Advertisement
Mayo Clinic Proceedings Home

Long-term Care After Percutaneous Coronary Intervention: Focus on the Role of Antiplatelet Therapy

      Arterial wall injury caused by percutaneous coronary intervention (PCI) triggers transient platelet activation and mural thrombosis; these effects are superimposed on the preexisting platelet hyperreactivity associated with underlying atherothrombosis. Platelet activation has been implicated in the major complications of PCI: acute and subacute thrombosis and restenosis. Antithrombotic and anticoagulant therapy minimizes thrombotic complications after PCI. Aspirin plus a thienopyridine (ticlopidine or clopidogrel) is more effective than aspirin plus heparin and extended warfarin therapy in preventing periprocedural ischemic events and subsequent stent thrombosis and results in less major and minor bleeding. Dual antiplatelet therapy with aspirin and clopidogrel (the preferred thienopyridine because of its superior hematologic safety) is recommended for at least 4 weeks to prevent subacute stent thrombosis with bare-metal stents and 3 to 6 months to prevent late-stent thrombosis with drug-eluting stents. Coronary atherothrombosis is a diffuse vascular disease, and reduction of the risk of future ischemic events requires strategies that extend beyond the focal treatment of stenotic lesions. Optimal long-term care after PCI requires aggressive systemic pharmacotherapy (antiplatelet agents, statins, β-blockers, and angiotensin-converting enzyme inhibitors) in conjunction with therapeutic lifestyle changes (smoking cessation, weight reduction, dietary measures, and exercise). In this context, dual antiplatelet therapy (aspirin plus clopidogrel) is recommended for at least 12 months after PCI for prophylaxis of future atherothrombotic events.
      ACC (American College of Cardiology), ACE (angiotensin-converting enzyme), AHA (American Heart Association), CI (confidence interval), CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events), CREDO (Clopidogrel for the Reduction of Events During Observation), GP (glycoprotein), NSTEMI (myocardial infarction without ST-segment elevation), PCI (percutaneous coronary intervention), STEMI (myocardial infarction with ST-segment elevation), UA (unstable angina)
      The introduction of percutaneous transluminal coronary angioplasty in 1977 significantly changed the treatment of patients with coronary artery disease. The early days of percutaneous coronary intervention (PCI) were, however, characterized by a high rate of complications and frequent restenosis, a result of reliance on balloon angioplasty and suboptimal adjunctive pharmacotherapy. Because of refinements in technique and medications, most notably the use of intracoronary stents and the availability of potent antiplatelet agents, PCI is now feasible in most patients who require coronary revascularization. Collectively, the various nonsurgical procedures for coronary revascularization (balloon angioplasty, atherectomy, laser angioplasty, and stenting) are classified as PCI. The latest estimates suggest that more than 1 million PCI procedures are performed annually in the United States.
      • American Heart Association

      THE ROLE OF THE PLATELET IN ATHEROTHROMBOSIS

      Coronary atherosclerosis is a diffuse, multifocal disease process that affects the entire coronary arterial tree.
      • Mintz GS
      • Painter JA
      • Pichard AD
      • et al.
      Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations.
      • Casscells W
      • Naghavi M
      • Willerson JT
      Vulnerable atherosclerotic plaque: a multifocal disease.
      When the diameter stenosis of a lesion exceeds 70%, angina and exercise-induced ischemia often result. However, less severely stenotic plaques may rupture and cause myocardial infarction and/or sudden cardiac death. Vulnerable (potentially unstable) plaques include not only rupture-prone plaques but also those with a high likelihood of thrombotic complications and rapid progression of stenosis.
      • Naghavi M
      • Libby P
      • Falk E
      • et al.
      From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies, part I.
      Atherothrombosis describes the formation of a thrombus on a ruptured or eroded atherosclerotic plaque. Inflammation underlies all stages of atherothrombosis, including initiation, progression, and the ultimate thrombotic complication of the atheromatous plaque.
      • Libby P
      • Ridker PM
      • Maseri A
      Inflammation and atherosclerosis.
      Platelets play a pivotal role in the stimulation of the inflammatory response and in the pathophysiology of atherothrombosis. Evolution from a quiescent atherosclerotic plaque to an acute atherothrombotic (ischemic) event is triggered by rupture of the thin fibrous plaque cap (in approximately 70% of cases) or superficial erosion of the vascular intima (in approximately 30% of cases), resulting in exposure of thrombogenic substrates (primarily tissue factor) within the lipid-rich plaque core and arterial wall to circulating blood and coagulation factors.
      • Shah PK
      Mechanisms of plaque vulnerability and rupture.
      • Corti R
      • Fuster V
      • Badimon JJ
      Pathogenetic concepts of acute coronary syndromes.
      Activation of the coagulation cascade (triggered by local generation of thrombin) promotes local fibrin deposition and platelet adhesion, activation, and aggregation, leading to formation of an occlusive or nonocclusivethrombus.
      • Brass LF
      Thrombin and platelet activation.
      • Cimminiello C
      • Toschi V
      Atherothrombosis: the role of platelets.
      Platelets are attracted to the site of vascular injury and adhere to exposed collagen and von Willebrand factor in the subendothelial matrix via specific surface-bound glycoprotein (GP) integrin receptors. Adherent platelets are activated by various mediators, including exposed collagen and locally generated thrombin and adenosine diphosphate, resulting in platelet degranulation and secretion of agonists (including adenosine diphosphate, thromboxane A2, and platelet-activating factor) that stimulate further platelet recruitment. In addition, previously inactive GPIIb/IIIa receptors on the platelet surface are transformed into an active configuration capable of binding fibrinogen and von Willebrand factor. This conformational change promotes cross-linking of adjacent platelets and the formation of a platelet-rich thrombus (Figure 1).
      • Nguyen CM
      • Harrington RA
      Glycoprotein IIb/IIIa receptor antagonists: a comparative review of their use in percutaneous coronary intervention.
      Coronary thrombosis leading to abrupt disruption or cessation of coronary flow and/or distal embolization is responsible for most acute coronary syndromes: unstable angina, myocardial infarction, and sudden cardiac death.
      • Falk E
      Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion.
      Figure thumbnail gr1
      FIGURE 1Factors involved in platelet aggregation and the points of action (parallel lines) of various antithrombotic and anticoagulant drugs. ADP = adenosine diphosphate; LMWHs = low-molecular-weight heparins; UFH = unfractionated heparin. From Am J Cardiovasc Drugs,
      • Nguyen CM
      • Harrington RA
      Glycoprotein IIb/IIIa receptor antagonists: a comparative review of their use in percutaneous coronary intervention.
      with permission from Wolters Kluwer Health.
      Coronary angiography has had a major impact on the diagnosis and management of ischemic heart disease, identifying lesions suitable for both surgical and percutaneous coronary revascularization procedures. Although its value remains unquestioned, angiography is limited to demonstrating the degree that atherosclerotic lesions encroach on the vessel lumen, and it is not a reliable indicator of plaque vulnerability. Therefore, angiography is likely to underestimate the true extent of atherosclerosis and the propensity for destabilization.
      • Topol EJ
      • Nissen SE
      Our preoccupation with coronary luminology: the dissociation between clinical and angiographic findings in ischemic heart disease.
      Intravascular ultrasound studies indicate that patients with stable and unstable coronary artery disease are likely to have multiple ruptured or rupture-prone plaques.
      • Asakura M
      • Ueda Y
      • Yamaguchi O
      • et al.
      Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction.
      • Goldstein JA
      • Demetriou D
      • Grine CL
      • Pica M
      • Shoukfeh M
      • O'Neill WW
      Multiple complex coronary plaques in patients with acute myocardial infarction.
      • Rioufol G
      • Finet G
      • Ginon I
      • et al.
      Multiple atherosclerotic plaque rupture in acute coronary syndrome.
      • 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.
      Moreover, the ischemic events that occur after PCI are often caused by atherosclerotic disease progression at sites remote from the culprit lesion; future myocardial infarctions are more likely to result from angiographically mild or moderate than severe stenoses.
      • Ambrose JA
      • Tannenbaum MA
      • Alexopoulos D
      • et al.
      Angiographic progression of coronary artery disease and the development of myocardial infarction.
      • Little WC
      • Constantinescu M
      • Applegate RJ
      • et al.
      Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?.
      • Glaser R
      • Selzer F
      • Faxon DP
      • et al.
      Clinical progression of incidental, asymptomatic lesions discovered during culprit coronary intervention.
      Given the diffuse nature of coronary atherosclerosis and the limitations of coronary angiography in determining plaque burden and vulnerability to rupture, it is no surprise that focal mechanical treatment with PCI alone has proved largely ineffective in reducing mortality and myocardial infarction rates. Optimal long-term care requires systemic pharmacotherapy (antiplatelet agents, statins, β-blockers, and angiotensin-converting enzyme [ACE] inhibitors) and lifestyle modifications (smoking cessation, weight reduction, dietary measures, and exercise) aimed at stabilizing atherosclerotic plaques throughout the vascular tree, thereby reducing the likelihood of future ischemic events after PCI.
      • Smith Jr, SC
      • Dove JT
      • Jacobs AK
      • et al.
      ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
      • Pearson TA
      • McBride PE
      • Miller NH
      • Smith Jr, SC
      Task Force 8:organization of preventive cardiology service.

