elsewhere (12). Bleeding was adjudicated according to the protocol definition (11) as well as on the basis of the Thrombolysis In Myocardial Infarction (TIMI) and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) scales. Stent thrombosis was defined according to the AcaNycomed, Orbus-Neich, Pfizer, Possis, Promed, Sanofi-Aventis, Siemens, Solvay, Terumo, and Tyco. Dr. Stuckey serves on the Speakers’ Bureau and medical advisory board for Boston Scientific. Dr. Stone serves as a consultant to Boston Scientific, Abbott Vascular, The Medicines Company, Merck, Eli Lilly, AstraZeneca, and Bristol-Myers Squibb-Sanofi. All other authors have reported that they have no relationships to disclose. Manuscript received February 15, 2011; revised manuscript received April 4, 2011, accepted April 13, 2011.
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Table 1. Baseline Characteristics According to Diabetic Status Diabetes
Variable Age, yrs
No Diabetes
Bivalirudin (n ⴝ 281)
Heparin Plus GPI (n ⴝ 312)
64.4 [55.8, 71.5]
64.5 [56.3, 72.1]
p Value
Bivalirudin (n ⴝ 1,518)
0.61
59.3 [51.1, 68.7]
Male
70.5 (198)
76.3 (238)
0.11
78.3 (1,189)
Heparin Plus GPI (n ⴝ 1,488) 59.8 [52.4, 69.6] 76.1 (1,133)
p Value 0.15 0.15
Insulin-treated diabetes
25.6 (72)
27.9 (87)
0.53
0 (0)
0 (0)
Hypertension
73.7 (207)
70.8 (221)
0.44
47.7 (724)
51.9 (772)
Hyperlipidemia
64.4 (181)
56.1 (175)
0.04
39.5 (600)
39.9 (594)
0.83
History of smoking
53.0 (148)
60.5 (188)
0.07
67.9 (1,025)
61.9 (917)
0.0006
Prior myocardial infarction
17.8 (50)
15.7 (49)
0.50
9.0 (137)
10.5 (156)
0.18
Prior PCI
15.7 (44)
17.3 (54)
0.60
9.5 (144)
10.5 (156)
0.86
5.7 (16)
5.1 (16)
0.76
2.8 (43)
2.0 (30)
0.15
Prior CABG surgery
0.02
Weight, kg
85.0 [77.0, 95.0]
85.0 [75.0, 97.0]
0.41
80.0 [70.0, 90.0]
80.0 [70.0, 90.0]
0.86
BMI, kg/m2
29.4 [26.1, 32.0]
28.5 [25.7, 31.8]
0.20
26.8 [89.0, 105.0]
26.8 [24.4, 29.7]
0.61
1.84 [1.00, 3.17]
1.66 [0.92, 3.03]
0.11
7.7 (115)
0.99
1.0 (13/1,358)
0.91
Symptom onset to hospital arrival, h
2.0 [1.0, 3.8]
2.5 [1.5, 4.3]
0.11
Killip class 2–4
12.9 (36)
11.9 (37)
0.72
7.7 (117)
Qualifying electrocardiogram (core laboratory) Left bundle branch block ST-segment elevation* Other*
2.3 (6/265)
1.8 (5/281)
0.69
96.5 (250/259)
96.7 (267/276)
0.89
3.5 (9/259)
3.3 (9/276)
0.89
1.0 (14/1,402) 97.8 (1,355/1,386) 2.2 (31/1,386)
97.3 (1,306/1,342) 2.7 (36/1,342)
0.45 0.45
Creatinine clearance ⬍60 ml/min
18.1 (47)
20.5 (60)
0.46
15.3 (215)
16.8 (232)
0.31
Anemia†
14.2 (38)
16.4 (49)
0.48
9.7 (139)
9.5 (133)
0.87
Thrombocytopenia‡
6.3 (17)
5.2 (16)
0.58
3.2 (47)
4.6 (66)
0.05
Left ventricular ejection fraction§
50 [45, 60]
48 [38, 55]
0.001
50 [45, 60]
50 [44, 60]
0.75
Values are median [25th, 75th percentile] or % (n). *Excluding left bundle branch block; †hematocrit value at initial presentation ⬍39% for men and ⬍36% for women; ‡⬍150,000 cells/mm3 at baseline; §visual assessment from the baseline contrast left ventriculogram. BMI ⫽ body mass index; CABG ⫽ coronary artery bypass grafting; GPI ⫽ glycoprotein IIb/IIIa inhibitor; PCI ⫽ percutaneous coronary intervention.
demic Research Consortium classification (14). Noncardiac death was defined as a death not due to cardiac causes, including bleeding-related death. All primary and secondary endpoint events were adjudicated by a clinical events committee using original source documents, blinded to treatment assignment. Diabetes was defined as a history of hyperglycemia managed by insulin, oral hypoglycemic agents, or diet. Categorical outcomes were compared by chi-square test or Fisher exact test. Continuous variables were compared by means of the Wilcoxon rank-sum test. Time-to-event outcomes, determined with Kaplan-Meier methods, were compared by the log-rank test. Independent correlates of 30-day and 1-year mortality in the entire randomized population and in the cohort undergoing primary PCI were determined by Cox proportional hazards regression. Results
with diet alone. Of those, 281 patients were randomized to anticoagulant treatment with bivalirudin, and 312 were randomized to heparin plus a GPI. The baseline features and procedural data in patients randomized to bivalirudin versus heparin plus a GPI were well-matched in the diabetic and nondiabetic cohort (Tables 1 and 2). Among patients with diabetes, there were no significant differences in management strategy after coronary angiography: PCI was subsequently performed in 92.2% of the bivalirudin-treated group and in 91.7% of the heparin plus GPI group (p ⫽ 0.82), coronary artery bypass grafting without PCI was subsequently performed in 2.1% versus 3.5%, respectively (p ⫽ 0.31), and medical management was subsequently performed in 5.7 versus 4.8%, respectively (p ⫽ 0.63). Thienopyridine use before admission was slightly higher in the diabetic patients randomized to heparin plus GPI, and the percentage of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers at discharge was slightly lower in nondiabetic patients randomized to bivalirudin (Table 2).
Patients and procedures. Of 3,602 patients with STEMI
Clinical outcomes in diabetic and nondiabetic patients.
undergoing primary PCI and enrolled in the HORIZONSAMI trial, 593 patients (16.5%) had diabetes mellitus. This included 159 (26.8%) treated with insulin, 322 (54.3%) treated with oral medications without insulin, and 107 (18.0%) treated
Among the diabetic cohort, there were no significant differences in the rates of NACE, MACE, all-cause mortality, or major bleeding events in patients assigned to bivalirudin versus heparin plus GPI at 30 days (Table 3). However, bivalirudin
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Table 2. Procedures and Medications According to Diabetic Status Diabetes
Variable
Bivalirudin (n ⴝ 281)
No Diabetes
Heparin Plus GPI (n ⴝ 312)
p Value
Bivalirudin (n ⴝ 1,518)
Heparin Plus GPI (n ⴝ 1,488)
p Value
Infarct-related artery Left anterior descending
40.1 (109)
45.6 (139)
0.18
39.1 (595)
41.2 (610)
0.24
Left circumflex
18.0 (272)
12.5 (38)
0.06
16.2 (246)
15.8 (233)
0.74
Right coronary artery
0.64
40.4 (110)
39.3 (120)
0.79
42.8 (650)
41.9 (620)
Left main
0.7 (2)
0.3 (1)
0.60
0.7 (11)
0.4 (6)
0.25
Saphenous vein graft
0.7 (2)
2.3 (7)
0.18
1.1 (16)
0.7 (10)
0.27
65.5 (184)
67.6 (211)
0.58
65.6 (994)
65.1 (968)
0.81
Heparin before procedure Antithrombin during procedure
2.1 (6)
99.0 (301)
⬍0.0001
95.7 (269)
0.3 (1)
⬍0.0001
97.1 (1,472)
In the cath lab, any
8.6 (24)
94.2 (294)
⬍0.0001
6.9 (105)
94.5 (1,405)
⬍0.0001
Abciximab
3.9 (11)
47.1 (147)
⬍0.0001
4.0 (61)
50.5 (750)
⬍0.0001
Eptifibatide
4.6 (13)
46.8 (146)
⬍0.0001
2.8 (43)
43.9 (652)
⬍0.0001
Tirofiban
0.0 (0)
0.3 (1)
1.00
0.1 (2)
0.2 (3)
0.68
Heparin Bivalirudin
2.6 (40)
98.9 (1,469) 0.5 (7)
⬍0.0001 ⬍0.0001
GPI IIb/IIIa inhibitor
Aspirin use Before admission
44.1 (124)
39.1 (122)
0.21
23.6 (358)
24.5 (364)
0.59
During hospitalization
98.9 (278)
100.0 (312)
0.11
99.8 (1,513)
99.8 (1,483)
1.00
At discharge
98.2 (267)
97.0 (291)
0.37
98.1 (1,462)
97.1 (1,406)
0.07
Thienopyridine use Before admission
2.5 (7)
6.1 (19)
0.03
Loading dose, any
95.7 (269)
95.8 (299)
0.95
97.2 (1,473)
97.0 (1,442)
0.84
Clopidogrel 300 mg
35.9 (101)
37.8 (118)
0.64
32.6 (494)
33.6 (500)
0.54
Clopidogrel 600 mg
59.1 (166)
56.7 (177)
0.56
63.3 (959)
61.5 (914)
0.32
93.0 (253)
92.3 (277)
0.76
93.8 (1,399)
92.8 (1,344)
0.30
Beta-blockers
90.0 (253)
87.4 (271)
0.32
89.1 (1,346)
88.4 (1,308)
0.58
ACE inhibitors or ARB
81.6 (222)
75.3 (226)
0.67
73.6 (1,098)
77.3 (1,120)
0.02
Statins
93.8 (255)
95.0 (285)
0.52
93.7 (1,397)
93.6 (1,356)
0.90
At discharge
3.7 (56)
4.1 (61)
0.57
Medications at discharge
Values are % (n). ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker; cath lab ⫽ catheterization laboratory; GPI ⫽ glycoprotein IIb/IIIa inhibitor.
