A 74-year-old man was admitted for right transradial amputation for Scedosporium prolificans invasive fungal infection of the right wrist. Perioperatively, he was treated with voriconazole. Ten months earlier, he had a non–ST elevation myocardial infarction (MI) treated with drug-eluting stents (DES) to his left anterior descending coronary artery. He was subsequently treated with aspirin (81 mg/day) and clopidogrel (75 mg/day).

• 
  

  What duration of aspirin and clopidogrel treatment is recommended in a patient after DES placement?

  
  
  
  
  • a.
    

    Twelve months of aspirin and 12 months of clopidogrel

    
    
  • b.
    

    Twelve months of aspirin and 1 month of clopidogrel

    
    
  • 
    

    Lifelong aspirin and 12 months of clopidogrel

    
    
  • d.
    

    Lifelong aspirin and 1 month of clopidogrel

    
    
  • e.
    

    Lifelong aspirin and 6 months of clopidogrel

  
  

Regardless of which stent type is deployed, aspirin should be continued lifelong in any patient with known coronary artery disease. Although the duration of dual-antiplatelet therapy (APT) is dependent on the drug eluted (answer E, 3 months for sirolimus and 6 months for paclitaxel) , the minimum recommended duration of clopidogrel therapy is 12 months, especially in patients with low risk for bleeding (answer C) . There is no clear evidence of benefit beyond this, and the risk/benefit ratio may be in favor of discontinuation of dual APT. However, in 1 observational study, patients self-reporting extended clopidogrel and aspirin use beyond 1 year had reduced occurrence of death or MI. Studies are under way to further investigate this issue.

Newer randomized studies have suggested that a shorter period of dual APT may be possible without increased risk for adverse events. The Real Safety and Efficacy of 3-Month Dual Antiplatelet Therapy Following Endeavor Zotarolimus-Eluting Stent Implantation trial compared 3 months of dual APT with 12 months (although different stents were used) and found no difference in the primary end point, including stent thrombosis (ST). Although underpowered, the noninferiority Efficacy of Xience/Promus Versus Cypher to Reduce Late Loss After Stenting trial suggested that 6 (as opposed to 12) months of dual APT did not increase the risk for target vessel failure. Worth noting is that adverse cardiac events are often related to nonstented lesions after the first year after coronary stent (CS) placement, likely secondary to native disease progression or plaque rupture in new coronary segments.

In patients with unstable angina pectoris and non–ST-segment elevation myocardial infarctions treated medically, the American College of Cardiology Foundation and American Heart Association 2011 focused update recommends continuation of clopidogrel for ≥1 month, preferably for 1 year (answer B) . The American College of Cardiology Foundation and American Heart Association guidelines recommend continuation of clopidogrel for ≥1 month after implantation of a bare-metal stent (BMS) (answer D) . As mentioned earlier, aspirin should be continued lifelong (answers A and B) .

• 
  

  In this patient, when is the optimum time to discontinue aspirin and clopidogrel therapy before noncardiac surgery?

  
  
  
  
  • 
    

    Continue aspirin and stop clopidogrel 5 days before surgery

    
    
  • b.
    

    Stop aspirin and clopidogrel 5 days before surgery

    
    
  • c.
    

    Continue aspirin and clopidogrel

    
    
  • d.
    

    Stop aspirin and clopidogrel and commence a glycoprotein IIb/IIIa inhibitor

  
  

The guidelines for patients with CS who undergo noncardiac surgery are similar to the guidelines for those who undergo cardiac surgery. The American College of Cardiology Foundation and American Heart Association 2007 guidelines state that dual APT, or at least aspirin, should be continued if scheduled within the time frame that would usually require continuation of these. However, in the setting of a DES, it may be acceptable to stop clopidogrel 5 days before surgery and continue with aspirin if 6 to 12 months have elapsed (answer A) .