      PLATELET ACTIVATION IN PATIENTS UNDERGOING PCI

      Platelet activation occurs in patients undergoing PCI as a result of the PCI procedure itself and the underlying atherothrombotic disease process. Percutaneous revascularization techniques cause denudation of the arterial endothelium and mechanical disruption of the coronary plaque, thereby exposing the subendothelium to circulating blood.
      • Schwartz RS
      • Henry TD
      Pathophysiology of coronary artery restenosis.
      Platelets are a pivotal mediator of the vascular response to PCI; trauma to the arterial wall triggers thrombin generation, platelet deposition, mural thrombosis, and (through the release of platelet-derived cytokines and growth factors) smooth muscle cell proliferation and neointimal hyperplasia.
      • Schwartz RS
      • Henry TD
      Pathophysiology of coronary artery restenosis.
      • Marmur JD
      • Merlini PA
      • Sharma SK
      • et al.
      Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty.
      • Le Breton H
      • Plow EF
      • Topol EJ
      Role of platelets in restenosis after percutaneous coronary revascularization.
      • Chandrasekar B
      • Tanguay JF
      Platelets and restenosis.
      Platelet deposition occurs immediately after arterial injury; the intensity of the effect depends on the extent of arterial wall injury.
      • Wilentz JR
      • Sanborn TA
      • Haudenschild CC
      • Valeri CR
      • Ryan TJ
      • Faxon DP
      Platelet accumulation in experimental angioplasty: time course and relation to vascular injury.
      • Merino A
      • Cohen M
      • Badimon JJ
      • Fuster V
      • Badimon L
      Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: definition of a thrombotic shear rate threshold.
      Balloon dilation of the coronary artery causes short-lasting (approximately 48 hours) local platelet activation,
      • Gasperetti CM
      • Gonias SL
      • Gimple LW
      • Powers ER
      Platelet activation during coronary angioplasty in humans.
      • Kolarov P
      • Tschoepe D
      • Nieuwenhuis HK
      • Gries FA
      • Strauer B
      • Schultheiss HP
      PTCA: periprocedural platelet activation: part II of the Duesseldorf PTCA Platelet Study (DPSS).
      • Neumann FJ
      • Ott I
      • Gawaz M
      • Schomig A
      Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty.
      • Inoue T
      • Hoshi K
      • Fujito T
      • Sakai Y
      • Morooka S
      • Sohma R
      Early detection of platelet activation after coronary angioplasty.
      • Inoue T
      • Hoshi K
      • Yaguchi I
      • Iwasaki Y
      • Takayanagi K
      • Morooka S
      Serum levels of circulating adhesion molecules after coronary angioplasty.
      • Mizuno O
      • Hojo Y
      • Ikeda U
      • et al.
      Assessment of coagulation and platelet activation in coronary sinus blood induced by transcatheter coronary intervention for narrowing of the left anterior descending coronary artery.
      which is part of a broader systemic inflammatory response characterized by leukocyte and platelet activation and C-reactive protein release.
      • Serrano CV
      • Ramires JA
      • Venturinelli M
      • et al.
      Coronary angioplasty results in leukocyte and platelet activation with adhesion molecule expression: evidence of inflammatory responses in coronary angioplasty.
      • Azar RR
      • McKay RG
      • Kiernan FJ
      • et al.
      Coronary angioplasty induces a systemic inflammatory response.
      Coronary stenting leads to more pronounced platelet activation than balloon angioplasty alone,
      • Gawaz M
      • Neumann FJ
      • Ott I
      • May A
      • Rudiger S
      • Schomig A
      Changes in membrane glycoproteins of circulating platelets after coronary stent implantation.
      • Markovitz JH
      • Roubin GS
      • Parks JM
      • Bittner V
      Platelet activation and restenosis after coronary stenting: flow cytometric detection of wound-induced platelet activation.
      • Inoue T
      • Sohma R
      • Miyazaki T
      • Iwasaki Y
      • Yaguchi I
      • Morooka S
      Comparison of activation process of platelets and neutrophils after coronary stent implantation versus balloon angioplasty for stable angina pectoris.
      presumably because of the added vessel trauma caused by stent insertion and the thrombogenic stimulus provided by the stent itself.
      • Parsson H
      • Cwikiel W
      • Johansson K
      • Swartbol P
      • Norgren L
      Deposition of platelets and neutrophils in porcine iliac arteries after angioplasty and Wallstent placement compared with angioplasty alone.
      Vascular injury and the accompanying platelet activation and neointimal tissue proliferation that follow PCI may be important in the development of several major complications of this procedure: abrupt vessel closure, subacute thrombosis, and restenosis.
      • Le Breton H
      • Plow EF
      • Topol EJ
      Role of platelets in restenosis after percutaneous coronary revascularization.
      • Adams PC
      • Badimon JJ
      • Badimon L
      • Chesebro JH
      • Fuster V
      Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty.
      • Libby P
      • Schwartz D
      • Brogi E
      • Tanaka H
      • Clinton SK
      A cascade model for restenosis: a special case of atherosclerosis progression.
      • Neumann FJ
      • Gawaz M
      • Ott I
      • May A
      • Mossmer G
      • Schomig A
      Prospective evaluation of hemostatic predictors subacute stent thrombosis after coronary Palmaz-Schatz stenting.
      Abrupt vessel closure typically occurs within the first 24 hours after PCI, affects approximately 1% to 2% of patients (although this complication occurred in as many as 5% to 10% of patients before the introduction of the thienopyridines), and can be caused by mechanical disruption (eg, vessel dissection, plaque extrusion) or acute mural thrombosis; typical clinical manifestations include unstable angina, myocardial infarction, and death.
      • Grech ED
      Percutaneous coronary intervention: history and development.
      Restenosis (gradual renarrowing with >50% stenosis severity at the original site of angioplasty) affects approximately 30% to 40% of patients during the first 6 to 8 months after balloon percutaneous transluminal coronary angioplasty and is mainly caused by smooth muscle cell proliferation, neointimal hyperplasia, vessel recoil, and negative vessel remodeling (late shrinkage).
      • Levine GN
      • Chodod AP
      • Loscalzo J
      Restenosis following coronary angioplasty: clinical presentations and therapeutic options.
      In-stent restenosis occurs in approximately 20% of patients after bare-metal stenting and in up to 10% of patients after deployment of a drug-eluting stent and is largely the result of neointimal proliferation.
      • Terstein P
      • Reilly JP
      Late stent thrombosis in brachytherapy: the role of long-term antiplatelet therapy.
      The enhanced platelet activation seen after coronary stenting has been implicated in the development of subacute stent thrombosis, which typically occurs within the first few days to weeks of stent placement and affects approximately 1% of patients. The presentation of subacute thrombosis resembles that of acute vessel closure, but the prognosis is even worse because it typically occurs after hospital discharge; as a result, more than 80% of affected patients experience a large myocardial infarction, and the 30-day mortality rate is approximately 20% to 25%.
      • Shaknovich A
      Complications of coronary stenting.
      • Mak K-H
      • Belli G
      • Ellis SG
      • Moliterno DJ
      Subacute stent thrombosis: evolving issues and current concepts.
      • Cutlip DE
      • Baim DS
      • Ho KK
      • et al.
      Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials.
      Iakovou et al
      • Iakovou I
      • Schmidt T
      • Bonizzoni E
      • et al.
      Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.
      reported a case fatality rate of 45% in patients developing stent thrombosis. Similarly, platelets play a central role in the development of late-stent thrombosis (thrombotic stent occlusion that occurs >30 days after stenting).
      • Terstein P
      • Reilly JP
      Late stent thrombosis in brachytherapy: the role of long-term antiplatelet therapy.
      • Gurbel PA
      • Bliden KP
      • Samara W
      • et al.
      Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study.
      In patients with acute coronary syndromes (unstable angina [UA], myocardial infarction without ST-segment elevation [NSTEMI], and myocardial infarction with ST-segment elevation [STEMI]), the short-term platelet activation associated with PCI occurs against a background of persistent platelet hyperreactivity and thrombin generation.
      • Merlini PA
      • Bauer KA
      • Oltrona L
      • et al.
      Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.
      This prothrombotic environment is maintained for months after the initial ischemic event and is likely to contribute to the recurrence of ischemic events in the long term.
      • Mehta SR
      • Yusuf S
      Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention.

