© 2013, Wiley Periodicals, Inc. DOI: 10.1111/joic.12081
CORONARY ARTERY DISEASE Low‐Dose Heparin for Elective Percutaneous Coronary Intervention MICHAEL S. LEE, M.D., 1 JARED OYAMA, M.D., 1 ZAHID IQBAL, M.D., 2 and GIUSEPPE TARANTINI, M.D. 3 From the 1UCLA Medical Center, Los Angeles, California; 2UC Davis Medical Center, Davis, California; and 3Padova University Hospital, Padova, Italy
Objectives: We evaluated the safety and efficacy of low‐dose heparin (40 IU/kg) for elective percutaneous coronary intervention (PCI). Background: Current guidelines recommend a 70–100 IU/kg bolus of heparin for elective PCI, but this dose may be associated with increased bleeding risk. Low‐dose heparin may have an advantage in this regard, but has not been well studied. Methods: From January 2008 to October 2012, 300 patients underwent elective transfemoral PCI and were treated with an initial bolus of 40 IU/kg of heparin at the UCLA Medical Center. Dual antiplatelet therapy with clopidogrel and aspirin was administered prior to or just after diagnostic coronary angiography. The primary end‐point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding within 30 days after PCI. Results: The mean activating clotting time was 233 28 seconds. The primary end‐point occurred in 2.3%. The cardiac death rate was 0.3% but was not related to the PCI. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). The major bleeding rate was 0.3%. No stent thrombosis occurred. Conclusion: Using a lower dose of heparin with dual antiplatelet therapy is safe and is associated with a low bleeding risk after transfemoral PCI while providing suppression of ischemic events. This may also represent a cost savings compared with other antithrombotic strategies. A randomized clinical trial comparing low‐dose heparin with bivalirudin in patients is required to determine the optimal anticoagulation strategy. (J Interven Cardiol 2014;27:58–62)
Background Unfractionated heparin remains a commonly used anticoagulant to minimize acute thrombotic complications during percutaneous coronary intervention (PCI). When glycoprotein IIb/IIIa inhibitors are not planned, the American College of Cardiology Foundation/ American Heart Association/Society of Coronary Angiography and Interventions guidelines recommend a 70–100 IU/kg bolus of heparin to achieve an activated clotting time (ACT) of 250–300 seconds for Hemotec and 300–350 seconds for Hemochron systems.1 However, the optimal dosing regimen of heparin during elective PCI is unknown. Previously, large doses of Address for reprints: Michael S. Lee, M.D., 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Fax: 310‐825‐9012; e‐mail: [email protected]
58
heparin, often in the range of 10,000 to 15,000 IU, were given prior to PCI. However, subsequent prospective and randomized studies have demonstrated the feasibility and safety of using heparin at lower fixed (5,000 IU)2–5 or weight‐based (100 IU/kg) doses.6 An individual patient’s response to heparin remains difficult to predict. Previous studies have demonstrated an association between bleeding frequency and high ACT as well as increased ischemic complications with low ACT.7–9 A pooled analysis of 6 randomized trials revealed fewer ischemic complications but more bleeding with higher doses of heparin.8 However, ischemic complications did not increase at the lowest ACT levels, whereas bleeding complications were reduced at lower ACT levels.10 Anticoagulation strategies must be designed to avoid major bleeding complications as they are associated with increased 1‐year mortality.11,12
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Using low‐dose heparin has the theoretical advantage of reducing the risk of bleeding complications during PCI. However, the risk of ischemic complications is unknown. Therefore, an initial bolus of low‐ dose heparin (40 IU/kg) in patients undergoing elective transfemoral PCI was evaluated.
