Aspirin

Aspirin is a class 1 (Level of evidence A) recommendation for all patients presenting with UA/NSTEMI, regardless of whether or not they are scheduled to undergo PCI. Aspirin therapy in the setting of UA/NSTEMI offers a 46% reduction in the combined outcome of nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular (CV) death. In the setting of PCI, initial studies with aspirin alone or in combination with dipyridamole have been shown to significantly reduce the need for revascularization and MI. ^, An initial loading dose of 162 to 325 mg of non-enteric coated aspirin is recommended for rapid absorption at the time of presentation with UA/NSTEMI. ^, However, despite multiple trials demonstrating the benefit of aspirin in the setting of UA/NSTEMI, the most appropriate maintenance dose is yet to be determined.

In an effort to understand the impact of aspirin dosing, the Antithrombotic Trialists’ Collaboration (ATC) overview made indirect comparisons between trials evaluating different aspirin doses versus placebo. They found that the relative benefit of aspirin was no greater in the trials evaluating higher doses of aspirin versus placebo compared with the trials evaluating lower doses of aspirin (<100 mg/day) versus placebo. A low dose is commonly used based on these results, and two observational analyses evaluating aspirin dose in acute coronary syndromes (ACS) suggested that bleeding risks increase with increasing aspirin dose with no improvement in efficacy outcomes. ^,

The CURRENT-OASIS 7 trial is a large randomized comparison of aspirin dosing in 25,000 patients with ACS. After receiving a loading dose of at least 300 mg on day 1, patients with UA/NSTEMI or STEMI will be randomized to receive either high-dose aspirin (≥300 mg) versus low-dose aspirin (≤100 mg) for 30 days. There was no significant difference between higher-dose versus low-dose aspirin in the primary outcome of cardiovascular death, myocardial (re)-infarction or stroke at 30 days (4.2% vs. 4.4%; HR 0.97; 95% CI 0.86-1.09; P = 0.61).

Thienopyridines

Thienopyridines, including ticlopidine, clopidogrel, and prasugrel, are a separate class of antiplatelet agents recommended in the management of patients with UA/NSTEMI as well as in patients undergoing PCI. Thienopyridines are used in conjunction with aspirin therapy.

A meta-analysis of the early studies with aspirin and ticlopidine demonstrated a reduction in stent thrombosis and bleeding complications when compared with warfarin. However, hematologic side effects, including neutropenia and agranulocytosis, are of concern and limit the use of ticlopidine. Ticlopidine was subsequently replaced by the more favorable side-effect profile of clopidogrel. Ticlopidine remains an acceptable alternative in peri-PCI patients with a clopidogrel allergy.

In the CAPRI study, clopidogrel monotherapy was at least as effective as aspirin for secondary prevention in patients with prior MI, prior stroke, or peripheral arterial disease. In patients with UA/NSTEMI, the CURE trial demonstrated a significant 20% reduction in the combined outcome of CV death, MI, or stroke when clopidogrel was compared with placebo, on top of background therapy with aspirin ( Fig. 28-1 ). ^, The benefits of clopidogrel became apparent early, with a reduction in ischemia as early as 24 hours after the loading dose was given. There was also a significant benefit of clopidogrel in reducing the composite of death, MI or stroke from day 30 to 1 year, suggesting that the optimal duration of therapy should be for 1 year. An increased risk of major bleeding, but not life-threatening bleeding, was also observed in the dual antiplatelet therapy group. The risk of major bleeding seemed to be related to the aspirin dose, with higher doses increasing bleeding complications without improving benefit.

PCI-CURE: Composite of MI or cardiovascular death from randomization to end of follow-up in PCI patients with ACS.

(From Mehta SR, Yusuf S, Peters RJ, et al for the CURE Investigators: Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001;358:527-533.)

