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Two thienopyridines—ticlopidine and clopidogrel—are ADP receptor (P2Y12) antagonists that are approved for anti- platelet therapy (383). The platelet effects of ticlopidine and clopidogrel are irreversible but take several days to achieve

Figure 11. Long-Term Anticoagulant Therapy at Hospital Discharge After UA/NSTEMI

*For aspirin (ASA) allergic patients, use clopidogrel alone (indefinitely), or try aspirin desensitization. †For clopidogrel allergic patients, use ticlopidine, 250 mg by mouth twice daily.‡Continue ASA indefinitely and warfarin longer term as indicated for specific conditions such as atrial fibrillation; LV thrombus; cerebral, venous, or pulmonary emboli. §When warfarin is added to aspirin plus clopidogrel, an INR of 2.0 to 2.5 is recommended. INR_⫽international normalized ratio; LOE_⫽level of evidence; LV_⫽left ventricular; UA/NSTEMI⫽unstable angina/non–ST-elevated myocardial infarction.

maximal effect in the absence of a loading dose. The administration of a loading dose can shorten the time to achievement of effective levels of antiplatelet therapy. Be- cause the mechanisms of the antiplatelet effects of ASA and ADP antagonists differ, a potential exists for additive benefit with the combination. In patients with a history of gastrointestinal bleeding, when ASA or a thienopyridine is administered alone or in combination, drugs to minimize the risk of recurrent gastrointestinal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly (384–386).

Ticlopidine has been used successfully for the secondary prevention of stroke and MI and for the prevention of stent closure and graft occlusion (387). The adverse effects of ticlopidine limit its usefulness: gastrointestinal problems (diarrhea, abdominal pain, nausea, and vomiting), neutro- penia in approximately 2.4% of patients, severe neutropenia in 0.8% of patients, and, rarely, thrombotic thrombocytopenia purpura (388). Neutropenia usually resolves within 1 to 3 weeks of discontinuation of therapy but very rarely may be fatal. Thrombotic thrombocytopenia purpura, which is a very uncommon, life-threatening complication, requires immediate plasma exchange. Monitoring of ticlopidine therapy requires a complete blood count that includes a differential count every 2 weeks for the first 3 months of therapy.

Extensive clinical experience with clopidogrel is derived in part from the Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (389). A total of 19,185 patients were randomized to receive ASA 325 mg per d or clopidogrel 75 mg per d. Entry criteria consisted of atherosclerotic vascular disease manifested as recent isch- emic stroke, recent MI, or symptomatic peripheral arterial disease. Follow-up extended for 1 to 3 years. The RR of ischemic stroke, MI, or vascular death was reduced by 8.7% in favor of clopidogrel from 5.8% to 5.3% (p⫽ 0.04). The benefit was greatest for patients with peripheral arterial disease. This group had a 24% relative risk reduction (p⫽

0.03). There was a slightly increased, but minimal, inci- dence of rash and diarrhea with clopidogrel treatment and slightly more bleeding with ASA. There was no excess neutropenia with clopidogrel, which contrasts with ticlopi- dine. The results provide evidence that clopidogrel is at least as effective as ASA and appears to be modestly more effective. In 1 report, 11 severe cases of thrombotic throm- bocytopenia purpura were described as occurring within 14 d after the initiation of clopidogrel; plasma exchange was required in 10 of the patients, and 1 patient died (390). These cases occurred among more than 3 million patients treated with clopidogrel.

Clopidogrel is reasonable antiplatelet therapy for second- ary prevention, with an efficacy at least similar to that of ASA. Clopidogrel is indicated in patients with UA/ NSTEMI who are unable to tolerate ASA due to either hypersensitivity or major gastrointestinal contraindications, principally recent significant bleeding from a peptic ulcer or gastritis. In patients with a history of gastrointestinal bleed- ing while taking ASA, when a thienopyridine is adminis-

tered, drugs to minimize the risk of recurrent gastrointesti- nal bleeding (e.g., proton-pump inhibitors) should be prescribed concomitantly (384 –386). When treatment with thienopyridines is considered during the acute phase, it should be recognized that there is a delay before attainment of the full antiplatelet effect. Clopidogrel is preferred to ticlopidine because it more rapidly inhibits platelets and appears to have a more favorable safety profile.