treatment was associated with a significantly reduced 30-day rate of cardiac death (2.1% vs. 5.5%, p ⫽ 0.04) and stroke (0% vs. 2.0%, p ⫽ 0.02). Noncardiac mortality was higher at 30 days with bivalirudin, however (1.4% vs. 0%, p ⫽ 0.05), and as such there was no significant difference in all-cause mortality between the 2 therapies. At 1 year, of the rate of cardiac mortality in diabetic patients was significantly reduced with bivalirudin compared with heparin plus GPI (2.5% vs. 7.1%, p ⫽ 0.01), and the difference in noncardiac mortality was no longer significant (2.2% vs. 0.7%, p ⫽ 0.12). All-cause mortality at 1 year occurred in 4.7% of diabetic patients treated with bivalirudin compared with 7.8% treated with heparin plus GPI (p ⫽ 0.13). There were no significant differences in the 1-year rates of NACE, MACE, and major bleeding according to assigned treatment (Fig. 1). Among nondiabetic patients, randomization to bivalirudin resulted in a significant reduction of NACE (at 30 days: 8.8%
vs. 11.9%, p ⫽ 0.005; at 1 year: 14.7% vs. 17.5%, p ⫽ 0.03) and major bleeding (at 30 days: 4.7% vs. 8.6%, p ⬍ 0.0001; at 1 year 5.3% vs. 9.0%, p ⬍ 0.0001), with nonsignificant differences in MACE (Fig. 1, Table 3). Further analysis of the diabetic patients according to insulin-treated and noninsulin-treated cohorts did not reveal any significant differences of bivalirudin or heparin plus GP IIb/IIIa treatment for NACE or major adverse clinical or bleeding events, whereas there was a significant advantage in favor of bivalirudin treatment among insulin-treated patients with regard to cardiac death at 1 year (1.4% vs. 9.4%, p ⫽ 0.04) (Fig. 2, Table 4). Formal interaction testing demonstrated that the favorable effects of bivalirudin compared with heparin plus GPI in reducing the 1-year rates of major bleeding, NACE, all-cause mortality, and cardiac mortality in the entire study population (12) were independent of diabetic
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Table 3. Clinical Outcomes at 30 Days According to Diabetic Status Diabetes
No Diabetes
Bivalirudin Heparin Plus Bivalirudin Heparin Plus GPI (n ⴝ 281) GPI (n ⴝ 312) p Value (n ⴝ 1,518) (n ⴝ 1,488) p Value Net adverse clinical events
12.5 (35)
16.4 (51)
0.20
8.8 (133)
11.9 (177)
Major adverse cardiac events
6.4 (18)
9.6 (30)
0.16
5.3 (80)
4.7 (70)
0.45
0.0005
Death (all-cause)
0.12
3.6 (10)
5.5 (17)
0.28
1.8 (27)
2.6 (39)
Cardiac
2.1 (6)
5.5 (17)
0.04
1.7 (26)
2.4 (35)
0.22
Noncardiac
1.4 (4)
0.0 (0)
0.05
0.1 (1)
0.3 (4)
0.17
Reinfarction
2.2 (6)
2.9 (9)
0.57
1.9 (28)
1.6 (23)
0.52
Q-wave
1.8 (5)
2.3 (7)
0.69
1.4 (21)
1.0 (15)
0.34
Non–Q-wave
0.4 (1)
1.0 (3)
0.37
0.5 (7)
0.6 (9)
0.59
TVR
3.3 (9)
2.9 (9)
0.81
2.7 (40)
1.8 (27)
0.12
Stroke
0.0 (0)
2.0 (6)
0.02
0.9 (14)
0.4 (6)
Major bleeding (non–CABG-related)
7.9 (22)
10.3 (32)
0.33
4.7 (70)
8.6 (127)
⬍0.0001
11.9 (33)
12.9 (40)
0.72
6.1 (92)
11.0 (162)
⬍0.0001
4.3 (12)
4.9 (15)
0.78
1.8 (27)
3.5 (52)
0.003
TIMI major bleeding
6.9 (19)
5.2 (16)
0.40
2.6 (39)
5.3 (78)
0.0002
TIMI minor bleeding
4.0 (11)
5.2 (16)
0.50
2.7 (40)
4.6 (68)
0.004
Life-threatening or severe bleeding
0.4 (1)
1.0 (3)
0.37
0.5 (8)
0.5 (8)
0.97
Moderate bleeding
6.1 (17)
6.9 (21)
0.78
2.7 (40)
4.9 (72)
0.001
Major bleeding (including CABG-related) Blood transfusion
0.08
TIMI classification
GUSTO classification
Values are % (n). CABG ⫽ coronary artery bypass graft surgery; GPI ⫽ glycoprotein IIb/IIIa inhibitor; GUSTO ⫽ Global Strategies for Opening Occluded Coronary Arteries; MACE ⫽ major adverse cardiovascular event(s) (death, myocardial infarction, ischemic target vessel revascularization, or stroke); PCI ⫽ percutaneous coronary intervention; TIMI ⫽ Thrombolysis in Myocardial Infarction; TVR ⫽ target vessel revascularization.
status (pint ⫽ 0.26, 0.64, 0.55, and 0.19, respectively). Similarly, bivalirudin compared with heparin plus GPI resulted in nonsignificantly different rates of MACE, noncardiac mortality, and stroke in the entire study population (12), effects which were also independent of diabetic status (pint ⫽ 0.38, 0.17, and 0.06, respectively). Stent thrombosis. The overall rate of definite/probable stent thrombosis at 1 year did not differ among diabetic patients who received bivalirudin compared with those treated with heparin plus GPI (4.2% vs. 3.8%, p ⫽ 0.85). Similarly, there was no difference in the 1-year rates of stent thrombosis between the randomized antithrombotic regimens in the nondiabetic subgroup (3.5% vs. 3.1%, p ⫽ 0.54) (Table 5), and interaction testing for an effect of diabetic status on stent thrombosis by randomization was negative (p ⫽ 0.93). There were also no significant differences in the rate of stent thrombosis between the 2 treatment arms when the diabetic patients were further separated into insulin-treated or non–insulin-treated groups (Table 5). Discussion Diabetic patients presenting with STEMI have a substantially greater incidence of early and late death or myocardial infarction compared with nondiabetic subjects (15–17).
