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IIIa Inhibitors in Patients Undergoing Primary Angioplasty in the Setting of Cardiogenic Shock
Bivalirudin With Provisional Glycoprotein IIb/IIIa Inhibitors in Patients Undergoing Primary Angioplasty in the Setting of Cardiogenic Shock Laurent Bonello, MD, Axel De Labriolle, MD, Probal Roy, MBBS, Daniel H. Steinberg, MD, Tina L. Pinto Slottow, MD, Zhenyi Xue, MS, Kimberley Smith, BS, Rebecca Torguson, MPH, William O. Suddath, MD, Lowell F. Satler, MD, Kenneth M. Kent, MD, PhD, Augusto D. Pichard, MD, and Ron Waksman, MD* In patients undergoing percutaneous coronary intervention (PCI), clinical trials have demonstrated that the use of bivalirudin with provisional glycoprotein IIb/IIIa inhibitors is not inferior to heparin with systematic glycoprotein IIb/IIIa inhibitors on major adverse cardiac events and is associated with lower rates of bleeding in various clinical settings. Patients with cardiogenic shock (CS), however, have been excluded from all pivotal trials. A retrospective analysis of 86 consecutive patients undergoing PCI for acute myocardial infarction complicated by CS in our center from April 2003 to September 2007 was performed. In-hospital death, major adverse cardiac events, and bleeding rates were compared in 37 patients who received bivalirudin with or without glycoprotein IIb/IIIa inhibitors and 49 patients who were treated with heparin and glycoprotein IIb/IIIa inhibitors as anticoagulation management. Baseline demographic, clinical, and biological characteristics were similar in the 2 groups. The in-hospital death rate was significantly lower in the bivalirudin group (5.4 vs 32.7%, p ⴝ 0.002). There were no differences in the rate of major hematoma between the bivalirudin group and the heparin group (3 vs 2.6%, p ⴝ 0.46). In conclusion, bivalirudin with provisional use of glycoprotein IIb/IIIa inhibitors appears to be a safe and effective anticoagualtion strategy in patients undergoing primary PCI for acute myocardial infarction complicated by CS. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:287–291)
As a pharmacological strategy, the addition of glycoprotein IIb/IIIa inhibitor infusion in primary angioplasty for acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) has been shown to improve 30-day outcome when compared to heparin alone1 and is broadly used for this indication. Recently, bivalirudin, a new direct thrombin inhibitor with provisional glycoprotein IIb/IIIa inhibitors, has been shown not to be inferior to the association of heparin and glycoprotein IIb/IIIa inhibitors with regard to ischemic outcome. It is also associated with less bleeding in patients undergoing percutaneous coronary intervention (PCI) in various clinical settings.2– 4 However, no studies have addressed its clinical impact in patients suffering from AMI complicated by CS. This study aimed to evaluate the safety and efficacy of a regimen of bivalirudin plus provisional glycoprotein IIb/IIIa inhibitors compared with heparin plus systematic glycoprotein IIb/IIIa inhibitors on in-hospital clinical outcome of patients with AMI complicated by CS.
Department of Internal Medicine, Division of Cardiology, Washington Hospital Center, Washington, DC. Manuscript received January 10, 2008; revised manuscript received and accepted March 7, 2008. *Corresponding author: Tel: 202-877-2812; fax: 202-877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.03.052
Methods Patient population: A cohort of 86 consecutive patients who presented with AMI complicated by CS and who were treated by primary angioplasty at Washington Hospital Center from April 2003 to September 2007 were studied. After we obtained approval for a Health Insurance Portability and Accountability Act waiver from our local Institutional Review Board, we extracted from the entire database all patients corresponding to the inclusion criteria and conducted a retrospective analysis of the clinical in-hospital outcomes. The patients were divided into 2 groups depending on the antithrombotic regimen received during PCI. The bivalirudin group included all patients who received bivalirudin with or without glycoprotein IIb/IIIa inhibitors. The heparin group was composed of all patients who received heparin and glycoprotein IIb/IIIa inhibitors. AMI was defined as chest pain with ⱖ1 mm of STsegment elevation on ⱖ2 contiguous electrocardiogram leads, chest pain refractory to medical therapy with associated ST-segment depression in leads V2 to V5 (consistent with posterior injury), or left bundle branch block. CS was defined as a subject presenting on admission a maximum systolic blood pressure ⬍90 mm Hg for ⱖ30 minutes unless treated with inotropes or intra-aortic balloon counterpulsation insertion or pump failure as manifested by a cardiac index ⬍2.2 and a pulmonary capillary wedge pressure ⬎18 mm Hg, and/or persistence of hypotension or pump failure www.AJConline.org
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after correction of extra myocardial factors (e.g., hypovolemia, arrhythmia, pain, vasovagal reactions, hypoxemia, acidosis), and/or the presence of peripheral signs of hypoperfusion, as evidenced by peripheral vasoconstriction or urine output ⬍30 cc/hour or altered sensorium. Patients for whom primary angioplasty was not the first line therapy were excluded from the study. Procedure: Contemporary PCI was performed according to guidelines current at the time of implantation. In all cases, the interventional strategy, including the use of direct stenting, pre- or postdilatation, intravascular ultrasound, use of ablative devices, choice of periprocedural adjunctive antiplatelet therapy, and choice of antithrombotic regimen, was at the discretion of the responsible physician. Angiographic success was defined as a stenosis of ⱕ30% with a Thrombolysis in Myocardial Infarction flow grade 3. All patients received aspirin 325 mg/day before the intervention, which was continued indefinitely. Additional antiplatelet therapy with either clopidogrel 75 mg/day (after a loading dose of 300 to 600 mg) or ticlopidine 250 mg twice daily was instituted in all patients and was continued for ⱖ1 year. The patients receiving bivalirudin