Methods From July 2008 to October 2012, a total of 300 patients scheduled for elective transfemoral PCI with either drug‐eluting or bare metal stents at the UCLA Medical Center who received 40 IU/kg of heparin were included. Patients were excluded from the study if there was a history of heparin‐induced thrombocytopenia, bleeding diathesis, coagulopathy (international normalized ratio >1.5), or thrombocytopenia (platelet count less than 50,000 cells per cubic millimeter). Approval of the Institutional Review Board was obtained to review the data for this study. PCI was performed via the femoral approach according to standard procedures. After 40 IU/kg of heparin was administered intra‐arterially through the sheath, activating clotting time was measured with a Hemochron system after 5 minutes. Aspirin 325 mg and clopidogrel 600 mg were administered before the procedure or just after diagnostic angiography and continued for at least 1 month for bare metal stents and 1 year for drug‐eluting stents. A bolus dose of glycoprotein IIb/IIIa inhibitors was administered at the discretion of the operator. A vascular closure device was used whenever feasible. The primary end‐point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding. Myocardial infarction was defined as the development of pathologic Q waves (30 milliseconds in duration and 0.1 mV in depth) in 2 or more contiguous precordial leads or 2 or more adjacent limb leads, or an elevation of creatine kinase‐MB isoenzyme levels (or total creatine kinase if measures of CK‐MB were not available) to at least 2 times the upper limit of the normal range.13 Urgent target vessel revascularization was defined as coronary artery bypass surgery or repeat PCI due to myocardial ischemia within 30 days after index revascularization. Major bleeding was defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin of more than 3 g/dL; any decrease in
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hemoglobin of more than 4 g/dL; or transfusion of 2 or more units of packed red cells or whole blood.14 Stent thrombosis was defined according to the Academic Research Consortium criteria.15 Hemoglobin and platelet count were measured on the day of PCI. Profound thrombocytopenia was defined as a platelet count of less than 20,000 cells per cubic millimeter. Patient data were collected from medical records, and adverse clinical events were recorded into a dedicated PCI database. Continuous variables are presented as mean SD, and categorical variables are presented as percentages. Statistical analysis was performed with SAS software (version 9.1, SAS Institute, Inc., Cary, NC, USA).
Results Baseline Characteristics. Baseline characteristics of the 300 patients are summarized in Table 1. The mean age was 62.9 14.3 years. Procedural characteristics are listed in Table 2. The mean activating clotting time obtained 5 minutes after heparin was administered was 233 28 seconds. Patients were pretreated with clopidogrel prior to diagnostic coronary angiography in 38% of cases. Vascular closure devices were used in 93%. Clinical Outcomes at 30 Days. There was no death, stent thrombosis, or major bleeding in the cardiac catheterization laboratory (Table 3). A 77‐year‐ old female had a spiral dissection of the right coronary artery after predilatation with a 2.0‐mm balloon. This was subsequently treated with multiple stents. The primary end‐point occurred in 2.3%. Cardiac death occurred in 1 patient (0.3%). A 76‐year‐old female died suddenly 17 days after PCI of the left anterior
Table 1. Baseline Clinical Characteristics Number of patients Age (years) Male gender, n (%) Diabetes mellitus, n (%) Body weight (kg) Hypertension, n (%) Hypercholesterolemia, n (%) Prior stroke, n (%) Previous myocardial infarction, n (%) Previous percutaneous coronary intervention, n (%) Previous coronary artery bypass surgery, n (%) Left ventricular ejection fraction (%)
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300 63 14 212 (71) 81 (27) 78 18 190 (63) 177 (59) 38 (13) 69 (23) 85 (28) 31 (10) 51 15
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LEE, ET AL. Table 2. Procedural Characteristics 233 28 113 (38)
Mean activating clotting time (seconds) Patients treated with pre‐clopidogrel, n (%) Target vessel, n (%) Left main coronary artery Left anterior descending artery Left circumflex artery Right coronary artery Saphenous vein graft Type of stent, n (%) Drug‐eluting stent Bare metal stent Stents per case Vessels treated Intravascular ultrasound, n (%) Bail‐out use of GP IIb/IIIa inhibitors, n (%) Final TIMI flow, n (%) 0–1% 2% 3% French size, n (%) 6F 7F 8F Modality of hemostasis, n (%) Vascular closure device Manual
10 (3) 108 (36) 90 (30) 102 (34) 4 (1) 220 (73) 86 (29) 1.4 0.7 1.1 0.2 185 (62) 7 (2) 0 0 300 (100) 285 (95) 1 (0.3) 14 (5) 278 (93) 22 (7)
diagonal branch that was treated with balloon angioplasty. The major bleeding rate was 0.3%. A 56‐year‐old male with a history of orthotopic heart transplantation had severe transplant coronary artery disease with a chronic total occlusion of the left anterior descending artery and left circumflex artery as well as severe left ventricular dysfunction. After PCI of the right coronary artery, a vascular closure device was not deployed because the location of the arteriotomy was in the superficial femoral artery. The 7F sheath was pulled and hemostasis was obtained with manual compression. Later that evening, the patient developed a pseudoaneurysm that ruptured, leading to hemorrhagic shock and hemodynamic collapse, had cardiac arrest, and subsequently expired within 24 hours of the PCI. Another access site complication occurred in a 59‐year‐ old male who developed a small pseudoaneurysm. It was treated conservatively and resolved with manual compression. There was no intracranial, retroperitoneal, pericardial, gastrointestinal, or urogenital hemorrhage. No patients developed profound thrombo- cytopenia. No acute or subacute stent thrombosis occurred.