Overall, there was no significant increase in bleeding in patients undergoing coronary artery bypass surgery (CABG) in the CURE study. However, most patients had stopped clopidogrel for various time periods prior to CABG. When clopidogrel was stopped more than 5 days prior to CABG (5 days is the biological half-life of clopidogrel), there was no excess in major bleeding, as defined by the CURE trial criteria. When clopidogrel was continued to within 5 days of CABG, there was an increased major bleeding risk (relative risk [RR], 1.55, P = .06). Therefore, in the minority of patients who require CABG surgery after ACS, it is recommended, if possible, that clopidogrel be withheld for about 5 days prior to surgery. Of the approximately 8% of ACS patients who require CABG, only a small portion require emergent surgery (<1%-2%), allowing clopidogrel to be withheld safely prior to the procedure in the majority. A strategy of delaying the administration of clopidogrel until after the coronary anatomy is defined would allow withholding of clopidogrel in the small number of patients requiring emergent surgery, but would deprive the majority of patients (>95%) the potential benefits of early treatment.

In patients requiring emergent CABG surgery who are on clopidogrel, several general recommendations can be considered. First, if possible, the surgery should be delayed for at least 24 hours from the last dose of clopidogrel, as the pharmacologic half-life of the active metabolite is less than 24 hours. If a platelet transfusion is necessary because of increased intraoperative bleeding or oozing, the newly transfused platelets should be functional as there would be no active metabolite present in the circulation. Second, after the surgery, tranexamic acid, which is an antifibrinolytic agent, can be considered. Finally, in cases were there is evidence of active bleeding, red blood cells and fresh frozen plasma or cryoprecipitate transfusion can be considered. The threshold for using these blood products will differ, depending on the center and the surgeon performing the procedure.

Pretreatment with clopidogrel (i.e., early initiation of clopidogrel before a PCI procedure) was evaluated in three studies: PCI-CURE, CREDO, and PCI-CLARITY. The PCI-CURE and PCI-CLARITY trials were predefined, postrandomization subgroup analyses of patients undergoing PCI in the CURE and CLARITY trials, respectively. CREDO was a stand-alone randomized trial of patients undergoing PCI for mostly stable angina. In the PCI-CURE trial, there was a 30% reduction in CV death, MI, or urgent revascularization at 30 days with clopidogrel pretreatment, and in the PCI-CLARITY trial, there was a 46% reduction in CV death, MI, or stroke at 30 days. ^, The CREDO study suggested that pretreatment with clopidogrel at a 300-mg loading dose, should be administered at least 6 hours and ideally 15 hours prior to PCI, for optimal platelet inhibition and clinical benefit. Analysis of in vitro and small randomized clinical trials have suggested that a loading dose of 600 mg can achieve maximal platelet inhibition within 2 hours and improve clinical outcomes, without an associated increased bleeding risk in patients undergoing PCI for both stable angina and UA/NSTEMI. Therefore, given the significant clinical benefit of pretreatment with clopidogrel prior to PCI and the minimal risk of bleeding in the few patients advanced for CABG as outlined above, a clopidogrel loading dose of 300 mg at the time of presentation with UA/NSTEMI is strongly recommended. The CURRENT OASIS 7 trial is a randomized, double blind comparison of a higher loading and maintenance dose regimen of clopidogrel (600 mg followed by 150 mg maintenance dose for 1 week, then 75 mg daily) versus the standard dosing regimen of 300 mg followed by 75 mg daily. 25,086 patients with an acute coronary syndrome referred for an invasive strategy underwent randomization. The primary outcome of cardiovascular death, myocardial (re)-infarction or stroke at 30 days occurred in 4.2% in the double-dose clopidogrel group and 4.4% in the standard-dose group (hazard ratio [HR] 0.94; 95% CI 0.83-1.06; P = 0.30). Major bleeding was 2.5% in the double-dose group and 2.0% in the standard-dose group (HR 1.24; 95% CI 1.05-1.46; P = 0.012). In the large number of patients who underwent PCI ( N = 17,263), there was a significant reduction in the secondary outcome of stent thrombosis with double-dose clopidogrel (1.7% vs. 2.4%; HR 0.69; 95% CI 0.56-0.86; P < 0.001).

