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Pharmacotherapy in the Modern Interventional Suite
The major aims of pharmacotherapy during percutaneous coronary intervention (PCI) and invasive cardiac procedures are to avoid the adverse consequences related to iatrogenic plaque rupture during balloon angioplasty and stent deployment, to reduce the hazards of thrombus formation on the intracoronary PCI equipment, and to mitigate myocardial ischemia and all periprocedural complications. The informed, effective, and judicious use of drugs in the modern interventional suite allows invasive cardiovascular procedures to be performed safely while maintaining hemodynamic and electrical stability of patients and minimizing complications.
Pathophysiology of Arterial Thrombosis
Thrombosis is fundamental to the process of arterial injury associated with both acute coronary syndromes (ACSs) and PCIs. The pathogenesis of coronary arterial thrombosis is characterized by atherosclerotic plaque disruption (usually rupture or erosion), followed by platelet activation and aggregation and resultant thrombus formation. Irrespective of whether plaque disruption occurs spontaneously or as a result of mechanical disruption during balloon angioplasty, platelets first adhere to the injured endothelium by binding to Class I glycoproteins (GP) ( Figure 4-1 ). Thrombin and other agonists, such as adenosine diphosphate (ADP) and epinephrine, activate the platelets and precipitates conformational changes in the GP IIb/IIIa receptor and platelet degranulation. This results in the release of more vasoactive substances such as serotonin, thromboxane A2 (TXA2), and more ADP, which are important mediators of thrombosis that stimulate further platelet activation and recruitment. Activation of the ADP-specific purinergic P2Y 12 receptor results in activation of the GP IIb/IIIa receptor, granule release, amplification of platelet aggregation, and stabilization of the platelet aggregate. TXA2 is another key platelet agonist which is derived from arachidonic acid through conversion by cyclooxygenase-1 and thromboxane synthase. The binding of these agonists to their platelet receptors ultimately activates the GP IIb/IIIa receptor, which promotes the interaction of adjacent platelets through fibrinogen, forming cross-bridges between activated platelets and leading to platelet aggregation ( Figure 4-2 ).
![FIGURE 4-1, Following vascular injury, platelet adhesion is generally the first step during which single platelets bind through specific membrane receptors (e.g., glycoprotein [GP] Ib/IX/V, GP VI) to the extracellular matrix constituents of the vessel wall (e.g., collagen, von Willebrand factor, fibronectin). Platelets then become activated and release multiple mediators including thromboxane A2 (TXA2) and adenosine diphosphate (ADP) that bind to TXA2 and P2Y 12 receptors, respectively. Activation of the GP IIb/IIIa receptor, release of more vasoactive substances from the platelets, and platelet aggregation finally ensue.](https://storage.googleapis.com/dl.dentistrykey.com/clinical/PharmacotherapyintheModernInterventionalSuite/0_3s20B9780323262194000049.jpg "FIGURE 4-1, Following vascular injury, platelet adhesion is generally the first step during which single platelets bind through specific membrane receptors (e.g., glycoprotein [GP] Ib/IX/V, GP VI) to the extracellular matrix constituents of the vessel wall (e.g., collagen, von Willebrand factor, fibronectin). Platelets then become activated and release multiple mediators including thromboxane A2 (TXA2) and adenosine diphosphate (ADP) that bind to TXA2 and P2Y 12 receptors, respectively. Activation of the GP IIb/IIIa receptor, release of more vasoactive substances from the platelets, and platelet aggregation finally ensue.")
The platelet-clot is stabilized by fibrin derived from the coagulation cascade ( Figure 4-3 ). Initiation of blood coagulation occurs mainly through tissue factor (TF), a membrane GP that becomes exposed to blood after plaque disruption. Thrombin is another potent platelet agonist that activates platelet by binding protease-activated receptor (PAR-1) on the platelet surface. Thrombin-mediated cleavage of fibrinogen into fibrin is even more important for hemostasis than thrombin-mediated platelet activation.
Aspirin
When aspirin was marketed in 1899 for its efficacy in relieving rheumatological conditions, its manufacturer issued a reassurance for the public that it had no harmful effects on the heart. More than a century later, aspirin is one the most commonly used medications worldwide. It is an inexpensive, safe, and effective antiplatelet drug that irreversibly inhibits cyclooxygenase, an enzyme responsible for the formation of eicosanoids (such as PGI 2 and TXA2). Because TXA2 promotes platelet aggregation, the acetylation of cyclooxygenase by aspirin decreases its generation in platelets and therefore platelet aggregability throughout the platelet's 7- to 10-day lifetime. Aspirin reaches appreciable plasma levels by 20 minutes and exerts its platelet-inhibitory effect within 60 minutes ( Table 4-1 ). The use of enteric-coated and buffered formulations does not reduce the gastrointestinal bleeding (GIB) complications, as these are largely related to aspirin's systemic effects.