were given a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. Abciximab was administrated in 7 patients (19%) using a bolus of 0.25 mg/kg followed by a 12-hour infusion at 10 g/min. In the heparin group, intraprocedural anticoagulation was ensured using unfractionated heparin to achieve an activated clotting time of 200 to 250 seconds associated with an abciximab dose of 0.25 mg/kg bolus followed by a 12-hour infusion at 10 g/min. Clinical follow-up and end points: The end point for analysis in this study was defined as major adverse cardiac events. A dedicated data-coordinating center (Data Center, MedStar Research Institute, Washington, DC) performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel who were unaware of the objectives of the study. Death was defined as all causes of mortality. Myocardial infarctions were defined as a total creatinine kinase elevation ⱖ3 times normal and/or creatinine kinase-MB ⱖ20 ng/ml ⫾ new pathological Q waves in ⱖ2 contiguous leads. Target lesion revascularization and target vessel revascularization were characterized by repeat percutaneous or surgical intervention of the treated lesion or vessel, respectively, and were clinically driven. Major adverse cardiac events were defined as a composite of death, myocardial infarction, or repeat revascularizations. All clinical events were adjudicated by source documentation by independent physicians who were not involved in the procedures. Major hematoma was defined as measuring ⱖ2 ⫻ 4 cm or requiring transfusion or necessitating prolonged hospitalization. Statistical analysis: Statistical analysis was performed using the Statistical Analysis System version 8.2 (SAS Institute Inc., Cary, North Carolina). Data are expressed as mean ⫾ SD for continuous variables and as percentages for categorical variables. Student’s t test was used to compare continuous variables and the chi-square test or Fischer’s
Table 1 Baseline clinical characteristics Variable
Bivalirudin (n ⫽ 37)
Heparin (n ⫽ 49)
p Value
Age (yrs), mean ⫾ SD Men Body mass index (5 kg/m2), mean ⫾ SD Current smoker Diabetes mellitus Hyperlipidemia Systemic hypertension History of coronary artery disease Family history of coronary artery disease History of heart failure Dialysis Creatinine clearance (mg/L), mean ⫾ SD Glucose (mg/L), mean ⫾ SD White blood cells (g/L), mean ⫾ SD Left ventricular ejection fraction, mean ⫾ SD
59.6 ⫾ 20.2 25 (67.6%) 29.5 ⫾ 6.2
64.8 ⫾ 14 32 (65.3%) 27.4 ⫾ 5.7
0.19 0.12 0.14
9 (24.3%) 16 (43.2%) 32 (86.5%) 29 (80.6%) 32 (86.5%)
17 (34.7%) 14 (31.1%) 32 (76.2%) 32 (72.7%) 36 (75%)
0.3 0.26 0.24 0.41 0.19
13 (43.3%)
20 (54.1%)
0.38
8 (23.5%) 3 (8.1%) 56 ⫾ 31
14 (31.1%) 1 (2.2%) 54 ⫾ 21
0.46 0.32 0.88
224 ⫾ 61 12.7 ⫾ 6.7
162 ⫾ 77 13.5 ⫾ 6
0.13 0.56
0.36 ⫾ 12
0.35 ⫾ 0.14
0.74
exact test was used to compare categorical variables. A p value ⬍0.05 was considered to indicate statistical significance. Cox proportional hazard analysis was used to identify predictors of major adverse cardiac events. Cox proportional regression models were used to control for differences in the groups. Variables included in the univariate model were age, gender, systemic hypertension, diabetes mellitus, hypercholesterolemia, current smoking, left ventricular ejection fraction on admission, number of diseased vessels, number of treated vessels and intra-aortic balloon counterpulsation use; 3 variables (age, current smoking, and bivalirudin use) with p values ⬍0.2 in the univariate model were entered into the multivariate model. Results Baseline clinical characteristics: Of the 86 patients included, 25 (29%) had intra-aortic balloon counterpulsation insertion for hemodynamic stabilization during the procedure. The 2 groups had similar baseline characteristics and prevalence of risk factors. In particular, the frequency of diabetes mellitus was not different (43.2% in the bivalirudin group vs 31.1% in the heparin group, p ⫽ 0.26). Main biological data on admission were similar in the 2 groups (Table 1). Angiographic and interventional characteristics: Angiographic characteristics were similar in the 2 groups and are summarized in Table 2. There was a high rate of complex lesions (type C) according to the American College of Cardiology/American Heart Association classification. Further, a high number of diseased vessels per patient was noted in the bivalirudin versus heparin group (2.6 ⫾ 0.7 and 2.4 ⫾ 0.85, respectively, p ⫽ 0.46). There was no significant difference in the rate of intra-aortic balloon counterpulsation insertion during the procedure in the 2 groups
Coronary Artery Disease/Bivalirudin in Angioplasty with Cardiogenic Shock Table 3 In-hospital complications and outcome
Table 2 Angiographic and procedural characteristics Variable Coronary narrowing location Left main Left anterior descending Left circumflex Right Saphenous vein graft Number of diseased vessels, mean ⫾ SD Lesion type (ACC/AHA class) Type A Type B Type C Procedural details Angiographic success No reflow Number of lesions treated, mean ⫾ SD Number of implanted stents, mean ⫾ SD Drug-eluting stents Stent diameter, mm ⫾ SD Stent length, mm ⫾ SD Predilatation Antithrombotics Maximum activated clotting time (sec), mean ⫾ SD Final activated clotting time (sec), mean ⫾ SD Glycoprotein IIb/IIIa inhibitors Intra aortic balloon counterpulsation Left ventricular ejection fraction, mean ⫾ SD Closure devices Length of intensive care unit stay (days), mean ⫾ SD Length of hospital stay (days), mean ⫾ SD
Bivalirudin (n ⫽ 69)
Heparin (n ⫽ 82)
p Value
1 (1.4%) 13 (35.1%) 10 (27%) 11 (29.7%) 3 (8.1%) 2.6 ⫾ 0.7
2 (2.4%) 29 (35.4%) 20 (24.4%) 26 (31.7%) 5 (6.1%) 2.4 ⫾ 0.85
1 0.91 0.55 0.69 1 0.46
2 (5.4%) 21 (56.8%) 14 (37.8%)
6 (7.7%) 42 (53.8%) 30 (38.5%)
0.28 0.98 0.54
64 (94.1%) 1 (1.5%) 1.8 ⫾ 1.5
76 (93.8%) 3 (3.7%) 1.5 ⫾ 0.9
1 0.63 0.33
0.97 ⫾ 1.24
0.68 ⫾ 0.67
0.28
35 (52.2%) 4.1 ⫾ 0.4 19.8 ⫾ 7.3 26 (41.3%)
15 (37.5%) 3.1 ⫾ 0.4 23.4 ⫾ 4.6 20 (43.5%)
0.14 0.41 0.15 0.8
316 ⫾ 82
261 ⫾ 56
0.002
318 ⫾ 81
257 ⫾ 55
⬍0.001
7 (18.9%)
49 (100%)
⬍0.001
9 (24.3%)
16 (33.3%)
0.37
0.36 ⫾ 12
0.35 ⫾ 0.14
0.74
15 (40.5%) 4.8 ⫾ 3.8
15 (31.9%) 5.8 ⫾ 3.8
0.45 0.44
11 ⫾ 9
289
9 ⫾ 7.4
0.28
ACC/AHA ⫽ American College of Cardiology/American Heart Association.