With contemporary interventional approaches, the procedural success rate of primary PCI in diabetic patients with STEMI is equivalent to nondiabetic patients, as reinforced in the present report (16,18). However, diabetic patients with STEMI compared with nondiabetic patients are less likely to achieve normal myocardial perfusion (as measured by reduced restoration of normal angiographic myocardial blush and ST-segment resolution, and a greater incidence of distal embolization), which has been associated with higher mortality (2,18,19). Glycoprotein IIb/IIIa inhibitors might improve myocardial perfusion and survival (20,21), particularly in patients with diabetes. In the ADMIRAL (Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up) trial (6), the 6-month rates of mortality and target vessel revascularization after primary stenting were reduced in the 53 diabetic patients randomized to abciximab versus placebo (mortality: 0% vs. 16.7%, p ⫽ 0.02; target vessel revascularization: 3.7% vs. 37.5%, p ⫽ 0.046). However, this result was not reproduced in the larger CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial with 346 diabetic patients enrolled (22,23). A meta-analysis based on individual specific data from the ISAR-2
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25
A
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20
B
18
20
16
MACE (%)
NACE (%)
14
15
10
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
2 0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
250 234 1246 1325
241 226 1216 1288
235 220 1190 1263
213 202 1067 1141
0
1
6 4 Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
2
4
5
270 251 1347 1376
10
6
7
8
9
10
11
12
259 241 1313 1338
253 235 1286 1309
225 215 1154 1179
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
9
Cardiac mortality (%)
8
3
Months
12 10
2
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
D
14
Major bleeding (non CABG) (%)
8
4
0
C
10
6
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
5
12
8 7 6 5 4 3 2 1 0
0
0 Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
1
2
3
4
5
6
7
8
9
10
11
12
Months 260 244 1281 1376
258 241 1272 1360
255 239 1258 1347
228 221 1139 1227
0
1
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 1518 No diabetes / Bivalirudin
2
3
4
5
6
7
8
9
10
11
12
Months 285 263 1391 1441
282 258 1380 1426
279 256 1366 1413
246 236 1239 1284
Figure 1. Kaplan-Meier Curves Through 1 Year for NACE, MACE, Major Bleeding, and Cardiac Mortality Kaplan-Meier curves through 1 year for (A) net adverse clinical events (NACE); (B) major adverse cardiac events (MACE); (C) major bleeding not related to coronary artery bypass grafting (CABG); and (D) cardiac mortality, according to diabetic status. GPI ⫽ glycoprotein IIb/IIIa inhibitor.
(Intracoronary Stenting and Antithrombotic Regimen-2) (24), ADMIRAL (6), and ACE (Abciximab-Carbostent Evaluation) (25) studies including 183 diabetic patients reported that death and reinfarction were significantly lower in diabetic patients treated with abciximab compared with UFH alone (26). We have previously reported that patients randomized to bivalirudin rather than heparin plus GPI in the HORIZONS-AMI trial benefitted from a pronounced reduction in bleeding events, along with NACE and allcause and cardiac mortality (11,27). However, a recent meta-regression analysis suggested that the benefits from adjunctive GPI in improving survival are most evidenced in high-risk patients, such as those with diabetes mellitus (28). With this background, the current report in 593 diabetic patients enrolled in the HORIZONS-AMI trial represents the largest analysis of diabetic STEMI patients treated by contemporary primary PCI to date and demonstrates that bivalirudin compared with heparin plus GPI significantly reduces cardiac mortality in the high-risk diabetic cohort as well as patients without diabetes. Although cardiac mortality and stroke were reduced in diabetic patients treated with bivalirudin rather than hepa-
rin plus GPI, total mortality, major bleeding, and NACE were not significantly reduced in the diabetic cohort with bivalirudin. However, interaction testing demonstrated that the relative reductions in bleeding, NACE, and all-cause and cardiac mortality with bivalirudin compared with heparin plus GPI were not significantly different in the diabetic and nondiabetic groups. Given that subgroups are inherently underpowered (29), the most appropriate interpretation of these data is that the overall benefits with bivalirudin seen in the main trial seem to apply to patients both with and without diabetes. However, we cannot exclude a modest difference in the relative effect of bivalirudin versus heparin plus GPI in patients with versus without diabetes. Moreover, previous studies have suggested a higher rate of stent thrombosis in diabetic patients, particularly those insulin-treated (30,31). In the present analysis the overall rate of stent thrombosis in the diabetic subgroup was comparable in patients treated with bivalirudin or those treated with heparin plus GPI. In the HORIZONS-AMI trial, study medications were most commonly initiated in the catheterization laboratory. Previous analyses suggest that an “upstream” pre-catheterization
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Figure 2. Subgroup Analyses: 1-Year Rates of NACE and Major Bleeding Subgroup analyses: hazard ratios with 95% confidence intervals for the 1-year rates of NACE, major bleeding not related to CABG, MACE, and cardiac death, in the overall study population and according to diabetic status, for insulin-treated and non–insulin-treated diabetic patients, nondiabetic patients, and overall study population. *For cardiac mortality among insulin-treated diabetic patients, the 95% confidence interval of the hazard ratio crosses unity, despite the p value being 0.037, because the former is calculated from a Cox model and the latter from the log-rank. Abbreviations as in Figure 1.
start of GPI therapy might be beneficial before primary PCI in STEMI. A recent meta-analysis of 281 diabetic patients from 11 randomized trials of early versus late administration
of GPI in STEMI found that upstream GPI was associated with significant improvements in pre- and post-procedural TIMI flow and myocardial perfusion (distal embolization,
Table 4. Clinical Outcomes at 1 Year According to Insulin Treatment in Patients With Diabetes Insulin-Treated Diabetes
NonInsulin-Treated Diabetes
Bivalirudin (n ⴝ 72)
Heparin Plus GPI (n ⴝ 87)
p Value
Bivalirudin (n ⴝ 209)
Heparin Plus GPI (n ⴝ 225)
p Value
Net adverse clinical events
28.9 (20)
24.6 (21)
0.58
17.4 (36)
21.0 (47)
0.30
Major adverse cardiac events
19.3 (13)
18.8 (16)
0.97
12.6 (26)
15.3 (34)
0.40
Death (all-cause)
4.4 (3)
10.6 (9)
0.15
4.8 (10)
6.7 (15)
0.41
Cardiac
1.4 (1)
9.4 (8)
0.04
2.9 (6)
6.3 (14)
0.10
Noncardiac
3.0 (2)
1.3 (1)
0.45
2.0 (4)
0.5 (1)
0.16
16.9 (12)
10.5 (9)
0.23
6.9 (14)
11.7 (26)
0.09
Major bleeding (non–CABG-related) Values are % (n). Abbreviations as in Table 3.
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Table 5. Stent Thrombosis at 1 Year According to Diabetic Status Diabetes Bivalirudin (n ⴝ 281) Definite or probable
Heparin Plus GPI (n ⴝ 312)
No Diabetes
p Value
Bivalirudin (n ⴝ 1,518)
Heparin Plus GPI (n ⴝ 1,488)
p Value
4.2 (10)
3.8 (10)
0.85
3.5 (47)
3.1 (40)
0.54
Definite
3.8 (9)
2.3 (6)
0.35
3.2 (43)
2.4 (31)
0.20
Probable
0.4 (1)
1.5 (4)
0.21
0.3 (4)
0.7 (9)
0.15
Insulin-Treated Diabetes
Definite or probable
Bivalirudin (n ⴝ 72)
Heparin Plus GPI (n ⴝ 87)
NonInsulin-Treated Diabetes
p Value
Bivalirudin (n ⴝ 209)
Heparin Plus GPI (n ⴝ 225)
p Value
9.8 (6)
10.4 (8)
0.87
2.8 (5)
1.6 (3)
0.44
Definite
8.3 (5)
5.2 (4)
0.52
2.2 (4)
1.1 (2)
0.38
Probable
1.6 (1)
3.9 (3)
0.41
0.0 (0)
0.5 (1)
0.33
Values are % (n). Stent thrombosis definition according to Academic Research Consortium criteria. GPI ⫽ glycoprotein IIb/IIIa inhibitor.
myocardial blush grade); however, complete ST-segment resolution, enzymatic infarct size, and—most importantly— mortality at 1 year (8.3% vs. 9.5%) was not improved (32). Therefore, it is unlikely that systematic early administration of GPI in the HORIZONS-AMI trial would have had a significant impact on the results overall and in the diabetic subgroup. Study limitations. First, although the present diabetic analysis was a pre-specified substudy, the HORIZONS-AMI trial was not powered for subgroup analysis. As such, despite the large number of diabetic patients enrolled, these results should be considered exploratory and hypothesisgenerating. Second, the open-label design of the study might have introduced potential bias. However, all clinical events were adjudicated by an independent clinical events committee blinded to all procedural medications. Third, as is common in all such substudies, diabetes was diagnosed on admission according to prior history and not by glucose or insulin level testing. It is possible that serial testing of diabetic state might have identified a high-risk diabetic group more prone to benefit with either bivalirudin or heparin plus GPI. This is unlikely, however, given the negative interaction testing from the present analysis and the comparable results with both regimens in patients with insulin treatment. Conclusions The HORIZONS-AMI diabetes substudy demonstrates that, in both high-risk patients with diabetes and nondiabetic patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin monotherapy (with bail-out GPI in 7.6% of patients for refractory thrombotic complications) compared with heparin plus the routine use of a GPI seems to significantly improve 30-day and 1-year net clinical outcomes and survival.
