EDITORIAL COMMENT
Coronary Intervention Without a Safety Net*
Harold L. Dauerman, MD, FACC*
University of Vermont College of Medicine, Burlington, Vermont
* Reprint requests and correspondence: Dr. Harold L. Dauerman, Cardiac Unit, McClure 1, Fletcher Allen Health Care, 111 Colchester Avenue, Burlington, Vermont 05401 (Email: harold.dauerman{at}vtmednet.org).
Key Words: pharmacology • bleeding • percutaneous coronary intervention
The words "randomized clinical trial" may seem to present an unassailable truth (1). In this issue of the Journal, Stabile et al. (2) present the CIAO (Coronary Interventions Antiplatelet-based Only) randomized clinical trial with the following abstract conclusion: "In the treatment of uncomplicated lesions and in the presence of dual antiplatelet therapy, elective percutaneous coronary intervention (PCI) can be safely performed without systemic anticoagulation and is associated with a reduced incidence of bleeding complications." The authors are to be congratulated for examining a new PCI pharmacology regimen in a randomized clinical trial. But despite the randomized examination and thought-provoking conclusion, might there be a significant clinical risk in abandoning the time-tested approach of combined antiplatelet and antithrombotic therapy for elective PCI?
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Pathophysiology of elective percutaneous coronary intervention
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The CIAO trial randomly allocated 700 patients undergoing elective PCI to dual oral antiplatelet therapy versus dual oral antiplatelet therapy plus unfractionated heparin: major adverse cardiovascular events were similar at 30 days (3.7% vs. 2.0%, p = 0.17 for control group vs. no heparin group). One interpretation of the CIAO trial is that thrombus generation is not a critical component of elective PCI, and thus intravenous antithrombotic therapy is not needed. Thrombus presence and generation is critical in the setting of PCI for acute coronary syndromes: angioscopy and intravascular ultrasonography have demonstrated thrombus and/or plaque rupture in more than two-thirds of patients with acute coronary syndromes (3,4). As seen in the acute coronary syndrome patients of the OASIS (Optimal Antiplatelet Strategy for Interventions)-5 trial and the WEST (Which Early ST-Elevation Myocardial Infarction Therapy) trial, inadequate thrombin inhibition with fondaparinux and enoxaparin during the PCI procedure led to catheter thrombus and a need for supplemental unfractionated heparin (5,6).
But elective PCI has a potential thrombotic component as well. In angioscopy studies of patients presenting with stable angina, intracoronary thrombus may be seen in 17% to 65% of patients (3,7). Similarly, complex plaque rupture may be found in 19% to 35% of patients with stable angina undergoing elective PCI (4,8). Furthermore, stenting itself generates early thrombotic and inflammatory responses (9,10). Thus, pre-existing thrombus, thrombus generation, platelet activation, and systemic inflammation are part of all PCI procedures, and the designation "elective" lessens but does not eliminate the consequences of this pathophysiology.
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Pharmacology of elective coronary intervention
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If the pathophysiology of elective PCI may still involve thrombus, then the CIAO trial challenges us to accept a new therapeutic paradigm: potent inhibition of platelet activation and aggregation will decrease thrombin generation so profoundly that any form of intravenous antithrombin therapy is obviated. This concept is supported by 1 single-center registry and the randomized REMOVE (Reduction in Major and Minor Adverse Events With Eptifibatide-Based Pharmacotherapy in Percutaneous Coronary Intervention) clinical trial (n = 180) in which elective PCI was performed with aspirin, clopidogrel, and glycoprotein IIb/IIIa inhibitors with no significant increased risk of ischemic events as compared with patients who also received unfractionated heparin (11,12). Similarly, recent analyses of stent trials have challenged the prior assumptions on heparin dosing (13) and have not clearly identified a lower limit for activated clotting time (14). But the CIAO trial takes us to an extreme never before examined: it states that we do not even need a potent glycoprotein receptor inhibitor to indirectly suppress thrombin generation. Rather, aspirin and thienopyridine alone can prevent pre-existing, contact- and stent-mediated thrombus formation from generating ischemic complications. This hypothesis is put forward even in the setting of significant known variations in individual responsiveness to oral antiplatelet therapy (15).