(bivalirudin group 24.3% vs heparin group 33.3%, p ⫽ 0.37). The number of treated lesions was high in the bivalirudin and heparin groups (1.8 ⫾ 1.5 vs 1.5 ⫾ 0.9, respectively, p ⫽ 0.33). Other characteristics of intervention were similar in the groups, including the rate of predilatation (41.3 vs 43.5%, p ⫽ 0.8). The rates of angiographic success and of no-reflow were not different between groups (94.1 vs 93.8%, p ⫽ 1, and 1.5 vs 3.7%, p ⫽ 0.63). In-hospital outcomes: There was no difference in the rate of major hematoma or transfusion between the bivalirudin group and the heparin group (3 vs 2.6%, p ⫽ 0.46, and 36.1 vs 37.2%, p ⫽ 0.9, respectively,). The majority of bleedings complications were in the gastrointestinal hemorrhage. The rate of death was significantly lower in the bivalirudin group compared with the heparin group (5.4 vs
Variable
Bivalirudin (n ⫽ 37)
Heparin (n ⫽ 49)
p Value
Death Major adverse cardiac event Coronary bypass (postprocedure) Major hematoma Transfusion Neurologic event Acute kidney failure Abrupt vessel closure Subacute stent thrombosis
2 (5.4%) 3 (8.1%) 9 (24.3%) 1 (3%) 13 (36.1%) 0 2 (5.6%) 2 (5.4%) 0
16 (32.7%) 17 (34.7%) 7 (15.6%) 1 (2.6%) 16 (37.2%) 0 6 (12.5%) 3 (6.4%) 0
0.002 0.004 0.3 0.46 0.9 — 0.46 1 —
Table 4 Univariate predictors Observation Bivalirudin use Age Men Systemic hypertension Hypercholesterolemia Diabetes mellitus Current smoker Number of diseased vessels Intra-aortic balloon counterpulsation (per procedure) Number of treated vessels
Hazard Ratio
95% CI for Hazard Ratio
p Value
0.2 1.0 0.6 1.9 0.8 1.3 0.4 1.1 1.1
0.1–0.6 1.0–1.1 0.3–1.3 0.7–5.7 0.3–2.3 0.6–3 0.1–1.3 0.6–2.1 0.5–2.5
0.005 0.016 0.212 0.233 0.610 0.486 0.140 0.814 0.849
1.0
0.7–1.4
0.832
32.7%, p ⫽ 0.002). The overall rate of major adverse cardiac events was significantly lower in the bivalirudin group (8.1 vs 34.7%, p ⫽ 0.004) (Table 3). Univariate and multivariate predictors of major adverse cardiac events: Univariate predictors of in-hospital major adverse cardiac events were bivalirudin use with a hazard ratio of 0.2 (95% confidence interval [CI] 0.1 to 0.6, p ⫽ 0.005) and age with a hazard ratio of 1 (95% CI 1 to 1.1, p ⫽ 0.016). In multivariate analysis, only bivalirudin was found to be significantly associated with in-hospital major adverse cardiac events with a hazard ratio of 0.3 (95% CI 0.1 to 0.9, p ⫽ 0.025) (Table 4). Discussion The results of this study suggest that for patients treated with primary angioplasty for AMI complicated by CS, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors is safe, efficient, and associated with low rates of in-hospital death. Thus, this study suggests that bivalirudin use in PCI could be safely extended to patients with CS. CS is associated with high mortality rates, which have been reduced by recent advances in PCI, including early revascularization, wide use of mechanical support such as intra-aortic balloon counterpulsation, and the addition of glycoprotein IIb/IIIa inhibitors to heparin.1,5,6 In our study, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors is associated with a significantly lower risk of in-hospital death when compared with heparin plus
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glycoprotein IIb/IIIa inhibitors. This could be a result of chance; however, this potential superiority was also observed in previous trials.7,8 Consistently, in the Horizon AMI trial, which focused on patients with AMI, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors demonstrated a significant decrease in cardiac death at 30 days. No study has investigated the potential superiority of a bivalirudin- over heparin-based regimen. In fact, several advantages of bivalirudin over heparin could have a beneficial role in patients with CS relating to the complex pathogenesis of the disease. Bivalirudin is a direct thrombin inhibitor that acts by bivalently binding to the thrombin action site. Its antithrombotic effects are not dependent on a cofactor such as antithrombin III to inhibit thrombin and have no known inhibitors, such as platelet factor 4. Unlike heparin, bivalirudin acts on clot-bound thrombin together with circulating thrombin. In addition, the direct thrombin inhibitors are not limited by the same pharmacokinetic and pharmacodynamic heterogeneity as heparin, which could be of importance when considering the several biological abnormalities present in CS that may interact with drug properties.9 –11 Moreover, bivalirudin does not act only by inhibiting thrombin generation but also platelet activation and clot formation.12 In fact, bivalirudin exhibits antiplatelet properties contrary to heparin, which induces platelet activation.13,14 Moreover, Schneider et al14 have demonstrated that bivalirudin had greater inhibitory effects compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation.15 CS is associated with a systemic inflammatory response. The levels of inflammatory markers, like interleukin 6, have been shown to be independent predictors of mortality at 30 days.16 Consistent with this pivotal role of inflammation in CS, the use of anti-inflammatory drugs, such as statins, have been associated with improved in-hospital outcome.17 A beneficial effect of bivalirudin may therefore be related to the lack of proinflammatory properties compared with heparin.18 –20 The present study did not detect any difference in bleeding rates between the 2 groups. This could be related to nearly 20% of the patients in the bivalirudin group receiving glycoprotein IIb/IIIa, which increased the rate of bleeding in this group. Other factors that could explain the lack of difference in the bleeding rate are the relatively small number of patients in the study and that, in this particular setting, bleedings are less dependent on antithrombotic therapy and more related to procedure factors such as large sheath insertion and delayed closure with the use of intra-aortic balloon counterpulsation.21 Despite a low frequency of major hematoma, the rate of transfusion was high. This may be related to the high frequency of a history of chronic kidney disease, dialysis, and heart failure in the included patients, which are associated with anemia.22,23 Moreover, as observed in the Global Registry of Acute Coronary Events (GRACE) registry, the main site of bleedings was the gastrointestinal tract, which may be less influenced by the antithrombotic strategy than the entry point site.24 Finally, such critically ill patients develop anemia in the intensive care unit, which may be responsible for a higher percentage of transfusions than bleedings. Anemia related to this etiol-