Discussion descending artery. Autopsy demonstrated a thrombotic occlusion of the left circumflex artery and a widely patent stent in the left anterior descending artery. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). After PCI of the left anterior descending artery, the patient complained of severe chest pain. Repeat coronary angiography revealed compromise of the Table 3. Clinical Events at 30 Days Cardiac death, myocardial infarction, target vessel revascularization, and bleeding, n (%) Cardiac death, myocardial infarction, target vessel revascularization, n (%) Cardiac death, n (%) Myocardial infarction, n (%) Urgent target vessel revascularization, n (%) Bleeding complications, n (%) Intracranial bleeding Retroperitoneal bleeding Hemoglobin decrease 3 g/dL with overt source Hemoglobin decrease 4 g/dL without overt source Blood transfusion Guide catheter thrombosis, n (%) Stent thrombosis, n (%)
60
7 (2) 7 (2) 1 4 1 1 0 0 1 0 1 0 0
(0.3) (1) (0.3) (0.3) (0) (0) (0.3) (0) (0.3) (0) (0)
In this prospective single‐center study of elective transfemoral PCI, low‐dose heparin was associated with low ischemic and bleeding complications at 30 days. No patient experienced stent thrombosis. Major bleeding after PCI is a predictor of ischemic events and mortality.10,11,12,16 Various strategies including technique and adjunctive pharmacotherapy have been used to minimize the risk of bleeding. Transradial intervention decreases the risk of major bleeding compared with transfemoral intervention in ST‐elevation myocardial infarction.17 However, the dose of heparin used in the study was 105 IU/kg, and 45% of patients received glycoprotein IIb/IIIa inhibitors. Bivalirudin is a direct thrombin inhibitor that is commonly used instead of heparin during PCI. In the Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR‐ REACT) 3 trial, patients with stable or unstable angina who underwent PCI had less major bleeding and similar clinical outcomes with bivalirudin compared to heparin after pretreatment with clopidogrel.13 When compared with 60–65 IU/kg of heparin plus glycoprotein IIb/IIIa inhibitors, bivalirudin has been shown to provide similar suppression of ischemia in patients who
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undergo PCI for stable angina and non‐ST‐segment elevation acute coronary syndromes but less major bleeding.14,18 In ST‐segment elevation myocardial infarction, bivalirudin was also associated with lower mortality and periprocedural bleeding compared with 60 IU/kg of heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing primary PCI.19 However, planned glycoprotein IIb/IIIa inhibition is not routinely used in contemporary practice, especially in elective PCI, and the increased bleeding in the heparin groups may have been related to the use of glycoprotein IIb/ IIIa inhibitors. Another strategy to reduce the risk of bleeding complications after PCI is using lower doses of heparin. Achieving low rates of bleeding and thrombosis is a tight balancing act. The ideal dosing regimen for heparin to prevent ischemic and hemorrhagic complications remains unclear. Current guidelines are largely based on older studies, many of which predated the widespread use of P2Y12 inhibitors, and therefore required larger doses of anticoagulation. Various dosing regimens have been studied before, ranging from no heparin to high‐dose heparin. The Coronary Interventions Antiplatelet‐based Only (CIAO) trial demonstrated that elective PCI can be performed safely and effectively without heparin if patients are pretreated with dual antiplatelet therapy.20 However, PCI was performed only in simple uncomplicated lesions. A prospective registry of 418 patients who underwent PCI with 30 IU/kg of heparin reported a 2.9% rate of in‐ hospital death, MI, or repeat revascularization at 1 month.21 Serious vascular complication requiring a blood transfusion and surgical repair only occurred in 1 patient (0.24%). The average dose of heparin was 2,253 IU, and the final ACT was 174 seconds. Most of these patients were not pretreated with dual antiplatelet therapy. In the ISAR‐REACT 3 trial, patients with stable or unstable angina who underwent PCI with 140 IU/kg of heparin had similar composite end‐point of death, myocardial infarction, urgent target vessel revascularization, or major bleeding as compared to those treated with bivalirudin after pretreatment with clopidogrel.13 However, the incidence of major bleeding was higher with heparin, though this may be explained by the high bolus dose of heparin. The ISAR‐REACT 3A trial was a follow‐up study where 100 IU/kg of heparin was utilized after clopidogrel pretreatment in biomarker negative patients undergoing PCI and reported a net clinical benefit when compared with the ISAR‐REACT patients as a