TABLE 4-1
Oral Antiplatelet Drugs in Patients Undergoing PCI
| DRUG | ROUTE | REVERSIBILITY | DOSE | HALF-LIFE | TIME TO PLATELET INHIBITION | INDICATIONS | CONTRAINDICATIONS | TRANSITION TO CABG SURGERY | COMMENTS |
|---|---|---|---|---|---|---|---|---|---|
| Aspirin | Oral | Irreversible | 81-325 mg daily | Dose dependent: 15-20 min for parent compound; 2-3 hours after a single dose, and up to 2-19 hours for higher doses | Varies according to formulation: within 30-60 min for immediate-release tablets; up to 45 min for coated tablets | All patients with CAD and/or clinical atherosclerotic CV disease | Hypersensitivity (i.e., anaphylaxis, urticaria, or bronchospasm) to aspirin, gastrointestinal or active bleeding, severe thrombocytopenia | Recommended to be continued unless contraindications present—to be re-instituted within 6 h after CABG surgery | Available as a variety of formulations including a rectal suppository; higher doses associated with GI toxicity; desensitization studies are considered in cases of allergy where long-term use needed |
| Clopidogrel | Oral | Irreversible | Loading dose: 300-600 mg (a 600-mg loading dose is recommended at the time of PCI) Maintenance dose: 75 mg daily Following a loading dose of 600 mg, a 150 mg daily dose may be considered for the first 6 days and then 75 mg daily (as part of a double-dose clopidogrel regimen among ACS patients undergoing PCI). |
6 h | 2 h | All patients with CAD and/or clinical atherosclerotic CV disease | Patients with active pathological bleeding (peptic ulcer, ICH); patients with hypersensitivity to clopidogrel; severe thrombocytopenia | 5 days | Manufacturer warning of diminished effectiveness in poor metabolizers; labeling: avoid concomitant use with omeprazole or esomeprazole; CYP2C19 genotyping available although unproven; desensitization studied and considered for specific allergies where long-term use needed |
| Prasugrel | Oral | Irreversible | Loading dose: 60 mg daily Maintenance dose: 10 mg daily (5 mg daily in patients with age ≥75 or weight <60 kg) |
2-15 h | 1-2 h | Patients with ACS who are managed with PCI (after angiography to delineating the coronary anatomy) | Patients with active pathological bleeding (peptic ulcer, ICH); patients with hypersensitivity to prasugrel; severe thrombocytopenia Patients with previous TIA/stroke SHOULD NOT receive prasugrel (black box warning by FDA) |
7 days | Much less variability in response; no benefit in medically managed patients or those ≥75 yo unless prior MI or DM. A 5 mg dose is used in the elderly (≥75 yo), but remains unproven for CV outcomes |
| Ticagrelor | Oral | Reversible | Loading dose: 180 mg daily Maintenance dose: 90 mg twice daily |
6-13 h | 2 h (maximum platelet inhibition) | Patients with ACS including patients who are managed with PCI or conservatively) | Active bleeding, previous ICH, severe thrombocytopenia, severe bradycardia | 5 d | Aspirin maintenance dose should not exceed 100 mg daily. CYP3A4/5 substrate, so it is predisposed to numerous interactions: phenobarbital, carbamazepine, dexamethasone, rifampin, phenytoin may all decrease effectiveness Proven efficacy and safety in ACS patients with CKD (compared with clopidogrel) |
ACS, Acute coronary syndrome; CABG, coronary artery bypass graft; CAD, coronary artery disease; CKD, chronic kidney disease; CV, cardiovascular; h, hour; ICH, intracranial hemorrhage; min, minute; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.
Aspirin Dosage
In a collaborative meta-analysis performed by the Antithrombotic Trialists' collaboration, low-dose aspirin (75-150 mg daily) was shown effective for long-term use. A substudy from the PCI-CURE trial demonstrated that low-dose aspirin (≤100 mg) is effective in preventing ischemic events and causes lesser bleeding risk compared with higher doses. The 2011 ACC/AHA PCI guideline recommended treating patients with 81-325 mg before PCI when already receiving chronic aspirin therapy. However, if they are aspirin naive, they should receive at least one non-enteric aspirin 325-mg dose before PCI (given at least 2 hours and preferably 24 hours before the procedure). The 2011 PCI guideline also reiterated that it is reasonable to use a daily 81-mg aspirin dose in preference to higher maintenance doses. The use of low-dose aspirin (81 mg in the United States, 75 mg or 100 mg elsewhere) is supported by the saturability of its antiplatelet effect at low doses, the lack of dose-response relationship in studies evaluating its clinical anti-ischemic effects, and the dose-dependent response associated with its bleeding side effects.