      THE ROLE OF ANTIPLATELET THERAPY IN PCI

      In light of the evidence presented herein for the involvement of platelets in the pathogenesis of atherothrombosis and the thrombotic complications of PCI, it follows that antiplatelet therapy forms an integral component of patient management during and after PCI (Figure 2).
      • Blann AD
      • Landray MJ
      • Lip GY
      ABC of antithrombotic therapy: an overview of antithrombotic therapy.
      Advances in stent technology and appropriate use of adjunctive pharmacotherapy have improved short-term procedural outcomes, with angiographic success rates of 96% to 99% and in-hospital mortality rates of 0.5% to 1.4% in elective PCI.
      • Smith Jr, SC
      • Dove JT
      • Jacobs AK
      • et al.
      ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
      However, prevention of recurrent ischemic events after PCI requires that antiplatelet therapy is maintained in the long term. The American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the use of antiplatelet therapy in patients presenting with UA/NSTEMI and STEMI and those undergoing PCI are given in Table 1.
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      • Antman EM
      • Anbe DT
      • Armstrong PW
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention.
      Figure thumbnail gr2
      FIGURE 2Mechanisms of action of antiplatelet drugs and the routes to inhibiting platelet function. ADP = adenosine diphosphate; GP = glycoprotein. From BMJ,
      • Blann AD
      • Landray MJ
      • Lip GY
      ABC of antithrombotic therapy: an overview of antithrombotic therapy.
      with permission from BMJ Publishing Group Ltd.
      TABLE 1ACC/AHA Guidelines for the Use of Antiplatelet and Anticoagulant Therapy in UA/NSTEMI, STEMI, and PCI Patients
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention.
      ACC = American College of Cardiology; ACS = acute coronary syndrome; AHA = American Heart Association; CABG = coronary artery bypass grafting; GP = glycoprotein; NSTEMI = myocardial infarction without ST-segment elevation; PCI = percutaneous coronary intervention; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.
      ConditionRecommended antiplatelet and anticoagulant therapy
      Treatment of patients with UA/NSTEMI
       All patients presenting with STEMI not allergic or intolerant to aspirinAspirin initiated as soon as possible
       All patients presenting with STEMI with aspirin allergy or intoleranceSubstitute aspirin with clopidogrel
       Patients with possible ACS at low riskAspirin
       Patients with likely or definite ACSClopidogrel, aspirin, and low-molecular-weight or unfractionated heparin
       Patients with ACS at high riskClopidogrel, aspirin, low-molecular-weight or unfractionated heparin, and intravenous GPIIb/IIIa antagonists if considered necessary (either initiated in the emergency department or reserved for selective use just before PCI)
       Patients for whom cardiovascular interventions are not immediately plannedClopidogrel should be added to aspirin therapy for ≥ 1–9 mo
       After UA/NSTEMILifelong aspirin, 75–325 mg/d, or clopidogrel, 75 mg/d, if aspirin is not tolerated; combination therapy with aspirin and clopidogrel should be continued for 9 mo
      Treatment of patients with STEMI
       All patients presenting with STEMI not allergic or intolerant to aspirinLifelong aspirin therapy beginning on day 1 (162–325 mg initially, then 75–162 mg as maintenance)
       All patients presenting with STEMI with aspirin allergy or intoleranceSubstitute aspirin with clopidogrel, 75 mg/d, if true aspirin allergy is present; alternatively ticlopidine, 250 mg/d, may be considered
      Treatment of patients undergoing PCI
       Before PCIPatients already receiving long-term aspirin therapy should take 75–325 mg of aspirin before PCI; patients not receiving long-term aspirin therapy should take 300–325 mg of aspirin preferably 2–24 h before PCI; a loading dose of at least 300 mg of clopidogrel should be administered at least 6 h before PCI; in UA/NSTEMI patients undergoing PCI without clopidogrel administration, a GPIIb/IIIa inhibitor should be administered; a GPIIb/IIIa inhibitor may also be administered with clopidogrel; in STEMI patients it is reasonable to administer abciximab as early as possible; unfractionated heparin should be administered to patients undergoing PCI; low-molecular-weight heparin may be considered as an alternative in patients with UA/NSTEMI undergoing PCI; bivalirudin may be used as an alternative to heparin and GPIIb/IIIa inhibitors in non-high-risk patients undergoing PCI
       After PCIAspirin, 325 mg/d, should be given for at least 1 mo after bare-metal stent implantation, 3 mo after sirolimus-eluting stents, and 6 mo after paclitaxel-eluting stents, after which aspirin, 75–162 mg/d, should be continued indefinitely; clopidogrel, 75 mg/d, should be given for at least 1 mo after bare-metal stent implantation, 3 mo after sirolimus-eluting stents, and 6 mo after paclitaxel-eluting stents; ideally, clopidogrel should be continued for up to 12 mo in patients not at high risk of bleeding
      Treatment of patients undergoing CABGWithhold clopidogrel for 5–7 d before CABG, unless the urgency of revascularization outweighs the risks of excess bleeding; aspirin should not be withheld before elective or nonelective CABG after STEMI; aspirin, 75–325 mg/d, should be prescribed within 24 h of CABG unless contraindicated
      * ACC = American College of Cardiology; ACS = acute coronary syndrome; AHA = American Heart Association; CABG = coronary artery bypass grafting; GP = glycoprotein; NSTEMI = myocardial infarction without ST-segment elevation; PCI = percutaneous coronary intervention; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.

      PREVENTION OF PERIPROCEDURAL AND SHORT-TERM COMPLICATIONS OF PCI

      Aspirin pretreatment is effective in reducing perioperative ischemic events during balloon angioplasty,
      • Schwartz L
      • Bourassa MG
      • Lesperance J
      • et al.
      Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
      • Lembo NJ
      • Black AJ
      • Roubin GS
      • et al.
      Effect of pre-treatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty.
      and current guidelines recommend routine administration of aspirin (75-325 mg) at least 2 hours before patients undergo PCIprocedures.
      • Smith Jr, SC
      • Dove JT
      • Jacobs AK
      • et al.
      ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
      ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention.
      However, aspirin is a relatively weak antiplatelet agent and inhibits only one of several pathways that lead to platelet activation (generation of thromboxane A2). The thienopyridines (ticlopidine and clopidogrel), which irreversibly inhibit adenosine diphosphate-mediated platelet aggregation, act additively or synergistically with aspirin through complementary and independent mechanisms. The combination of aspirin and ticlopidine reduces the risk of subacute stent thrombosis and is associated with a lower risk of bleeding than anticoagulant regimens (aspirin with heparin or warfarin) after stent placement.
      • Schomig A
      • Neumann FJ
      • Kastrati A
      • et al.
      A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary artery stents.
      • Bertrand ME
      • Legrand V
      • Boland J
      • et al.
      Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study.
      • Leon MB
      • Baim DS
      • Popma JJ
      • et al.
      A randomized trial comparing three drug regimens to prevent thrombosis following elective coronary stenting.
      • Urban P
      • Macaya C
      • Rupprecht HJ
      • et al.
      Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS).
      However, ticlopidine has rare but potentially fatal hematologic effects (neutropenia and thrombotic thrombocytopenic purpura) that have curbed its routine use in PCI. Clopidogrel, which is safer and better tolerated than ticlopidine
      • Bertrand ME
      • Rupprecht H-J
      • Urban P
      • Gershlick AH
      • CLASSICS Investigators
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).
      and at least as effective in preventing subacute stent thrombosis and periprocedural ischemia,
      • Bertrand ME
      • Rupprecht H-J
      • Urban P
      • Gershlick AH
      • CLASSICS Investigators
      Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).
      • Muller C
      • Buttner HJ
      • Petersen J
      • Roskamm H
      A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary artery stents.
      • Bhatt DL
      • Bertrand ME
      • Berger PB
      • et al.
      Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.
      has essentially replaced ticlopidine in this setting. In the PCI-Clopidogrel in Unstable Angina to Prevent Recurrent Events (PCI-CURE) trial, pretreatment with clopidogrel and aspirin provided an approximately 30% reduction relative to aspirin alone in the incidence of cardiovascular death, myocardial infarction, or urgent target vessel revascularization in the first month after PCI in patients with UA.
      • Mehta SR
      • Yusuf S
      • Peters RJ
      • et al.
      Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      In the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, 2116 patients who were to undergo elective PCI were randomly assigned to receive a 300-mg loading dose of clopidogrel or placebo 3 to 24 hours before PCI.
      • Steinhubl SR
      • Berger PB
      • Mann III, JT
      • CREDO Investigators
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published correction appears in JAMA. 2003;289:987].
      Thereafter, all patients received clopidogrel, 75 mg, for 28 days. From day 29 through 12 months, patients in the loading dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. Clopidogrel pretreatment did not significantly reduce the combined risk of death, myocardial infarction, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% confidence interval [CI], -14.2% to 41.8%; P=.23). However, in a prespecified subgroup analysis, patients pretreated with clopidogrel, 300 mg, at least 6 hours before PCI experienced a relative risk reduction of 38.6%(95% CI, -1.6% to 62.9%; P=.05) for this end point compared with no reduction in patients pretreated less than 6 hours before PCI.
      • Steinhubl SR
      • Berger PB
      • Mann III, JT
      • CREDO Investigators
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published correction appears in JAMA. 2003;289:987].
      The incidence of cardiovascular death, myocardial infarction, or stroke after PCI was significantly reduced by the administration of clopidogrel, 300 mg, within 45 minutes of the start of fibrinolytic therapy (optimally within 10 minutes) in the PCI-Clopidogrel as Adjunctive Reperfusion Therapy trial.
      • Sabatine MS
      • Cannon CP
      • Gibson CM
      • Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators
      • et al.
      Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study.
      Compared with placebo, the adjusted odds ratio for post-PCI cardiovascular death, myocardial infarction, or stroke was 0.54 (95% CI, 0.35-0.85). Overall, pretreatment with clopidogrel was associated with a significant reduction in the incidence of these events through 30 days (adjusted odds ratio, 0.59; 95% CI, 0.43-0.81).
      Evidence indicates that a 600-mg loading dose of clopidogrel results in a more pronounced antiplatelet effect than a 300-mg loading regimen.
      • Müller I
      • Seyfarth M
      • Rudiger S
      • et al.
      Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement.
      The Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty study was the first prospective, randomized trial to compare the safety and efficacy of pretreatment with a 600-mg loading dose vs a 300-mg loading dose of clopidogrel in improving ischemic outcomes in patients undergoing coronary intervention.
      • Patti G
      • Colonna G
      • Pasceri V
      • Pepe LL
      • Montinaro A
      • Di Sciascio G
      Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study.
      The results showed that a 600-mg loading dose of clopidogrel 4 to 8 hours before PCI safely and more effectively reduced the occurrence of periprocedural infarctions than did a 300-mg loading dose. However, data from the recently presented Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation, and Ongoing Necrosis trial suggest that even the 600-mg loading dose may be suboptimal.

      Montalescot G. Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation, and Ongoing Necrosis (ALBION) trial. Presented at: EuroPCR Congress; Paris, France, May 24, 2005.