Reprint requests and correspondence: Dr. Gregg W. Stone, Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022. E-mail: [email protected].
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1. Roffi M, Topol EJ. Percutaneous coronary intervention in diabetic patients with non-ST-segment elevation acute coronary syndromes. Eur Heart J 2004;25:190 – 8. 2. De Luca G, Gibson CM, Bellandi F, et al. Diabetes mellitus is associated with distal embolization, impaired myocardial perfusion, and higher mortality in patients with ST-segment elevation myocardial infarction treated with primary angioplasty and glycoprotein IIb-IIIa inhibitors. Atherosclerosis 2009;207:181–5. 3. Bhatt DL, Marso SP, Lincoff AM, et al. Abciximab reduces mortality in diabetics following percutaneous coronary intervention. J Am Coll Cardiol 2000;35:922– 8. 4. Marso SP, Lincoff AM, Ellis SG, et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999;100:2477– 84. 5. Theroux P, Alexander J Jr., Pharand C, et al. Glycoprotein IIb/IIIa receptor blockade improves outcomes in diabetic patients presenting with unstable angina/non-ST-elevation myocardial infarction: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISMPLUS) study. Circulation 2000;102:2466 –72. 6. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med 2001;344:1895–903. 7. Kushner FG, Hand M, Smith SC Jr., et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with STelevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205– 41. 8. Mehilli J, Kastrati A, Schulz S, et al. Abciximab in patients with acute ST-segment-elevation myocardial infarction undergoing primary percutaneous coronary intervention after clopidogrel loading: a randomized double-blind trial. Circulation 2009;119:1933– 40.
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9. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853– 63. 10. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203–16. 11. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358: 2218 –30. 12. Mehran R, Brodie B, Cox DA, et al. The Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction (HORIZONS-AMI) Trial: study design and rationale. Am Heart J 2008;156:44 –56. 13. Stone GW, Lansky AJ, Pocock SJ, et al. Paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction. N Engl J Med 2009;360:1946 –59. 14. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation 2007;115:2344 –51. 15. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229 –34. 16. Harjai KJ, Stone GW, Boura J, et al. Comparison of outcomes of diabetic and nondiabetic patients undergoing primary angioplasty for acute myocardial infarction. Am J Cardiol 2003;91:1041–5. 17. Mak KH, Moliterno DJ, Granger CB, et al., for the GUSTO-I Investigators. Influence of diabetes mellitus on clinical outcome in the thrombolytic era of acute myocardial infarction. Global Utilization of streptokinase and tissue plasminogen activator for Occluded Coronary arteries. J Am Coll Cardiol 1997;30:171–9. 18. Prasad A, Stone GW, Stuckey TD, et al. Impact of diabetes mellitus on myocardial perfusion after primary angioplasty in patients with acute myocardial infarction. J Am Coll Cardiol 2005;45:508 –14. 19. Timmer JR, van der Horst IC, de Luca G, et al. Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction with versus without diabetes mellitus. Am J Cardiol 2005;95:1375–7. 20. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. JAMA 2005;293: 1759 – 65. 21. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation 1998;98:2695–701.
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22. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med 2002;346:957– 66. 23. Stuckey TD, Stone GW, Cox DA, et al. Impact of stenting and abciximab in patients with diabetes mellitus undergoing primary angioplasty in acute myocardial infarction (the CADILLAC trial). Am J Cardiol 2005;95:1–7. 24. Neumann FJ, Kastrati A, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade with abciximab on clinical and angiographic restenosis rate after the placement of coronary stents following acute myocardial infarction. J Am Coll Cardiol 2000;35:915–21. 25. Antoniucci D, Rodriguez A, Hempel A, et al. A randomized trial comparing primary infarct artery stenting with or without abciximab in acute myocardial infarction. J Am Coll Cardiol 2003;42:1879 – 85. 26. Montalescot G, Antoniucci D, Kastrati A, et al. Abciximab in primary coronary stenting of ST-elevation myocardial infarction: a European meta-analysis on individual patients’ data with long-term follow-up. Eur Heart J 2007;28:443–9. 27. Mehran R, Lansky AJ, Witzenbichler B, et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009;374:1149 –59. 28. De Luca G, Navarese E, Marino P. Risk profile and benefits from Gp IIb-IIIa inhibitors among patients with ST-segment elevation myocardial infarction treated with primary angioplasty: a meta-regression analysis of randomized trials. Eur Heart J 2009;30:2705–13. 29. Hernandez AV, Boersma E, Murray GD, Habbema JD, Steyerberg EW. Subgroup analyses in therapeutic cardiovascular clinical trials: are most of them misleading? Am Heart J 2006;151:257– 64. 30. Akin I, Bufe A, Schneider S, et al. Clinical outcomes in diabetic and non-diabetic patients with drug-eluting stents: results from the first phase of the prospective multicenter German DES.DE registry. Clin Res Cardiol 2010:99:393– 400. 31. Aoki J, Lansky AJ, Mehran R, et al. Early stent thrombosis in patients with acute coronary syndromes treated with drug-eluting and bare metal stents: the Acute Catheterization and Urgent Intervention Triage Strategy trial. Circulation 2009;119:687–98. 32. De Luca G, Michael-Gibson C, Bellandi F, et al. Benefits of pharmacological facilitation with glycoprotein IIb-IIIa inhibitors in diabetic patients undergoing primary angioplasty for STEMI. A subanalysis of the EGYPT cooperation. J Thromb Thrombolysis 2009;28:288 –98.
Key Words: diabetes mellitus 䡲 major adverse cardiac event(s) 䡲 primary percutaneous coronary intervention 䡲 stent thrombosis 䡲 ST-segment elevation myocardial infarction.
VOL. 4, NO. 7, 2011
© 2011 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER INC.
