Antithrombotic therapy for elective percutaneous coronary intervention General use

INTRODUCTION 

Percutaneous coronary intervention (PCI) disrupts the coronary endothelium, leading to the exposure of subendothelial tissue factors to blood. Intracoronary thrombosis may result during or soon after the procedure. In addition, metal (which is procoagulant) stents can trigger thrombus formation. Stent thrombosis can be a life-threatening event.  

Aggressive antithrombotic therapy with aspirin, platelet P2Y12 receptor blockers, glycoprotein (GP) IIb/IIIa inhibitors, and parenteral anticoagulants is used to decrease the risk of early intracoronary thrombosis. Recommendations for the use of these agents in stable patients before and within the first few days of stent placement will be the focus of this topic. The studies supporting these recommendations are presented separately.  

The use of antithrombotic therapy in the setting of acute coronary syndromes (ACS) is discussed elsewhere.  

THE APPROACH 

We prescribe antithrombotic therapy to stable patients undergoing elective PCI with stenting in the following sequential manner:

●We give aspirin 75 to 100 mg daily to all patients scheduled for stenting. For patients not previously taking aspirin, we give a single loading dose of 300 to 325 mg.

●For patients who have previously undergone diagnostic coronary angiography and in whom a decision has been made to proceed with PCI, we give clopidogrel 600 mg as a single loading dose 24 hours or more (but at least two hours) before the procedure. We then give clopidogrel 75 mg daily until the PCI. For patients who are undergoing diagnostic coronary angiography and who may receive PCI with stenting at the same procedure, we withhold clopidogrel until a decision to proceed with stenting has been made.

●After the decision to proceed with PCI, we give unfractionated heparin  using a weight-adjusted bolus of 60 international units/kg, unless heparin has previously been administered for a radial artery access diagnostic procedure. Additional heparin is administered to achieve an activated clotting time (ACT) between 250 to 350 seconds (depending upon the ACT device). Although we prefer heparin,bivalirudin is a reasonable alternative for patients at high bleeding risk or those with heparin-induced thrombocytopenia; we give a loading dose of 0.75 mg/kg and an infusion according to renal function . In uncomplicated procedures, the heparin or bivalirudin is stopped at the end of the procedure. For femoral access, sheath removal should be accomplished when the ACT falls to less than 150 to 180 for heparin (or two hours after discontinuation for bivalirudin) or a vascular closure device can be used immediately when there is suitable vascular anatomy.

●For patients who are at high risk for acute stent thrombosis based on angiographic criteria (visible thrombus, persistent dissection, postprocedure Thrombolysis in Myocardial Infarction [TIMI] flow grade <3), we add a glycoprotein IIb/IIIa inhibitor. We start eptifibatide  with a 180 mcg/kg intravenous bolus given twice, 10 min apart (maximum dose of 22.6 mg each bolus). We then start an infusion of 2mcg/kg/min (maximum dose of 15 mg/hr) after first bolus. The drug is continued for 2 to 18 hours; the duration depends on balancing the risks for thrombosis and bleeding.

ASPIRIN — All patients with coronary artery disease should receive aspirin. Aspirin is specifically recommended for patients undergoing coronary stenting, based primarily upon data from early randomized trials of aspirin or aspirin plus dipyridamole compared with placebo in patients undergoing percutaneous transluminal coronary (balloon) angioplasty (PTCA)

For patients not receiving long-term aspirin, we pretreat with 300 to 325 mg, preferably given at least two hours before the procedure. In addition, this dose and time is used for those taking a maintenance dose of less than 325 mg.

For aspirin allergic patients, we usually recommend desensitization therapy before the stent procedure. Patients who cannot tolerate long-term aspirin are usually treated with clopidogrel.  

For these aspirin-allergic patients who need to undergo PCI prior to desensitization, the optimal approach is not known. Our experts use one of the following two approaches, which have not been formally evaluated, in patients who cannot be desensitized before the procedure:

●Administer a P2Y12 receptor blocker alone. With this approach, some experts prefer the more potent agents prasugrel or ticagrelor to clopidogrel.