This is a concerning hypothesis. First, the protocol of the REMOVE trial had to be amended because of spontaneous thrombus formation during elective bifurcation lesion PCI (despite use of a glycoprotein receptor inhibitor), suggesting a pre-existing recognition of clinical risk in the "no antithrombin" approach (12). Second, the investigators appropriately recognized that there would be a low ischemic complication rate (2.5%) in the selected elective PCI population. But, the upper margin for defining noninferiority in the CIAO trial is more than double the event rate for the control group—thus, one could have a 5.4% ischemic complication rate in the tested group and a 2.5% rate in the heparin group and still meet noninferiority criteria.
The upper margin to define noninferiority in other PCI pharmacology trials is usually in the range of 25% to 50% higher than the point estimate for the event in the control group (16). The CIAO trial's liberal definition of noninferiority has a basis in reality: to do a noninferiority trial with an ischemic complication rate of 2.5% and an upper margin 25% higher than the control group, one would have to randomize more than 30,000 patients to prove aspirin/clopidigrel alone regimens are noninferior to aspirin/clopidogrel/heparin-based regimens.
Finally, was the tested group (aspirin/clopidogrel alone) superior to the control group (aspirin/clopidogrel/heparin)? The potential benefits of removing heparin from elective PCI are real: for example, unfractionated heparin is a first-generation antithrombin that may activate platelets (17), be contaminated (18), or increase bleeding complications (19). Although reduction of bleeding complications has clear merit (20), it is not clear that the CIAO trial demonstrates a consistent reduction in bleeding complications. Similar to the REMOVE trial, a clear reduction in Thrombolysis In Myocardial Infarction major or minor bleeding was not seen. Although other definitions suggest a bleeding reduction is possible, it does not reach the significance or consistency of bleeding reduction seen in comparing newer antithrombin agents to heparin-based regimens (5,16).
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Applying randomized clinical trials to PCI pharmacology choices
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Bleeding complications are related to early and 1-year mortality (21). Thus, attempts to decrease bleeding complications with better access techniques, arterial management strategies, and improved PCI pharmacology are laudable. If one believes that the CIAO trial does demonstrate bleeding reduction with removal of the coronary intervention safety net, how would one apply these findings to everyday clinical practice? The Northern New England Cardiovascular Consortium estimates that approximately 20% of all PCI fit the "elective" category (W. Piper and D. J. Malenka, personal communication, June 2, 2006). Thus, first, we must apply these results to only the 20% of patients undergoing a elective PCI; second, we must read their Methods section and similarly exclude elective PCI patients with angiographic high-risk characteristics such as calcification, long lesions, thrombus, small vessels, bifurcation lesions, and vein graft lesions that might lengthen procedure time to longer than the 11-min average seen in this study. One may estimate that approximately 50% of elective PCI patients would have been angiographically excluded from trials such as the CIAO and REMOVE trials, and so we may be left with a new PCI pharmacology paradigm that would apply to only 10% of our PCI population.
The history of interventional cardiology is one of applying new medications and technologies beyond the description of the clinical trials (22). Whereas that may be benign in some situations, the application of a "no antithrombin" approach to higher risk PCI may be potentially life threatening. Thus, we can applaud the researchers of the CIAO trial for pushing the boundaries of elective PCI pharmacology to new levels of minimalism in the valid hope of reducing bleeding complications; the reader, though, should heed the investigators' valid and important conclusion that "this paper is not intended to provide false reassurance. . . ." And, before we apply a "no antithrombin" approach to a minority of PCI patients in future randomized clinical trials, we may want to consider the relatively similar pathophysiology of both elective and urgent coronary interventions and instead pursue the goal of replacing flawed first-generation antithrombins with better and safer antithrombin therapy.