ISSN 1936-8798/$36.00 DOI: 10.1016/j.jcin.2011.04.008
CLINICAL RESEARCH
Impact of Diabetes Mellitus on the Safety and Effectiveness of Bivalirudin in Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty Analysis From the HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) Trial Bernhard Witzenbichler, MD,* Roxana Mehran, MD,# Giulio Guagliumi, MD,† Dariusz Dudek, MD,‡ Kurt Huber, MD,§ Ran Kornowski, MD,储 Thomas D. Stuckey, MD,¶ Martin Fahy, SCD,# Helen Parise, SCD,# Gregg W. Stone, MD# Berlin, Germany; Bergamo, Italy; Krakow, Poland; Vienna, Austria; Petach Tikva, Israel; Greensboro, North Carolina; and New York, New York Objectives We sought to evaluate the safety and efficacy of bivalirudin compared with glycoprotein IIb/IIIa inhibitors (GPI) in diabetic patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Background Prior studies have demonstrated that GPI are especially beneficial in patients with diabetes with acute coronary syndromes and/or those undergoing PCI. Methods In the multicenter, prospective HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial, 3,602 patients with STEMI were randomized to bivalirudin or unfractionated heparin plus a GPI. Clinical outcomes were analyzed at 30 days and 1 year in patients with diabetes. Results Diabetes mellitus was present in 593 patients (16.5%). The rates of cardiac death were significantly lower in diabetic patients treated with bivalirudin compared with heparin plus GPI (30 days: 2.1% vs. 5.5%, p ⫽ 0.04; 1 year: 2.5% vs. 7.1%, p ⫽ 0.01), and bivalirudin resulted in lower 30-day rates of stroke (0% vs. 2%, p ⫽ 0.02). There were no significant differences among diabetic patients randomized to bivalirudin versus heparin plus GPI in the 1-year rates of major adverse cardiac events (14.2% vs. 16.2%, p ⫽ 0.44), major bleeding (8.7% vs. 10.7%, p ⫽ 0.42), or stent thrombosis (4.2% vs. 3.8%, p ⫽ 0.85). By interaction testing, the relative effects of bivalirudin compared with heparin plus GPI were not significantly different in patients with and without diabetes. Conclusions In patients with diabetes mellitus presenting with STEMI undergoing primary PCI, anticoagulant therapy with bivalirudin compared with heparin plus GPI is safe and effective and might reduce cardiac mortality at 30 days and 1 year. (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction; NCT00433966) (J Am Coll Cardiol Intv 2011;4:760 – 8) © 2011 by the American College of Cardiology Foundation
From the *Department of Cardiology and Pneumology, Charité Campus Benjamin Franklin, Berlin, Germany; †Ospedali Riuniti di, Bergamo, Bergamo, Italy; ‡Jagiellonian University, Krakow, Poland; §Wilhelminenhospital, Vienna, Austria; 储Rabin Medical Center, Petach Tikva, Israel; ¶LeBauer Cardiovascular Research Foundation and Moses Cone Hospital, Greensboro, North Carolina; and the #Columbia University Medical Center and the Cardiovascular Research Foundation, New York, New York. This work was sponsored by the Cardiovascular Research Foundation (New York, New York) with grant support from Boston Scientific and The Medicines Company. Dr. Witzenbichler has received lecture fees from Boston Scientific, Abbott Vascular, and The Medicines Company. Dr. Mehran serves on advisory boards for/consultant to Abbott Vascular, AstraZeneca, OrthoMcNeil,
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Patients with diabetes mellitus and acute coronary syndromes— both non–ST-segment elevation acute myocardial infarction (NSTEMI) (1) and ST-segment elevation acute myocardial infarction (STEMI) (2)—are at greater risk of death and myocardial infarction compared with patients without diabetes mellitus. Previous studies have suggested that glycoprotein IIb/IIIa inhibitors (GPI) improve the prognosis in diabetic patients, including those undergoing percutaneous coronary intervention (PCI) for stable ischemic heart disease (3,4), for NSTEMI (1,5) and STEMI (6). However, most of the evidence favoring GPI in STEMI patients undergoing primary PCI was established in the era before thienopyridines (7). A recent study demonstrated that the GPI abciximab does not reduce infarct size or improve clinical outcomes in STEMI patients within 24 h of symptom onset treated with dual antiplatelet therapy, whether diabetic or not (8). Bivalirudin is a direct thrombin inhibitor with antiischemic properties and favorable bleeding event rates when used in elective PCI (9), in acute coronary syndromes patients (10) and STEMI patients treated with primary PCI (11). However, the impact of bivalirudin in high-risk patients with diabetes and STEMI undergoing PCI has not been reported. Therefore, we evaluated the safety and efficacy of bivalirudin in comparison with treatment with heparin plus GPI in diabetic patients with STEMI undergoing primary PCI from the randomized, prospective multicenter HORIZONS-AMI (Harmonizing Outcomes with RevasculariZatiON and Stents in Acute Myocardial Infarction) trial.
Methods Patient population and study protocol. The HORIZONS-
AMI study design has been previously described in detail (11,12). In summary, the HORIZONS-AMI trial was a prospective, open-label, randomized, multicenter trial in which 3,602 patients with STEMI presenting within 12 h of symptom onset and undergoing a primary PCI management strategy were randomized 1:1 to bivalirudin alone versus unfractionated heparin plus a GPI (the control group). After angiography, eligible patients were randomized again in a 3:1 ratio to either TAXUS Express paclitaxel-eluting stents or otherwise identical uncoated Express bare-metal stents (Boston Scientific, Natick, Massachusetts). The study was approved by the institutional and Regado Sciences, and has received research support from Bristol-Myers Squibb/ sanofi-aventis. Dr. Guagliumi serves as a consultant for Boston Scientific, Volcano, and Cordis, and has received research grant support from Medtronic, Boston Scientific, LightLab Imaging, and Abbott Vascular. Dr. Dudek has received research grants or served as consultant/advisory board member for Abbott, Adamed, Biotronik, Balton, Bayer, BBraun, BioMatrix, Boston Scientific, Boehringer, Ingelheim, Bristol-Myers Squibb, Cordis, Cook, Eli Lilly, EuroCor, GlaxoSmithKline, Invatec, Medtronic, The Medicines Company, Merck Sharp & Dohme,
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review board or ethics committee at each participating center, and all patients signed informed consent. Patient eligibility criteria has also been described previously (11–13). In summary, consecutive patients ⱖ18 years of age with symptom onset within 12 h of duration and ST-segment elevation of ⱖ1 mm in ⱖ2 contiguous leads, new left bundle branch block, or true posterior myocardial infarction were considered for enrollment. Principal exclusion criteria included contraindications to any of the study medications; prior administration of fibrinolytic therapy, bivalirudin, GPI, low molecular weight heparin, or fondaparinux for the present admission (prior unfractionated heparin was allowed); current use of coumadin; history of bleeding diathesis, conditions predisposing to hemorrhagic risk, or refusal to receive blood transfusions; stroke or transient ischemic attack within 6 months or any permanent neurological deficit; recent or known platelet count ⬍100,000 cells/mm3 or hemoglobin ⬍10 g/dl; planned elective surgical proAbbreviations cedure that would necessitate inand Acronyms terruption of thienopyridines GPI ⴝ glycoprotein IIb/IIIa during the first 6 months after inhibitor enrollment; coronary stent imMACE ⴝ major adverse plantation within 30 days; and cardiovascular event(s) noncardiac comorbid conditions NACE ⴝ net adverse clinical with life expectancy ⬍1 year or event(s) that might result in protocol nonNSTEMI ⴝ non–ST-segment compliance. elevation acute myocardial Endpoints and statistical analysis.
infarction
The 2 primary endpoints of the PCI ⴝ percutaneous coronary intervention HORIZONS-AMI trial were major bleeding (not related to STEMI ⴝ ST-segment elevation acute myocardial coronary artery bypass grafting) infarction and net adverse clinical events TIMI ⴝ Thrombolysis in (NACE), defined as the combiMyocardial Infarction nation of major bleeding or major adverse cardiovascular events (MACE). Major adverse cardiovascular events comprised death, reinfarction, target vessel revascularization for ischemia, or stroke. The endpoint definitions have been detailed elsewhere (12). Bleeding was adjudicated according to the protocol definition (11) as well as on the basis of the Thrombolysis In Myocardial Infarction (TIMI) and GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) scales. Stent thrombosis was defined according to the AcaNycomed, Orbus-Neich, Pfizer, Possis, Promed, Sanofi-Aventis, Siemens, Solvay, Terumo, and Tyco. Dr. Stuckey serves on the Speakers’ Bureau and medical advisory board for Boston Scientific. Dr. Stone serves as a consultant to Boston Scientific, Abbott Vascular, The Medicines Company, Merck, Eli Lilly, AstraZeneca, and Bristol-Myers Squibb-Sanofi. All other authors have reported that they have no relationships to disclose. Manuscript received February 15, 2011; revised manuscript received April 4, 2011, accepted April 13, 2011.