      In that study, ex vivo measures of platelet function showed that a 900-mg loading dose of clopidogrel tended to provide an even greater and more rapid antiplatelet effect than 600 mg. However, this finding was not supported by the results of the recent Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect trial.
      • von Beckerath N
      • Taubert D
      • Pogatsa-Murray G
      • Schomig E
      • Kastrati A
      • Schomig A
      Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial.
      In that study, 60 patients admitted to the hospital for coronary angioplasty were randomized to 1 of 3 clopidogrel loading doses: 300, 600, or 900 mg. Plasma concentrations of the active metabolite of clopidogrel and suppression of adenosine diphosphate-induced platelet aggregation 4 hours after drug administration were greater with a 600-mg loading dose compared with a 300-mg loading dose. No significant differences occurred, however, in these measures comparing a 600-mg and 900-mg loading dose. Consequently, on the basis of the currently available data, a 600-mg loading dose before PCI is recommended, especially in patients undergoing the procedure within 6 hours of treatment.
      Adjunctive use of intravenous GPIIb/IIIa antagonists (which inhibit the final common pathway of platelet aggregation) is beneficial in reducing the risk of periprocedural ischemic events associated with PCI.
      • Smith Jr, SC
      • Dove JT
      • Jacobs AK
      • et al.
      ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
      The ACC/AHA guidelines give a class Ia recommendation for the use of GPIIb/IIIa inhibitors in UA/STEMI patients undergoing PCI, started either routinely upfront in all patients at moderate to high risk on clinical presentation or reserved for selective use in the cardiac catheterization laboratory in patients undergoing PCI.
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      When used in an “all-comers” PCI population, abciximab, eptifibatide, and tirofiban have been shown to reduce the composite end points of death, myocardial infarction, and urgent revascularization at 4 weeks by approximately 30% to 60%,
      • EPIC Investigators
      Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty.
      • EPISTENT Investigators
      Randomized placebo-controlled and balloon angioplasty controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade.
      • RESTORE Investigators
      Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty.
      • ESPRIT Investigators
      Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial [published correction appears in Lancet. 2001;357:1370].
      with the benefits persisting for up to 6 or 12 months. However, their anti-ischemic benefits do not appear to extend to percutaneous revascularization of coronary bypass grafts
      • Roffi M
      • Mukherjee D
      • Chew DP
      • et al.
      Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials.
      or to low-to-intermediate risk patients without UA/STEMI who have received a relatively large loading dose (600 mg) of clopidogrel.
      • RESTORE Investigators
      Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty.
      In the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment study, 2159 patients with coronary artery disease who underwent PCI were randomly assigned in a double-blind manner to receive abciximab (n=1079) or placebo (n=1080).
      • Kastrati A
      • Mehilli J
      • Schühlen H
      • Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators
      • et al.
      A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel.
      All patients were pretreated with a 600-mg dose of clopidogrel at least 2 hours before the procedure. The primary end point of the trial was the composite of death, myocardial infarction, and urgent target-vessel revascularization within 30 days after randomization. Abciximab was associated with no additional clinically measurable benefit when given to patients who had been treated with a 600-mg loading dose of clopidogrel before PCI. However, patients with type 1 diabetes mellitus, UA, recent myocardial infarction, and thrombotic lesions were excluded from the trial.
      The Intracoronary Stenting and Antithrombotic Regimen: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetics trial was designed to evaluate the incremental benefit of abciximab in patients with diabetes undergoing elective PCI after treatment with a high loading dose of clopidogrel.
      • Mehilli J
      • Kastrati A
      • Schühlen H
      • Intracoronary Stenting and Antithrombotic Region: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetes (ISAR-SWEET) Study Investigators
      • et al.
      Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel.
      In total, 351 patients were randomly assigned to abciximab and 350 to placebo. The primary end point was the composite incidence of death and myocardial infarction at 1 year. The frequency of angiographic restenosis (diameter stenosis ≥50%) was the secondary end point. The results did not support a significant impact of abciximab on the risk of death and myocardial infarction in diabetic patients undergoing PCI after pretreatment with a 600-mg loading dose of clopidogrel at least 2 hours before the procedure. The findings instead suggested that abciximab reduces the risk of restenosis in diabetic patients who received bare-metal stents; however, the importance of this result is questionable given the wide-spread adoption of drug-eluting stents.
      Recently, the direct thrombin inhibitor bivalirudin was shown to be as effective as heparin and GPIIb/IIIa antagonists in reducing the short-term risk of ischemic events after PCI and to cause less major bleeding.
      • Lincoff A
      • Bittl JA
      • Harrington RA
      • REPACE-2 Investigators
      • 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 [published correction appears in JAMA. 2003;289:1638].
      In addition, long-term data suggest that survival with bivalirudin is similar to that with heparin plus GPIIb/IIIa antagonists after PCI.
      • Lincoff AM
      • Kleiman NS
      • Kereiakes DJ
      • REPACE-2 Investigators
      • 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.
      As a result, at many centers, bivalirudin has become the anticoagulant of choice for most patients undergoing PCI, with heparin and GPIIb/IIIa antagonists being reserved for the highest-risk procedures (eg, primary PCI in acute myocardial infarction and in patients with thrombus). Ongoing studies are examining the role of bivalirudin in patients with acute coronary syndromes.
      • Stone GW
      • Bertrand M
      • Colombo A
      • et al.
      Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale.
      However, even with bivalirudin, event rates are lower in patients pretreated with clopidogrel.
      • Lincoff A
      • Bittl JA
      • Harrington RA
      • REPACE-2 Investigators
      • 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 [published correction appears in JAMA. 2003;289:1638].
      There has also been some debate about the study design and results of the pivotal Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events 2 trial.
      • Lincoff A
      • Bittl JA
      • Harrington RA
      • REPACE-2 Investigators
      • 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 [published correction appears in JAMA. 2003;289:1638].
      • Lincoff AM
      • Kleiman NS
      • Kereiakes DJ
      • REPACE-2 Investigators
      • 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.
      Patients undergoing urgent or elective PCI were randomized to bivalirudin with provisional GPIIb/IIIa inhibition or to heparin with planned GPIIb/IIIa inhibition. Two possible treatment arms that were not included were heparin plus provisional GPIIb/IIIa inhibition and bivalirudin plus planned GPIIb/IIIa inhibition. Had the latter treatment arm been used, it may have resulted in less of a bleeding advantage with bivalirudin, although possibly with greater suppression of periprocedural ischemic events.
      • Antman EM
      Should bivalirudin replace heparin during percutaneous coronary interventions?.
      Pharmacological strategies for prevention of subacute thrombosis after stent implantation are crucial since this complication, which usually occurs in the first month after stenting (ie, after hospital discharge), almost invariably results in myocardial infarction or death.
      • Shaknovich A
      Complications of coronary stenting.
      For this purpose, it is recommended that, after implantation of bare-metal stents, patients receive dual aspirin and clopidogrel therapy for 4 weeks after PCI.
      • Levine GN
      • Kern MJ
      • Berger PB
      • et al.
      Management of patients undergoing percutaneous coronary revascularization.
      Similarly, it is recommended that aspirin and clopidogrel be continued for at least 3 to 6 months after drug-eluting stenting to prevent subacute stent thrombosis. In view of the life-threatening consequences of subacute stent thrombosis, it is important that treatment is not interrupted for minor bleeding, and elective invasive or surgical procedures should be deferred for at least 4 weeks after PCI, if possible,
      • Levine GN
      • Kern MJ
      • Berger PB
      • et al.
      Management of patients undergoing percutaneous coronary revascularization.
      and ideally for a year or longer in patients receiving drug-eluting stents.