Recent observational data support the notion that a poor pharmacodynamic response to clopidogrel is associated with a higher risk of adverse ischemic events. The response to clopidogrel, as measured by platelet aggregation studies, takes on a normal distribution, with the majority having a good response, and small number having a poor response or hyper-response. One approach to dealing with clopidogrel response variability could be to measure platelet function using a reliable assay. If the patient is found to be a poor responder, the dose of clopidogrel could be increased or an alternative thienopyridine such as prasugrel could be considered. If the patient has an adequate response, the standard dose of clopidogrel can be used. This approach requires evaluation in randomized trials before being widely recommended. At least one randomized trial, the GRAVITAS trial, is currently evaluating this approach using the VerifyNow purinergic G protein–coupled P2Y 12 (P2Y12) receptor assay.

Prasugrel is the newest thienopyridine to be studied. Like clopidogrel, it is a pro-drug that is metabolized by the cytochrome P-450 system in the liver. However, the metabolism of prasugrel into the active metabolite is more efficient, resulting in higher levels of the active metabolite producing a more rapid and potent antiplatelet effect with less inter-individual variability in response. This pharmacodynamic profile may be favorable, especially when prompt platelet inhibition is required in the peri-PCI setting. The Triton-TIMI 38 trial, evaluating 13,608 patients undergoing PCI in the setting of NSTEMI and STEMI, showed a significant clinical benefit in the primary outcome of CV death, MI, or stroke at 15 months with prasugrel therapy when compared with standard dose clopidogrel (9.9% vs. 12.1%, P < .001) ( Fig. 28-2 ). In addition, prasugrel resulted in a 1.3% absolute risk reduction ( P < .001) in definite or probable stent thrombosis ( Fig. 28-3 ). There was a significant increase in TIMI major bleeding, life-threatening bleeding, and fatal bleeding in the prasugrel group. The Triton-TIMI 38 trial compared a 60-mg loading dose of prasugrel to a 300-mg load of clopidogrel. Whether the clinical benefits achieved would have been observed if prasugrel was compared with a 600-mg clopidogrel loading dose followed by a 150-mg maintenance dose is not known. The lack of pretreatment in this trial may also have disadvantaged clopidogrel. Nevertheless, the results of the Triton trial do suggest that faster and greater inhibition of platelet function will result in improved efficacy outcomes at the cost of an increase in bleeding complications.

Triton-TIMI 38: Cumulative Kaplan-Meies estimates for the primary efficacy and safety end-points during the follow-up period.

(From Wiviott SD, Braunwald E, McCabe CH, et al for the Triton-TIMI 38 investigators: Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-2015.)

Triton-TIMI 38: Definite/probable stent thrombosis at 1 year ( N = 12,844).

(From Wiviott SD, Braunwald E, McCabe CH, et al for the Triton-TIMI 38 investigators: N Engl J Med 2007;357:2001-2015.)

Ticagrelor is a reversible, non-thienopyridine, direct-acting inhibitor of the adenosine diphosphate receptor (P2Y12). It is a promising new oral antiplatelet agent evaluated in the management of patients presenting with an ACS, with or without ST-segment elevation. The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial randomized 18,624 patients to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter) ( Fig. 28-4 ). Study drug was administered early and, in contrast to the TRITON study, before coronary angiography. Approximately 60% of all patients underwent PCI during the index hospitalization. The primary end-point (a composite of death from vascular causes, myocardial infarction, or stroke) was significantly reduced in patients receiving ticagrelor (9.8% vs. 11.7%, P < 0.001). These benefits were observed early (i.e., within the first 30 days) and later (after 30 days to 1 year). In addition, ticagrelor resulted in lower rates of death due to vascular causes (4.0% vs. 5.1%, P = 0.001) and myocardial infarction (5.8% vs. 6.9%, P = 0.005). Definite stent thrombosis was also reduced with ticagrelor (1.3% vs. 1.9%, P = 0.009). Consistent reductions in the primary outcome were observed in patients scheduled to undergo an invasive strategy. The rates of total major bleeding did not differ between ticagrelor and clopidogrel (11.6% and 11.2%, respectively; P = 0.43), however ticagrelor was associated with a higher rate of major bleeding in the majority of patients not undergoing CABG surgery (4.5% vs. 3.8%, P = 0.03). Compared with clopidogrel, ticagrelor was associated with a higher rate of ventricular pauses more than 3 seconds (5.8% vs. 3.6%, P = 0.01) and was more frequently associated with dyspnea (13.8% vs. 7.8%, P < 0.001), including dyspnea resulting in discontinuation of study drug (0.9% vs. 0.1%, P < 0.001). The data were consistent in most of the large number of pre-specified subgroups, with the exception of region. In those patients enrolled in North America, there appeared to be nominally significant heterogeneity ( P < 0.05) with an apparent worse outcome with ticagrelor versus clopidogrel (data) compared with the rest of the world. While this result was most likely due to the play of chance, other possible explanations (such as variations in aspirin dose) need to be excluded.