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historical control.22 Additionally, the lower heparin dose met the criterion for noninferiority when compared with the historical bivalirudin arm. As the optimal dosing regimen for heparin continues to be refined in elective PCI, our data demonstrate that low‐dose heparin provided excellent protection from bleeding complications without an increase in ischemic events. Our bleeding rates were low and compared favorably with other studies. The lower dose of heparin may decrease the rate of bleeding and provide bleeding rates comparable to PCI with bivalirudin. One major benefit of heparin is that it is much less expensive compared with bivalirudin.23 A study utilizing the results of ISAR‐REACT 3 to generate a cost prediction model demonstrated increased costs associated with the use of bivalirudin in all but a minority of patients at high risk for bleeding.24 The use of low‐dose heparin regimens may be cost‐effective compared with using bivalirudin (approximately $400 to $500 per PCI compared with $10 for heparin) while reducing hemorrhagic complications and maintaining adequate protection against ischemic events. Stent thrombosis did not occur with low‐dose heparin. The loading dose of clopidogrel used in our study was 600 mg. The higher loading dose of clopidogrel may have offset the potential increased risk of ischemic events with a lower dose of heparin. Because heparin activates platelets, lower heparin doses and heightened inhibition of platelets may explain the excellent protection from ischemic events. Study Limitations. This was a nonrandomized study from a single center with a small number of patients. These results need to be validated in a randomized trial. Unlike other trials with low‐dose or no heparin, not all patients were pretreated with dual antiplatelet therapy prior to PCI. Because the ACTs were measured with the Hemochron system, ACTs drawn with the Hemotec system need to be validated. Postprocedural cardiac biomarkers and platelet counts were not drawn on all patients. Therefore, the rate of occult biomarker elevation and thrombocytopenia is unknown. These results cannot be applied to patients with ST‐elevation myocardial infarction where the thrombotic milieu is high and requires higher levels of anticoagulation. PCI was relatively simple with a mean of 1.4 stents used per case. PCI with low‐dose heparin may not be applicable to complex, multivessel PCI. IVUS was used in 62% of cases. Therefore, the results of this study may not reflect “real‐world” practice.
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LEE, ET AL.
Conclusion 11.
Elective PCI with low‐dose heparin via the transfemoral route is feasible, safe, and is associated with low ischemic and bleeding complications. This may represent a cost‐saving strategy as compared with bivalirudin with no increase in adverse clinical outcomes. A large‐scale, randomized clinical trial comparing low‐dose heparin with bivalirudin or low‐ molecular weight heparin in patients is required to determine the optimal anticoagulation strategy.
12.
13. 14.
References 15. 1. Levine GN, Bates ER, Blankenship JC, et al. ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58(24):E44–E122. 2. Vainer J, Fleisch M, Gunnes P, et al. Low‐dose heparin for routine coronary angioplasty and stenting. Am J Cardiol 1996;78:964–966. 3. Koch KT, Piek JJ, de Winter RJ, et al. Early ambulation after coronary angioplasty and stenting with six French guiding catheters and low‐dose heparin. Am J Cardiol 1997;80:1084–1086. 4. Koch KT, Piek JJ, de Winter RJ, et al. Safety of low dose heparin in elective coronary angioplasty. Heart 1997;77:517–522. 5. Liem A, Zijlstra F, Ottervanger JP, et al. High dose heparin as pretreatment for primary angioplasty in acute myocardial infarction: The Heparin in Early Patency (HEAP) randomized trial. J Am Coll Cardiol 2000;35:600–604. 6. Boccara A, Benamer H, Juliard JM, et al. A randomized trial of a fixed high dose vs a weight‐adjusted low dose of intravenous heparin during coronary angioplasty. Eur Heart J 1997;18:631–635. 7. Ashby DT, Dangas G, Aymong EA, et al. Relation between the degree of procedural anticoagulation and complications after coronary stent implantation. Am J Cardiol 2003;92:319–322. 8. Chew DP, Bhatt DL, Lincoff AM, et al. Defining the optimal activated clotting time during percutaneous coronary intervention: Aggregate results from 6 randomized, controlled trials. Circulation 2001;103:961–966. 9. Ferguson JJ, Dougherty KG, Gaos CM, et al. Relation between procedural activated coagulation time and outcome after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 1994;23:1061–1065. 10. Tolleson TR, O’Shea JC, Bittl JA, et al. Relationship between heparin anticoagulation and clinical outcomes in coronary stent
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16. 17. 18. 19. 20.
21. 22.