      LONG-TERM PREVENTION OF RECURRENT ISCHEMIC EVENTS AFTER PCI

      The pathophysiological role of platelet activation in the late complications of PCI (particularly late stent thrombosis) and in the development of atherothrombotic events related to progression of disease remote from the angioplasty lesions provides the rationale for continuing dual antiplatelet therapy (clopidogrel plus aspirin) beyond the conventional 4-week treatment period required to prevent subacute stent thrombosis after bare-metal coronary stenting. Of importance, in many circumstances, PCI procedures (including the use of drug-eluting stents) are only palliative measures, and they do not modify the underlying atherosclerotic disease process. Patients with acute coronary syndromes remain at substantial risk of future ischemic events, as reflected in a 6% incidence of death, myocardial infarction, or stroke in the first 6 months after hospital discharge.
      • Yusuf S
      • Flather M
      • Pogue J
      • OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators
      • et al.
      Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation.
      Despite the use of short-term antithrombotic therapy, coronary thrombi remain detectable for 1 month after an acute ischemic event.
      • Van Belle E
      • Lablanche JM
      • Bauters C
      • Renaud N
      • McFadden EP
      • Bertrand ME
      Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis.
      Moreover, once antithrombotic therapy is discontinued, the clinical benefits cease. Thus, there is sound pathophysiological support for the suggestion that long-term antithrombotic therapy may be required to prevent further ischemic events. Aspirin not only reduces periprocedural ischemic events during balloon angioplasty
      • Schwartz L
      • Bourassa MG
      • Lesperance J
      • et al.
      Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
      • Lembo NJ
      • Black AJ
      • Roubin GS
      • et al.
      Effect of pre-treatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty.
      but also is associated with a 37% reduction in the risk of late vascular events among patients with established coronary artery disease and a 53% risk reduction in patients who have undergone PCI.
      • Antithrombotic Trialists' Collaboration
      Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients.
      The UA/NSTEMI guidelines recommend that aspirin, 75 to 325 mg/d, be initiated promptly after presentation and continued indefinitely (class Ia recommendation).
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      In hospitalized patients in whom PCI is planned, clopidogrel should be added to aspirin as soon as possible and administered for at least 1 month and for up to 9 months (class Ib). In patients with STEMI, the ACC/AHA guidelines state that aspirin, 75 to 162 mg/d, should be given indefinitely (class Ia).
      • Antman EM
      • Anbe DT
      • Armstrong PW
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      In patients for whom PCI is planned, clopidogrel therapy should be started and continued for at least 1 month after baremetal stent implantation and for up to 12 months in patients who are not at high risk of bleeding (class Ib).
      Findings from 2 major randomized trials highlight the clinical benefits to be gained from sustained dual antiplatelet therapy (clopidogrel plus aspirin) after PCI.
      • Mehta SR
      • Yusuf S
      • Peters RJ
      • et al.
      Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Steinhubl SR
      • Berger PB
      • Mann III, JT
      • CREDO Investigators
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published correction appears in JAMA. 2003;289:987].
      The PCI-CURE study compared the effects of pretreatment (median, 10 days) and long-term (mean, 9 months) therapy with clopidogrel vs placebo in 2658 aspirin-treated patients who underwent PCI after randomization for non-ST-segment elevation acute coronary syndromes.
      • Mehta SR
      • Yusuf S
      • Peters RJ
      • et al.
      Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      Both treatment groups received open-label clopidogrel for 4 weeks after coronary stenting with bare-metal stents. The overall study results (from randomization to the end of follow-up) revealed a highly significant 31% reduction in cardiovascular death or myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo, suggesting a combined benefit of pretreatment followed by sustained therapy after PCI. In the long term (ie, from the second month after PCI to the end of follow-up), significant clinical benefit was also seen with the clopidogrel plus aspirin combination compared with aspirin alone, with a 21% reduction relative to aspirin in cardiovascular death or myocardial infarction.
      • Mehta SR
      • Yusuf S
      • Peters RJ
      • et al.
      Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      The CREDO study compared the effects of both pretreatment and long-term (12 months) clopidogrel vs placebo therapy in 2116 aspirin-treated patients undergoing elective PCI.
      • Steinhubl SR
      • Berger PB
      • Mann III, JT
      • CREDO Investigators
      • et al.
      Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published correction appears in JAMA. 2003;289:987].
      Patients were pretreated with either aspirin or aspirin plus clopidogrel in the 24 hours preceding PCI, and all patients received aspirin plus clopidogrel for 4 weeks after PCI (ie, bare-metal stenting). At 12 months of follow-up, the dual antiplatelet regimen was associated with a significant 26.9% reduction relative to aspirin alone in the composite end point of death, myocardial infarction, or stroke (95% CI, 3.9%-44.4%; P=.02; absolute reduction, 3%). Analysis of long-term outcomes (ie, from month 2 to month 12) indicated that clopidogrel plus aspirin treatment resulted in a significant and incremental 37% relative risk reduction in the incidence of death, myocardial infarction, and stroke.
      • Aronow HD
      • Steinhubl SR
      • Brennan DM
      • Topol EJ
      Long-term clopidogrel therapy following percutaneous coronary intervention improves clinical outcome but is not associated with increased bleeding: new insights from the CREDO trial [abstract].
      The improved anti-ischemic outcome achieved with dual antiplatelet therapy over aspirin was not associated with any appreciable increase in the risk of major or life-threatening bleeding.
      • Mehta SR
      • Yusuf S
      • Peters RJ
      • et al.
      Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
      • Aronow HD
      • Steinhubl SR
      • Brennan DM
      • Topol EJ
      Long-term clopidogrel therapy following percutaneous coronary intervention improves clinical outcome but is not associated with increased bleeding: new insights from the CREDO trial [abstract].
      More prolonged clopidogrel therapy (>1 year) may be empirically used in higher-risk patients (those with diffuse or multivessel coronary disease, atherosclerotic disease in extracoronary beds, diabetes, or renal insufficiency) and in those who have experienced acute coronary events while taking aspirin, although data are lacking to support this strategy.
      In both the PCI-CURE and CREDO studies, patients were not randomized again after 28 days of therapy; consequently, it was not possible to completely separate the treatment benefit of long-term therapy with that of pretreatment. The CREDO investigators argued that it is difficult to postulate an influence of pretreatment on late thrombotic events. However, platelet inhibition during PCI with a GPIIb/IIIa inhibitor has been shown to improve long-term outcomes after the procedure.
      • Karvouni E
      • Katritsis DG
      • Ioannidis JP
      Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions.
      • Eriksson P
      Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the “Emperor's New Clothes” revisited.
      The risk of late stent thrombosis is increased by the use of vascular brachytherapy (intracoronary delivery of radiation) for prevention of in-stent restenosis, possibly because delayed endothelial regrowth leaves thrombogenic stent surfaces exposed for extended periods, thereby creating a prothrombotic environment.
      • Grech ED
      Percutaneous coronary intervention: history and development.
      This thrombotic risk is reduced by prolonged (>3 months) dual antiplatelet (aspirin plus thienopyridine) therapy.
      • Terstein P
      • Reilly JP
      Late stent thrombosis in brachytherapy: the role of long-term antiplatelet therapy.
      • Silber S
      • von Rottkay P
      • Lossl P
      • et al.
      Safety and feasibility of intracoronary brachytherapy with the Novoste system within the scope of international multicenter studies.
      Accordingly, antiplatelet therapy should be maintained for a minimum of 6 months and possibly for life in patients undergoing vascular brachytherapy.
      ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention.
      • Sapirstein W
      • Zuckerman B
      • Dillard J
      FDA approval of coronary artery brachytherapy.
      Similarly, patients treated with drug-eluting stents (which reduce neointimal proliferation) should receive dual aspirin plus clopidogrel therapy for at least 3 to 6 months to prevent possible late-stent thrombosis.
      • Levine GN
      • Kern MJ
      • Berger PB
      • et al.
      Management of patients undergoing percutaneous coronary revascularization.
      Current recommendations, based on the pivotal clinical investigations of these devices,
      • Moses JW
      • Leon MB
      • Popma JJ
      • et al.
      Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.
      • Stone GW
      • Ellis SG
      • Cox DA
      • et al.
      A polymer-based paclitaxel-eluting stent in patients with coronary artery disease.
      require at least 3 months of clopidogrel treatment after implantation of the sirolimus-eluting stent (CYPHER, Cordis Corp, Warren, NJ)
      • Moses JW
      • Leon MB
      • Popma JJ
      • et al.
      Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery.
      and at least 6 months of clopidogrel after implantation of the paclitaxel-eluting stent (TAXUS, Boston Scientific Corp, Natick, Mass),
      • Stone GW
      • Ellis SG
      • Cox DA
      • et al.
      A polymer-based paclitaxel-eluting stent in patients with coronary artery disease.
      which are the 2 currently approved drug-eluting stents in the United States. The optimal duration of clopidogrel therapy remains uncertain in patients with more complex anatomy, such as those with bifurcations, those with thrombus, and those receiving multiple stents. Data from the Rapamycin-Eluting Stent Evaluated at Rotterdam Cardiology Hospital Registry demonstrated that unrestricted use of sirolimus-eluting stents reduced both repeat revascularization and major cardiac events at 1 year compared with bare-metal stent implantation.
      • Lemos PA
      • Serruys PW
      • van Domburg RT
      • et al.
      Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world”: the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry.
      This was despite the fact that patients receiving sirolimus-eluting stents had a greater number and length of stents implanted, had more coronary segments dilated, had smaller vessels treated, and had more bifurcations treated than those receiving bare-metal stents. Patients received periprocedural GPIIb/IIIa inhibition at the discretion of the operator, and all were advised to maintain lifelong aspirin treatment. Clopidogrel, 75 mg/d, was initiated for 1 month before stenting and prescribed for at least 3 months to those treated with the sirolimus-eluting stents (unless the patient underwent multiple stent implantation [>3 stents], the total stent length exceeded 36 mm, or a chronic total occlusion or bifurcation was treated, in which case clopidogrel treatment was maintained for 6 months). Although stent manufacturers recommend 3 to 6 months of antiplatelet therapy, the question remains whether prolonged or lifelong antiplatelet therapy may be beneficial in routine or select cases to reduce the incidence of late stent thrombosis or subsequent atherothrombosis. Large-scale, prospective randomized controlled trials are required to answer this question.
      Resistance or nonresponsiveness to antiplatelet therapy has been reported in the literature.
      • Tantry US
      • Bliden KP
      • Gurbel PA
      Resistance to antiplatelet drugs: current status and future research.
      • Guthikonda S
      • Lev EI
      • Kleiman NS
      Resistance to antiplatelet therapy.
      Possible mechanisms of aspirin and clopidogrel resistance include alterations in genetic, pharmacokinetic, and platelet properties. Although several trials have investigated the phenomenon of the variability of response to clopidogrel, only 2 have concomitantly looked at clinical end points in addition to platelet aggregation.
      • Barragan P
      • Bouvier JL
      • Roquebert PO
      • et al.
      Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation.
      • Matetzky S
      • Shenkman B
      • Guetta V
      • et al.
      Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction.
      However, the small sample size, the differences in patient characteristics, and the use of different assays to quantify antiplatelet effects make it difficult to draw any definitive conclusions from these studies. Currently, no definite demonstration exists of an association between low responsiveness to clopidogrel and thrombotic events. Consequently, it is not thought justified to routinely look for clopidogrel resistance in clinical practice.
      • Nguyen TA
      • Diodati JG
      • Pharand C
      Resistance to clopidogrel: a review of the evidence.
      Studies of the role of antiplatelet resistance in the pathophysiology of stent thrombosis and atherothrombosis are needed.

      ADDITIONAL LONG-TERM MEASURES OF CARE AFTER PCI

      ACE inhibitors play an important role in the secondary prevention of coronary artery disease, reducing the risk of cardiovascular death, ischemic events, and repeat revascularization in both high-risk
      • Heart Outcomes Prevention Evaluation Study Investigators
      Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
      and low-risk
      • EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators
      Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
      patients. The ACC/AHA guidelines give a class IIa recommendation for the use of ACE inhibitors in all patients after myocardial infarction and a class Ib recommendation in specific circumstances (ie, when hypertension persists or in patients with diabetes).
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      Long-term β-blocker therapy is indicated in patients with a history of myocardial infarction.
      • Freemantle N
      • Urdahl H
      • Eastaugh J
      • Hobbs FD
      What is the place of beta-blockade in patients who have experienced a myocardial infarction with preserved left ventricular function? evidence and misinterpretation.
      The ACC/AHA guidelines give a class Ib recommendation for the long-term use of β-blockers as anti-ischemic therapy after myocardial infarction.
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).