Cumulative Kaplan–Meier Estimates of the Time to the First Adjudicated Occurrence of the Primary Efficacy End Point. The primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — occurred significantly less often in the ticagrelor group than in the clopidogrel group (9.8% vs. 11.7% at 12 months; hazard ratio, 0.84; 95% confidence interval, 0.77 to 0.92; P < 0.001).

(From Wallentin L, Becker RC, Budaj A, et al: Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009;361:1045–57.)

Glycoprotein IIb/IIIa Receptor Antagonists

Glycoprotein (GP) IIb/IIIa receptor antagonists are another class of antiplatelet agents frequently used in the management of patients undergoing PCI and presenting with UA/NSTEMI. A meta-analysis of more than 12,000 patients with UA/NSTEMI demonstrated a reduction in death and nonfatal MI when treated with a GP IIb/IIIa antagonist. Furthermore, the evidence suggests an independent mortality reduction in diabetic patients with UA/NSTEMI and undergoing PCI. Because the majority of evidence supporting the use of GP IIb/IIIa was published prior to the addition of clopidogrel therapy, the role of adding a GP IIb/IIIa antagonist on top of treatment with aspirin and clopidogrel has been debated. ^, The ISAR-REACT-2 trial demonstrated a significant benefit with the combination of abciximab (0.25 mg/kg bolus followed by a 12-hour infusion of 0.125 µg/kg per min, maximum 10 µg/min), and clopidogrel pre-treatment compared to clopidogrel alone. However, the reduction in the composite of death, MI, and urgent target vessel revascularization at 30 days was only noted in troponin-positive patients undergoing PCI. The ISAR-REACT-2 trial also demonstrated that low to moderate risk ACS patients can be safely treated with clopidogrel and aspirin as the only antiplatelet agents. The 2005 American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) PCI guidelines suggest that GP IIb/IIIa antagonist should be administered either “upstream” or in the catheterization laboratory if there is no pre-treatment with clopidogrel (Class 1, Level of Evidence A). The more recent 2007 ACC/AHA acute coronary syndrome guidelines suggest either GP IIb/IIIa or clopidogrel may be used in addition to aspirin therapy for the pre-treatment of lower risk patients presenting with UA/NSTEMI and undergoing PCI (Class I, Level of Evidence A). For multiple reasons, including lower cost, need for long-term clopidogrel therapy post PCI, and clinical benefit, clopidogrel is preferred over GP IIb/IIIa agents in lower risk patients presenting with UA/NSTEMI and undergoing PCI. However, given the results of the ISAR-REACT-2 trial, guidelines suggest that both agents in combination with aspirin therapy should be used for higher risk, troponin-positive, ACS patients undergoing PCI. ^, Appropriate patient selection is required prior to the initiation of GP IIb/IIIa inhibitors, given the majority of benefit is noted in troponin-positive and diabetic patients with UA/NSTEMI. Furthermore the timing of GP IIb/IIIa inhibitor use peri-PCI in the setting of patients presenting with UA/NSTEMI has been evaluated in the Acuity Timing trial. A deferred strategy at time of PCI, rather than an upstream approach to GP IIb/IIIa inhibitor use was not significantly different with respect to the composite ischemic events ( P = .13). However, the deferred approach to GP IIb/IIIa inhibitor use resulted in a significant reduction in 30-day rates of major bleeding (4.9 vs. 6.1%, P = .009 for superiority).

