What is the role of antiplatelet therapy following percutaneous coronary intervention (PCI)?

Updated: Nov 27, 2019
  • Author: George A Stouffer, III, MD; Chief Editor: Karlheinz Peter, MD, PhD  more...
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The most feared complication of intracoronary stents has been thrombotic occlusion of a freshly deployed metallic endoprosthesis. Aggressive antiplatelet therapy has been shown to significantly reduce the risk of stent thrombosis and is required in all patients receiving a stent.

Patients receiving stents are now treated with a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor, or cangrelor); with this DAPT, the development of less thrombogenic stents and improvements in stent deployment technology, the incidence of subacute thrombosis currently is less than 1%.

Today, DAPT is provided to all stent patients for a minimum of 4 weeks after a bare-metal stent (BMS) is placed and for a minimum of 6-12 months when a DES is used. Several trials have suggested that a shorter duration of P2Y12 inhibitor administration may be safe in patients with second-generation DESs, but the guidelines still recommend 12 months of DAPT in patients who present with acute coronary syndrome.

For patients who undergo PCI for stable ischemic heart disease (SIHD), the American College of Cardiology (ACC) and the American Heart Association (AHA) now recommend a shorter duration of DAPT. [100] Patients who receive DESs for SIHD should receive DAPT (with clopidogrel) for 6 months (class I recommendation). If such a patient is at high risk for severe bleeding (eg, is undergoing major intracranial surgery) or develops a high risk of bleeding (eg, needs treatment with oral anticoagulation), the P2Y12 inhibitor could be discontinued at 3 months after stent implantation (class II b recommendation).

Issues remain as to whether the duration of aspirin and P2Y12 inhibitor therapy should be longer in patients who received first-generation DESs. In the authors’ view, treatment with 81 mg of aspirin should be maintained for life in all DES patients, and lifetime P2Y12 inhibitor therapy should be considered unless bleeding contraindications restrict its use. Currently, there are multiple ongoing studies designed to evaluate the question of optimal DAPT duration for second-generation DESs.

Although pretreatment with P2Y12 inhibitors has been recommended by the guidelines for years, there has been no evidence supporting this strategy. The ACCOAST (Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) study was very important, in that it was the first, and to date the only, randomized controlled trial to have examined a pretreatment strategy. [101] The results, surprisingly to many, showed that pretreatment had no benefit in terms of MACE and was associated with an increase in bleeding.

The ACCOAST study compared pretreatment with prasugrel 30 mg and a further 30 mg dose before PCI with a regimen of prasugrel 60 mg after diagnostic angiography but before PCI among 4033 patients with NSTEMI who were scheduled for an early invasive strategy. [101] The median duration of pretreatment was 4.3 hours. Of the 4033 patients, 69% underwent PCI, 6% required surgical revascularization, and the remainder were treated conservatively.

At 7 days, patients randomized to the pretreatment arm experienced no reduction (hazard ratio [HR], 1.02; 95% CI, 0.84-1.25; P = 0.81) in the primary end point (ie, cardiovascular death, recurrent MI, stroke, urgent revascularization, and bailout use of GPIIb/IIIa inhibitors), and no benefits emerged at 30 days. [101] TIMI major bleeds were significantly increased in the pretreatment group at 7 days (2.6% for pretreatment vs 1.4% for no pretreatment; HR, 1.90; 95% CI, 1.19-3.02; P = 0.006).

As the 2015 ESC guidelines stated, [102] "Initiation of P2Y12 inhibitors soon after the diagnosis of NSTE-ACS irrespective of management strategy has been recommended. This implies pretreatment, defined as P2Y12 inhibitor administration before coronary angiography, in patients scheduled for an invasive approach.... As the optimal timing of ticagrelor or clopidogrel administration in NSTE-ACS patients scheduled for an invasive strategy has not been adequately investigated, no recommendation for or against pretreatment with these agents can be formulated.”

Concerns still exist regarding the risk of bleeding and platelet transfusion requirements in patients taking a P2Y12 inhibitor who require urgent CABG. Because emergency CABG is rare, there may be time to risk-stratify patients and to give a P2Y12 inhibitor before cardiac catheterization. If CABG is required, the effect of a P2Y12 inhibitor usually diminishes within 5 days.

Another important consideration is the clopidogrel loading dose. ACC/AHA guidelines recommend giving 600 mg within the 6 hours preceding PCI with stenting. [3]

Results of the HORIZONS-AMI study also indicated that a 600-mg loading dose of clopidogrel yielded better clinical outcomes than a 300-mg dose. [103] The 2158 patients in the 600-mg group had significantly lower unadjusted 30-day mortality than the 1153 in the 300-mg group (1.9% vs 3.1%), as well as lower rates of reinfarction (1.3% vs 2.3%) and stent thrombosis (1.7% vs 2.8%). Bleeding rates did not differ. Similar differences were shown in patients who received either bivalirudin or UFH plus a GP inhibitor.

The GRAVITAS (Gauging Responsiveness with A VerifyNow Assay—Impact on Thrombosis And Safety) study, which enrolled 2214 patients with high on-treatment reactivity 12-24 hours after PCI, found that high-dose clopidogrel (600 mg initially, 150 mg/day thereafter) provided a 22% absolute reduction in the rate of high on-treatment reactivity at 30 days in comparison with standard treatment (no additional loading dose, 75 mg/day). [104]

However, the GRAVITAS investigators noted no difference in the primary endpoint of 6-month incidence of death from cardiovascular causes, nonfatal MI, or stent thrombosis. [104] Severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition was lower in the standard group, but the decrease did not reach statistical significance.

