Risk of Bleeding after Elective Percutaneous Coronary Intervention
http://www.100md.com
《新英格兰医药杂志》
About 2.2 million percutaneous coronary interventions (PCIs) were performed worldwide in 2004 (Mead D: personal communication). Success rates of more than 97%, mortality rates of less than 0.5%, and rates of emergency bypass surgery of less than 0.5% can be anticipated with elective procedures. Major obstacles initially confronting the field — including the inability to reach complex or tortuous lesions, to cross lesions, and to dilate lesions, as well as bifurcation disease, occlusive dissection, and abrupt closure — have largely been overcome. Restenosis has been markedly reduced with the advent of drug-eluting stents.1
As the technical obstacles to safe, effective, and sustained coronary dilatation are overcome, attention is focusing on the remaining safety issues. One of the most important risks associated with PCI is the risk of bleeding after the procedure. Major bleeding has been reported in 7% of cases of PCI for unstable angina in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial2 and in 4% of elective cases in which unfractionated heparin was used in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial.3 This complication costs in excess of $10,000 per event,4 adding an average of $400 to the cost of each PCI.5 In addition to the economic cost, the length of stay of the patient in the hospital is prolonged, the incidence of ancillary diagnostic testing is increased, and reparative surgical procedures are frequently required.
Blood loss most often occurs at the femoral access site. Percutaneous access is achieved by means of fluoroscopic visualization of bony landmarks and is guided by palpation of the femoral pulse. This technique has not changed since the inception of angioplasty. Since arterial access is largely a blind procedure, anatomical variation, obesity, and incorrect needle positioning can all lead to perivascular hematoma, arteriovenous fistula, arterial pseudoaneurysm, rectus-sheath hematoma, or retroperitoneal hemorrhage. In addition to the anatomical factors that enhance the risk of bleeding, systemic anticoagulation further increases the risks of perivascular and systemic bleeding.
As a result of bleeding, rates of blood transfusion as high as 16% have been reported in major trials.2 Transfusion carries the inherent risk of transmission of blood-borne illnesses and has been shown to increase mortality rates after PCI. Increased mortality rates after transfusion have been reported during procedures performed for acute myocardial infarction,6 during acute coronary syndrome,7 and during elective procedures.8 Thus, transfusion has adverse economic effects, results in prolonged and complicated admissions, and is associated with an increased mortality rate.
In this issue of the Journal, Montalescot et al.9 address the effect of anticoagulation on the risk of bleeding after elective PCI. The authors describe a well-designed, open-label, randomized trial of intravenous unfractionated heparin, as compared with two doses of intravenous enoxaparin (0.5 mg per kilogram and 0.75 mg per kilogram). Elective PCI was performed in a setting of oral aspirin and thienopyridine therapy. About 40% of patients received intravenous glycoprotein IIb/IIIa inhibitors. The population studied was at low risk for ischemic and bleeding complications. With regard to their primary end point, the incidence of major or minor bleeding not related to coronary-artery bypass grafting, the authors concluded that the 0.5-mg dose of enoxaparin is superior to the higher dose and to unfractionated heparin.