●Administer an intravenous glycoprotein (GP) IIb/IIIa antagonist during the procedure.

When the patient is stable, an evaluation for possible aspirin desensitization can be performed by an allergy expert.  

P2Y12 RECEPTOR BLOCKERS — A P2Y12 receptor blocker (usually clopidogrel) is given to all patients either before or at the time of elective coronary artery stenting to reduce the risk of periprocedural and early (within 30 days) stent thrombosis. The efficacy of these agents has been demonstrated in numerous randomized trials.  

Clopidogrel is the preferred platelet P2Y12 receptor blocker in patients with stable coronary artery disease undergoing PCI. We suggest pretreatment (prior to PCI) with clopidogrel for stable patients whose coronary anatomy is known from a recent diagnostic coronary angiogram. We give a loading dose of 600 mg of clopidogrel, starting preferably 24 hours or more, but at least two hours, before scheduled or anticipated PCI in most patients. Our recommendation to pretreat with clopidogrel in some patients is based on one randomized trial (CREDO).  

For stable patients whose coronary anatomy is not known and who are scheduled for diagnostic coronary angiography with possible PCI, we suggest withholding the drug until after diagnostic coronary angiography as many patients will either not have disease that needs revascularization or will have disease that requires coronary artery bypass surgery. In these situations, the patient will have been unnecessarily exposed to clopidogrel if it is given prior to angiography. The role of periprocedural glycoprotein (GP) IIb/IIIa inhibitor therapy for these patients is discussed below.  

Clopidogrel has been extensively evaluated in patients undergoing elective stent implantation and is the focus of the discussion below. The other P2Y12 receptor blockers include:

Ticlopidine was the first widely used thienopyridine for the prevention of stent thrombosis. In early randomized trials of patients receiving bare metal stents, ticlopidine significantly lowered the risk of stent thrombosis at 30 days when given with aspirin. However, hematologic side effects, such as neutropenia and thrombotic thrombocytopenia purpura-hemolytic uremic syndrome, limit its use.  

Prasugrel and ticagrelor have not been extensively evaluated in patients with stable disease undergoing PCI.  

Cangrelor is an intravenous P2Y12 receptor blocker that has been compared with either clopidogrel or placebo in three trials that have included patients with stable coronary disease.  Cangrelor was approved for use by the United States Food and Drug Administration in June of 2015 as an adjunct to PCI in patients who have not been treated with a P2Y12 platelet inhibitor and who are not being given a GP IIb/IIIa inhibitor [3,4]. We believe it is reasonable to use cangrelor in patients not previously loaded with an oral P2Y12 receptor blocker.

Evidence regarding timing and dose — A 2012 meta-analysis evaluated the optimal timing of clopidogrel using data from six randomized trials and nine observational studies [5]. The principal analysis was limited to the randomized trials (approximately 8600 patients), in which 25 percent of patients had elective PCI. Clopidogrel pretreatment, compared with treatment after catheterization, was not associated with a statistically significant reduction in mortality (absolute risk 1.54 versus 1.97 percent, respectively, odds ratio [OR] 0.80, 95% CI 0.57-1.11), but was associated with a lower risk of a secondary composite endpoint of myocardial infarction (MI), stroke, or urgent revascularization (9.83 versus 12.35 percent, OR 0.77, 95% CI 0.66-0.89). Bleeding rates were comparable (3.57 versus 3.08 percent).

The majority of the stable patients in the meta-analysis came from the CREDO trial, in which 2116 patients with stable angina were randomly assigned to clopidogrel (300 mg loading dose) or no pretreatment [6]. Clopidogrel loading was associated with a nonsignificant reduction in risk (6.8 versus 8.3 percent; relative risk reduction 18.5 percent, 95% CI -14.2 to 41.8) in the combined endpoint of death, MI, or urgent target vessel revascularization at 28 days. Additional details of CREDO are presented separately.  