An oral loading dose (300 mg) of clopidogrel is typically used to achieve more rapid platelet inhibition. The optimal loading dose with clopidogrel has not been rigorously established. The greatest amount of general clinical experi- ence and randomized trial data exist for a clopidogrel loading dose of 300 mg, which is the approved loading dose. Higher loading doses (600 to 900 mg) have been evaluated (391,392). They appear to be safe and more rapidly acting; however, it must be recognized that the database for such higher loading doses is not sufficiently robust to formulate definitive recommendations. Most studies to date with higher loading doses of clopidogrel have examined surro- gates for clinical outcomes, such as measurements of 1 or more markers of platelet aggregation or function. When groups of patients are studied, a general dose response is observed with increasing magnitude and speed of onset of inhibition of platelet aggregation in response to agonists such as ADP as the loading dose increases. However, considerable interindividual variation in antiplatelet effect also is observed with all loading doses of clopidogrel, which makes it difficult to predict the impact of different loading doses of clopidogrel in a specific patient. Small to moderate- sized trials have reported favorable outcomes with a 600-mg versus a 300-mg loading dose in patients undergoing PCI (393); however, large-scale randomized trials are still needed to definitively compare the efficacy and safety of different loading regimens of clopidogrel. This is of partic- ular importance because it is known that patients undergo- ing CABG surgery shortly after receiving 300 mg of clopidogrel have an increased risk of bleeding (394); the relative risk of bleeding associated with higher loading doses of clopidogrel remains to be established. The Writing Committee endorses the performance of appropriately de- signed clinical trials to identify the optimal loading dose of clopidogrel.

Two randomized trials compared clopidogrel with ticlo- pidine. In 1 study, 700 patients who successfully received a stent were randomized to receive 500 mg of ticlopidine or 75 mg of clopidogrel, in addition to 100 mg of ASA, for 4 weeks (395). Cardiac death, urgent target-vessel revascular- ization, angiographically documented thrombotic stent oc- clusion, or nonfatal MI within 30 d occurred in 3.1% of patients who received clopidogrel and 1.7% of patients who received ticlopidine (p ⫽ 0.24), and noncardiac death, stroke, severe peripheral vascular hemorrhagic events, or any adverse event that resulted in the discontinuation of the study medication occurred in 4.5% and 9.6% of patients, respectively (p ⫽ 0.01). The CLopidogrel ASpirin Stent

International Cooperative Study (CLASSICS) (396) was conducted in 1,020 patients. A loading dose of 300 mg of clopidogrel followed by 75 mg per d was compared to a daily dose of 75 mg without a loading dose and with a loading dose of 150 mg of ticlopidine followed by 150 mg twice per day (patients in each of the 3 arms also received ASA). The first dose was administered 1 to 6 h after stent implantation; the treatment duration was 28 d. The trial showed better tolerance to clopidogrel with or without a loading dose than to ticlopidine. Stent thrombosis or major complications occurred at the same frequency in the 3 groups.

The CURE trial randomized 12,562 patients with UA and NSTEMI presenting within 24 h to placebo or clopi- dogrel (loading dose of 300 mg followed by 75 mg daily) and followed them for 3 to 12 months (243). All patients received ASA. Cardiovascular death, MI, or stroke occurred in 11.5% of patients assigned to placebo and 9.3% assigned to clopidogrel (RR⫽0.80,pless than 0.001). In addition, clopidogrel was associated with significant reductions in the rate of in-hospital severe ischemia and revascularization, as well as the need for fibrinolytic therapy or intravenous GP IIb/IIIa receptor antagonists. These results were observed across a wide variety of subgroups. A reduction in recurrent ischemia was noted within the first few hours after randomization.

There was an excess of major bleeding (2.7% in the placebo group vs. 3.7% in the clopidogrel group,p⫽0.003) and of minor bleeding but not of life-threatening bleeding. The risk of bleeding was increased in patients undergoing CABG surgery within the first 5 d of stopping clopidogrel. The CURE study was conducted at centers in which there was no routine policy regarding early invasive procedures; revascularization was performed during the initial admission in only 23% of the patients. Although the addition of a platelet GP IIb/IIIa inhibitor in patients receiving ASA, clopidogrel, and heparin in CURE was well tolerated, fewer than 10% of patients received this combination. Therefore, additional in- formation on the safety of an anticoagulant and a GP IIb/IIIa inhibitor in patients already receiving ASA and clopidogrel should be obtained. Accurate estimates of the treatment benefit of clopidogrel in patients who received GP IIb/IIIa antagonists remain ill-defined.

The CURE trial also provides strong evidence for the addition of clopidogrel to ASA on admission in the man- agement of patients with UA and NSTEMI in whom a noninterventional approach is intended, an especially useful approach in hospitals that do not have a routine policy about early invasive procedures. The event curves for the 2 groups separate early. The optimal duration of therapy with clopi- dogrel in patients who have been managed exclusively medically has not been determined, but the favorable results in CURE were observed over a period averaging 9 months and for up to 1 year.