In summary, there are several options for antiplatelet therapy in the treatment of UA/NSTEMI patients scheduled for early revascularization with PCI. Given the evidence to date, the ideal antiplatelet regimen must include aspirin (minimum 160 mg load and 81 mg daily). Early initiation of clopidogrel has proven benefits in all patients (low, intermediate, and high risk) presenting with UA/NSTEMI, whether or not they undergo PCI. Therefore, clopidogrel pre-treatment with a minimum loading dose of 300 mg should be instituted in the majority of patients with UA/NSTEMI. The addition of GP IIb/IIIa inhibitor is indicated in patients presenting with UA/NSTEMI and undergoing PCI if one of the following criteria is met: diabetes, troponin-positive acute coronary syndrome, or no pretreatment with clopidogrel.

Unfractionated Heparin

Unfractionated heparin (UFH) is the most widely used anticoagulant for both the conservative and invasive management of patients presenting with UA/NSTEMI (Class 1, Level of Evidence A). However, the majority of the evidence evaluating UFH was prior to therapies currently used in the management of patients presenting with ACS. Unfractionated heparin (UFH) has minimal renal clearance and usually does not require dose adjustment in patients with reduced creatinine clearance. When added to aspirin, UFH has been shown to almost halve the rates of death and recurrent MI compared with aspirin alone in patients presenting with UA/NSTEMI. UFH is most effective when administered as a weight-based bolus and subsequent IV infusion (60 U/kg initial bolus followed by an infusion of 12 U/kg per hour, adjusted to a goal activated partial thromboplastin time [aPTT] of 50 to 70 seconds). Upstream use of UFH prior to PCI is only indicated in patients presenting with an ACS. Elective PCI patients do not require upstream treatment with UFH.

Low–Molecular-Weight Heparin

Low–molecular-weight heparin (LMWH), and more specifically enoxaparin, is well established in the management of patients presenting with UA/NSTEMI (Class 1, Level of Evidence A). Enoxaparin offers benefits including less heparin induced thrombocytopenia (HIT) and ease of administration (twice daily, subcutaneous dosing at 1 mg/kg), without the need for regular monitoring. However, because of its renal clearance, enoxaparin requires careful dose adjustments in the setting of reduced creatinine clearance and this may prohibit its use in some patients with significant renal dysfunction. Early trials of enoxaparin in patients treated with a conservative strategy suggested an overall clinical benefit with respect to death, MI, and recurrent angina when compared to UFH. However, these trials employed a conservative strategy and were conducted before the use of clopidogrel and GP IIb/IIIa inhibitors. One trial has demonstrated the benefit of enoxaparin in patients receiving eptifibatide. More recent trials, including A to Z and SYNERGY, incorporating PCI and the use of adjuvant antiplatelet agents, did not demonstrate superiority of enoxaparin when compared with UFH and suggested an increase in bleeding complications. ^,