The PRAGUE-8 (stable angina) and ARMYDA-5 PRELOAD (61 percent stable angina) trials demonstrated equivalent efficacy and safety with clopidogrel 600 mg given either before (mean of 19 and 6 hours, respectively, in the two trials) or after elective coronary arteriography (CAG) but before PCI.  

The possible efficacy of higher loading doses, such as 900 or even 1200 mg, is discussed separately.  

Patients who undergo PCI with stenting must be properly informed of the importance of compliance to recommendations made regarding long-term dual antiplatelet therapy. Most patients will be discharged on clopidogrel 75 mg daily for a variable minimum duration depending on stent type and aspirin 75 to 100 mg daily.  

Patients already taking clopidogrel — Our experts feel the evidence is not robust enough to make a strong suggestion for or against clopidogrel reloading. They suggest clopidogrel reloading with 600 mg of clopidogrel in patients on long-term clopidogrel therapy either who undergo PCI at the time of ACS or who are at high risk of stent thrombosis.  

The issue of whether patients who are receiving chronic clopidogrel therapy require an additional loading dose before PCI to reduce periprocedural events has not been well studied. Two randomized trials that included both stable and ACS patients taking clopidogrel for at least seven days have attempted to address this issue:

●In the RELOAD trial, 166 patients were randomly assigned to receive clopidogrel reloading with 900, 600, or 300 mg. The primary outcome was the relative change, compared with baseline, in the inhibition or residual platelet function at four hours after dosing. The 900 mg dose produced a significantly greater reduction in platelet function compared with either of the lower doses.

●In the ARMYDA-4 RELOAD trial, 503 patients were randomly assigned to receive either clopidogrel 600 mg or placebo loading four to eight hours before PCI [8]. There was no significant difference in the primary combined endpoint of the 30-day incidence of death, MI, or target vessel revascularization (6.7 versus 8.8 percent, respectively). Almost all of the events were attributable to a rise in biomarker. There were no episodes of major bleeding in either group. The clinical relevance of this finding remains to be determined. In the subset of patients with ACS there was a significant benefit (6.4 versus 16.3 percent; OR 0.34, 95% CI 0.32-0.90).

Possible coronary artery bypass graft surgery — An occasional stable patient may need coronary artery bypass graft surgery (CABG) soon after catheterization. The 2011 American College of CardiologyFoundation/American Heart Association guideline on CABG recommended that clopidogrel should be discontinued for at least five days before CABG, based on the recognition of an increase in perioperative bleeding in patients taking clopidogrel [9]. The management of platelet P2Y12 receptor blocker therapy in patients needing urgent or emergent CABG is discussed separately.  

Problems with clopidogrel use

Resistance/nonresponse to clopidogrel is discussed separately.  

Use with proton pump inhibitors – Gastrointestinal bleeding is a risk of dual antiplatelet therapy with aspirin and clopidogrel, particularly in the time around placement of an intracoronary stent when other antithrombotic therapy may be used.  

Proton pump inhibitors (PPIs) have been recommended for the prevention of gastrointestinal bleeding in patients at high risk for clinically important gastrointestinal bleeding. However, reports in 2008 and 2009 have raised concerns that some, but not necessarily all, PPIs interfere with the ability of clopidogrel to inhibit platelet function and thereby increase the likelihood of coronary artery stent thrombosis, MI, or cardiovascular death.
 
Our recommendations for the use of PPIs in patients on dual antiplatelet therapy, including those patients who have undergone PCI, are presented elsewhere.
 

Thrombotic microangiopathy (TMA) – Some case reports have described an association between clopidogrel and thrombotic microangiopathy (a thrombotic thrombocytopenic purpura-like syndrome of hemolytic anemia and thrombocytopenia that may be life-threatening) [10]. However, some experts do not believe this is a causal association. Additional information and an approach to the evaluation and management of a patient with microangiopathic hemolytic anemia and thrombocytopenia are presented separately.  