ogy may not be influenced by antithrombotic strategy at the time of PCI.25 There are several limitations to the present study. It is a small, retrospective study, which does not allow for definitive conclusion and presents the common potential skews associated with this type of study. Nevertheless, conducting a large, prospective study in patients with CS is challenging. To overcome these limitations we have performed a multivariate analysis to minimize the effects of confounding factors. Prospective studies are now required to confirm these preliminary data. 1. Giri S, Mitchel J, Azar RR, Kiernan FJ, Fram DB, McKay RG, Mennett R, Clive J, Hirst JA. Results of primary percutaneous transluminal coronary angioplasty plus abciximab with or without stenting for acute myocardial infarction complicated by cardiogenic shock. Am J Cardiol 2002;89:126 –131. 2. Stone GW for the Horizon AMI Investigators. A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction–30 Day Results. Presented at Transcatheter Cardiovascular Therapeutics (TCT) 2007, Washington, DC. 3. Stone GW, Ware JH, Bertrand ME, Lincoff AM, Moses JW, Ohman EM, White HD, Feit F, Colombo A, McLaurin BT, et al, for the ACUITY Investigators. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 2007;298:2497– 2506. 4. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al, for the REPLACE-2 Investigators. 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– 863. 5. Hochman JS, Boland J, Sleeper LA, Porway M, Brinker J, Col J, Jacobs A, Slater J, Miller D, Wasserman H, et al, and the SHOCK Registry Investigators. Current spectrum of cardiogenic shock and effect of early revascularization on mortality: results of an International Registry. Circulation 1995;91:873– 881. 6. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:e1– e211. 7. Wolfram R, Leborgne L, Cheneau E, Pinnow EE, Canos DA, Hellinga D, Satler LF, Pichard AD, Kent KM, Waksman R. Comparison of effectiveness and safety of three different antithrombotic regimens (bivalirudin, eptifibatide, and heparin) in preventing myocardial ischemia during percutaneous coronary intervention. Am J Cardiol 2003; 92:1080 –1083. 8. Lincoff AM, Kleiman NS, Kereiakes DJ, Feit F, Bittl JA, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al, for the REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696 –703. 9. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin–antithrombin III but is susceptible to inactivation by antithrombin III–independent inhibitors. J Clin Invest 1990;86:385–391. 10. Eitzman DT, Chi L, Saggin L, Schwartz RS, Lucchesi BR, Fay WP. Heparin neutralization by platelet-rich thrombi: role of platelet factor 4. Circulation 1994;89:1523–1529. 11. Hirsh J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1995;108:258S–75S.
Coronary Artery Disease/Bivalirudin in Angioplasty with Cardiogenic Shock 12. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention. J Thromb Thrombolysis 2002;13:161–165. 13. Anand SX, Kim MC, Kamran M, Sharma SK, Kini AS, Fareed J, Hoppensteadt DA, Carbon F, Cavusoglu E, Varon D, et al. Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol 2007;100:417– 424. 14. Schneider DJ, Keating F, Sobel BE. Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation. Coron Artery Dis 2006;17:471– 476. 15. Butenas S, Orfeo T, Brummel-Ziedins KE, Mann KG. Influence of bivalirudin on tissue factor-triggered coagulation. Blood Coagul Fibrinolysis 2007;18:407– 414. 16. Geppert A, Dorninger A, Delle-Karth G, Zorn G, Heinz G, Huber K. Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction. Crit Care Med 2006;34:2035–2042. 17. Schmidt H, Hennen R, Keller A, Russ M, Müller-Werdan U, Werdan K, Buerke M. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med 2006;32:1248 –1251.
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18. Harding SA, Din JN, Sarma J, Josephs DH, Fox KA, Newby DE. Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin. Heart 2006;92:1635–1638. 19. Li G, Keenan AC, Young JC, Hall MJ, Pamuklar Z, Ohman EM, Steinhubl SR, Smyth SS. Effects of unfractionated heparin and glycoprotein IIb/IIIa antagonists versus bivalirdin on myeloperoxidase release from neutrophils. Arterioscler Thromb Vasc Biol 2007;27: 1850 –1856. 20. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. Increased expression of platelet P-selectin and formation of plateletleukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thromb Res 2006;118:361–369. 21. Busch T, Sîrbu H, Zenker D, Dalichau H. Vascular complications related to intraaortic balloon counterpulsation: an analysis of ten years experience. Thorac Cardiovasc Surg 1997;45:55–59. 22. Berry C, Norrie J, Hogg K, Brett M, Stevenson K, McMurray JJ. The prevalence, nature, and importance of hematologic abnormalities in heart failure. Am Heart J 2006;151:1313–1321. 23. Schiller GJ, Berkman SA. Hematologic aspects of renal insufficiency. Blood Rev 1989;3:141–146. 24. Moscucci M, Fox KA, Cannon CP, Klein W, López-Sendón J, Montalescot G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815–1823. 25. Shander A. Anemia in the critically ill. Crit Care Clin 2004;20:159 –178.