      CARDIAC REHABILITATION AFTER PCI

      Secondary prevention of coronary artery disease is critical for reducing the risk of future ischemic events after PCI.
      • Smith Jr, SC
      • Dove JT
      • Jacobs AK
      • et al.
      ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
      Therefore, it is important in the patient who has undergonePCI to implement a comprehensive cardiac rehabilitation program based on risk factor modification and therapeutic lifestyle changes in addition to pharmacotherapy (Tables TABLE 2, TABLE 3). The benefits of cholesterol lowering in the secondary prevention of coronary artery disease are well documented, and statin therapy initiated shortly before PCI
      • Pasceri V
      • Patti G
      • Nusca A
      • Pristipino C
      • Richichi G
      • Di Sciascio G
      • ARMYDA Investigators
      Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study.
      or immediately after PCI
      • Serruys PWJC
      • de Feyter P
      • Macaya C
      • Lescol Intervention Prevention Study (LIPS) Investigators
      • et al.
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      reduces the risk of ischemic cardiac events. Intensive lipid lowering provides greater cardiovascular protection than moderate lipid lowering after acute coronary syndromes.
      • Cannon CP
      • Braunwald E
      • McCabe CH
      • et al.
      Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
      Statin therapy appears to be more effective when initiated in the in-patient setting after PCI rather than at a later stage after hospital discharge.
      • Aronow HD
      • Novaro GM
      • Lauer MS
      • et al.
      In-hospital initiation of lipid-lowering therapy after coronary intervention as a predictor of long-term utilization: a propensity analysis.
      Hypertension is a significant risk factor for coronary artery disease,
      • MacMahon S
      • Peto R
      • Cutler J
      • et al.
      Blood pressure, stroke and coronary heart disease, part I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.
      and there is abundant evidence that blood pressure control can reduce the risks of coronary artery disease.
      • Pasternak RC
      • Grundy SM
      • Levy D
      • Thompson PD
      Task Force 3: spectrum of risk factors for coronary heart disease.
      Tight glycemic control reduces the risk of microvascular complications such as retinopathy in type 2 diabetes mellitus.
      • UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      The American Association of Clinical Endocrinologists recommends that in diabetic patients a target hemoglobin A1c level lower than 6.5% be set after PCI.
      • American Association of Clinical Endocrinologists
      Medical Guidelines for the Management of Diabetes Mellitus: the AACE system of intensive diabetes self management—2002 update.
      TABLE 2Cardiac Rehabilitation After Percutaneous Coronary Intervention
      BMI = body mass index; LDL-C = low-density lipoprotein cholesterol; NSTEMI = myocardial infarction without ST-segment elevation; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.
      Cardiac risk factorUA/NSTEMI guideline recommendations
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      STEMI guideline recommendations
      • Antman EM
      • Anbe DT
      • Armstrong PW
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      HypertensionBlood pressure goal of <130/85 mm Hg (class lb)Blood pressure goal of <140/90 mm Hg or <130/80 mm Hg if kidney disease or diabetes present (class lb)
      HyperlipidemiaInitiate statin if LDL-C >130 mg/dL (class la)Initiate statin if LDL-C >100 mg/dL (class la)
      DiabetesTight control of hyperglycemia (class lb)Hypoglycemic therapy initiated to achieve hemoglobin A1c <7% (class lb)
      SmokingCessation (class lb)Cessation (class lb)
      ObesityMaintenance of optimal weight (class lb)BMI goal of 18.5–24.9 (class lb)
      Physical inactivityMaintenance of daily exercise (class lb)Daily goal of at least 30 min of exercise (class lb)
      High-fat dietMaintenance of appropriate diet (class lb)Switch to a low-fat diet; increase fresh fruit and vegetable intake (class la)
      * BMI = body mass index; LDL-C = low-density lipoprotein cholesterol; NSTEMI = myocardial infarction without ST-segment elevation; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.
      TABLE 3Medication Management After Percutaneous Coronary Intervention
      ACE = angiotensin-converting enzyme; LDL-C = low-density lipoprotein cholesterol; NSTEMI = myocardial infarction without ST-segment elevation; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.
      MedicationUA/NSTEMI guideline recommendations
      • Braunwald E
      • Antman EM
      • Beasley JW
      • et al.
      ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
      STEMI guideline recommendations
      • Antman EM
      • Anbe DT
      • Armstrong PW
      • et al.
      ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
      Indefinite aspirin therapy75–325 mg/d (class la)75–162 mg/d (class la)
      Long-term clopidogrel therapy75 mg/d (class la)75 mg/d if patient is allergic to aspirin (class Ic)
      Indefinite statin therapyIf LDL-C >130 mg/dL (class la)If LDL-C >100 mg/dL (class la)
      ACE inhibitor therapyClass Ha recommendation for use in all post-acute coronary syndrome patients; class lb recommendation in specific circumstancesPrescribed in all patients indefinitely (class la)
      Use of β-blocker therapyClass lb recommendation for long-term useStart in all patients and continue indefinitely (class la)
      * ACE = angiotensin-converting enzyme; LDL-C = low-density lipoprotein cholesterol; NSTEMI = myocardial infarction without ST-segment elevation; STEMI = myocardial infarction with ST-segment elevation; UA = unstable angina.
      Cigarette smoking has long been established as a powerful, independent, and reversible risk factor for coronary artery disease.
      • Kannel WB
      Cigarette smoking and coronary heart disease.
      Smoking adversely affects the serum lipid profile, elevating triglyceride and reducing high-density lipoprotein cholesterol levels, promotes formation of proatherogenic oxidized particles, and enhances the prothrombotic state.
      • Duthie GG
      • Arthur JR
      • Beattie JA
      • et al.
      Cigarette smoking, antioxidants, lipid peroxidation and coronary heart disease.
      Smoking cessation is beneficial in reducing the ischemic risk in coronary artery disease, and patients who are smokers at the time of hospitalization for PCI should be encouraged to quit smoking after discharge.
      Physical inactivity is a common modifiable risk factor for coronary artery disease and is associated with at least a 2-fold increase in the risk of coronary events.
      • Thompson PD
      • Buchner D
      • Pina IL
      • et al.
      Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity and Metabolism (Subcommittee on Physical Activity).
      Regular physical exercise has beneficial effects on weight control, lipid profile, blood pressure, and insulin sensitivity and plays a useful role in both primary and secondary prevention of ischemic heart disease.
      • Thompson PD
      • Buchner D
      • Pina IL
      • et al.
      Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity and Metabolism (Subcommittee on Physical Activity).
      Exercise training has been shown to improve functional capacity and to reduce recurrent ischemic events in patients who have undergone PCI.
      • Belardinelli R
      • Paolini I
      • Cianci G
      • Piva R
      • Georgiou D
      • Purcaro A
      Exercise training intervention after coronary angioplasty: the ETICA trial.
      Dietary advice should focus on reducing intake of saturated fats and increasing fresh fruit and vegetable consumption since there is good evidence that a diet low in total and saturated fats and high in 3ω fatty acids, fruit, and vegetables can reduce the recurrence of coronary artery disease.
      • Burr ML
      • Fehily AM
      • Gilbert JF
      • et al.
      Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART).
      • De Lorgeril M
      • Salen P
      • Martin JL
      • Monjaud I
      • Delaye J
      • Mamelle N
      Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction: final results of the Lyon Diet Heart Study.
      Patients with a body mass index (calculated as weight in kilograms divided by the square of height in meters) greater than 25 should be targeted for weight reduction because this can substantially reduce cardiovascular risk factors such as dyslipidemia and insulin resistance.
      • Tremblay A
      • Doucet E
      • Imbeault P
      • Mauriege P
      • Despres JP
      • Richard D
      Metabolic fitness in active reduced-obese individuals.

      CONCLUSION

      Percutaneous coronary intervention is a focal treatment of a systemic disease process, and patients require lifelongsecondary preventive interventions to minimize the risk of atherothrombotic events. Long-term (at least 9 to 12 months) dual antiplatelet therapy (clopidogrel plus aspirin) is safe and effective in preventing stent thrombosis and recurrent ischemic events after PCI. Evidence increasingly suggests that the longer such therapy is maintained after PCI the better the outcome. Finally, all patients undergoing PCI should be instructed about necessary lifestyle changes and risk factor modification before hospital discharge.

      Acknowledgments

      We thank Andrew Fitton and Neil Marmont for editorial support in the preparation of the submitted manuscript.