Hypersensitivity – Hypersensitivity to clopidogrel develops in 1 to 4 percent of patients and typically appears between 5 and 10 days after initiation of therapy. The most common presentation is an erythematous, macular, pruritic rash, which typically begins on the face, chest, or abdomen, then spreads and becomes confluent. Given the importance of prolonged dual antiplatelet therapy in patients who receive intracoronary stents, those who develop an apparent hypersensitivity to clopidogrel need the issue addressed in a timely manner. We suggest referring these patients to a specialist in the care of patients with medication allergies. This issue is discussed in detail elsewhere.  

GP IIb/IIIa INHIBITORS — For patients pretreated with clopidogrel and aspirin, we do not routinely give a glycoprotein (GP) IIb/IIIa inhibitor. There is no evidence that doing so improves outcomes, and it increases the risk of periprocedural bleeding.  

Similarly, for patients who have not received the recommended dose and timing of clopidogrel before PCI, we do not routinely add a GP IIb/IIIa inhibitor. While there is some rationale for doing so, based upon its known immediate antiplatelet effect, studies such as ISAR-REACT and in a subgroup analysis from the ESPRIT trial found no benefit when patients were pretreated with high-dose (600 mg) clopidogrel at least two hours before the procedure.  

We limit the use of GP IIb/IIIa inhibitors during elective PCI to patients with a suboptimal angiographic result. Our use in patients with a suboptimal angiographic result is based on our clinical experience as no studies have directly addressed this issue. In addition, we believe this is a reasonable approach as GP IIb/IIIa inhibitors have some role in patients with non-ST elevation acute coronary syndromes (ACS).  

The timing and dose of these drugs are presented separately . The optimal duration of treatment with GP IIb/IIIa inhibitors for those patients who have received adequate pretreatment with clopidogrel has not been well studied. In such patients, experts vary between discontinuation after PCI to as long as recommended in the package inserts for each drug.

Risk for bleeding — The risk of a major bleeding complication, including gastrointestinal bleeding after PCI, in patients treated with aspirin and clopidogrel is mildly increased in those who have received GP IIb/IIIainhibitors. The risk is particularly increased in older adults, women, or those with renal insufficiency.  

Thrombocytopenia — Abciximab and eptifibatide, but not tirofiban, are associated with an increased risk of thrombocytopenia. This subject is discussed separately.  

Choice of agent — In terms of the choice of drug, abciximab has no persistent advantage over tirofiban for nonemergent stenting. The initial benefit is probably due to more complete platelet inhibition with the regimens used. Tirofiban and eptifibatide are substantially less expensive than abciximab, and their use is associated with lower hospital and 30-day costs [14].

We generally prefer eptifibatide for elective PCI and for more urgent PCI in non-ST elevation ACS because of lower cost and comparable efficacy to abciximab and because the optimal dosing regimen to achieve the desired level of early platelet inhibition is more clearly defined   than with tirofiban  .

When PCI for ACS is delayed, tirofiban using current dosing regimens is a reasonable alternative. High-dose tirofiban, used in the EVEREST and ADVANCE trials , may also be beneficial compared with abciximab. The large TENACITY trial designed to address this question has been halted due to lack of funding.

ANTICOAGULANTS — We treat all patients undergoing elective PCI with anticoagulant therapy. Based on the evidence presented below, we prefer unfractionated heparin for most patients

Heparin — The practice of giving intravenous unfractionated heparin before PCI to prevent intracoronary or device-related thrombosis was initiated when percutaneous transluminal coronary angioplasty was the procedure of choice (ie, before the stent era) and prior to the routine use of dual antiplatelet therapy with aspirin and a P2Y12 receptor blocker . The rationale for anticoagulation is that the procedure is associated with factors that predispose to thrombosis: stasis within the coronary artery and catheters and exposure of the clotting elements of the blood to an injured endothelium and to catheters and wires. There are no randomized trials of patients undergoing PCI in which unfractionated heparin (or other anticoagulant) has been compared with placebo.