As a pharmacological strategy, the addition of glycoprotein IIb/IIIa inhibitor infusion in primary angioplasty for acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) has been shown to improve 30-day outcome when compared to heparin alone1 and is broadly used for this indication. Recently, bivalirudin, a new direct thrombin inhibitor with provisional glycoprotein IIb/IIIa inhibitors, has been shown not to be inferior to the association of heparin and glycoprotein IIb/IIIa inhibitors with regard to ischemic outcome. It is also associated with less bleeding in patients undergoing percutaneous coronary intervention (PCI) in various clinical settings.2– 4 However, no studies have addressed its clinical impact in patients suffering from AMI complicated by CS. This study aimed to evaluate the safety and efficacy of a regimen of bivalirudin plus provisional glycoprotein IIb/IIIa inhibitors compared with heparin plus systematic glycoprotein IIb/IIIa inhibitors on in-hospital clinical outcome of patients with AMI complicated by CS.
Department of Internal Medicine, Division of Cardiology, Washington Hospital Center, Washington, DC. Manuscript received January 10, 2008; revised manuscript received and accepted March 7, 2008. *Corresponding author: Tel: 202-877-2812; fax: 202-877-2715. E-mail address: [email protected] (R. Waksman). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.03.052
Methods Patient population: A cohort of 86 consecutive patients who presented with AMI complicated by CS and who were treated by primary angioplasty at Washington Hospital Center from April 2003 to September 2007 were studied. After we obtained approval for a Health Insurance Portability and Accountability Act waiver from our local Institutional Review Board, we extracted from the entire database all patients corresponding to the inclusion criteria and conducted a retrospective analysis of the clinical in-hospital outcomes. The patients were divided into 2 groups depending on the antithrombotic regimen received during PCI. The bivalirudin group included all patients who received bivalirudin with or without glycoprotein IIb/IIIa inhibitors. The heparin group was composed of all patients who received heparin and glycoprotein IIb/IIIa inhibitors. AMI was defined as chest pain with ⱖ1 mm of STsegment elevation on ⱖ2 contiguous electrocardiogram leads, chest pain refractory to medical therapy with associated ST-segment depression in leads V2 to V5 (consistent with posterior injury), or left bundle branch block. CS was defined as a subject presenting on admission a maximum systolic blood pressure ⬍90 mm Hg for ⱖ30 minutes unless treated with inotropes or intra-aortic balloon counterpulsation insertion or pump failure as manifested by a cardiac index ⬍2.2 and a pulmonary capillary wedge pressure ⬎18 mm Hg, and/or persistence of hypotension or pump failure www.AJConline.org
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after correction of extra myocardial factors (e.g., hypovolemia, arrhythmia, pain, vasovagal reactions, hypoxemia, acidosis), and/or the presence of peripheral signs of hypoperfusion, as evidenced by peripheral vasoconstriction or urine output ⬍30 cc/hour or altered sensorium. Patients for whom primary angioplasty was not the first line therapy were excluded from the study. Procedure: Contemporary PCI was performed according to guidelines current at the time of implantation. In all cases, the interventional strategy, including the use of direct stenting, pre- or postdilatation, intravascular ultrasound, use of ablative devices, choice of periprocedural adjunctive antiplatelet therapy, and choice of antithrombotic regimen, was at the discretion of the responsible physician. Angiographic success was defined as a stenosis of ⱕ30% with a Thrombolysis in Myocardial Infarction flow grade 3. All patients received aspirin 325 mg/day before the intervention, which was continued indefinitely. Additional antiplatelet therapy with either clopidogrel 75 mg/day (after a loading dose of 300 to 600 mg) or ticlopidine 250 mg twice daily was instituted in all patients and was continued for ⱖ1 year. The patients receiving bivalirudin were given a bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. Abciximab was administrated in 7 patients (19%) using a bolus of 0.25 mg/kg followed by a 12-hour infusion at 10 g/min. In the heparin group, intraprocedural anticoagulation was ensured using unfractionated heparin to achieve an activated clotting time of 200 to 250 seconds associated with an abciximab dose of 0.25 mg/kg bolus followed by a 12-hour infusion at 10 g/min. Clinical follow-up and end points: The end point for analysis in this study was defined as major adverse cardiac events. A dedicated data-coordinating center (Data Center, MedStar Research Institute, Washington, DC) performed all data management and analyses. Prespecified clinical and laboratory data during hospitalization periods were obtained from hospital charts reviewed by independent research personnel who were unaware of the objectives of the study. Death was defined as all causes of mortality. Myocardial infarctions were defined as a total creatinine kinase elevation ⱖ3 times normal and/or creatinine kinase-MB ⱖ20 ng/ml ⫾ new pathological Q