Oral P2Y 12 Receptor Inhibitors
For over a decade, dual antiplatelet therapy (DAPT) with aspirin and clopidogrel has been the mainstay of antiplatelet management after PCI. Atherothrombotic events, however, continue to occur in a relevant proportion of subjects despite the benefit of this combination, which has led to the clinical development of newer and more potent antiplatelet drugs. Two of these, prasugrel and ticagrelor, have been approved for clinical use by the FDA in 2009 and 2011, respectively ( Table 4-1 and ).
Ticlopidine
Ticlopidine was the first clinically used P2Y 12 receptor inhibitor and demonstrated superiority (as part of a DAPT regimen with aspirin) in reducing stent thrombosis and ischemic complications during coronary stenting. In a meta-analysis of studies comparing ticlopidine with clopidogrel in patients receiving coronary stents, clopidogrel had more tolerability and fewer side effects and was at least as effective as ticlopidine in reducing major adverse cardiovascular events (MACEs). Ticlopidine is a thienopyridine administered orally twice daily (250 mg bid). Its use was eclipsed by the use of safer and more potent P2Y 12 receptor inhibitors, especially given its significant hematologic toxicity (e.g., neutropenia, agranulocytosis).
Clopidogrel
Mechanism of Action
Clopidogrel is a thienopyridine analog that binds irreversibly to the platelet ADP P2Y 12 receptor, and inhibits the binding of ADP to its receptor. It has a quicker onset of action and appears to be safer than ticlopidine. It is a pro-drug that requires a two-step hepatic bioconversion to its active metabolite.
Evidence
Clopidogrel has a similar clinical efficacy as ticlopidine in preventing stent thrombosis. Because of its better safety profile, it has replaced ticlopidine as the favored thienopyridine following stent implantation. The Clopidogrel for the Reduction of Events During Observation (CREDO) trial showed that long-term therapy (1 year) with clopidogrel following elective PCI significantly reduces the risk of MACEs. A pre-treatment strategy with clopidogrel at least 6 hours before PCI resulted in lower incidence of the composite MACE in patients undergoing elective PCI compared with no reduction with treatment administered <6 h before PCI. The PCI-CURE trial demonstrated that among patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) undergoing PCI, pretreatment with clopidogrel followed by long-term therapy (for a mean of 8 months—on the background of aspirin therapy) was associated with a lower MACEs rate and no increase in major bleeding. The PCI-Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trial extended the efficacy of clopidogrel to patients receiving fibrinolytics for ST-elevation myocardial infarction (STEMI).
Indications
Clopidogrel is indicated for both ACS and non-ACS patients undergoing PCI on top of aspirin.
Dosage
A loading dose of 600 mg of clopidogrel should be given to both ACS and non-ACS patients before PCI ( ). However, the loading dose of clopidogrel for patients undergoing PCI after fibrinolytic therapy should be 300 mg within 24 hours and 600 mg >24 hours after receiving fibrinolytic therapy. A 75-mg daily maintenance dose of clopidogrel is recommended thereafter.
Variability in Responsiveness to Clopidogrel
Limitations of clopidogrel include a broad variability in platelet inhibition, with a percentage of low responders ranging from 5% to 40%, mostly attributable to genetic, cellular, and clinical mechanisms including non-compliance. Poor responsiveness to clopidogrel is related to increased adverse ischemic outcomes.
The Clopidogrel and Aspirin Optimal Dose Usage to Reduce Recurrent Events—Seventh Organization to Assess Strategies in Ischemic Syndromes (CURRENT-OASIS 7) trial investigators demonstrated that in patients undergoing PCI for ACS, a 7-day double-dose clopidogrel regimen was associated with a reduction in MACE and stent thrombosis compared with the standard dose. This was proposed as a possible strategy to reduce the variability in response to clopidogrel. However, the aforementioned findings were from a subgroup analysis from a trial that did not meet its prespecified primary outcome in the overall population studied. Recent prospective randomized trials of platelet function testing (PFT) did not demonstrate clinical benefit. It is unclear whether treatment modification based on current PFT platforms can actually impact clinical outcomes. Updated American and European practice guidelines have issued a Class IIb recommendation for PFT to facilitate the choice of P2Y 12 receptor inhibitor in selective high-risk patients treated with PCI, although routine testing is not recommended (Class III). Importantly, recent data suggest that low on-treatment platelet reactivity to ADP may still be associated with a higher risk of bleeding, lending credence to the concept of a therapeutic window for P2Y 12 inhibitor therapy.