23. 24.
intervention: Observations from the ESPRIT trial. J Am Coll Cardiol 2003;41:386–393. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1‐year outcome after percutaneous coronary interventions: Appropriateness of including bleeding as a component of a quadruple end point. J Am Coll Cardiol 2008;51:690–697. Feit F, Voeltz MD, Attubato MJ, et al. Predictors and impact of major hemorrhage on mortality following percutaneous coronary intervention from the REPLACE‐2 Trial. Am J Cardiol 2007;100:1364–1369. Kastrati A, Neumann FJ, Mehilli J, et al. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008;359:688–696. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. 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. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: A case for standardized definitions. Circulation 2007;115:2344–2351. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006;114:774–782. Bernat I. STEMI‐RADIAL: A prospective, randomized trial of radial vs. femoral access in patients with ST‐segment elevation myocardial infarction. TCT 2012; October 26, 2012; Miami, FL. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203– 2216. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218–2230. Stabile E, Nammas W, Salemme L, et al. The CIAO (Coronary Interventions Antiplatelet‐based Only) study: A randomized study comparing standard anticoagulation regimen to absence of anticoagulation for elective percutaneous coronary intervention. J Am Coll Cardiol 2008;52:1293–1298. Godon P, Rioufol G, Finet G, et al. Efficacy and safety of low‐ dose heparin (30 IU/kg) during coronary angioplasty. Arch Mal Coeur Vaiss 2001;94:984–988. Schulz S, Mehilli J, Neumann F, et al. ISAR‐REACT3A: A study of reduced dose of unfractionated heparin in biomarker negative patients undergoing percutaneous coronary intervention. Eur Heart J 2010;31:2482–2491. Caruba T, Chaib A, Danchin N, et al. Clinical and economical evaluation of bivalirudin during percutaneous coronary interventions. Ann Cardiol Angeiol (Paris) 2010;59:72–78. Amin AP, Marso SP, Rao SV, et al. Cost‐effectiveness of targeting patients undergoing percutaneous coronary intervention for therapy with bivalirudin versus heparin monotherapy according to predicted risk of bleeding. Circ Cardiovasc Qual Outcomes 2010;3:358–365.
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CORONARY ARTERY DISEASE Low‐Dose Heparin for Elective Percutaneous Coronary Intervention MICHAEL S. LEE, M.D., 1 JARED OYAMA, M.D., 1 ZAHID IQBAL, M.D., 2 and GIUSEPPE TARANTINI, M.D. 3 From the 1UCLA Medical Center, Los Angeles, California; 2UC Davis Medical Center, Davis, California; and 3Padova University Hospital, Padova, Italy
Objectives: We evaluated the safety and efficacy of low‐dose heparin (40 IU/kg) for elective percutaneous coronary intervention (PCI). Background: Current guidelines recommend a 70–100 IU/kg bolus of heparin for elective PCI, but this dose may be associated with increased bleeding risk. Low‐dose heparin may have an advantage in this regard, but has not been well studied. Methods: From January 2008 to October 2012, 300 patients underwent elective transfemoral PCI and were treated with an initial bolus of 40 IU/kg of heparin at the UCLA Medical Center. Dual antiplatelet therapy with clopidogrel and aspirin was administered prior to or just after diagnostic coronary angiography. The primary end‐point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding within 30 days after PCI. Results: The mean activating clotting time was 233 28 seconds. The primary end‐point occurred in 2.3%. The cardiac death rate was 0.3% but was not related to the PCI. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). The major bleeding rate was 0.3%. No stent thrombosis occurred. Conclusion: Using a lower dose of heparin with dual antiplatelet therapy is safe and is associated with a low bleeding risk after transfemoral PCI while providing suppression of ischemic events. This may also represent a cost savings compared with other antithrombotic strategies. A randomized clinical trial comparing low‐dose heparin with bivalirudin in patients is required to determine the optimal anticoagulation strategy. (J Interven Cardiol 2014;27:58–62)
Background Unfractionated heparin remains a commonly used anticoagulant to minimize acute thrombotic complications during percutaneous coronary intervention (PCI). When glycoprotein IIb/IIIa inhibitors are not planned, the American College of Cardiology Foundation/ American Heart Association/Society of Coronary Angiography and Interventions guidelines recommend a 70–100 IU/kg bolus of heparin to achieve an activated clotting time (ACT) of 250–300 seconds for Hemotec and 300–350 seconds for Hemochron systems.1 However, the optimal dosing regimen of heparin during elective PCI is unknown. Previously, large doses of Address for reprints: Michael S. Lee, M.D., 100 Medical Plaza, Suite 630, Los Angeles, CA 90095. Fax: 310‐825‐9012; e‐mail: [email protected]
58
heparin, often in the range of 10,000 to 15,000 IU, were given prior to PCI. However, subsequent prospective and randomized studies have demonstrated the feasibility and safety of using heparin at lower fixed (5,000 IU)2–5 or weight‐based (100 IU/kg) doses.6 An individual patient’s response to heparin remains difficult to predict. Previous studies have demonstrated an association between bleeding frequency and high ACT as well as increased ischemic complications with low ACT.7–9 A pooled analysis of 6 randomized trials revealed fewer ischemic complications but more bleeding with higher doses of heparin.8 However, ischemic complications did not increase at the lowest ACT levels, whereas bleeding complications were reduced at lower ACT levels.10 Anticoagulation strategies must be designed to avoid major bleeding complications as they are associated with increased 1‐year mortality.11,12
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Using low‐dose heparin has the theoretical advantage of reducing the risk of bleeding complications during PCI. However, the risk of ischemic complications is unknown. Therefore, an initial bolus of low‐ dose heparin (40 IU/kg) in patients undergoing elective transfemoral PCI was evaluated.