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Table 1. Baseline Characteristics According to Diabetic Status Diabetes
Variable Age, yrs
No Diabetes
Bivalirudin (n ⴝ 281)
Heparin Plus GPI (n ⴝ 312)
64.4 [55.8, 71.5]
64.5 [56.3, 72.1]
p Value
Bivalirudin (n ⴝ 1,518)
0.61
59.3 [51.1, 68.7]
Male
70.5 (198)
76.3 (238)
0.11
78.3 (1,189)
Heparin Plus GPI (n ⴝ 1,488) 59.8 [52.4, 69.6] 76.1 (1,133)
p Value 0.15 0.15
Insulin-treated diabetes
25.6 (72)
27.9 (87)
0.53
0 (0)
0 (0)
Hypertension
73.7 (207)
70.8 (221)
0.44
47.7 (724)
51.9 (772)
Hyperlipidemia
64.4 (181)
56.1 (175)
0.04
39.5 (600)
39.9 (594)
0.83
History of smoking
53.0 (148)
60.5 (188)
0.07
67.9 (1,025)
61.9 (917)
0.0006
Prior myocardial infarction
17.8 (50)
15.7 (49)
0.50
9.0 (137)
10.5 (156)
0.18
Prior PCI
15.7 (44)
17.3 (54)
0.60
9.5 (144)
10.5 (156)
0.86
5.7 (16)
5.1 (16)
0.76
2.8 (43)
2.0 (30)
0.15
Prior CABG surgery
0.02
Weight, kg
85.0 [77.0, 95.0]
85.0 [75.0, 97.0]
0.41
80.0 [70.0, 90.0]
80.0 [70.0, 90.0]
0.86
BMI, kg/m2
29.4 [26.1, 32.0]
28.5 [25.7, 31.8]
0.20
26.8 [89.0, 105.0]
26.8 [24.4, 29.7]
0.61
1.84 [1.00, 3.17]
1.66 [0.92, 3.03]
0.11
7.7 (115)
0.99
1.0 (13/1,358)
0.91
Symptom onset to hospital arrival, h
2.0 [1.0, 3.8]
2.5 [1.5, 4.3]
0.11
Killip class 2–4
12.9 (36)
11.9 (37)
0.72
7.7 (117)
Qualifying electrocardiogram (core laboratory) Left bundle branch block ST-segment elevation* Other*
2.3 (6/265)
1.8 (5/281)
0.69
96.5 (250/259)
96.7 (267/276)
0.89
3.5 (9/259)
3.3 (9/276)
0.89
1.0 (14/1,402) 97.8 (1,355/1,386) 2.2 (31/1,386)
97.3 (1,306/1,342) 2.7 (36/1,342)
0.45 0.45
Creatinine clearance ⬍60 ml/min
18.1 (47)
20.5 (60)
0.46
15.3 (215)
16.8 (232)
0.31
Anemia†
14.2 (38)
16.4 (49)
0.48
9.7 (139)
9.5 (133)
0.87
Thrombocytopenia‡
6.3 (17)
5.2 (16)
0.58
3.2 (47)
4.6 (66)
0.05
Left ventricular ejection fraction§
50 [45, 60]
48 [38, 55]
0.001
50 [45, 60]
50 [44, 60]
0.75
Values are median [25th, 75th percentile] or % (n). *Excluding left bundle branch block; †hematocrit value at initial presentation ⬍39% for men and ⬍36% for women; ‡⬍150,000 cells/mm3 at baseline; §visual assessment from the baseline contrast left ventriculogram. BMI ⫽ body mass index; CABG ⫽ coronary artery bypass grafting; GPI ⫽ glycoprotein IIb/IIIa inhibitor; PCI ⫽ percutaneous coronary intervention.
demic Research Consortium classification (14). Noncardiac death was defined as a death not due to cardiac causes, including bleeding-related death. All primary and secondary endpoint events were adjudicated by a clinical events committee using original source documents, blinded to treatment assignment. Diabetes was defined as a history of hyperglycemia managed by insulin, oral hypoglycemic agents, or diet. Categorical outcomes were compared by chi-square test or Fisher exact test. Continuous variables were compared by means of the Wilcoxon rank-sum test. Time-to-event outcomes, determined with Kaplan-Meier methods, were compared by the log-rank test. Independent correlates of 30-day and 1-year mortality in the entire randomized population and in the cohort undergoing primary PCI were determined by Cox proportional hazards regression. Results
with diet alone. Of those, 281 patients were randomized to anticoagulant treatment with bivalirudin, and 312 were randomized to heparin plus a GPI. The baseline features and procedural data in patients randomized to bivalirudin versus heparin plus a GPI were well-matched in the diabetic and nondiabetic cohort (Tables 1 and 2). Among patients with diabetes, there were no significant differences in management strategy after coronary angiography: PCI was subsequently performed in 92.2% of the bivalirudin-treated group and in 91.7% of the heparin plus GPI group (p ⫽ 0.82), coronary artery bypass grafting without PCI was subsequently performed in 2.1% versus 3.5%, respectively (p ⫽ 0.31), and medical management was subsequently performed in 5.7 versus 4.8%, respectively (p ⫽ 0.63). Thienopyridine use before admission was slightly higher in the diabetic patients randomized to heparin plus GPI, and the percentage of angiotensinconverting enzyme inhibitors or angiotensin receptor blockers at discharge was slightly lower in nondiabetic patients randomized to bivalirudin (Table 2).
Patients and procedures. Of 3,602 patients with STEMI
Clinical outcomes in diabetic and nondiabetic patients.
undergoing primary PCI and enrolled in the HORIZONSAMI trial, 593 patients (16.5%) had diabetes mellitus. This included 159 (26.8%) treated with insulin, 322 (54.3%) treated with oral medications without insulin, and 107 (18.0%) treated
Among the diabetic cohort, there were no significant differences in the rates of NACE, MACE, all-cause mortality, or major bleeding events in patients assigned to bivalirudin versus heparin plus GPI at 30 days (Table 3). However, bivalirudin
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Table 2. Procedures and Medications According to Diabetic Status Diabetes
Variable
Bivalirudin (n ⴝ 281)
No Diabetes
Heparin Plus GPI (n ⴝ 312)
p Value
Bivalirudin (n ⴝ 1,518)
Heparin Plus GPI (n ⴝ 1,488)
p Value
Infarct-related artery Left anterior descending
40.1 (109)
45.6 (139)
0.18
39.1 (595)
41.2 (610)
0.24
Left circumflex
18.0 (272)
12.5 (38)
0.06
16.2 (246)
15.8 (233)
0.74
Right coronary artery
0.64
40.4 (110)
39.3 (120)
0.79
42.8 (650)
41.9 (620)
Left main
0.7 (2)
0.3 (1)
0.60
0.7 (11)
0.4 (6)
0.25
Saphenous vein graft
0.7 (2)
2.3 (7)
0.18
1.1 (16)
0.7 (10)
0.27
65.5 (184)
67.6 (211)
0.58
65.6 (994)
65.1 (968)
0.81
Heparin before procedure Antithrombin during procedure
2.1 (6)
99.0 (301)
⬍0.0001
95.7 (269)
0.3 (1)
⬍0.0001
97.1 (1,472)
In the cath lab, any
8.6 (24)
94.2 (294)
⬍0.0001
6.9 (105)
94.5 (1,405)
⬍0.0001
Abciximab
3.9 (11)
47.1 (147)
⬍0.0001
4.0 (61)
50.5 (750)
⬍0.0001
Eptifibatide
4.6 (13)
46.8 (146)
⬍0.0001
2.8 (43)
43.9 (652)
⬍0.0001
Tirofiban
0.0 (0)
0.3 (1)
1.00
0.1 (2)
0.2 (3)
0.68
Heparin Bivalirudin
2.6 (40)
98.9 (1,469) 0.5 (7)
⬍0.0001 ⬍0.0001
GPI IIb/IIIa inhibitor
Aspirin use Before admission
44.1 (124)
39.1 (122)
0.21
23.6 (358)
24.5 (364)
0.59
During hospitalization
98.9 (278)
100.0 (312)
0.11
99.8 (1,513)
99.8 (1,483)
1.00
At discharge
98.2 (267)
97.0 (291)
0.37
98.1 (1,462)
97.1 (1,406)
0.07
Thienopyridine use Before admission
2.5 (7)
6.1 (19)
0.03
Loading dose, any
95.7 (269)
95.8 (299)
0.95
97.2 (1,473)
97.0 (1,442)
0.84
Clopidogrel 300 mg
35.9 (101)
37.8 (118)
0.64
32.6 (494)
33.6 (500)
0.54
Clopidogrel 600 mg
59.1 (166)
56.7 (177)
0.56
63.3 (959)
61.5 (914)
0.32
93.0 (253)
92.3 (277)
0.76
93.8 (1,399)
92.8 (1,344)
0.30
Beta-blockers
90.0 (253)
87.4 (271)
0.32
89.1 (1,346)
88.4 (1,308)
0.58
ACE inhibitors or ARB
81.6 (222)
75.3 (226)
0.67
73.6 (1,098)
77.3 (1,120)
0.02
Statins
93.8 (255)
95.0 (285)
0.52
93.7 (1,397)
93.6 (1,356)
0.90
At discharge
3.7 (56)
4.1 (61)
0.57
Medications at discharge
Values are % (n). ACE ⫽ angiotensin-converting enzyme; ARB ⫽ angiotensin receptor blocker; cath lab ⫽ catheterization laboratory; GPI ⫽ glycoprotein IIb/IIIa inhibitor.