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Footnotes
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Dr. Dauerman is on the steering committee for the CHAMPION PCI (Cangrelor versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition, Percutaneous Coronary Intervention) trial and is a consultant to The Medicines Company.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. DeMaria AN. Clinical trials and clinical judgment J Am Coll Cardiol 2008;51:1120-1122.[Free Full Text]2. 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.[Abstract/Free Full Text] 3. de Feyter PJ, Ozaki Y, Baptista J, et al. Ischemia-related lesion characteristics in patients with stable or unstable angina. A study with intracoronary angioscopy and ultrasound. Circulation 1995;92:1408-1413.[Abstract/Free Full Text] 4. Hong MK, Mintz GS, Lee CW, et al. Comparison of coronary plaque rupture between stable angina and acute myocardial infarction: a three-vessel intravascular ultrasound study in 235 patients Circulation 2004;110:928-933.[Abstract/Free Full Text] 5. Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes N Engl J Med 2006;354:1464-1476.[Abstract/Free Full Text] 6. 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.[Web of Science][Medline] 7. Hopp HW, Karabacak S, Stoll R, Karasch T, Franzen D. Intracoronary thrombi in stable angina: observations with angioscopy Catheter Cardiovasc Interv 2000;51:18-19.[CrossRef][Web of Science][Medline] 8. Mintz GS, Maehara A, Bui AB, Weissman NJ. Multiple versus single coronary plaque ruptures detected by intravascular ultrasound in stable and unstable angina pectoris and in acute myocardial infarction Am J Cardiol 2003;91:1333-1335.[CrossRef][Web of Science][Medline] 9. Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans Circulation 1999;99:44-52.[Abstract/Free Full Text] 10. Aggarwal A, Schneider DJ, Terrien EF, Terrien Jr. CM, Sobel BE, Dauerman HL. Comparison of effects of abciximab versus eptifibatide on C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist after coronary arterial stenting Am J Cardiol 2003;91:1346-1349.[CrossRef][Web of Science][Medline] 11. 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.[CrossRef][Web of Science][Medline] 12. Valencia R, Price MJ, Sawhney N, et al. Efficacy and safety of triple antiplatelet therapy with and without concomitant anticoagulation during elective percutaneous coronary intervention (the REMOVE trial) Am J Cardiol 2007;100:1099-1102.[CrossRef][Web of Science][Medline] 13. 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.[Abstract/Free Full Text] 14. Brener SJ, Moliterno DJ, Lincoff AM, Steinhubl SR, Wolski KE, Topol EJ. Relationship between activated clotting time and ischemic or hemorrhagic complications: analysis of 4 recent randomized clinical trials of percutaneous coronary intervention Circulation 2004;110:994-998.[Abstract/Free Full Text] 15. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurrent events post-stenting: results of the PREPARE POST-STENTING study J Am Coll Cardiol 2005;46:1820-1826.[Abstract/Free Full Text] 16. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes N Engl J Med 2006;355:2203-2216.[Abstract/Free Full Text] 17. Xiao Z, Theroux P. Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor Circulation 1998;97:251-256.[Abstract/Free Full Text] 18. Kishimoto TK, Viswanathan K, Ganguly T, et al. Contaminated heparin associated with adverse clinical events and activation of the contact system N Engl J Med 2008;358:2457-2467.[Abstract/Free Full Text] 19. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: final report reanalysis of the Bivalirudin Angioplasty Study Am Heart J 2001;142:952-959.[CrossRef][Web of Science][Medline] 20. Dauerman HL. Percutaneous coronary intervention pharmacology: from a triangle to a square J Am Coll Cardiol 2008;51:698-700.[Free Full Text] 21. 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.[Abstract/Free Full Text] 22. Gogo Jr. PB, Dauerman HL, Mulgund J, et al. Changes in patterns of coronary revascularization strategies for patients with acute coronary syndromes (from the CRUSADE quality improvement initiative) Am J Cardiol 2007;99:1222-1226.[CrossRef][Web of Science][Medline]
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S. J. Denardo
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E. Stabile and P. Rubino
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