Methods From July 2008 to October 2012, a total of 300 patients scheduled for elective transfemoral PCI with either drug‐eluting or bare metal stents at the UCLA Medical Center who received 40 IU/kg of heparin were included. Patients were excluded from the study if there was a history of heparin‐induced thrombocytopenia, bleeding diathesis, coagulopathy (international normalized ratio >1.5), or thrombocytopenia (platelet count less than 50,000 cells per cubic millimeter). Approval of the Institutional Review Board was obtained to review the data for this study. PCI was performed via the femoral approach according to standard procedures. After 40 IU/kg of heparin was administered intra‐arterially through the sheath, activating clotting time was measured with a Hemochron system after 5 minutes. Aspirin 325 mg and clopidogrel 600 mg were administered before the procedure or just after diagnostic angiography and continued for at least 1 month for bare metal stents and 1 year for drug‐eluting stents. A bolus dose of glycoprotein IIb/IIIa inhibitors was administered at the discretion of the operator. A vascular closure device was used whenever feasible. The primary end‐point was the composite of cardiac death, myocardial infarction, urgent target vessel revascularization for ischemia, or major bleeding. Myocardial infarction was defined as the development of pathologic Q waves (30 milliseconds in duration and 0.1 mV in depth) in 2 or more contiguous precordial leads or 2 or more adjacent limb leads, or an elevation of creatine kinase‐MB isoenzyme levels (or total creatine kinase if measures of CK‐MB were not available) to at least 2 times the upper limit of the normal range.13 Urgent target vessel revascularization was defined as coronary artery bypass surgery or repeat PCI due to myocardial ischemia within 30 days after index revascularization. Major bleeding was defined as intracranial, intraocular, or retroperitoneal hemorrhage; clinically overt blood loss resulting in a decrease in hemoglobin of more than 3 g/dL; any decrease in
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hemoglobin of more than 4 g/dL; or transfusion of 2 or more units of packed red cells or whole blood.14 Stent thrombosis was defined according to the Academic Research Consortium criteria.15 Hemoglobin and platelet count were measured on the day of PCI. Profound thrombocytopenia was defined as a platelet count of less than 20,000 cells per cubic millimeter. Patient data were collected from medical records, and adverse clinical events were recorded into a dedicated PCI database. Continuous variables are presented as mean SD, and categorical variables are presented as percentages. Statistical analysis was performed with SAS software (version 9.1, SAS Institute, Inc., Cary, NC, USA).