treatment was associated with a significantly reduced 30-day rate of cardiac death (2.1% vs. 5.5%, p ⫽ 0.04) and stroke (0% vs. 2.0%, p ⫽ 0.02). Noncardiac mortality was higher at 30 days with bivalirudin, however (1.4% vs. 0%, p ⫽ 0.05), and as such there was no significant difference in all-cause mortality between the 2 therapies. At 1 year, of the rate of cardiac mortality in diabetic patients was significantly reduced with bivalirudin compared with heparin plus GPI (2.5% vs. 7.1%, p ⫽ 0.01), and the difference in noncardiac mortality was no longer significant (2.2% vs. 0.7%, p ⫽ 0.12). All-cause mortality at 1 year occurred in 4.7% of diabetic patients treated with bivalirudin compared with 7.8% treated with heparin plus GPI (p ⫽ 0.13). There were no significant differences in the 1-year rates of NACE, MACE, and major bleeding according to assigned treatment (Fig. 1). Among nondiabetic patients, randomization to bivalirudin resulted in a significant reduction of NACE (at 30 days: 8.8%
vs. 11.9%, p ⫽ 0.005; at 1 year: 14.7% vs. 17.5%, p ⫽ 0.03) and major bleeding (at 30 days: 4.7% vs. 8.6%, p ⬍ 0.0001; at 1 year 5.3% vs. 9.0%, p ⬍ 0.0001), with nonsignificant differences in MACE (Fig. 1, Table 3). Further analysis of the diabetic patients according to insulin-treated and noninsulin-treated cohorts did not reveal any significant differences of bivalirudin or heparin plus GP IIb/IIIa treatment for NACE or major adverse clinical or bleeding events, whereas there was a significant advantage in favor of bivalirudin treatment among insulin-treated patients with regard to cardiac death at 1 year (1.4% vs. 9.4%, p ⫽ 0.04) (Fig. 2, Table 4). Formal interaction testing demonstrated that the favorable effects of bivalirudin compared with heparin plus GPI in reducing the 1-year rates of major bleeding, NACE, all-cause mortality, and cardiac mortality in the entire study population (12) were independent of diabetic
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Table 3. Clinical Outcomes at 30 Days According to Diabetic Status Diabetes
No Diabetes
Bivalirudin Heparin Plus Bivalirudin Heparin Plus GPI (n ⴝ 281) GPI (n ⴝ 312) p Value (n ⴝ 1,518) (n ⴝ 1,488) p Value Net adverse clinical events
12.5 (35)
16.4 (51)
0.20
8.8 (133)
11.9 (177)
Major adverse cardiac events
6.4 (18)
9.6 (30)
0.16
5.3 (80)
4.7 (70)
0.45
0.0005
Death (all-cause)
0.12
3.6 (10)
5.5 (17)
0.28
1.8 (27)
2.6 (39)
Cardiac
2.1 (6)
5.5 (17)
0.04
1.7 (26)
2.4 (35)
0.22
Noncardiac
1.4 (4)
0.0 (0)
0.05
0.1 (1)
0.3 (4)
0.17
Reinfarction
2.2 (6)
2.9 (9)
0.57
1.9 (28)
1.6 (23)
0.52
Q-wave
1.8 (5)
2.3 (7)
0.69
1.4 (21)
1.0 (15)
0.34
Non–Q-wave
0.4 (1)
1.0 (3)
0.37
0.5 (7)
0.6 (9)
0.59
TVR
3.3 (9)
2.9 (9)
0.81
2.7 (40)
1.8 (27)
0.12
Stroke
0.0 (0)
2.0 (6)
0.02
0.9 (14)
0.4 (6)
Major bleeding (non–CABG-related)
7.9 (22)
10.3 (32)
0.33
4.7 (70)
8.6 (127)
⬍0.0001
11.9 (33)
12.9 (40)
0.72
6.1 (92)
11.0 (162)
⬍0.0001
4.3 (12)
4.9 (15)
0.78
1.8 (27)
3.5 (52)
0.003
TIMI major bleeding
6.9 (19)
5.2 (16)
0.40
2.6 (39)
5.3 (78)
0.0002
TIMI minor bleeding
4.0 (11)
5.2 (16)
0.50
2.7 (40)
4.6 (68)
0.004
Life-threatening or severe bleeding
0.4 (1)
1.0 (3)
0.37
0.5 (8)
0.5 (8)
0.97
Moderate bleeding
6.1 (17)
6.9 (21)
0.78
2.7 (40)
4.9 (72)
0.001
Major bleeding (including CABG-related) Blood transfusion
0.08
TIMI classification
GUSTO classification
Values are % (n). CABG ⫽ coronary artery bypass graft surgery; GPI ⫽ glycoprotein IIb/IIIa inhibitor; GUSTO ⫽ Global Strategies for Opening Occluded Coronary Arteries; MACE ⫽ major adverse cardiovascular event(s) (death, myocardial infarction, ischemic target vessel revascularization, or stroke); PCI ⫽ percutaneous coronary intervention; TIMI ⫽ Thrombolysis in Myocardial Infarction; TVR ⫽ target vessel revascularization.
status (pint ⫽ 0.26, 0.64, 0.55, and 0.19, respectively). Similarly, bivalirudin compared with heparin plus GPI resulted in nonsignificantly different rates of MACE, noncardiac mortality, and stroke in the entire study population (12), effects which were also independent of diabetic status (pint ⫽ 0.38, 0.17, and 0.06, respectively). Stent thrombosis. The overall rate of definite/probable stent thrombosis at 1 year did not differ among diabetic patients who received bivalirudin compared with those treated with heparin plus GPI (4.2% vs. 3.8%, p ⫽ 0.85). Similarly, there was no difference in the 1-year rates of stent thrombosis between the randomized antithrombotic regimens in the nondiabetic subgroup (3.5% vs. 3.1%, p ⫽ 0.54) (Table 5), and interaction testing for an effect of diabetic status on stent thrombosis by randomization was negative (p ⫽ 0.93). There were also no significant differences in the rate of stent thrombosis between the 2 treatment arms when the diabetic patients were further separated into insulin-treated or non–insulin-treated groups (Table 5). Discussion Diabetic patients presenting with STEMI have a substantially greater incidence of early and late death or myocardial infarction compared with nondiabetic subjects (15–17).
With contemporary interventional approaches, the procedural success rate of primary PCI in diabetic patients with STEMI is equivalent to nondiabetic patients, as reinforced in the present report (16,18). However, diabetic patients with STEMI compared with nondiabetic patients are less likely to achieve normal myocardial perfusion (as measured by reduced restoration of normal angiographic myocardial blush and ST-segment resolution, and a greater incidence of distal embolization), which has been associated with higher mortality (2,18,19). Glycoprotein IIb/IIIa inhibitors might improve myocardial perfusion and survival (20,21), particularly in patients with diabetes. In the ADMIRAL (Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up) trial (6), the 6-month rates of mortality and target vessel revascularization after primary stenting were reduced in the 53 diabetic patients randomized to abciximab versus placebo (mortality: 0% vs. 16.7%, p ⫽ 0.02; target vessel revascularization: 3.7% vs. 37.5%, p ⫽ 0.046). However, this result was not reproduced in the larger CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial with 346 diabetic patients enrolled (22,23). A meta-analysis based on individual specific data from the ISAR-2
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25
A
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20
B
18
20
16
MACE (%)
NACE (%)
14
15
10
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
2 0
0
1
2
3
4
5
6
7
8
9
10
11
12
Months
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
250 234 1246 1325
241 226 1216 1288
235 220 1190 1263
213 202 1067 1141
0
1
6 4 Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
2
4
5
270 251 1347 1376
10
6
7
8
9
10
11
12
259 241 1313 1338
253 235 1286 1309
225 215 1154 1179
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
9
Cardiac mortality (%)
8
3
Months
12 10
2
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
D
14
Major bleeding (non CABG) (%)
8
4
0
C
10
6
Diabetes / Heparin plus GPI (n=312) Diabetes / Bivalirudin (n=281) No diabetes / Heparin plus GPI (n=1488) No diabetes / Bivalirudin (n=1518)
5
12
8 7 6 5 4 3 2 1 0
0
0 Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 No diabetes / Bivalirudin 1518
1
2
3
4
5
6
7
8
9
10
11
12
Months 260 244 1281 1376
258 241 1272 1360
255 239 1258 1347
228 221 1139 1227
0
1
Number at risk 312 Diabetes / Heparin + GPI 281 Diabetes / Bivalirudin No diabetes / Heparin + GPI 1488 1518 No diabetes / Bivalirudin
2
3
4
5
6
7
8
9
10
11
12
Months 285 263 1391 1441
282 258 1380 1426
279 256 1366 1413
246 236 1239 1284
Figure 1. Kaplan-Meier Curves Through 1 Year for NACE, MACE, Major Bleeding, and Cardiac Mortality Kaplan-Meier curves through 1 year for (A) net adverse clinical events (NACE); (B) major adverse cardiac events (MACE); (C) major bleeding not related to coronary artery bypass grafting (CABG); and (D) cardiac mortality, according to diabetic status. GPI ⫽ glycoprotein IIb/IIIa inhibitor.