The PCI-CURE study was an observational substudy of the patients undergoing PCI within the larger CURE trial (397). In the PCI-CURE study, 2,658 patients had previ- ously been randomly assigned to double-blind treatment

with clopidogrel (n⫽ 1313) as per the CURE protocol or placebo (n ⫽ 1,345). Patients were pretreated with ASA and the study drug for a median of 10 d. After PCI, most patients received open-label thienopyridine for approxi- mately 4 weeks, after which the blinded study drug was restarted for a mean of 8 months. Fifty-nine patients (4.5%) in the clopidogrel group had the primary end point (a composite of cardiovascular death, MI, or urgent target- vessel revascularization) within 30 d of PCI compared with 86 (6.4%) in the placebo group (RR⫽0.70, 95% CI 0.50 to 0.97, p⫽0.03). Overall, including events before and after PCI, there was a 31% reduction in cardiovascular death or MI (p⫽0.002). Thus, in patients with UA and NSTEMI receiving ASA and undergoing PCI, a strategy of clopi- dogrel pretreatment followed by up to 1 year of clopidogrel use (and probably at least 1 year in those with DES; see below) is beneficial in reducing major cardiovascular events compared with placebo and appears to be cost-effective (the incremental cost-effectiveness ratio for clopidogrel plus ASA compared with ASA alone was $15,400 per quality-adjusted life-year) (398). Therefore, clopidogrel should be used rou- tinely in patients who undergo PCI.

Pathological and clinical evidence particularly highlights the need for longer-term ADP-receptor blockade in pa- tients who receive DES (399). DESs consistently have been shown to reduce stent restenosis. However, this same antiproliferative action can delay endothelialization, predis- posing to stent thrombosis including late (beyond 3– 6 months) or very late (after 1 year) thrombosis after stent placement (399,399a,400). These concerns have raised questions about the ideal duration of dual antiplatelet therapy (DAT) and the overall balance of benefit/risk of DES compared with bare-metal stents (401). A number of comparisons of outcomes up to 4 years after DES and bare-metal stent implantation, including the initial FDA approval trials, have been published (400,402– 404,404a– 404f). These confirm a marked reduction in restenosis and consequent repeat revascularization procedures with DES (404c). However, although results have varied, they also suggest a small incremental risk (of about 0.5%) of stent thrombosis (404a– 404c). Reassuringly, they have not shown an overall increase in death or MI after DES versus bare-metal stents, suggesting offsetting advantages of im- proved revascularization versus increased stent thrombosis risk. These observations also emphasize the need for a continued search for more biocompatible stents that mini- mize restenosis without increasing the risks of thrombosis. In the ISAR-REACT-2 trial, patients undergoing PCI were assigned to receive either abciximab (bolus of 0.25 mg per kg of body weight, followed by a 0.125-mg per kg per min [maximum, 10 mg per min] infusion for 12 h, plus heparin 70 U per kg of body weight) or placebo (placebo bolus and infusion of 12 h, plus heparin bolus, 140 U per kg) (244). All patients received 600 mg of clopidogrel at least 2 h before the procedure, as well as 500 mg of oral or intravenous ASA. Of 2,022 patients enrolled, 1,012 were

assigned to abciximab and 1,010 to placebo. The primary end point was reached in 90 patients (8.9%) assigned to abciximab versus 120 patients (11.9%) assigned to placebo, a 25% reduction in risk with abciximab (RR⫽0.75, 95% CI 0.58 to 0.97,p⫽0.03) (244). Among patients without an elevated cTn level, there was no difference in the incidence of primary end-point events between the abciximab group (23 [4.6%] of 499 patients) and the placebo group (22 [4.6%] of 474 patients; RR⫽0.99, 95% CI 0.56 to 1.76,p ⫽0.98), whereas among patients with an elevated cTn level, the incidence of events was significantly lower in the abciximab group (67 [13.1%] of 513 patients) than in the placebo group (98 [18.3%] of 536 patients), which corre- sponds to an RR of 0.71 (95% CI 0.54 to 0.95,p⫽0.02;p ⫽ 0.07 for interaction). There were no significant differ- ences between the 2 groups with regard to the risk of major or minor bleeding or the need for transfusion. Thus, it appears beneficial to add an intravenous GP IIb/IIIa inhib- itor to thienopyridine treatment if an invasive strategy is planned in patients with high-risk features (e.g., elevated cTn level; Figs. 7,8, and9).