Results Baseline Characteristics. Baseline characteristics of the 300 patients are summarized in Table 1. The mean age was 62.9 14.3 years. Procedural characteristics are listed in Table 2. The mean activating clotting time obtained 5 minutes after heparin was administered was 233 28 seconds. Patients were pretreated with clopidogrel prior to diagnostic coronary angiography in 38% of cases. Vascular closure devices were used in 93%. Clinical Outcomes at 30 Days. There was no death, stent thrombosis, or major bleeding in the cardiac catheterization laboratory (Table 3). A 77‐year‐ old female had a spiral dissection of the right coronary artery after predilatation with a 2.0‐mm balloon. This was subsequently treated with multiple stents. The primary end‐point occurred in 2.3%. Cardiac death occurred in 1 patient (0.3%). A 76‐year‐old female died suddenly 17 days after PCI of the left anterior
Table 1. Baseline Clinical Characteristics Number of patients Age (years) Male gender, n (%) Diabetes mellitus, n (%) Body weight (kg) Hypertension, n (%) Hypercholesterolemia, n (%) Prior stroke, n (%) Previous myocardial infarction, n (%) Previous percutaneous coronary intervention, n (%) Previous coronary artery bypass surgery, n (%) Left ventricular ejection fraction (%)
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300 63 14 212 (71) 81 (27) 78 18 190 (63) 177 (59) 38 (13) 69 (23) 85 (28) 31 (10) 51 15
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LEE, ET AL. Table 2. Procedural Characteristics 233 28 113 (38)
Mean activating clotting time (seconds) Patients treated with pre‐clopidogrel, n (%) Target vessel, n (%) Left main coronary artery Left anterior descending artery Left circumflex artery Right coronary artery Saphenous vein graft Type of stent, n (%) Drug‐eluting stent Bare metal stent Stents per case Vessels treated Intravascular ultrasound, n (%) Bail‐out use of GP IIb/IIIa inhibitors, n (%) Final TIMI flow, n (%) 0–1% 2% 3% French size, n (%) 6F 7F 8F Modality of hemostasis, n (%) Vascular closure device Manual
10 (3) 108 (36) 90 (30) 102 (34) 4 (1) 220 (73) 86 (29) 1.4 0.7 1.1 0.2 185 (62) 7 (2) 0 0 300 (100) 285 (95) 1 (0.3) 14 (5) 278 (93) 22 (7)
diagonal branch that was treated with balloon angioplasty. The major bleeding rate was 0.3%. A 56‐year‐old male with a history of orthotopic heart transplantation had severe transplant coronary artery disease with a chronic total occlusion of the left anterior descending artery and left circumflex artery as well as severe left ventricular dysfunction. After PCI of the right coronary artery, a vascular closure device was not deployed because the location of the arteriotomy was in the superficial femoral artery. The 7F sheath was pulled and hemostasis was obtained with manual compression. Later that evening, the patient developed a pseudoaneurysm that ruptured, leading to hemorrhagic shock and hemodynamic collapse, had cardiac arrest, and subsequently expired within 24 hours of the PCI. Another access site complication occurred in a 59‐year‐ old male who developed a small pseudoaneurysm. It was treated conservatively and resolved with manual compression. There was no intracranial, retroperitoneal, pericardial, gastrointestinal, or urogenital hemorrhage. No patients developed profound thrombo- cytopenia. No acute or subacute stent thrombosis occurred.
Discussion descending artery. Autopsy demonstrated a thrombotic occlusion of the left circumflex artery and a widely patent stent in the left anterior descending artery. The myocardial infarction rate was 1.3%. Urgent target vessel revascularization occurred in 1 patient (0.3%). After PCI of the left anterior descending artery, the patient complained of severe chest pain. Repeat coronary angiography revealed compromise of the Table 3. Clinical Events at 30 Days Cardiac death, myocardial infarction, target vessel revascularization, and bleeding, n (%) Cardiac death, myocardial infarction, target vessel revascularization, n (%) Cardiac death, n (%) Myocardial infarction, n (%) Urgent target vessel revascularization, n (%) Bleeding complications, n (%) Intracranial bleeding Retroperitoneal bleeding Hemoglobin decrease 3 g/dL with overt source Hemoglobin decrease 4 g/dL without overt source Blood transfusion Guide catheter thrombosis, n (%) Stent thrombosis, n (%)
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7 (2) 7 (2) 1 4 1 1 0 0 1 0 1 0 0
(0.3) (1) (0.3) (0.3) (0) (0) (0.3) (0) (0.3) (0) (0)
In this prospective single‐center study of elective transfemoral PCI, low‐dose heparin was associated with low ischemic and bleeding complications at 30 days. No patient experienced stent thrombosis. Major bleeding after PCI is a predictor of ischemic events and mortality.10,11,12,16 Various strategies including technique and adjunctive pharmacotherapy have been used to minimize the risk of bleeding. Transradial intervention decreases the risk of major bleeding compared with transfemoral intervention in ST‐elevation myocardial infarction.17 However, the dose of heparin used in the study was 105 IU/kg, and 45% of patients received glycoprotein IIb/IIIa inhibitors. Bivalirudin is a direct thrombin inhibitor that is commonly used instead of heparin during PCI. In the Intracoronary Stenting and Antithrombotic Regimen Rapid Early Action for Coronary Treatment (ISAR‐ REACT) 3 trial, patients with stable or unstable angina who underwent PCI had less major bleeding and similar clinical outcomes with bivalirudin compared to heparin after pretreatment with clopidogrel.13 When compared with 60–65 IU/kg of heparin plus glycoprotein IIb/IIIa inhibitors, bivalirudin has been shown to provide similar suppression of ischemia in patients who