waves in ⱖ2 contiguous leads. Target lesion revascularization and target vessel revascularization were characterized by repeat percutaneous or surgical intervention of the treated lesion or vessel, respectively, and were clinically driven. Major adverse cardiac events were defined as a composite of death, myocardial infarction, or repeat revascularizations. All clinical events were adjudicated by source documentation by independent physicians who were not involved in the procedures. Major hematoma was defined as measuring ⱖ2 ⫻ 4 cm or requiring transfusion or necessitating prolonged hospitalization. Statistical analysis: Statistical analysis was performed using the Statistical Analysis System version 8.2 (SAS Institute Inc., Cary, North Carolina). Data are expressed as mean ⫾ SD for continuous variables and as percentages for categorical variables. Student’s t test was used to compare continuous variables and the chi-square test or Fischer’s
Table 1 Baseline clinical characteristics Variable
Bivalirudin (n ⫽ 37)
Heparin (n ⫽ 49)
p Value
Age (yrs), mean ⫾ SD Men Body mass index (5 kg/m2), mean ⫾ SD Current smoker Diabetes mellitus Hyperlipidemia Systemic hypertension History of coronary artery disease Family history of coronary artery disease History of heart failure Dialysis Creatinine clearance (mg/L), mean ⫾ SD Glucose (mg/L), mean ⫾ SD White blood cells (g/L), mean ⫾ SD Left ventricular ejection fraction, mean ⫾ SD
59.6 ⫾ 20.2 25 (67.6%) 29.5 ⫾ 6.2
64.8 ⫾ 14 32 (65.3%) 27.4 ⫾ 5.7
0.19 0.12 0.14
9 (24.3%) 16 (43.2%) 32 (86.5%) 29 (80.6%) 32 (86.5%)
17 (34.7%) 14 (31.1%) 32 (76.2%) 32 (72.7%) 36 (75%)
0.3 0.26 0.24 0.41 0.19
13 (43.3%)
20 (54.1%)
0.38
8 (23.5%) 3 (8.1%) 56 ⫾ 31
14 (31.1%) 1 (2.2%) 54 ⫾ 21
0.46 0.32 0.88
224 ⫾ 61 12.7 ⫾ 6.7
162 ⫾ 77 13.5 ⫾ 6
0.13 0.56
0.36 ⫾ 12
0.35 ⫾ 0.14
0.74
exact test was used to compare categorical variables. A p value ⬍0.05 was considered to indicate statistical significance. Cox proportional hazard analysis was used to identify predictors of major adverse cardiac events. Cox proportional regression models were used to control for differences in the groups. Variables included in the univariate model were age, gender, systemic hypertension, diabetes mellitus, hypercholesterolemia, current smoking, left ventricular ejection fraction on admission, number of diseased vessels, number of treated vessels and intra-aortic balloon counterpulsation use; 3 variables (age, current smoking, and bivalirudin use) with p values ⬍0.2 in the univariate model were entered into the multivariate model. Results Baseline clinical characteristics: Of the 86 patients included, 25 (29%) had intra-aortic balloon counterpulsation insertion for hemodynamic stabilization during the procedure. The 2 groups had similar baseline characteristics and prevalence of risk factors. In particular, the frequency of diabetes mellitus was not different (43.2% in the bivalirudin group vs 31.1% in the heparin group, p ⫽ 0.26). Main biological data on admission were similar in the 2 groups (Table 1). Angiographic and interventional characteristics: Angiographic characteristics were similar in the 2 groups and are summarized in Table 2. There was a high rate of complex lesions (type C) according to the American College of Cardiology/American Heart Association classification. Further, a high number of diseased vessels per patient was noted in the bivalirudin versus heparin group (2.6 ⫾ 0.7 and 2.4 ⫾ 0.85, respectively, p ⫽ 0.46). There was no significant difference in the rate of intra-aortic balloon counterpulsation insertion during the procedure in the 2 groups
Coronary Artery Disease/Bivalirudin in Angioplasty with Cardiogenic Shock Table 3 In-hospital complications and outcome
Table 2 Angiographic and procedural characteristics Variable Coronary narrowing location Left main Left anterior descending Left circumflex Right Saphenous vein graft Number of diseased vessels, mean ⫾ SD Lesion type (ACC/AHA class) Type A Type B Type C Procedural details Angiographic success No reflow Number of lesions treated, mean ⫾ SD Number of implanted stents, mean ⫾ SD Drug-eluting stents Stent diameter, mm ⫾ SD Stent length, mm ⫾ SD Predilatation Antithrombotics Maximum activated clotting time (sec), mean ⫾ SD Final activated clotting time (sec), mean ⫾ SD Glycoprotein IIb/IIIa inhibitors Intra aortic balloon counterpulsation Left ventricular ejection fraction, mean ⫾ SD Closure devices Length of intensive care unit stay (days), mean ⫾ SD Length of hospital stay (days), mean ⫾ SD
Bivalirudin (n ⫽ 69)
Heparin (n ⫽ 82)
p Value
1 (1.4%) 13 (35.1%) 10 (27%) 11 (29.7%) 3 (8.1%) 2.6 ⫾ 0.7
2 (2.4%) 29 (35.4%) 20 (24.4%) 26 (31.7%) 5 (6.1%) 2.4 ⫾ 0.85
1 0.91 0.55 0.69 1 0.46
2 (5.4%) 21 (56.8%) 14 (37.8%)
6 (7.7%) 42 (53.8%) 30 (38.5%)
0.28 0.98 0.54
64 (94.1%) 1 (1.5%) 1.8 ⫾ 1.5
76 (93.8%) 3 (3.7%) 1.5 ⫾ 0.9
1 0.63 0.33
0.97 ⫾ 1.24
0.68 ⫾ 0.67
0.28
35 (52.2%) 4.1 ⫾ 0.4 19.8 ⫾ 7.3 26 (41.3%)
15 (37.5%) 3.1 ⫾ 0.4 23.4 ⫾ 4.6 20 (43.5%)
0.14 0.41 0.15 0.8
316 ⫾ 82
261 ⫾ 56
0.002
318 ⫾ 81
257 ⫾ 55
⬍0.001
7 (18.9%)
49 (100%)
⬍0.001
9 (24.3%)
16 (33.3%)
0.37
0.36 ⫾ 12
0.35 ⫾ 0.14
0.74
15 (40.5%) 4.8 ⫾ 3.8
15 (31.9%) 5.8 ⫾ 3.8
0.45 0.44
11 ⫾ 9
289
9 ⫾ 7.4
0.28
ACC/AHA ⫽ American College of Cardiology/American Heart Association.