      REFERENCES

        • American Heart Association
        2001 Heart and Stroke Statistical Update. American Heart Association, Dallas, Tex2002
        • Mintz GS
        • Painter JA
        • Pichard AD
        • et al.
        Atherosclerosis in angiographically “normal” coronary artery reference segments: an intravascular ultrasound study with clinical correlations.
        J Am Coll Cardiol. 1995; 25: 1479-1485
        • Casscells W
        • Naghavi M
        • Willerson JT
        Vulnerable atherosclerotic plaque: a multifocal disease.
        Circulation. 2003; 107: 2072-2075
        • Naghavi M
        • Libby P
        • Falk E
        • et al.
        From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies, part I.
        Circulation. 2003; 108: 1664-1672
        • Libby P
        • Ridker PM
        • Maseri A
        Inflammation and atherosclerosis.
        Circulation. 2002; 105: 1135-1143
        • Shah PK
        Mechanisms of plaque vulnerability and rupture.
        J Am Coll Cardiol. 2003; 41: 15S-22S
        • Corti R
        • Fuster V
        • Badimon JJ
        Pathogenetic concepts of acute coronary syndromes.
        J Am Coll Cardiol. 2003; 41: 7S-14S
        • Brass LF
        Thrombin and platelet activation.
        Chest. 2003; 124: 18S-25S
        • Cimminiello C
        • Toschi V
        Atherothrombosis: the role of platelets.
        Eur Heart J. 1999; 1: A8-A13
        • Nguyen CM
        • Harrington RA
        Glycoprotein IIb/IIIa receptor antagonists: a comparative review of their use in percutaneous coronary intervention.
        Am J Cardiovasc Drugs. 2003; 3: 423-436
        • Falk E
        Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion.
        Circulation. 1985; 71: 699-708
        • Topol EJ
        • Nissen SE
        Our preoccupation with coronary luminology: the dissociation between clinical and angiographic findings in ischemic heart disease.
        Circulation. 1995; 92: 2333-2342
        • Asakura M
        • Ueda Y
        • Yamaguchi O
        • et al.
        Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction.
        J Am Coll Cardiol. 2001; 37: 1284-1288
        • Goldstein JA
        • Demetriou D
        • Grine CL
        • Pica M
        • Shoukfeh M
        • O'Neill WW
        Multiple complex coronary plaques in patients with acute myocardial infarction.
        N Engl J Med. 2000; 343: 915-922
        • Rioufol G
        • Finet G
        • Ginon I
        • et al.
        Multiple atherosclerotic plaque rupture in acute coronary syndrome.
        Circulation. 2002; 106: 804-808
        • 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
        • Ambrose JA
        • Tannenbaum MA
        • Alexopoulos D
        • et al.
        Angiographic progression of coronary artery disease and the development of myocardial infarction.
        J Am Coll Cardiol. 1988; 12: 56-62
        • Little WC
        • Constantinescu M
        • Applegate RJ
        • et al.
        Can coronary angiography predict the site of a subsequent myocardial infarction in patients with mild-to-moderate coronary artery disease?.
        Circulation. 1988; 78: 1157-1166
        • Glaser R
        • Selzer F
        • Faxon DP
        • et al.
        Clinical progression of incidental, asymptomatic lesions discovered during culprit coronary intervention.
        Circulation. 2005; 111: 143-149
        • Smith Jr, SC
        • Dove JT
        • Jacobs AK
        • et al.
        ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines)—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).
        Circulation. 2001; 103: 3019-3041
        • Pearson TA
        • McBride PE
        • Miller NH
        • Smith Jr, SC
        Task Force 8:organization of preventive cardiology service.
        J Am Coll Cardiol. 1996; 27: 1039-1047
        • Schwartz RS
        • Henry TD
        Pathophysiology of coronary artery restenosis.
        Rev Cardiovasc Med. 2002; 3: S4-S9
        • Marmur JD
        • Merlini PA
        • Sharma SK
        • et al.
        Thrombin generation in human coronary arteries after percutaneous transluminal balloon angioplasty.
        J Am Coll Cardiol. 1994; 24: 1484-1491
        • Le Breton H
        • Plow EF
        • Topol EJ
        Role of platelets in restenosis after percutaneous coronary revascularization.
        J Am Coll Cardiol. 1996; 28: 1643-1651
        • Chandrasekar B
        • Tanguay JF
        Platelets and restenosis.
        J Am Coll Cardiol. 2000; 35: 555-562
        • Wilentz JR
        • Sanborn TA
        • Haudenschild CC
        • Valeri CR
        • Ryan TJ
        • Faxon DP
        Platelet accumulation in experimental angioplasty: time course and relation to vascular injury.
        Circulation. 1987; 75: 636-642
        • Merino A
        • Cohen M
        • Badimon JJ
        • Fuster V
        • Badimon L
        Synergistic action of severe wall injury and shear forces on thrombus formation in arterial stenosis: definition of a thrombotic shear rate threshold.
        J Am Coll Cardiol. 1994; 24: 1091-1097
        • Gasperetti CM
        • Gonias SL
        • Gimple LW
        • Powers ER
        Platelet activation during coronary angioplasty in humans.
        Circulation. 1993; 88: 2728-2734
        • Kolarov P
        • Tschoepe D
        • Nieuwenhuis HK
        • Gries FA
        • Strauer B
        • Schultheiss HP
        PTCA: periprocedural platelet activation: part II of the Duesseldorf PTCA Platelet Study (DPSS).
        Eur Heart J. 1996; 17: 1216-1222
        • Neumann FJ
        • Ott I
        • Gawaz M
        • Schomig A
        Neutrophil and platelet activation at balloon-injured coronary artery plaque in patients undergoing angioplasty.
        J Am Coll Cardiol. 1996; 27: 819-824
        • Inoue T
        • Hoshi K
        • Fujito T
        • Sakai Y
        • Morooka S
        • Sohma R
        Early detection of platelet activation after coronary angioplasty.
        Coron Artery Dis. 1996; 7: 529-534
        • Inoue T
        • Hoshi K
        • Yaguchi I
        • Iwasaki Y
        • Takayanagi K
        • Morooka S
        Serum levels of circulating adhesion molecules after coronary angioplasty.
        Cardiology. 1999; 91: 236-242
        • Mizuno O
        • Hojo Y
        • Ikeda U
        • et al.
        Assessment of coagulation and platelet activation in coronary sinus blood induced by transcatheter coronary intervention for narrowing of the left anterior descending coronary artery.
        Am J Cardiol. 2000; 85: 154-160
        • Serrano CV
        • Ramires JA
        • Venturinelli M
        • et al.
        Coronary angioplasty results in leukocyte and platelet activation with adhesion molecule expression: evidence of inflammatory responses in coronary angioplasty.
        J Am Coll Cardiol. 1997; 29: 1276-1283
        • Azar RR
        • McKay RG
        • Kiernan FJ
        • et al.
        Coronary angioplasty induces a systemic inflammatory response.
        Am J Cardiol. 1997; 80: 1476-1478
        • Gawaz M
        • Neumann FJ
        • Ott I
        • May A
        • Rudiger S
        • Schomig A
        Changes in membrane glycoproteins of circulating platelets after coronary stent implantation.
        Heart. 1996; 76: 166-172
        • Markovitz JH
        • Roubin GS
        • Parks JM
        • Bittner V
        Platelet activation and restenosis after coronary stenting: flow cytometric detection of wound-induced platelet activation.
        Coron Artery Dis. 1996; 7: 657-665
        • Inoue T
        • Sohma R
        • Miyazaki T
        • Iwasaki Y
        • Yaguchi I
        • Morooka S
        Comparison of activation process of platelets and neutrophils after coronary stent implantation versus balloon angioplasty for stable angina pectoris.
        Am J Cardiol. 2000; 86: 1057-1062
        • Parsson H
        • Cwikiel W
        • Johansson K
        • Swartbol P
        • Norgren L
        Deposition of platelets and neutrophils in porcine iliac arteries after angioplasty and Wallstent placement compared with angioplasty alone.
        Cardiovasc Intervent Radiol. 1994; 17: 190-196
        • Adams PC
        • Badimon JJ
        • Badimon L
        • Chesebro JH
        • Fuster V
        Role of platelets in atherogenesis: relevance to coronary arterial restenosis after angioplasty.
        Cardiovasc Clin. 1987; 18: 49-71
        • Libby P
        • Schwartz D
        • Brogi E
        • Tanaka H
        • Clinton SK
        A cascade model for restenosis: a special case of atherosclerosis progression.
        Circulation. 1992; 86: III47-III52
        • Neumann FJ
        • Gawaz M
        • Ott I
        • May A
        • Mossmer G
        • Schomig A
        Prospective evaluation of hemostatic predictors subacute stent thrombosis after coronary Palmaz-Schatz stenting.
        J Am Coll Cardiol. 1996; 27: 15-21
        • Grech ED
        Percutaneous coronary intervention: history and development.
        BMJ. 2003; 326: 1080-1082
        • Levine GN
        • Chodod AP
        • Loscalzo J
        Restenosis following coronary angioplasty: clinical presentations and therapeutic options.
        Clin Cardiol. 1995; 18: 693-703
        • Terstein P
        • Reilly JP
        Late stent thrombosis in brachytherapy: the role of long-term antiplatelet therapy.
        J Invas Cardiol. 2002; 14: 109-114
        • Shaknovich A
        Complications of coronary stenting.
        Coron Artery Dis. 1994; 5: 583-589
        • Mak K-H
        • Belli G
        • Ellis SG
        • Moliterno DJ
        Subacute stent thrombosis: evolving issues and current concepts.
        J Am Coll Cardiol. 1996; 27: 494-503
        • Cutlip DE
        • Baim DS
        • Ho KK
        • et al.
        Stent thrombosis in the modern era: a pooled analysis of multicenter coronary stent clinical trials.
        Circulation. 2001; 103: 1967-1971
        • Iakovou I
        • Schmidt T
        • Bonizzoni E
        • et al.
        Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents.
        JAMA. 2005; 293: 2126-2130
        • Gurbel PA
        • Bliden KP
        • Samara W
        • et al.
        Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study.
        J Am Coll Cardiol. 2005; 46: 1827-1832
        • Merlini PA
        • Bauer KA
        • Oltrona L
        • et al.
        Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.
        Circulation. 1994; 90: 61-68
        • Mehta SR
        • Yusuf S
        Short- and long-term oral antiplatelet therapy in acute coronary syndromes and percutaneous coronary intervention.
        J Am Coll Cardiol. 2003; 41: 79S-88S
        • Blann AD
        • Landray MJ
        • Lip GY
        ABC of antithrombotic therapy: an overview of antithrombotic therapy.
        BMJ. 2002; 325: 762-765
        • Braunwald E
        • Antman EM
        • Beasley JW
        • et al.
        ACC/AHA 2002 guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina).
        J Am Coll Cardiol. 2002; 40: 1366-1374
        • Antman EM
        • Anbe DT
        • Armstrong PW
        • et al.
        ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction).
        Circulation. 2004; 110: 588-636
      1. ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention.
        (Accessed March 23, 2006.)
        • Schwartz L
        • Bourassa MG
        • Lesperance J
        • et al.
        Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty.
        N Engl J Med. 1988; 318: 1714-1719
        • Lembo NJ
        • Black AJ
        • Roubin GS
        • et al.
        Effect of pre-treatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty.
        Am J Cardiol. 1990; 65: 422-426
        • Schomig A
        • Neumann FJ
        • Kastrati A
        • et al.
        A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary artery stents.
        N Engl J Med. 1996; 334: 1084-1089
        • Bertrand ME
        • Legrand V
        • Boland J
        • et al.
        Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study.
        Circulation. 1998; 98: 1597-1603
        • Leon MB
        • Baim DS
        • Popma JJ
        • et al.
        A randomized trial comparing three drug regimens to prevent thrombosis following elective coronary stenting.
        N Engl J Med. 1998; 339: 1665-1671
        • Urban P
        • Macaya C
        • Rupprecht HJ
        • et al.
        Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS).
        Circulation. 1998; 98: 2126-2132
        • Bertrand ME
        • Rupprecht H-J
        • Urban P
        • Gershlick AH
        • CLASSICS Investigators
        Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting: the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).
        Circulation. 2000; 102: 624-629
        • Muller C
        • Buttner HJ
        • Petersen J
        • Roskamm H
        A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary artery stents.
        Circulation. 2000; 101: 590-593
        • Bhatt DL
        • Bertrand ME
        • Berger PB
        • et al.
        Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.
        J Am Coll Cardiol. 2002; 39: 9-14
        • Mehta SR
        • Yusuf S
        • Peters RJ
        • et al.
        Effects of pre-treatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.
        Lancet. 2001; 358: 527-533
        • Steinhubl SR
        • Berger PB
        • Mann III, JT
        • CREDO Investigators
        • et al.
        Early and sustained dual antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial [published correction appears in JAMA. 2003;289:987].
        JAMA. 2002; 288: 2411-2420
        • Sabatine MS
        • Cannon CP
        • Gibson CM
        • Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators
        • et al.
        Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study.
        JAMA. 2005; 294: 1224-1232
        • Müller I
        • Seyfarth M
        • Rudiger S
        • et al.
        Effect of a high loading dose of clopidogrel on platelet function in patients undergoing coronary stent placement.
        Heart. 2001; 85: 92-93
        • Patti G
        • Colonna G
        • Pasceri V
        • Pepe LL
        • Montinaro A
        • Di Sciascio G
        Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study.
        Circulation. 2005; 111: 2099-2106
      2. Montalescot G. Assessment of the best Loading dose of clopidogrel to Blunt platelet activation, Inflammation, and Ongoing Necrosis (ALBION) trial. Presented at: EuroPCR Congress; Paris, France, May 24, 2005.