Dosing and monitoring — For PCI, the optimal dose of heparin is that which balances the risks of thrombosis and bleeding  . There are no randomized trials comparing different heparin doses or activated clotting time (ACT) goals in patients with stable coronary artery disease and who have been pretreated with aspirin and a thienopyridine. Thus, current recommendations for dosing and monitoring, including those from societal guidelines, are based upon older studies and observational evidence.

Monitoring of heparin effect is usually performed in an attempt to avoid over- or under-anticoagulation. When chosen, monitoring is usually performed using the ACT since the partial thromboplastin time often becomes infinitely prolonged at the high heparin concentrations that are attained in these procedures .

The 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Intervention guideline update for PCI recommended that, in patients not receiving a glycoprotein (GP) IIb/IIIa inhibitor, unfractionated heparin should be given using a weight-adjusted bolus of 70 to 100 international units/kg to achieve an ACT between 250 to 350 seconds (depending upon the ACT device) . Further heparin boluses are given if the goal ACT is not achieved .

The recommendation for 100 international units/kg as the upper limit of the heparin bolus range was supported by findings in the ISAR-REACT 3A study, in which elective PCI with stenting was performed in over 2500 stable patients pretreated with aspirin and clopidogrel; all patients were given a heparin bolus of 100 international units/kg . Outcomes were compared with those of the heparin (140 international units/kg)cohort in ISAR-REACT 3 trial. The rate of the primary composite endpoint (death, myocardial infarction [MI], urgent target vessel revascularization within 30 days, or major bleeding) was similar in both groups, and there was a trend toward a lower rate of bleeding at the lower dose

Use with GP IIb/IIIa inhibitors — For patients who are treated with a GP IIb/IIIa inhibitor, we suggest a heparin bolus of 50 to 70 international units/kg, a dose lower than that in ISAR-REACT 3A, as we are concerned that a dose of 100 international units/kg will lead to an ACT that frequently exceeds the desired ACT goal of >250 to 300 seconds. The ACT is targeted at 200 to 250 seconds, and it is checked 10 minutes after the bolus. These recommendations are based upon the following observations:

●In the ESPRIT trial, 2064 patients were randomly assigned to eptifibatide or placebo prior to PCI; all patients received stents  . The incidence of death or MI at 48 hours was 5.5, 6.1, and 6.1 percent for patients treated with eptifibatide with an ACT of <244, 244 to 292, or >292 seconds, respectively. The risk of major bleeding was lowest in the low-ACT group, though the differences were not statistically significant.

●A meta-analysis of four trials (CREDO, TARGET, REPLACE-1, and REPLACE-2) included 8369 patients with ACT data; 93 percent received a stent, and 89 percent received a GP IIb/IIIa inhibitor . The incidence of death, MI, or target vessel revascularization was similar for patients with ACT <256, 257 to 296, 297 to 347, and >348 (6.2, 6.8, 6.0, and 5.7 percent, respectively). The incidence of major or minor bleeding at 48 hours increased with increasing quartile of ACT. In a multivariate analysis, the risk of bleeding increased with increasing ACT up to 356 seconds, with a nonsignificant decline in risk at higher ACT values.

Patients taking oral anticoagulants — It has been estimated that at least 5 percent of patients undergoing PCI have been receiving oral anticoagulation for diseases such as atrial fibrillation (AF). The optimal anticoagulant strategy in these patients is unknown, and approaches have included discontinuation of oral anticoagulation and bridging with heparin or continuation of oral anticoagulation with or without additional heparin. A 2010 meta-analysis of eight moderate- to low-quality studies of patients undergoing elective coronary angiography with or without PCI found that a strategy of uninterrupted vitamin K antagonist (VKA) lowered the risk of access site bleeding by approximately 50 percent, compared with interrupted VKA  .