(bivalirudin group 24.3% vs heparin group 33.3%, p ⫽ 0.37). The number of treated lesions was high in the bivalirudin and heparin groups (1.8 ⫾ 1.5 vs 1.5 ⫾ 0.9, respectively, p ⫽ 0.33). Other characteristics of intervention were similar in the groups, including the rate of predilatation (41.3 vs 43.5%, p ⫽ 0.8). The rates of angiographic success and of no-reflow were not different between groups (94.1 vs 93.8%, p ⫽ 1, and 1.5 vs 3.7%, p ⫽ 0.63). In-hospital outcomes: There was no difference in the rate of major hematoma or transfusion between the bivalirudin group and the heparin group (3 vs 2.6%, p ⫽ 0.46, and 36.1 vs 37.2%, p ⫽ 0.9, respectively,). The majority of bleedings complications were in the gastrointestinal hemorrhage. The rate of death was significantly lower in the bivalirudin group compared with the heparin group (5.4 vs
Variable
Bivalirudin (n ⫽ 37)
Heparin (n ⫽ 49)
p Value
Death Major adverse cardiac event Coronary bypass (postprocedure) Major hematoma Transfusion Neurologic event Acute kidney failure Abrupt vessel closure Subacute stent thrombosis
2 (5.4%) 3 (8.1%) 9 (24.3%) 1 (3%) 13 (36.1%) 0 2 (5.6%) 2 (5.4%) 0
16 (32.7%) 17 (34.7%) 7 (15.6%) 1 (2.6%) 16 (37.2%) 0 6 (12.5%) 3 (6.4%) 0
0.002 0.004 0.3 0.46 0.9 — 0.46 1 —
Table 4 Univariate predictors Observation Bivalirudin use Age Men Systemic hypertension Hypercholesterolemia Diabetes mellitus Current smoker Number of diseased vessels Intra-aortic balloon counterpulsation (per procedure) Number of treated vessels
Hazard Ratio
95% CI for Hazard Ratio
p Value
0.2 1.0 0.6 1.9 0.8 1.3 0.4 1.1 1.1
0.1–0.6 1.0–1.1 0.3–1.3 0.7–5.7 0.3–2.3 0.6–3 0.1–1.3 0.6–2.1 0.5–2.5
0.005 0.016 0.212 0.233 0.610 0.486 0.140 0.814 0.849
1.0
0.7–1.4
0.832
32.7%, p ⫽ 0.002). The overall rate of major adverse cardiac events was significantly lower in the bivalirudin group (8.1 vs 34.7%, p ⫽ 0.004) (Table 3). Univariate and multivariate predictors of major adverse cardiac events: Univariate predictors of in-hospital major adverse cardiac events were bivalirudin use with a hazard ratio of 0.2 (95% confidence interval [CI] 0.1 to 0.6, p ⫽ 0.005) and age with a hazard ratio of 1 (95% CI 1 to 1.1, p ⫽ 0.016). In multivariate analysis, only bivalirudin was found to be significantly associated with in-hospital major adverse cardiac events with a hazard ratio of 0.3 (95% CI 0.1 to 0.9, p ⫽ 0.025) (Table 4). Discussion The results of this study suggest that for patients treated with primary angioplasty for AMI complicated by CS, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors is safe, efficient, and associated with low rates of in-hospital death. Thus, this study suggests that bivalirudin use in PCI could be safely extended to patients with CS. CS is associated with high mortality rates, which have been reduced by recent advances in PCI, including early revascularization, wide use of mechanical support such as intra-aortic balloon counterpulsation, and the addition of glycoprotein IIb/IIIa inhibitors to heparin.1,5,6 In our study, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors is associated with a significantly lower risk of in-hospital death when compared with heparin plus
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glycoprotein IIb/IIIa inhibitors. This could be a result of chance; however, this potential superiority was also observed in previous trials.7,8 Consistently, in the Horizon AMI trial, which focused on patients with AMI, bivalirudin with provisional glycoprotein IIb/IIIa inhibitors demonstrated a significant decrease in cardiac death at 30 days. No study has investigated the potential superiority of a bivalirudin- over heparin-based regimen. In fact, several advantages of bivalirudin over heparin could have a beneficial role in patients with CS relating to the complex pathogenesis of the disease. Bivalirudin is a direct thrombin inhibitor that acts by bivalently binding to the thrombin action site. Its antithrombotic effects are not dependent on a cofactor such as antithrombin III to inhibit thrombin and have no known inhibitors, such as platelet factor 4. Unlike heparin, bivalirudin acts on clot-bound thrombin together with circulating thrombin. In addition, the direct thrombin inhibitors are not limited by the same pharmacokinetic and pharmacodynamic heterogeneity as heparin, which could be of importance when considering the several biological abnormalities present in CS that may interact with drug properties.9 –11 Moreover, bivalirudin does not act only by inhibiting thrombin generation but also platelet activation and clot formation.12 In fact, bivalirudin exhibits antiplatelet properties contrary to heparin, which induces platelet activation.13,14 Moreover, Schneider et al14 have demonstrated that bivalirudin had greater inhibitory effects compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation.15 CS is associated with a systemic inflammatory response. The levels of inflammatory markers, like interleukin 6, have been shown to be independent predictors of mortality at 30 days.16 Consistent with this pivotal role of inflammation in CS, the use of anti-inflammatory drugs, such as statins, have been associated with improved in-hospital outcome.17 A beneficial effect of bivalirudin may therefore be related to the lack of proinflammatory properties compared with heparin.18 –20 The present study did not detect any difference in bleeding rates between the 2 groups. This could be related to nearly 20% of the patients in the bivalirudin group receiving glycoprotein IIb/IIIa, which increased the rate of bleeding in this group. Other factors that could explain the lack of difference in the bleeding rate are the relatively small number of patients in the study and that, in this particular setting, bleedings are less dependent on antithrombotic therapy and more related to procedure factors such as large sheath insertion and delayed closure with the use of intra-aortic balloon counterpulsation.21 Despite a low frequency of major hematoma, the rate of transfusion was high. This may be related to the high frequency of a history of chronic kidney disease, dialysis, and heart failure in the included patients, which are associated with anemia.22,23 Moreover, as observed in the Global Registry of Acute Coronary Events (GRACE) registry, the main site of bleedings was the gastrointestinal tract, which may be less influenced by the antithrombotic strategy than the entry point site.24 Finally, such critically ill patients develop anemia in the intensive care unit, which may be responsible for a higher percentage of transfusions than bleedings. Anemia related to this etiol-