Several aspects of the results require comment. The most troubling aspect is the fact that the independent data-monitoring committee recommended the termination of the 0.5-mg dose of enoxaparin late in the course of the trial. This recommendation was based on a significantly higher mortality rate among patients receiving this dose than among those receiving the 0.75-mg dose. Montalescot et al. downplayed the committee recommendations, and in fact, in the data reported no significant difference was found in the 30-day mortality rate between the group receiving 0.5 mg of enoxaparin per kilogram and either the higher-dose enoxaparin group or the heparin group. However, the causes of death for patients receiving the 0.5-mg dose of enoxaparin are troubling. Of the 10 deaths, 4 were considered treatment-related; of these, 2 were attributed to thrombosis and 2 to bleeding. In addition, three fatal hemorrhages occurred in the 0.5-mg enoxaparin group, whereas none occurred in the other two groups. Thus, at least half the deaths in the low-dose enoxaparin group were potentially related to the therapy and not to chance. Had two more deaths not occurred in the group receiving unfractionated heparin, the mortality rate would have been significantly increased in the 0.5-mg enoxaparin group. The overall mortality rate of 1.0% in the 0.5-mg enoxaparin group is twice that expected for patients undergoing elective PCI, especially patients at low risk for complications. These observations must be taken in context with the clotting of the catheter, thrombotic occlusion in the coronary artery, and stroke that have been reported among patients receiving 0.5 mg of enoxaparin per kilogram.10,11 Refractory clotting of the catheter, involving the propagation of intracoronary clots, is an alarming complication of subcutaneous enoxaparin therapy.12
In addition to this troubling safety concern, a brief comment on the primary efficacy end point is required. Montalescot et al. used unique definitions of major and minor bleeding. Theirs is at least the fourth scale of bleeding severity described in published studies of PCI, and it has not been previously shown to have prognostic value. When the authors used the standard TIMI (Thrombolysis in Myocardial Infarction) index, they found no significant difference in rates of major or minor bleeding between either enoxaparin group or the heparin group. With the use of the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) index, the 0.5-mg dose of enoxaparin resulted in a lower risk of bleeding than did unfractionated heparin. It appears that results vary depending on the bleeding index used. The field could be dramatically advanced if one standard, uniformly applied measurement of the risk of bleeding after PCI were adopted.
According to the authors, a major advantage of the use of enoxaparin is that anticoagulation levels need not be measured. However, wide variation in anti–factor Xa levels has been reported for the 0.5-mg enoxaparin dose.10,11 In the study with the lowest anti–factor Xa levels,10 a troubling incidence of thrombotic complications occurred. Furthermore, from a safety standpoint, the requirement of routine monitoring of anticoagulation levels during PCI is a potent reminder to nursing personnel and to the clinician to administer an anticoagulant before the procedure.
How, then, can we use the study by Montalescot et al. to improve the safety of elective PCI? On balance, the 0.75-mg dose of enoxaparin appears to be a safe alternative to weight-adjusted unfractionated heparin for elective PCI. Before the 0.5-mg dose of enoxaparin can be considered safe and effective, much larger numbers of patients need to be studied. Industry, investigators, and the Food and Drug Administration could cooperate to systematically collect outcome data on a large number of patients from well-designed registries. In the future, to make a safe procedure even safer, comparisons of unfractionated heparin with bivalirudin,3 fondaparinux,13 or even no antithrombin therapy14 should continue to focus on reducing the risk of bleeding during PCI.
Dr. O'Neill reports receiving grant support from Pfizer. No other potential conflict of interest relevant to this article was reported.
Source Information
From the University of Miami School of Medicine, Miami.
References
Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-1323.
Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.
Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-863.
Milkovich G, Gibson G. Economic impact of bleeding complications and the role of antithrombotic therapies in percutaneous coronary intervention. Am J Health Syst Pharm 2003;60:Suppl 3:S15-S21.
Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004;44:1792-1800.
Nikolsky E, Aymong ED, Halkin A, et al. Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial. J Am Coll Cardiol 2004;44:547-553.
Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-1562.
Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930-935.
Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006-1017.
Zalc S, Lemos PA, Esteves A, et al. Early ambulation and variability in anticoagulation during elective coronary stenting with a single intravenous bolus of low-dose, low-molecular-weight heparin enoxaparin. J Invasive Cardiol 2006;18:45-48.
Chen JL, Chen J, Qiao SB, et al. A randomized comparative study of using enoxaparin instead of unfractionated heparin in the intervention treatment of coronary heart disease. Chin Med J (Engl) 2006;119:355-359.
Buller CE, Pate GE, Armstrong PW, et al. Catheter thrombosis during primary percutaneous coronary intervention for acute ST elevation myocardial infarction despite subcutaneous low-molecular-weight heparin, acetylsalicylic acid, clopidogrel and abciximab pretreatment. Can J Cardiol 2006;22:511-515.
Mehta SR, Steg PG, Granger CB, et al. Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation (ASPIRE) Pilot Trial. Circulation 2005;111:1390-1397.
Denardo SJ, Davis KE, Tcheng JE. Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy. Am Heart J 2005;149:138-144.(William W. O'Neill, M.D.)