The optimal anticoagulant strategy in patients undergoing PCI was addressed in an observational study of 414 patients taking therapeutic doses of warfarin (International Normalized Ratio [INR] 2 to 3.5) for AF [30]. Individuals were almost evenly divided between those with stable and unstable disease; 218 patients received additional periprocedural heparin while 196 patients did not. In 122 propensity score-matched pairs, there was no significant difference in the rate of major adverse cardiac and cerebrovascular events or Thrombolysis in Myocardial Infarction (TIMI) major bleeding . However, there was a significantly higher rate of access site complications in those receiving heparin (13 versus 5.7 percent; p = 0.049).

Based on limited evidence, we believe it is reasonable to omit heparin in stable and unstable patients undergoing PCI who are receiving therapeutic oral anticoagulation with warfarin or those taking therapeutic doses of other oral anticoagulants.

Postprocedural management — Postprocedural heparin is not recommended in patients with an uncomplicated procedure . There is no evidence that prolonged use of postprocedural heparin or low-molecular-weight heparin prevents stent thrombosis or restenosis, and postprocedural heparin is associated with increased bleeding and vascular complications .

Sheath removal should be accomplished when the ACT falls to less than 150 to 180 seconds after the procedure to reduce the incidence of complications at the access site.

Heparin-induced thrombocytopenia — When heparin-induced thrombocytopenia (HIT) is present or suspected, possible substitutions for heparin are argatroban, lepirudin, and bivalirudin, although only argatroban is approved as adjunctive therapy for PCI in this setting. Low-molecular-weight heparin is contraindicated in such patients.  

Enoxaparin — Although seemingly safe and as effective as unfractionated heparin  , the clinical role of low-molecular-weight heparin in stable patients remains uncertain. It seems reasonable and is probably safer to continue enoxaparin than switching to heparin once it has been initiated for any reason, depending on timing and number of prior doses.  

Dosing of low-molecular-weight heparin has been based upon patient weight without laboratory monitoring. Enoxaparin does not reliably prolong the ACT at the doses used in PCI  

Bivalirudin — The relative efficacy and safety of bivalirudin compared with heparin has not been well studied in patients undergoing elective PCI who are treated using current antiplatelet drug recommendations. Many studies, including REPLACE-2, ISAR-REACT 3, and ACUITY have compared these two anticoagulants; however, the studies included patients who had acute coronary syndromes (ACS), were treated with routine GP IIb/IIIa inhibitors (which we do not recommend), or received a high-dose heparin regimen.  

A 2014 meta-analysis of 16 trials of stable and ACS patients found an increase in the incidence of major adverse cardiac events (death, MI, ischemia driven revascularization, and stent thrombosis) up to 30 days (risk ratio 1.09, 95% CI 1.01-1.17)  . In contrast, the rates of protocol-defined major bleeding were lower with bivalirudin. In the trials comparing bivalirudin with heparin monotherapy (no GP IIb/IIIa inhibitor), there was no significant difference in the bleeding rates. However, the wide diversity of patients and protocols in these studies included in the meta-analysis prevent us from relying on its conclusions.

Until this issue is studied further, we prefer heparin in most patients, but believe that bivalirudin is a reasonable alternative, particularly for patients at high bleeding risk or those with heparin-induced thrombocytopenia.  

BLEEDING — The prolonged use of antithrombotic therapy with dual antiplatelet therapy (aspirin and clopidogrel) or, on occasion, dual antiplatelet therapy and warfarin, can lead to major bleeding, usually in the form of gastrointestinal bleeding, and minor bleeding. This issue is discussed in detail elsewhere.  

PATIENTS TAKING LONG-TERM ORAL ANTICOAGULATION — As discussed above, warfarin has not been shown to be of benefit in the prevention of stent thrombosis.  

In patients who receive intracoronary stents and have other indications for anticoagulant therapy, such as atrial fibrillation (AF) or mechanical heart valves, the optimal management of the anticoagulant and antiplatelet regimens is unknown. This is a common problem as approximately one-third of patients with AF, many of whom are on chronic anticoagulant therapy, have concomitant coronary artery disease , and it is estimated that 5 to 10 percent of patients referred for PCI have a strong indication for long-term anticoagulation, such as AF  . In addition, patients with AF who undergo PCI with stenting are at high risk of adverse events. In a report of 426 such patients, a major adverse cardiovascular event (death, myocardial infarction [MI], or target lesion revascularization) rate of 32 percent at a median follow-up of 595 days after PCI  . All-cause mortality was 23 percent.