        • von Beckerath N
        • Taubert D
        • Pogatsa-Murray G
        • Schomig E
        • Kastrati A
        • Schomig A
        Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial.
        Circulation. 2005; 112: 2946-2950
        • EPIC Investigators
        Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty.
        N Engl J Med. 1994; 330: 956-961
        • EPISTENT Investigators
        Randomized placebo-controlled and balloon angioplasty controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade.
        Lancet. 1998; 352: 87-92
        • RESTORE Investigators
        Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty.
        Circulation. 1997; 96: 1445-1453
        • ESPRIT Investigators
        Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial [published correction appears in Lancet. 2001;357:1370].
        Lancet. 2000; 356: 2037-2044
        • Roffi M
        • Mukherjee D
        • Chew DP
        • et al.
        Lack of benefit from intravenous platelet glycoprotein IIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts: a pooled analysis of five randomized clinical trials.
        Circulation. 2002; 106: 3063-3067
        • Kastrati A
        • Mehilli J
        • Schühlen H
        • Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment Study Investigators
        • et al.
        A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel.
        N Engl J Med. 2004; 350: 232-238
        • Mehilli J
        • Kastrati A
        • Schühlen H
        • Intracoronary Stenting and Antithrombotic Region: Is Abciximab a Superior Way to Eliminate Elevated Thrombotic Risk in Diabetes (ISAR-SWEET) Study Investigators
        • et al.
        Randomized clinical trial of abciximab in diabetic patients undergoing elective percutaneous coronary interventions after treatment with a high loading dose of clopidogrel.
        Circulation. 2004; 110: 3627-3635
        • Lincoff A
        • Bittl JA
        • Harrington RA
        • REPACE-2 Investigators
        • 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 [published correction appears in JAMA. 2003;289:1638].
        JAMA. 2003; 289: 853-863
        • Lincoff AM
        • Kleiman NS
        • Kereiakes DJ
        • REPACE-2 Investigators
        • 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
        • Stone GW
        • Bertrand M
        • Colombo A
        • et al.
        Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale.
        Am Heart J. 2004; 148: 764-775
        • Antman EM
        Should bivalirudin replace heparin during percutaneous coronary interventions?.
        JAMA. 2003; 289: 903-905
        • Levine GN
        • Kern MJ
        • Berger PB
        • et al.
        Management of patients undergoing percutaneous coronary revascularization.
        Ann Intern Med. 2003; 139: 123-136
        • Yusuf S
        • Flather M
        • Pogue J
        • OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators
        • et al.
        Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation.
        Lancet. 1998; 352: 507-514
        • Van Belle E
        • Lablanche JM
        • Bauters C
        • Renaud N
        • McFadden EP
        • Bertrand ME
        Coronary angioscopic findings in the infarct-related vessel within 1 month of acute myocardial infarction: natural history and the effect of thrombolysis.
        Circulation. 1998; 90: 26-30
        • Antithrombotic Trialists' Collaboration
        Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high-risk patients.
        BMJ. 2002; 324: 71-86
        • Aronow HD
        • Steinhubl SR
        • Brennan DM
        • Topol EJ
        Long-term clopidogrel therapy following percutaneous coronary intervention improves clinical outcome but is not associated with increased bleeding: new insights from the CREDO trial [abstract].
        J Am Coll Cardiol. 2004; 43: 21A
        • Karvouni E
        • Katritsis DG
        • Ioannidis JP
        Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions.
        J Am Coll Cardiol. 2003; 41: 26-32
        • Eriksson P
        Long-term clopidogrel therapy after percutaneous coronary intervention in PCI-CURE and CREDO: the “Emperor's New Clothes” revisited.
        Eur Heart J. 2004; 25: 720-722
        • Silber S
        • von Rottkay P
        • Lossl P
        • et al.
        Safety and feasibility of intracoronary brachytherapy with the Novoste system within the scope of international multicenter studies.
        Kardiologie. 2000; 89: 323-329
        • Sapirstein W
        • Zuckerman B
        • Dillard J
        FDA approval of coronary artery brachytherapy.
        N Engl J Med. 2001; 344: 297-299
        • 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
        • Stone GW
        • Ellis SG
        • Cox DA
        • et al.
        A polymer-based paclitaxel-eluting stent in patients with coronary artery disease.
        N Engl J Med. 2004; 350: 221-231
        • Lemos PA
        • Serruys PW
        • van Domburg RT
        • et al.
        Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real world”: the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry.
        Circulation. 2004; 109: 190-195
        • Tantry US
        • Bliden KP
        • Gurbel PA
        Resistance to antiplatelet drugs: current status and future research.
        Expert Opin Pharmacother. 2005; 6: 2027-2045
        • Guthikonda S
        • Lev EI
        • Kleiman NS
        Resistance to antiplatelet therapy.
        Curr Cardiol Rep. 2005; 7: 242-248
        • Barragan P
        • Bouvier JL
        • Roquebert PO
        • et al.
        Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation.
        Catheter Cardiovasc Interv. 2003; 59: 295-302
        • Matetzky S
        • Shenkman B
        • Guetta V
        • et al.
        Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction.
        Circulation. 2004; 109: 3171-3175
        • Nguyen TA
        • Diodati JG
        • Pharand C
        Resistance to clopidogrel: a review of the evidence.
        J Am Coll Cardiol. 2005; 45: 1157-1164
        • Heart Outcomes Prevention Evaluation Study Investigators
        Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients.
        N Engl J Med. 2000; 342: 145-153
        • EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators
        Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study).
        Lancet. 2003; 362: 782-788
        • Freemantle N
        • Urdahl H
        • Eastaugh J
        • Hobbs FD
        What is the place of beta-blockade in patients who have experienced a myocardial infarction with preserved left ventricular function? evidence and misinterpretation.
        Prog Cardiovasc Dis. 2002; 44: 243-250
        • Pasceri V
        • Patti G
        • Nusca A
        • Pristipino C
        • Richichi G
        • Di Sciascio G
        • ARMYDA Investigators
        Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study.
        Circulation. 2004; 110: 674-678
        • Serruys PWJC
        • de Feyter P
        • Macaya C
        • Lescol Intervention Prevention Study (LIPS) Investigators
        • et al.
        Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
        JAMA. 2002; 287: 3215-3222
        • Cannon CP
        • Braunwald E
        • McCabe CH
        • et al.
        Intensive versus moderate lipid lowering with statins after acute coronary syndromes.
        N Engl J Med. 2004; 350: 1495-1504
        • Aronow HD
        • Novaro GM
        • Lauer MS
        • et al.
        In-hospital initiation of lipid-lowering therapy after coronary intervention as a predictor of long-term utilization: a propensity analysis.
        Arch Intern Med. 2003; 163: 2576-2582
        • MacMahon S
        • Peto R
        • Cutler J
        • et al.
        Blood pressure, stroke and coronary heart disease, part I: prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias.
        Lancet. 1990; 335: 765-774
        • Pasternak RC
        • Grundy SM
        • Levy D
        • Thompson PD
        Task Force 3: spectrum of risk factors for coronary heart disease.
        J Am Coll Cardiol. 1996; 27: 978-990
        • UK Prospective Diabetes Study (UKPDS) Group
        Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
        Lancet. 1998; 352: 837-853
        • American Association of Clinical Endocrinologists
        Medical Guidelines for the Management of Diabetes Mellitus: the AACE system of intensive diabetes self management—2002 update.
        Endocrinol Pract. 2002; 8: 40-82
        • Kannel WB
        Cigarette smoking and coronary heart disease.
        Ann Intern Med. 1964; 60: 1103-1106
        • Duthie GG
        • Arthur JR
        • Beattie JA
        • et al.
        Cigarette smoking, antioxidants, lipid peroxidation and coronary heart disease.
        Ann N Y Acad Sci. 1993; 686: 120-129
        • Thompson PD
        • Buchner D
        • Pina IL
        • et al.
        Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity and Metabolism (Subcommittee on Physical Activity).
        Circulation. 2003; 107: 3109-3116
        • Belardinelli R
        • Paolini I
        • Cianci G
        • Piva R
        • Georgiou D
        • Purcaro A
        Exercise training intervention after coronary angioplasty: the ETICA trial.
        J Am Coll Cardiol. 2001; 37: 1891-1900
        • Burr ML
        • Fehily AM
        • Gilbert JF
        • et al.
        Effects of changes in fat, fish, and fibre intakes on death and myocardial reinfarction: Diet and Reinfarction Trial (DART).
        Lancet. 1989; 2: 757-761
        • De Lorgeril M
        • Salen P
        • Martin JL
        • Monjaud I
        • Delaye J
        • Mamelle N
        Mediterranean diet, traditional risk factors and the rate of cardiovascular complications after myocardial infarction: final results of the Lyon Diet Heart Study.
        Circulation. 1999; 99: 779-785
        • Tremblay A
        • Doucet E
        • Imbeault P
        • Mauriege P
        • Despres JP
        • Richard D
        Metabolic fitness in active reduced-obese individuals.
        Obes Res. 1999; 7: 556-563