In coronary artery bypass grafting, preoperative aspirin use is associated with decreased mortality. The data are less robust in patients who undergo noncardiac surgery. Furthermore, in those with, or at risk for, ischemic heart disease who undergo surgery in general, aspirin nonadherence or withdrawal is associated with an increased risk for major adverse cardiac events. Therefore, it is important to review the risk for perioperative hemorrhage compared with benefit of reducing perioperative vascular complications. Practice is variable, and guidelines differ; generally, if there is minimal risk for perioperative hemorrhage, and the patient is believed to have excess risk for perioperative vascular complications, dual APT should be continued (answer C) . However, it should be withheld in those who undergo procedures when perioperative hemorrhage could severely impair outcomes, such as central nervous system surgery. Postoperative bleeding in this patient would compromise stump healing; thus, clopidogrel should be discontinued 5 days before surgery. Newer antiplatelet agents such as ticagrelor and prasugrel should be discontinued ≥5 and ≥7 days before surgery, respectively.

Abrupt APT cessation and concomitant surgery result in an inflammatory or prothrombotic state. In the setting of DES, this can lead to ST. As such, it is worthwhile attempting to continue APT (answer B) . Heparin bridging in the absence of APT is not recommended, because heparin cessation can result in platelet activation with a rebound phenomenon, increasing the risk for ST. Although there is no evidence that warfarin or glycoprotein IIb/IIIa inhibitors reduce the risk for ST after the discontinuation of oral antiplatelet agents, the addition of a glycoprotein IIb/IIIa antagonist until the time of surgery may be attempted; tirofiban can be continued until the moment of incision, whereas eptifibatide and abciximab can be discontinued 2 to 4 and 12 to 24 hours before, respectively (answer D) . These are general guidelines and do not replace clinical judgment for patients in whom ST may be especially catastrophic.

• 
  

  Which genetic polymorphism leads to reduced clopidogrel activity?

  
  
  
  
  • 
    

    CYP2C19*2

    
    
  • b.
    

    CYP2C19*1

    
    
  • c.
    

    CYP3A4

    
    
  • d.
    

    CYP2B6

    
    
  • e.
    

    CYP1A2

  
  

Clopidogrel, a thienopyridine prodrug indicated for the prevention of atherothrombosis in adults with histories of MI, ischemic stroke, or established peripheral arterial disease is hepatically metabolized through 2 metabolic pathways: (1) by hydrolysis into an inactive derivative and (2) by cytochrome P450 (CYP) enzymes (3A4, 2C19, 1A2, and 2B6) in which an active thiol derivative is formed. The active metabolite selectively and irreversibly inhibits the binding of adenosine diphosphate to its platelet P2Y ₁₂ receptor. Therefore, subsequent adenosine diphosphate–mediated activation of the glycoprotein IIb/IIIa complex and amplification of platelet activation are inhibited, preventing aggregation.

Because of CYP polymorphism, the degree of platelet inhibition manifests interindividual variability. Identified polymorphisms are autosomal recessive; therefore, only homozygous (or compound heterozygous) patients are poor metabolizers. CYP2C19 polymorphisms may lead to poor-metabolizer status; the CYP2C19*2 variant in particular encodes a nonfunctional protein. As with other genetic polymorphisms, the rate is variable among ethnic groups. Although 25% of Caucasians carry ≥1 copy of the CYP2C19*2 allele, the rate is higher in African-American and Chinese populations. Patients with CYP2C19*2 polymorphisms (answer A) have lower systemic exposure to the active clopidogrel metabolite and, therefore, have reduced platelet inhibition with worse outcomes. However, recent meta-analyses report discrepant findings. In 1 meta-analysis of 9,685 patients, those with reduced-function CYP2C19 alleles had significantly increased risk for major adverse cardiac events (including ST) compared with noncarriers. A subsequent meta-analysis, however, did not show such a correlation. In response to the former study, the US Food and Drug Administration issued a black-box warning regarding CYP2C19 testing. It is important to note that this warning is meant to “inform healthcare professionals that tests are available to identify genetic differences in CYP2C19 function,” while advising to “consider use of other anti-platelet medications or alternative dosing in poor metabolizers.” No recommendation or requirement is specified for genetic testing. Several studies have assessed the effect of higher doses for poor metabolizers; although inconclusive, recent evidence suggests that clopidogrel doses >150 mg are needed. Alternative agents include ticagrelor and prasugrel, which are not affected by CYP2C19 status. Clopidogrel resistance may also be because of genetic polymorphisms in the efflux transporter and P2Y ₁₂ receptor.