There is substantial evidence that the rate of major bleeding is increased in patients taking two antiplatelet agents plus warfarin (triple-drug therapy), compared with those not on warfarin.  

On the other hand, there is some evidence of a higher rate of adverse cardiovascular events in patients undergoing PCI with stenting who are candidates for triple therapy but are not treated with warfarin. The following observations in two studies of such patients illustrate the range of findings :

●In a case-control study of 239 patients on long-term warfarin, those who received triple therapy after discharge (compared with those who receive dual antiplatelet therapy) had lower unadjusted rates of stroke and stent thrombosis (2.8 versus 8.8 and 1.9 versus 5.9) but a higher rate of MI (8.5 versus 5.9 percent)  .

●In a retrospective review of 426 patients, dual antiplatelet therapy was associated with a significantly increased risk of major adverse cardiovascular events (death, MI, or target vessel revascularization), compared with triple therapy (38 versus 26 percent; hazard ratio 4.9, 95% CI 2.17-11.1)  .

The optimal antithrombotic duration and intensity of a triple-drug regimen in such patients is unknown since adding aspirin and clopidogrel to warfarin increases the bleeding risk, while reducing the intensity of antiplatelet therapy in patients on warfarin will increase the risk of stent thrombosis.  

Our approach to oral anticoagulation — For patients taking an oral anticoagulant who are scheduled for elective PCI, periprocedural antithrombotic therapy should be individualized in an attempt to balance the risks of major bleeding with the risk of stent thrombosis. In the absence of data, we suggest the following approach:

●If time permits, warfarin is discontinued and PCI is not performed until the International Normalized Ratio (INR) is <1.5 in patients undergoing femoral access. In patients undergoing a radial artery approach, some of our experts proceed with INR in therapeutic range while others feel it is reasonable to perform PCI when the INR has fallen below 2.0.  

If it is felt that it would be unsafe to withhold anticoagulation for several days (eg, because of a mechanical heart valve), the patient can be treated with heparin or low-molecular-weight heparin (bridging therapy).

●If time does not permit waiting for the effect of warfarin to wane, we suggest that the patient accept the increased bleeding risk but often administer fresh frozen plasma if the INR is supratherapeutic. We do not give subcutaneous or intravenous vitamin K since the abrupt normalization of the INR can precipitate thrombotic complications and make it more difficult to reinstitute anticoagulation.

In such patients, we may choose a radial rather than femoral artery approach, since bleeding is more easily controlled. However, a femoral approach can be used with careful front-wall puncture and use of a closure device, if appropriate.

●Patients should be reassessed for their need for chronic anticoagulation prior to reinitiation of warfarin.

Warfarin is restarted as soon as possible after PCI, while aspirin and clopidogrel are continued to minimize the risk of stent thrombosis. We usually aim for an INR on the lower end of the desired range. The duration of triple antithrombotic therapy is discussed separately

●Bare metal stents should be strongly considered in preference to drug-eluting stents (DES) in patients who require prolonged anticoagulation in order to minimize the duration of dual antiplatelet therapy. Patients for whom DES may be preferable include those with long lesions, small vessels, or diabetes  . This position is advocated in a consensus document of the European Society of Cardiology .

●The INR should be monitored closely, particularly in the first four weeks after discharge (high risk period for hemorrhage). If the indication for warfarin is AF, we believe that attempting to keep the INR in the 2 to 2.5 range is reasonable while the patient is on both antiplatelet and warfarin therapy.

●Long-term prophylactic proton-pump inhibition should be considered for patients with peptic ulcer disease and who receive aspirinclopidogrel, and warfarin.