Fondaparinux

Fondaparinux is an indirect parenteral factor Xa inhibitor that is recommended for the management of patients presenting with UA/NSTEMI (Class 1, Level of Evidence B). Fondaparinux is administered as a once a day subcutaneous injection of 2.5 mg. In the large scale OASIS 5 randomized controlled trial ( N = 20,078), fondaparinux was proven to be non-inferior to enoxaparin for efficacy, but there was a 50% reduction in bleeding, resulting in a highly significant net clinical benefit favoring fondapairnux. Moreover, the reduction in bleeding translated into a significant reduction in mortality in the fondaparinux group. Fondaparinux was superior to enoxaparin in terms of bleeding reduction at all levels of renal function (patients with a serum creatinine level of at least 3 mg per deciliter or 265 µmol per liter were excluded from the trial), with the greatest benefit in those with lowest renal function. The majority of patients in OASIS 5 were managed with an invasive strategy and of these, about 40% underwent PCI. In patients undergoing PCI, there was a significant reduction in the combined endpoint of death, MI, stroke, major bleeding, or any procedural complication in the fondaparinux group compared with the enoxaparin group (16.6% vs. 20.6%, P < .001). Further, the reduction in bleeding was observed as early as the first day after randomization, suggesting that a very short duration of fondaparinux was beneficial. Because fondaparinux inhibits only factor Xa, with no effect on thrombin, it is recommended that adjunctive intravenous UFH (50-60 IU/kg) be administered at the time of PCI. This is to protect against contact induced activation of the coagulation system, which can occur less than 1% of the time with fondaparinux. In the OASIS 5 trial, the use of adjunctive UFH did not appear to increase the bleeding risk and works well with fondaparinux given upstream. Therefore, fondaparinux is recommended over enoxaparin for all patients presenting with UA/NSTEMI, regardless of intervention, as per the 2007 European Society of Cardiology guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. The ACC/AHA UA/NSTEMI guidelines also list fondaparinux as a class 1 recommendation for both an invasive and a conservative management strategy, making it an ideal agent for early treatment of UA/NSTEMI (i.e., in the emergency room) when ultimate management strategy and need for revascularization is not known until diagnostic coronary angiography has been performed.

Direct Thrombin Inhibitors

Bivalirudin is a direct thrombin inhibitor that has been evaluated in the management of patients with UA/NSTEMI and in patients undergoing PCI. The use of bivalirudin in stable and ACS patients undergoing PCI was evaluated in the REPLACE 2 and the ISAAR-REACT 3 trials, respectively. ^, The REPLACE-2 trial evaluated more than 6000 patients undergoing both elective and urgent PCI. Bivalirudin with provisional GP IIb/IIIa was found to be non-inferior to UFH with planned GP IIb/IIIa with respect to the combined primary outcome of death, MI, or urgent repeat revascularization. There was a significant reduction in major bleeding in the bivalirudin group (2.4 vs. 4.1%, P < .001). The ISAAR-REACT 3 trial compared bivalirudin monotherapy with UFH monotherapy in patients with ACS undergoing PCI. All patients were pretreated with 600 mg of clopidogrel at least 2 hours prior to PCI. The bivalirudin group was no different than UFH with respect to the primary outcome of net clinical benefit. Major bleeding was lower with bivalirudin compared with UFH, but this may have been because the bolus dose of UFH used in the trial (140 IU/kg) was much higher than the upper limit of guideline recommended doses.

Finally bivalirudin monotherapy was compared with bivalirudin plus GP IIb/IIIa inhibitor, or UFH/enoxaparin plus GP IIb/IIIa inhibitor in patients with UA/NSTEMI undergoing an invasive strategy in the ACUITY trial. ^, The composite endpoint of death, MI, and unplanned revascularization at one year was not statistically different between the three groups, with 15.4% in the UFH/enoxaparin plus GP IIb/IIIa inhibitor group, 16% in the bivalirudin plus GP IIb/IIIa inhibitor group, and 16.2% in the bivalirudin monotherapy group ( P = .29). In patients pretreated with clopidogrel, bivalirudin alone demonstrated a significant reduction in major bleeding consistent with previous trials and was found to be non-inferior to UFH or enoxaparin plus GP IIb/IIIa with respect to the net clinical benefit. ^, Given bivalirudin, in conjunction with clopidogrel pretreatment, has been demonstrated to be as effective as UFH or enoxaparin plus GP IIb/IIIa in low to high risk ACS patients undergoing PCI, it is recommended in the invasive management of patients presenting with UA/NSTEMI (Class 1, Level of Evidence B). Bivalirudin is also a reasonable alternative for patients with a heparin allergy or HIT.

In summary, there are various anticoagulant agents including UFH, fondaparinux, enoxaparin, or bivalirudin, all indicated in the treatment of patients with UA/NSTEMI. The appropriate choice of anticoagulation therapy depends on various factors including the management strategy and timing of invasive intervention, the patient’s individual bleeding risk, renal function, level of clopidogrel pretreatment prior to PCI, and overall risk at time of presentation with UA/NSTEMI.