ogy may not be influenced by antithrombotic strategy at the time of PCI.25 There are several limitations to the present study. It is a small, retrospective study, which does not allow for definitive conclusion and presents the common potential skews associated with this type of study. Nevertheless, conducting a large, prospective study in patients with CS is challenging. To overcome these limitations we have performed a multivariate analysis to minimize the effects of confounding factors. Prospective studies are now required to confirm these preliminary data. 1. Giri S, Mitchel J, Azar RR, Kiernan FJ, Fram DB, McKay RG, Mennett R, Clive J, Hirst JA. Results of primary percutaneous transluminal coronary angioplasty plus abciximab with or without stenting for acute myocardial infarction complicated by cardiogenic shock. Am J Cardiol 2002;89:126 –131. 2. Stone GW for the Horizon AMI Investigators. A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction–30 Day Results. Presented at Transcatheter Cardiovascular Therapeutics (TCT) 2007, Washington, DC. 3. Stone GW, Ware JH, Bertrand ME, Lincoff AM, Moses JW, Ohman EM, White HD, Feit F, Colombo A, McLaurin BT, et al, for the ACUITY Investigators. Antithrombotic strategies in patients with acute coronary syndromes undergoing early invasive management: one-year results from the ACUITY trial. JAMA 2007;298:2497– 2506. 4. Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al, for the REPLACE-2 Investigators. 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– 863. 5. Hochman JS, Boland J, Sleeper LA, Porway M, Brinker J, Col J, Jacobs A, Slater J, Miller D, Wasserman H, et al, and the SHOCK Registry Investigators. Current spectrum of cardiogenic shock and effect of early revascularization on mortality: results of an International Registry. Circulation 1995;91:873– 881. 6. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, Hochman JS, Krumholz HM, Kushner FG, Lamas GA, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol 2004;44:e1– e211. 7. Wolfram R, Leborgne L, Cheneau E, Pinnow EE, Canos DA, Hellinga D, Satler LF, Pichard AD, Kent KM, Waksman R. Comparison of effectiveness and safety of three different antithrombotic regimens (bivalirudin, eptifibatide, and heparin) in preventing myocardial ischemia during percutaneous coronary intervention. Am J Cardiol 2003; 92:1080 –1083. 8. Lincoff AM, Kleiman NS, Kereiakes DJ, Feit F, Bittl JA, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, et al, for the REPLACE-2 Investigators. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004;292:696 –703. 9. Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin–antithrombin III but is susceptible to inactivation by antithrombin III–independent inhibitors. J Clin Invest 1990;86:385–391. 10. Eitzman DT, Chi L, Saggin L, Schwartz RS, Lucchesi BR, Fay WP. Heparin neutralization by platelet-rich thrombi: role of platelet factor 4. Circulation 1994;89:1523–1529. 11. Hirsh J, Raschke R, Warkentin TE, Dalen JE, Deykin D, Poller L. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 1995;108:258S–75S.
Coronary Artery Disease/Bivalirudin in Angioplasty with Cardiogenic Shock 12. Aggarwal A, Sobel BE, Schneider DJ. Decreased platelet reactivity in blood anticoagulated with bivalirudin or enoxaparin compared with unfractionated heparin: implications for coronary intervention. J Thromb Thrombolysis 2002;13:161–165. 13. Anand SX, Kim MC, Kamran M, Sharma SK, Kini AS, Fareed J, Hoppensteadt DA, Carbon F, Cavusoglu E, Varon D, et al. Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin. Am J Cardiol 2007;100:417– 424. 14. Schneider DJ, Keating F, Sobel BE. Greater inhibitory effects of bivalirudin compared with unfractionated heparin plus eptifibitide on thrombin-induced platelet activation. Coron Artery Dis 2006;17:471– 476. 15. Butenas S, Orfeo T, Brummel-Ziedins KE, Mann KG. Influence of bivalirudin on tissue factor-triggered coagulation. Blood Coagul Fibrinolysis 2007;18:407– 414. 16. Geppert A, Dorninger A, Delle-Karth G, Zorn G, Heinz G, Huber K. Plasma concentrations of interleukin-6, organ failure, vasopressor support, and successful coronary revascularization in predicting 30-day mortality of patients with cardiogenic shock complicating acute myocardial infarction. Crit Care Med 2006;34:2035–2042. 17. Schmidt H, Hennen R, Keller A, Russ M, Müller-Werdan U, Werdan K, Buerke M. Association of statin therapy and increased survival in patients with multiple organ dysfunction syndrome. Intensive Care Med 2006;32:1248 –1251.
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18. Harding SA, Din JN, Sarma J, Josephs DH, Fox KA, Newby DE. Promotion of proinflammatory interactions between platelets and monocytes by unfractionated heparin. Heart 2006;92:1635–1638. 19. Li G, Keenan AC, Young JC, Hall MJ, Pamuklar Z, Ohman EM, Steinhubl SR, Smyth SS. Effects of unfractionated heparin and glycoprotein IIb/IIIa antagonists versus bivalirdin on myeloperoxidase release from neutrophils. Arterioscler Thromb Vasc Biol 2007;27: 1850 –1856. 20. Keating FK, Dauerman HL, Whitaker DA, Sobel BE, Schneider DJ. Increased expression of platelet P-selectin and formation of plateletleukocyte aggregates in blood from patients treated with unfractionated heparin plus eptifibatide compared with bivalirudin. Thromb Res 2006;118:361–369. 21. Busch T, Sîrbu H, Zenker D, Dalichau H. Vascular complications related to intraaortic balloon counterpulsation: an analysis of ten years experience. Thorac Cardiovasc Surg 1997;45:55–59. 22. Berry C, Norrie J, Hogg K, Brett M, Stevenson K, McMurray JJ. The prevalence, nature, and importance of hematologic abnormalities in heart failure. Am Heart J 2006;151:1313–1321. 23. Schiller GJ, Berkman SA. Hematologic aspects of renal insufficiency. Blood Rev 1989;3:141–146. 24. Moscucci M, Fox KA, Cannon CP, Klein W, López-Sendón J, Montalescot G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24:1815–1823. 25. Shander A. Anemia in the critically ill. Crit Care Clin 2004;20:159 –178.