Use of newer intravenous (IV) antiplatelet agents such as cangrelor may help overcome these issues. In June 2015, cangrelor was approved by the US Food and Drug Administration (FDA) for use in adults undergoing PCI. Aspirin 325 mg should be given before all PCIs and then maintained at a dosage of 81 mg/day.

Clopidogrel is the most frequently utilized P2Y12 inhibitor. Numerous studies have shown the inconsistency in the metabolism of this drug as a result of variations in the CYP2C19 pathway. Clopidogrel is a prodrug that is metabolized to an active form by the cytochrome (CYP) 450 enzyme system in the liver. Research has demonstrated that genetic variation at the CYP450 2C19 locus results in decreased metabolic activation of clopidogrel and increased risk of stent thrombosis and ischemic events. Patients with two or three abnormal alleles in their CYP2C19 genotype are at higher risk for MACE when treated with clopidogrel. [105]

This finding led to an update to the package insert for clopidogrel, which now includes a “black box” warning for use in patients who are “poor metabolizers” (ie, those who have two abnormal alleles at the CYP 2C19 locus; approximately 2-4% of white patients fall into this category).

Individuals with a single abnormal allele have intermediate metabolism of clopidogrel to the active metabolite. In a meta-analysis of nine studies and almost 10,000 patients, Mega et al found that the presence of even one reduced-function CYP2C19 allele in patients treated with clopidogrel after PCI was associated with a significantly increased risk of MACE, particularly stent thrombosis. [106]

Studies of platelet function testing have shown variability in the pharmacodynamic response to clopidogrel, and studies of genetic testing have identified genetic polymorphisms that affect its absorption (ABCB1), metabolism (eg, CYP2C19) and ultimately its pharmacodynamic effects. Genetic testing for CYP2C19 polymorphisms has potentially important prognostic implications.

In population-based studies, patients with high on-treatment platelet reactivity have had an increased risk of MACE. Unfortunately, studies have not shown that measuring platelet reactivity in an individual patient (primarily with the VerifyNow assay) is useful for identifying those at risk. Currently, measurement of platelet reactivity is still reserved for use as a research tool. [107, 108]

Besides genetic polymorphisms, there are clinical factors to consider, such as obesity and diabetes mellitus, as well as potential drug interactions, such as those with calcium-channel blockers and proton pump inhibitors (PPIs). In particular, omeprazole was implicated in clopidogrel hyporesponsiveness. However, the COGENT trial demonstrated that there was no increase in MACE in patients who took clopidogrel plus a PPI as compared with clopidogrel alone. [109]

Prasugrel is a thienopyridine adenosine diphosphate (ADP) receptor inhibitor that inhibits platelet aggregation. It has been shown to reduce new and recurrent MIs. [110] The loading dose is 60 mg orally given once, and the maintenance dosage is 10 mg/day orally (given with aspirin 75-325 mg/day).

Prasugrel is indicated for reducing thrombotic cardiovascular events (including stent thrombosis) in patients with an ACS that is managed with PCI. It is used specifically for unstable angina or NSTEMI or for acute STEMI that is managed with primary or delayed PCI.

TRITON TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) 38 analyzed whether the type, size, and timing of MI affected prasugrel’s ability to reduce new or recurrent MI. [110] Compared with clopidogrel, prasugrel significantly reduced the overall risk of any type of MI (eg, procedure-related, nonprocedural, and consistently across MI size). Significant, sometimes fatal, bleeding occurred more often with prasugrel than with clopidogrel.

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is an oral P2Y12 receptor antagonist that reversibly inhibits platelets. It does not require hepatic bioactivation, because it is an active drug. The PLATO (Platelet Inhibition and Patient Outcomes) trial, looking at 18,264 patients with ACS (35% STEMI), showed that ticagrelor reduced the composite primary efficacy event (death, MI, or stroke) in comparison with clopidogrel (9.8% vs 11.7%) but increased non–CABG-related major bleeding (2.8% vs 2.2%) and fatal intracranial hemorrhage. [111]

Potential disadvantages of ticagrelor include side effects such as dyspnea, ventricular pauses, significantly greater cost than generic clopidogrel, and increased concentration of uric acid and creatinine.

On the basis of the benefit observed in these trials, current NSTE-ACS guidelines state that it is reasonable to use ticagrelor in preference to clopidogrel for DAPT in patients with NSTE-ACS who undergo an early invasive or ischemia-guided strategy. Prasugrel (at the time of PCI) may be chosen over clopidogrel for DAPT in patients with NSTE-ACS who undergo PCI and are not at high risk for bleeding complications.

In mid-2015, the FDA approved the IV antiplatelet drug cangrelor. It is indicated as an adjunct to PCI to reduce stent thrombosis, periprocedural MI, and repeat coronary revascularization in patients who were not treated with an oral P2Y12 inhibitor for any reason (eg, vomiting or intubation). It is a direct-acting P2Y12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. It is rapidly distributed and metabolized and reaches Cmax in 2 minutes of infusion. Its effect rapidly clears once the infusion is stopped, and platelet function returns to normal in 60 minutes.

An oral P2Y12 platelet inhibitor should be administered in order to maintain platelet inhibition after discontinuance of the cangrelor infusion. Whereas ticagrelor 180 mg could be initiated at any time during the cangrelor infusion, prasugrel 60 mg and clopidogrel 600 mg should only be given immediately after discontinuance of cangrelor.

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