As the technical obstacles to safe, effective, and sustained coronary dilatation are overcome, attention is focusing on the remaining safety issues. One of the most important risks associated with PCI is the risk of bleeding after the procedure. Major bleeding has been reported in 7% of cases of PCI for unstable angina in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial2 and in 4% of elective cases in which unfractionated heparin was used in the Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) trial.3 This complication costs in excess of $10,000 per event,4 adding an average of $400 to the cost of each PCI.5 In addition to the economic cost, the length of stay of the patient in the hospital is prolonged, the incidence of ancillary diagnostic testing is increased, and reparative surgical procedures are frequently required.
Blood loss most often occurs at the femoral access site. Percutaneous access is achieved by means of fluoroscopic visualization of bony landmarks and is guided by palpation of the femoral pulse. This technique has not changed since the inception of angioplasty. Since arterial access is largely a blind procedure, anatomical variation, obesity, and incorrect needle positioning can all lead to perivascular hematoma, arteriovenous fistula, arterial pseudoaneurysm, rectus-sheath hematoma, or retroperitoneal hemorrhage. In addition to the anatomical factors that enhance the risk of bleeding, systemic anticoagulation further increases the risks of perivascular and systemic bleeding.
As a result of bleeding, rates of blood transfusion as high as 16% have been reported in major trials.2 Transfusion carries the inherent risk of transmission of blood-borne illnesses and has been shown to increase mortality rates after PCI. Increased mortality rates after transfusion have been reported during procedures performed for acute myocardial infarction,6 during acute coronary syndrome,7 and during elective procedures.8 Thus, transfusion has adverse economic effects, results in prolonged and complicated admissions, and is associated with an increased mortality rate.
In this issue of the Journal, Montalescot et al.9 address the effect of anticoagulation on the risk of bleeding after elective PCI. The authors describe a well-designed, open-label, randomized trial of intravenous unfractionated heparin, as compared with two doses of intravenous enoxaparin (0.5 mg per kilogram and 0.75 mg per kilogram). Elective PCI was performed in a setting of oral aspirin and thienopyridine therapy. About 40% of patients received intravenous glycoprotein IIb/IIIa inhibitors. The population studied was at low risk for ischemic and bleeding complications. With regard to their primary end point, the incidence of major or minor bleeding not related to coronary-artery bypass grafting, the authors concluded that the 0.5-mg dose of enoxaparin is superior to the higher dose and to unfractionated heparin.
Several aspects of the results require comment. The most troubling aspect is the fact that the independent data-monitoring committee recommended the termination of the 0.5-mg dose of enoxaparin late in the course of the trial. This recommendation was based on a significantly higher mortality rate among patients receiving this dose than among those receiving the 0.75-mg dose. Montalescot et al. downplayed the committee recommendations, and in fact, in the data reported no significant difference was found in the 30-day mortality rate between the group receiving 0.5 mg of enoxaparin per kilogram and either the higher-dose enoxaparin group or the heparin group. However, the causes of death for patients receiving the 0.5-mg dose of enoxaparin are troubling. Of the 10 deaths, 4 were considered treatment-related; of these, 2 were attributed to thrombosis and 2 to bleeding. In addition, three fatal hemorrhages occurred in the 0.5-mg enoxaparin group, whereas none occurred in the other two groups. Thus, at least half the deaths in the low-dose enoxaparin group were potentially related to the therapy and not to chance. Had two more deaths not occurred in the group receiving unfractionated heparin, the mortality rate would have been significantly increased in the 0.5-mg enoxaparin group. The overall mortality rate of 1.0% in the 0.5-mg enoxaparin group is twice that expected for patients undergoing elective PCI, especially patients at low risk for complications. These observations must be taken in context with the clotting of the catheter, thrombotic occlusion in the coronary artery, and stroke that have been reported among patients receiving 0.5 mg of enoxaparin per kilogram.10,11 Refractory clotting of the catheter, involving the propagation of intracoronary clots, is an alarming complication of subcutaneous enoxaparin therapy.12
In addition to this troubling safety concern, a brief comment on the primary efficacy end point is required. Montalescot et al. used unique definitions of major and minor bleeding. Theirs is at least the fourth scale of bleeding severity described in published studies of PCI, and it has not been previously shown to have prognostic value. When the authors used the standard TIMI (Thrombolysis in Myocardial Infarction) index, they found no significant difference in rates of major or minor bleeding between either enoxaparin group or the heparin group. With the use of the GUSTO (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) index, the 0.5-mg dose of enoxaparin resulted in a lower risk of bleeding than did unfractionated heparin. It appears that results vary depending on the bleeding index used. The field could be dramatically advanced if one standard, uniformly applied measurement of the risk of bleeding after PCI were adopted.