The optimal timing of administration of the loading dose of clopidogrel for those who are managed with an early invasive strategy cannot be determined with certainty from PCI-CURE because there was no comparison of adminis- tration of the loading dose before diagnostic angiography (“upstream treatment”) versus at the time of PCI (“in-lab treatment”). However, based on the early separation of the curves, when there is delay to coronary angiography, pa- tients should receive clopidogrel as initial therapy (Figs. 7,8, and 9). The Clopidogrel for the Reduction of Events During Observation (CREDO) trial (405), albeit not de- signed specifically to study UA/NSTEMI patients, provides partially relevant information on the question of timing of the loading dose. Patients with symptomatic CAD and evidence of ischemia who were referred for PCI and those who were thought to be highly likely to require PCI were randomized to receive clopidogrel (300 mg) or matching placebo 3 to 24 h before PCI. All subjects received a maintenance dose of clopidogrel (75 mg daily) for 28 d. Thus, CREDO is really a comparison of the administration of a loading dose before PCI versus not administering a loading dose at all. There is no explicit comparison within CREDO of a pre-PCI loading dose versus a loading dose in the catheterization laboratory. In CREDO, the relative risk for the composite end point of death/MI/urgent target- vessel revascularization was 0.82, in favor of the group who received a loading dose before PCI compared with the opposite arm that did not receive a loading dose, but this did not reach statistical significance (p ⫽ 0.23). Subgroup analyses within CREDO suggest that if the loading dose is given at least 6 or preferably 15 h before PCI, fewer events occur compared with no loading dose being administered (406). One study from the Netherlands that compared pretreatment with clopidogrel before PCI versus adminis- tration of a loading dose at the time of PCI in patients

undergoing elective PCI showed no difference in biomarker release or clinical end points (407).

Thus, there now appears to be an important role for clopidogrel in patients with UA/NSTEMI, both in those who are managed conservatively and in those who undergo PCI, especially stenting, or who ultimately undergo CABG surgery (408). However, it is not entirely clear how long therapy should be maintained (409,410). Whereas increased hazard is clearly associated with premature discontinuation of dual antiplatelet therapy after DES (405,411,412), the benefit of extended therapy beyond 1 year is uncertain (401,403d,403e). Hence, the minimum requirements for DAT duration should be vigorously applied for each DES type. However, 1 year of DAT may be ideal for all UA/NSTEMI patients who are not at high risk of bleeding given the secondary preventive effects of DAT, perhaps especially after DES. On the other hand, the limited database at this point in time does not support a recom- mendation for DAT beyond 1 year for all DES-treated patients (401,403d,403e). For patients with clinical features associated with an increased risk of stent thrombosis, such as diabetes or renal insufficiency or procedural characteristics such as multiple stents or a treated bifurcation lesion, extended DAT may be reasonable. Data on the relative merits of DES versus bare-metal stents in “off-label” patients (such as multivessel disease or MI), who are at higher risk and experience higher event rates, and of the ideal duration of DAT in these patients, are limited and are currently insuffi- cient to draw separate conclusions (401,403d,403e).

Because of the importance of dual-antiplatelet therapy with ASA and a thienopyridine after implantation of a stent, especially if a DES is being considered, clinicians should ascertain whether the patient can comply with 1 year of dual-antiplatelet therapy. Patients should also be in- structed to contact their treating cardiologist before stop- ping any antiplatelet therapy, because abrupt discontinua- tion of antiplatelet therapy can put the patient at risk of stent thrombosis, an event that may result in MI or even death (411). Health care providers should postpone elective surgical procedures until beyond 12 months after DES implantation (411). If a surgical procedure must be per- formed sooner than 12 months, an effort should be made to maintain the patient on ASA and minimize the period of time of discontinuation of a thienopyridine (411).

In the CURE study, which predominantly involved medical management of patients with UA/NSTEMI, the relative risk reduction in events was of a similar magnitude (approximately 20%) during the first 30 d after randomiza- tion as during the ensuing cumulative 8 months (413). In contrast, clopidogrel was not beneficial in a large trial of high-risk primary prevention patients (414).

Because clopidogrel, when added to ASA, increases the risk of bleeding during major surgery, it has been recom- mended that clopidogrel be withheld for at least 5 d (243) and up to 7 d before surgery in patients who are scheduled for elective CABG (376,415). In many hospitals in which

patients with UA/NSTEMI undergo rapid diagnostic cath- eterization within 24 h of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. However, unstable patients should receive clopidogrel or be taken for immediate an- giography (Figs. 7,8, and9). A loading dose of clopidogrel can be given to a patient on the catheterization table if a PCI is to be performed immediately. If PCI is not per- formed, clopidogrel can be given after the catheterization. However, when clopidogrel is given before catheterization and urgent surgical intervention is indicated, some experi- ence suggests that “early” bypass surgery may be undertaken by experienced surgeons at acceptable incremental bleeding risk. Among 2,858 UA/NSTEMI patients in the CRU-