●For patients receiving long-term oral anticoagulation with one of the newer oral anticoagulant agents (eg dabigatranapixaban, or rivaroxaban), the optimal periprocedural antithrombotic approach is not known. For patients undergoing radial access, we suggest continuing anticoagulation. For patients undergoing femoral access catheterization, we suggest short-term interruption of these agents, with appropriate bridging for high-risk patients. Such patients might include those with prosthetic heart valves.  

PATIENTS UNDERGOING BALLOON ANGIOPLASTY 

We estimate that approximately 5 percent of patients who undergo PCI do not receive a stent and are treated with balloon angioplasty. For those patients in whom stenting is intended, preprocedural aspirin and a thienopyridine are appropriate.

No randomized trials have directly addressed the optimal long-term antiplatelet strategy in patients who undergo PCI but do not receive a stent. Some experts, including the authors of the Primary and Secondary Prevention of Cardiovascular Disease section of the 2012 American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis guidelines, suggest one month of dual antiplatelet therapy (aspirin and clopidogrel) due to concerns about an increase in thrombotic potential caused by iatrogenic plaque rupture .

While balloon angioplasty does disrupt the integrity of the vascular endothelium, acute intracoronary thrombosis rarely occurs after 48 hours. Thus, the theoretical benefit from one month of dual antiplatelet therapy must be weighed against the increased risk of bleeding during this time. Based on limited evidence, we suggest one month of dual antiplatelet therapy (aspirin and clopidogrel) in patients not at high risk of bleeding or planned surgery within 30 days; for those with either of these, we suggest dual antiplatelet therapy for at least 48 hours.

SUMMARY AND RECOMMENDATIONS

●Appropriate antithrombotic therapy using antiplatelet and anticoagulant drugs is essential to minimize the risk of coronary artery stent thrombosis while limiting complications of major bleeding. However, even with proper timing and dosing, the risk of stent thrombosis and other ischemic complications, as well as major bleeding, including gastrointestinal bleeding, persists.  

●For stable patients in whom percutaneous coronary intervention (PCI) with stenting is scheduled or anticipated, we recommend treatment with aspirin (Grade 1B). For those patients not on chronic aspirin therapy, as well as for those on a maintenance dose of <325 mg daily, we give 325 mg at least two hours before the procedure, if possible.  

●For stable patients in whom PCI with stenting is scheduled, we suggest pretreatment with clopidogrel (Grade 2B). The dose of clopidogrel is 600 mg, and it should be given at least two hours before the procedure.  

●For stable patients who are scheduled to undergo diagnostic coronary angiography with possible PCI, we suggest not giving clopidogrel until after coronary angiography when the decision to perform PCI is made (Grade 2B). For those in whom a decision is made to proceed with PCI after angiography and who have not received pretreatment, clopidogrel 600 mg should be given as soon as possible.
For patients in whom there is a high likelihood of proceeding to PCI after angiography, it is reasonable to pretreat with clopidogrel.

●For stable patients undergoing PCI who have been taking clopidogrel 75 mg per day, we suggest clopidogrel reloading in those at high risk of stent thrombosis (Grade 2C). Until further data are available, we suggest using 600 mg.  

●For all patients undergoing elective PCI, we recommend anticoagulant therapy with either unfractionated heparin or bivalirudin (Grade 1B). We suggest heparin rather than bivalirudin (Grade 2C).  

●For patients who by angiographic criteria are at high risk for a stent thrombosis, we suggest the addition of glycoprotein (GP) IIb/IIIa inhibitor therapy (Grade 2C). The doses and timing are presented separately  .  

 

●For patients who undergo PCI without stent placement (balloon angioplasty alone) and who are not at high risk of bleeding or planned surgery within 30 days, we suggest dual antiplatelet therapy with aspirinand clopidogrel for 30 days after the procedure (Grade 2C). For patients at high bleeding risk or in whom surgery is anticipated within 30 days, dual antiplatelet therapy for less than 30 days or single antiplatelet therapy are reasonable options.