CYP activity is modulated by many medications. Significant drug-drug interactions, possibly leading to reduced active metabolite, occur if clopidogrel is used with certain antireflux medications, selective serotonin reuptake inhibitors, antimicrobials and antiepileptic medications. CYP2C19*2, not CYP2C19*1 (answer B) , is associated with reduced clopidogrel activity. CYP3A is the largest subfamily of CYP enzymes, expressed in the liver and gastrointestinal tract, but genetic polymorphism is not associated with reduced clopidogrel activity (answer C) . CYP2B6 is important in the metabolism of some chemotherapeutic and antiretroviral agents, but it does not affect clopidogrel (answer D) . CYP1A2 (answer E) , of which cigarette smoke is an inducer, is important in antidepressant and antipsychotic drug metabolism. Notable substrates include theophylline, clozapine, and olanzapine. This patient was prescribed voriconazole; significant interactions include reduced clopidogrel activity (CYP2C19) and increased effect of calcium channel blockers (CYP3A4), anticoagulants (warfarin [CYP2C9], ticagrelor [CYP3A4]), and statins (CYP3A4). Caution is required with sotalol because of additive QT interval prolongation.

• 
  

  The following are associated with an increased risk for ST except?

  
  
  
  
  • a.
    

    Low flow through the stented lesion

    
    
  • 
    

    High-pressure stent deployment

    
    
  • c.
    

    Delayed endothelialization of the stent struts

    
    
  • d.
    

    Longer segments of stented artery

  
  

High-pressure stent deployment (>14 atm) with adequate postdeployment dilatation helps minimize ST (answer B) . Stent undersizing, especially in patients with extensive atherosclerotic burden, increases ST. Inadequate stent expansion, alignment, or apposition (absence of stent strut contact with the underlying endothelial wall) increases the risk for ST. Although intravascular ultrasound is used to aid in the correct sizing of stents, this has not been shown to improve outcomes. The stent should be placed in a vessel with sufficient run-off to support adequate flow (answer A) . The incidence of ST in patients may reflect their increased burden of coronary artery disease and thrombogenicity; coronary artery disease >50% proximal and distal to the lesion is associated with increased ST risk.

Although DES were created to reduce restenosis, delayed endothelialization (due to the antiproliferative effect of the drug eluted) results in longer duration of exposure to the thrombogenic stent struts, possibly increasing the incidence of late ST (answer C) . Furthermore, the stent polymer designed to release the antiproliferative agent can also delay endothelialization and cause a local hypersensitivity reaction, further increasing the risk for ST. Newer stents, for example the Genous bioengineered stent (OrbusNeich, Wanchai, China) may promote endothelialization, thus reducing thrombogenicity. Narrow and longer lesions (>28 mm) are at increased risk for ST and target vessel revascularization (answer D) . It is worth noting that the Food and Drug Administration’s on-label indication for de novo lesions is <30 mm in length with diameters of 2.5 to 3.5 mm for sirolimus-eluting stents and <28 mm in length with diameters of 2.5 to 3.75 mm diameter for paclitaxel-eluting stents. Off-label use of DES is associated with an increased risk for ST, likely representing a higher risk, more complex population.

• 
  

  How would you manage in-stent thrombosis?

  
  
  
  
  • a.
    

    Streptokinase

    
    
  • b.
    

    Coronary artery bypass grafting

    
    
  • c.
    

    Alteplase

    
    
  • 
    

    Immediate percutaneous coronary intervention

    
    
  • e.
    

    Tenecteplase

  
  

ST is a medical emergency. Its occurrence is suggested in patients with CS who develop cardiac chest pain, acute heart failure, cardiogenic shock, or life-threatening arrhythmias. After ST, the goal is to restore blood patency and, therefore, flow; patients with ST need urgent percutaneous coronary intervention (answer D) temporized with intravenous heparin and glycoprotein IIb/IIIa inhibitors. As with percutaneous coronary intervention in ST-segment elevation MI, the achievement of Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow during emergency percutaneous coronary intervention for ST is associated with a reduced risk for cardiac death. Coronary artery bypass grafting is required in the minority of patients in whom revascularization is not achieved with PCI (answer B) .

Although intracoronary fibrinolysis has been used previously with effective restoration of anterograde flow (answers A, C, and E) , outcomes were modest at best ; patients frequently required referral for surgical intervention because of residual thrombus and refractory angina, because ST is a platelet-driven phenomenon.