The clinical events related to late stent thrombosis, although rare, carry a mortality rate of up to 45%.12 The specific risk factors for late and very late stent thrombosis are less well defined but relate to delayed neointimal coverage, ongoing vessel inflammation, and the development of neoatherosclerosis within stents.13,14
Rationale for the Use of Dual Antiplatelet Regimen
Stent thrombosis is a platelet-mediated process related to a heightened state of systemic and intracoronary thrombogenicity and inflammation.15 Stent under-expansion enhances abnormal shear stress, which explains as many as 80% of these events.13,15,16 Stent thrombosis also has been frequently related to inadequate neointimal coverage.14 Angioscopic studies, especially with DES, suggest that stent endothelialization is delayed or incomplete, observing a correlation between the areas of uncovered stent surface and thrombosis.14,17
In the early days of coronary stenting, during the 1990s, the risk of acute and subacute stent thrombosis approached 20%.18,19 Initial attempts to reduce the risk included combining aspirin and warfarin, but at the expense of a marked increase in bleeding complications and prolonged hospital stays.20,21 In 1995, it became clear through the pivotal observations of Colombo and colleagues that incomplete expansion of the stent (documented by IVUS) was a major contributor to the risk of stent thrombosis.16 By using noncompliant balloons at high pressure (14-20 atmospheres) for stent postdilatation combined with DAPT (aspirin and ticlopidine), the high rates of early stent thrombosis were markedly reduced to the current level of 1% to 2%.16
Colombo and colleagues’ observations were prospectively evaluated in the Stent Anticoagulation Regimen Study (STARS) trial.22 Patients who underwent successful stenting were randomized to aspirin alone, aspirin and warfarin, or aspirin and ticlopidine. The STARS trial showed convincingly that the combination of aspirin and ticlopidine was superior to the other 2 regimens, reducing the stent thrombosis rate to only 0.5% (compared with 2.7% for aspirin and warfarin, and 3.6% for aspirin alone).22 Afterward, DAPT became the standard of care following coronary stenting.23
Although ticlopidine was the first widely used thienopyridine for the prevention of stent thrombosis, hematologic adverse events (AEs) (eg, neutropenia, thrombotic thrombocytopenia purpura) limited its use.24 Consequently, ticlopidine was replaced with clopidogrel, which seemed to offer similar efficacy but significantly fewer AEs.25
The current American College of Cardiology/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACC/AHA/SCAI) guidelines for the prevention of ST after coronary stent implantation state that after PCI:
- Aspirin use should be continued indefinitely.
- The duration of adenosine diphosphate antagonists depends on the stent type (BMS or DES) and the indication for implantation (ACS or non-ACS).
a. Patients receiving a stent (BMS or DES) for ACS therapy should be given 1 of the following for at least 12 months:
i. Clopidogrel 75 mg daily
ii. Prasugrel 10 mg daily
iii. Ticagrelor 90 mg twice dailyb. In patients receiving DES for a non-ACS indication, clopidogrel should be given for at least 12 months if the patient is not at high risk for bleeding.
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months.23
Clopidogrel Hyporesponse
As shown in case 1, stent thrombosis may still occur in a patient on DAPT because of individual variability in platelet response to clopidogrel.5 Clopidogrel hyporesponse, also known as clopidogrel resistance, has been recognized as clinically significant because of its prevalence and association with poor outcomes.5 Its prevalence may range between 4% and 30%, although the definitions of clopidogrel hyporesponse varied between studies.26
Clopidogrel hyporesponse is defined as an inadequate inhibition of platelet function measured by nonspecific ex-vivo laboratory methods.27,28 The relationship between clopidogrel resistance (nonresponders), stent thrombosis, and ischemic events has been clearly established.5,29
Given the devastating consequences of stent thrombosis, efforts were directed to identify those patients at highest risk. One such effort has been focused on the measurement of platelet function, allowing for the identification of patients who do not respond adequately to antiplatelet therapy.15,28,30,31 However, the treatment of high-residual platelet reactivity as confirmed by laboratory assessment has not shown to clinically correlate with any benefit in the prevention of ST.6,15,29-31 Therefore, the current ACC/AHA/SCAI PCI guidelines do not recommend the routine clinical use of platelet function testing to screen patients treated with clopidogrel who are undergoing PCI.23
Clopidogrel is a prodrug, metabolized to its active form via the cytochrome P450 enzyme system before it can inhibit platelet function.32 Accordingly, certain genetic variation in enzyme activity, or polymorphisms, would be expected to influence its clinical effectiveness.33,34 The most common of these polymorphisms, CYP2C19*2, has been associated (in vitro) with reduced concentrations of active clopidogrel metabolites and with diminished platelet inhibition.35,36 As a result, the FDA has added a safety alert to the prescribing information for clopidogrel concerning how genetic differences in the metabolism of this agent can affect its effectiveness, ways to test for these genetic differences, and advice concerning alternative dosing strategies or use of other medications in poor metabolizers of clopidogrel.37 Although the routine clinical use of genetic testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended, it may be considered in patients undergoing elective high-risk PCI procedures (eg, unprotected left main, last patent coronary artery, or bifurcating left main).23