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LOW‐DOSE HEPARIN IN PCI
undergo PCI for stable angina and non‐ST‐segment elevation acute coronary syndromes but less major bleeding.14,18 In ST‐segment elevation myocardial infarction, bivalirudin was also associated with lower mortality and periprocedural bleeding compared with 60 IU/kg of heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing primary PCI.19 However, planned glycoprotein IIb/IIIa inhibition is not routinely used in contemporary practice, especially in elective PCI, and the increased bleeding in the heparin groups may have been related to the use of glycoprotein IIb/ IIIa inhibitors. Another strategy to reduce the risk of bleeding complications after PCI is using lower doses of heparin. Achieving low rates of bleeding and thrombosis is a tight balancing act. The ideal dosing regimen for heparin to prevent ischemic and hemorrhagic complications remains unclear. Current guidelines are largely based on older studies, many of which predated the widespread use of P2Y12 inhibitors, and therefore required larger doses of anticoagulation. Various dosing regimens have been studied before, ranging from no heparin to high‐dose heparin. The Coronary Interventions Antiplatelet‐based Only (CIAO) trial demonstrated that elective PCI can be performed safely and effectively without heparin if patients are pretreated with dual antiplatelet therapy.20 However, PCI was performed only in simple uncomplicated lesions. A prospective registry of 418 patients who underwent PCI with 30 IU/kg of heparin reported a 2.9% rate of in‐ hospital death, MI, or repeat revascularization at 1 month.21 Serious vascular complication requiring a blood transfusion and surgical repair only occurred in 1 patient (0.24%). The average dose of heparin was 2,253 IU, and the final ACT was 174 seconds. Most of these patients were not pretreated with dual antiplatelet therapy. In the ISAR‐REACT 3 trial, patients with stable or unstable angina who underwent PCI with 140 IU/kg of heparin had similar composite end‐point of death, myocardial infarction, urgent target vessel revascularization, or major bleeding as compared to those treated with bivalirudin after pretreatment with clopidogrel.13 However, the incidence of major bleeding was higher with heparin, though this may be explained by the high bolus dose of heparin. The ISAR‐REACT 3A trial was a follow‐up study where 100 IU/kg of heparin was utilized after clopidogrel pretreatment in biomarker negative patients undergoing PCI and reported a net clinical benefit when compared with the ISAR‐REACT patients as a
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historical control.22 Additionally, the lower heparin dose met the criterion for noninferiority when compared with the historical bivalirudin arm. As the optimal dosing regimen for heparin continues to be refined in elective PCI, our data demonstrate that low‐dose heparin provided excellent protection from bleeding complications without an increase in ischemic events. Our bleeding rates were low and compared favorably with other studies. The lower dose of heparin may decrease the rate of bleeding and provide bleeding rates comparable to PCI with bivalirudin. One major benefit of heparin is that it is much less expensive compared with bivalirudin.23 A study utilizing the results of ISAR‐REACT 3 to generate a cost prediction model demonstrated increased costs associated with the use of bivalirudin in all but a minority of patients at high risk for bleeding.24 The use of low‐dose heparin regimens may be cost‐effective compared with using bivalirudin (approximately $400 to $500 per PCI compared with $10 for heparin) while reducing hemorrhagic complications and maintaining adequate protection against ischemic events. Stent thrombosis did not occur with low‐dose heparin. The loading dose of clopidogrel used in our study was 600 mg. The higher loading dose of clopidogrel may have offset the potential increased risk of ischemic events with a lower dose of heparin. Because heparin activates platelets, lower heparin doses and heightened inhibition of platelets may explain the excellent protection from ischemic events. Study Limitations. This was a nonrandomized study from a single center with a small number of patients. These results need to be validated in a randomized trial. Unlike other trials with low‐dose or no heparin, not all patients were pretreated with dual antiplatelet therapy prior to PCI. Because the ACTs were measured with the Hemochron system, ACTs drawn with the Hemotec system need to be validated. Postprocedural cardiac biomarkers and platelet counts were not drawn on all patients. Therefore, the rate of occult biomarker elevation and thrombocytopenia is unknown. These results cannot be applied to patients with ST‐elevation myocardial infarction where the thrombotic milieu is high and requires higher levels of anticoagulation. PCI was relatively simple with a mean of 1.4 stents used per case. PCI with low‐dose heparin may not be applicable to complex, multivessel PCI. IVUS was used in 62% of cases. Therefore, the results of this study may not reflect “real‐world” practice.
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Conclusion 11.
Elective PCI with low‐dose heparin via the transfemoral route is feasible, safe, and is associated with low ischemic and bleeding complications. This may represent a cost‐saving strategy as compared with bivalirudin with no increase in adverse clinical outcomes. A large‐scale, randomized clinical trial comparing low‐dose heparin with bivalirudin or low‐ molecular weight heparin in patients is required to determine the optimal anticoagulation strategy.
12.
13. 14.
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