According to the authors, a major advantage of the use of enoxaparin is that anticoagulation levels need not be measured. However, wide variation in anti–factor Xa levels has been reported for the 0.5-mg enoxaparin dose.10,11 In the study with the lowest anti–factor Xa levels,10 a troubling incidence of thrombotic complications occurred. Furthermore, from a safety standpoint, the requirement of routine monitoring of anticoagulation levels during PCI is a potent reminder to nursing personnel and to the clinician to administer an anticoagulant before the procedure.
How, then, can we use the study by Montalescot et al. to improve the safety of elective PCI? On balance, the 0.75-mg dose of enoxaparin appears to be a safe alternative to weight-adjusted unfractionated heparin for elective PCI. Before the 0.5-mg dose of enoxaparin can be considered safe and effective, much larger numbers of patients need to be studied. Industry, investigators, and the Food and Drug Administration could cooperate to systematically collect outcome data on a large number of patients from well-designed registries. In the future, to make a safe procedure even safer, comparisons of unfractionated heparin with bivalirudin,3 fondaparinux,13 or even no antithrombin therapy14 should continue to focus on reducing the risk of bleeding during PCI.
Dr. O'Neill reports receiving grant support from Pfizer. No other potential conflict of interest relevant to this article was reported.
Source Information
From the University of Miami School of Medicine, Miami.
References
Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315-1323.
Ferguson JJ, Califf RM, Antman EM, et al. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45-54.
Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-863.
Milkovich G, Gibson G. Economic impact of bleeding complications and the role of antithrombotic therapies in percutaneous coronary intervention. Am J Health Syst Pharm 2003;60:Suppl 3:S15-S21.
Cohen DJ, Lincoff AM, Lavelle TA, et al. Economic evaluation of bivalirudin with provisional glycoprotein IIb/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 2004;44:1792-1800.
Nikolsky E, Aymong ED, Halkin A, et al. Impact of anemia in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention: analysis from the Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) Trial. J Am Coll Cardiol 2004;44:547-553.
Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA 2004;292:1555-1562.
Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003;92:930-935.
Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med 2006;355:1006-1017.
Zalc S, Lemos PA, Esteves A, et al. Early ambulation and variability in anticoagulation during elective coronary stenting with a single intravenous bolus of low-dose, low-molecular-weight heparin enoxaparin. J Invasive Cardiol 2006;18:45-48.
Chen JL, Chen J, Qiao SB, et al. A randomized comparative study of using enoxaparin instead of unfractionated heparin in the intervention treatment of coronary heart disease. Chin Med J (Engl) 2006;119:355-359.
Buller CE, Pate GE, Armstrong PW, et al. Catheter thrombosis during primary percutaneous coronary intervention for acute ST elevation myocardial infarction despite subcutaneous low-molecular-weight heparin, acetylsalicylic acid, clopidogrel and abciximab pretreatment. Can J Cardiol 2006;22:511-515.
Mehta SR, Steg PG, Granger CB, et al. Randomized, blinded trial comparing fondaparinux with unfractionated heparin in patients undergoing contemporary percutaneous coronary intervention: Arixtra Study in Percutaneous Coronary Intervention: a Randomized Evaluation (ASPIRE) Pilot Trial. Circulation 2005;111:1390-1397.
Denardo SJ, Davis KE, Tcheng JE. Elective percutaneous coronary intervention using broad-spectrum antiplatelet therapy (eptifibatide, clopidogrel, and aspirin) alone, without scheduled unfractionated heparin or other antithrombin therapy. Am Heart J 2005;149:138-144.(William W. O'Neill, M.D.)