(Intracoronary Stenting and Antithrombotic Regimen-2) (24), ADMIRAL (6), and ACE (Abciximab-Carbostent Evaluation) (25) studies including 183 diabetic patients reported that death and reinfarction were significantly lower in diabetic patients treated with abciximab compared with UFH alone (26). We have previously reported that patients randomized to bivalirudin rather than heparin plus GPI in the HORIZONS-AMI trial benefitted from a pronounced reduction in bleeding events, along with NACE and allcause and cardiac mortality (11,27). However, a recent meta-regression analysis suggested that the benefits from adjunctive GPI in improving survival are most evidenced in high-risk patients, such as those with diabetes mellitus (28). With this background, the current report in 593 diabetic patients enrolled in the HORIZONS-AMI trial represents the largest analysis of diabetic STEMI patients treated by contemporary primary PCI to date and demonstrates that bivalirudin compared with heparin plus GPI significantly reduces cardiac mortality in the high-risk diabetic cohort as well as patients without diabetes. Although cardiac mortality and stroke were reduced in diabetic patients treated with bivalirudin rather than hepa-
rin plus GPI, total mortality, major bleeding, and NACE were not significantly reduced in the diabetic cohort with bivalirudin. However, interaction testing demonstrated that the relative reductions in bleeding, NACE, and all-cause and cardiac mortality with bivalirudin compared with heparin plus GPI were not significantly different in the diabetic and nondiabetic groups. Given that subgroups are inherently underpowered (29), the most appropriate interpretation of these data is that the overall benefits with bivalirudin seen in the main trial seem to apply to patients both with and without diabetes. However, we cannot exclude a modest difference in the relative effect of bivalirudin versus heparin plus GPI in patients with versus without diabetes. Moreover, previous studies have suggested a higher rate of stent thrombosis in diabetic patients, particularly those insulin-treated (30,31). In the present analysis the overall rate of stent thrombosis in the diabetic subgroup was comparable in patients treated with bivalirudin or those treated with heparin plus GPI. In the HORIZONS-AMI trial, study medications were most commonly initiated in the catheterization laboratory. Previous analyses suggest that an “upstream” pre-catheterization
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Figure 2. Subgroup Analyses: 1-Year Rates of NACE and Major Bleeding Subgroup analyses: hazard ratios with 95% confidence intervals for the 1-year rates of NACE, major bleeding not related to CABG, MACE, and cardiac death, in the overall study population and according to diabetic status, for insulin-treated and non–insulin-treated diabetic patients, nondiabetic patients, and overall study population. *For cardiac mortality among insulin-treated diabetic patients, the 95% confidence interval of the hazard ratio crosses unity, despite the p value being 0.037, because the former is calculated from a Cox model and the latter from the log-rank. Abbreviations as in Figure 1.
start of GPI therapy might be beneficial before primary PCI in STEMI. A recent meta-analysis of 281 diabetic patients from 11 randomized trials of early versus late administration
of GPI in STEMI found that upstream GPI was associated with significant improvements in pre- and post-procedural TIMI flow and myocardial perfusion (distal embolization,
Table 4. Clinical Outcomes at 1 Year According to Insulin Treatment in Patients With Diabetes Insulin-Treated Diabetes
NonInsulin-Treated Diabetes
Bivalirudin (n ⴝ 72)
Heparin Plus GPI (n ⴝ 87)
p Value
Bivalirudin (n ⴝ 209)
Heparin Plus GPI (n ⴝ 225)
p Value
Net adverse clinical events
28.9 (20)
24.6 (21)
0.58
17.4 (36)
21.0 (47)
0.30
Major adverse cardiac events
19.3 (13)
18.8 (16)
0.97
12.6 (26)
15.3 (34)
0.40
Death (all-cause)
4.4 (3)
10.6 (9)
0.15
4.8 (10)
6.7 (15)
0.41
Cardiac
1.4 (1)
9.4 (8)
0.04
2.9 (6)
6.3 (14)
0.10
Noncardiac
3.0 (2)
1.3 (1)
0.45
2.0 (4)
0.5 (1)
0.16
16.9 (12)
10.5 (9)
0.23
6.9 (14)
11.7 (26)
0.09
Major bleeding (non–CABG-related) Values are % (n). Abbreviations as in Table 3.
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Table 5. Stent Thrombosis at 1 Year According to Diabetic Status Diabetes Bivalirudin (n ⴝ 281) Definite or probable
Heparin Plus GPI (n ⴝ 312)
No Diabetes
p Value
Bivalirudin (n ⴝ 1,518)
Heparin Plus GPI (n ⴝ 1,488)
p Value
4.2 (10)
3.8 (10)
0.85
3.5 (47)
3.1 (40)
0.54
Definite
3.8 (9)
2.3 (6)
0.35
3.2 (43)
2.4 (31)
0.20
Probable
0.4 (1)
1.5 (4)
0.21
0.3 (4)
0.7 (9)
0.15
Insulin-Treated Diabetes
Definite or probable
Bivalirudin (n ⴝ 72)
Heparin Plus GPI (n ⴝ 87)
NonInsulin-Treated Diabetes
p Value
Bivalirudin (n ⴝ 209)
Heparin Plus GPI (n ⴝ 225)
p Value
9.8 (6)
10.4 (8)
0.87
2.8 (5)
1.6 (3)
0.44
Definite
8.3 (5)
5.2 (4)
0.52
2.2 (4)
1.1 (2)
0.38
Probable
1.6 (1)
3.9 (3)
0.41
0.0 (0)
0.5 (1)
0.33
Values are % (n). Stent thrombosis definition according to Academic Research Consortium criteria. GPI ⫽ glycoprotein IIb/IIIa inhibitor.
myocardial blush grade); however, complete ST-segment resolution, enzymatic infarct size, and—most importantly— mortality at 1 year (8.3% vs. 9.5%) was not improved (32). Therefore, it is unlikely that systematic early administration of GPI in the HORIZONS-AMI trial would have had a significant impact on the results overall and in the diabetic subgroup. Study limitations. First, although the present diabetic analysis was a pre-specified substudy, the HORIZONS-AMI trial was not powered for subgroup analysis. As such, despite the large number of diabetic patients enrolled, these results should be considered exploratory and hypothesisgenerating. Second, the open-label design of the study might have introduced potential bias. However, all clinical events were adjudicated by an independent clinical events committee blinded to all procedural medications. Third, as is common in all such substudies, diabetes was diagnosed on admission according to prior history and not by glucose or insulin level testing. It is possible that serial testing of diabetic state might have identified a high-risk diabetic group more prone to benefit with either bivalirudin or heparin plus GPI. This is unlikely, however, given the negative interaction testing from the present analysis and the comparable results with both regimens in patients with insulin treatment. Conclusions The HORIZONS-AMI diabetes substudy demonstrates that, in both high-risk patients with diabetes and nondiabetic patients with STEMI undergoing primary PCI, anticoagulation with bivalirudin monotherapy (with bail-out GPI in 7.6% of patients for refractory thrombotic complications) compared with heparin plus the routine use of a GPI seems to significantly improve 30-day and 1-year net clinical outcomes and survival.
Reprint requests and correspondence: Dr. Gregg W. Stone, Columbia University Medical Center, The Cardiovascular Research Foundation, 111 East 59th Street, 11th Floor, New York, New York 10022. E-mail: [email protected].
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Key Words: diabetes mellitus 䡲 major adverse cardiac event(s) 䡲 primary percutaneous coronary intervention 䡲 stent thrombosis 䡲 ST-segment elevation myocardial infarction.