Interaction with Proton Pump Inhibitors
The use of some proton pump inhibitors (PPIs) in conjunction with clopidogrel was shown to interfere with clopidogrel metabolism and to be associated with worse clinical outcomes in experimental and observational studies, respectively. The Clopidogrel and the Optimization of Gastrointestinal Events (COGENT) trial demonstrated no increase in cardiovascular ischemic events and a lower GI bleeding rate with the combination of clopidogrel and 20 mg omeprazole (in a single pill). Thus, most patients can be safely treated with a PPI and clopidogrel, although there should be a clear indication for PPI therapy.
The Role of Genotyping
Clopidogrel is a pro-drug that requires conversion to its active metabolite, through a 2-step process in the liver that involves several CYP450 isoenzymes, of which the CYP2C19 isoenzyme is the most important. At least 3 genetic polymorphisms of the CYP2C19 isoenzyme are associated with loss of function. Genotyping for a CYP2C19 loss of function variant in patients treated with clopidogrel may be considered if results of testing may alter management. Genotyping should be made on individual basis, as no definitive outcome data support its utility and cost effectiveness in the general population.
Prasugrel
Mechanism of Action
Prasugrel is a thienopyridine pro-drug that requires conversion to an active metabolite before binding to the platelet P2Y 12 receptor to confer antiplatelet effects. Prasugrel inhibits ADP-induced platelet aggregation faster, more consistently, and to a greater extent than clopidogrel.
Evidence
The Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel–Thrombolysis in Myocardial Infarction 38 (TRITON–TIMI 38) compared prasugrel head-to-head with clopidogrel among ACS (STEMI and NSTEMI) patients undergoing PCI. During a 15-month median follow-up, prasugrel was superior to clopidogrel in reducing the relative risk of the composite endpoint of cardiovascular death, myocardial infarction (MI), or stroke by 19% (2.2% absolute risk reduction), which was driven predominantly by a significant reduction in non-fatal MI. Stent thrombosis and urgent target vessel revascularization were also reduced by prasugrel. However, prasugrel was associated with higher rate of the key safety endpoint (major bleeding) and more life-threatening and fatal bleeding events.
Indications
Prasugrel is indicated for the treatment of ACS (STEMI and NSTEMI) patients undergoing PCI on top of aspirin (ASA). The utility of prasugrel in non-ACS patients undergoing PCI is not well studied and is off-label. Its risk-benefit ratio in medically treated ACS patients is similar to clopidogrel, but given that it is more expensive than clopidogrel, prasugrel in general should not be used in the medical management of ACS.
Dosage
A 60-mg loading dose of prasugrel should be administered as soon as possible for STEMI patients and once the coronary anatomy is delineated and before PCI among NSTEMI patients. A 10-mg daily maintenance dose of prasugrel should be continued thereafter.
Additional Considerations
Post hoc analyses demonstrated that underweight patients (<60 kg) and the elderly (≥75 years old) had no net clinical benefit, while patients with prior stroke or transient ischemic attack (TIA) experienced net clinical harm with prasugrel. Prasugrel should not be given to ACS patients with a prior history of stroke or TIA (“black box warning” by the FDA). Despite greater and more consistent inhibition of ADP-dependent platelet function and MACE reduction, there is still inter-patient variability in on-treatment platelet reactivity with prasugrel, albeit less than with clopidogrel.
Ticagrelor
Mechanism of Action
Unlike the thienopyridines clopidogrel and prasugrel, ticagrelor is a reversible and direct-acting oral antagonist of the ADP receptor P2Y 12 . It provides faster, greater, and more consistent P2Y 12 inhibition than clopidogrel.
Evidence
The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial was a randomized controlled trial comparing ticagrelor versus clopidogrel for the prevention of vascular events among 18,624 ACS patients (STEMI and NSTEMI). Compared with clopidogrel, ticagrelor reduced the composite endpoint of vascular death, MI, or stroke by 16% (absolute risk reduction of 1.9%), which was driven by reduction in both MI and vascular death events. Notably, ticagrelor treatment resulted in absolute risk reduction in overall mortality of 1.4% compared with clopidogrel at 12-month follow-up. Although ticagrelor was not associated with an increased rate of trial-defined major bleeding, it had a higher rate of major non-CABG-related bleeding and more fatal intracranial bleeding.
Indications
Ticagrelor is indicated in ACS patients (STEMI and NSTEMI) undergoing PCI, as well as in medically treated ACS, on top of low-dose aspirin (75 mg, 81 mg, or 100 mg).
Dosage
An oral loading dose of 180 mg of ticagrelor should be administered as early as possible or at time of PCI, followed by a maintenance dose of 90 mg twice daily.
Additional Considerations
Because of its reversible inhibition of the P2Y 12 receptor, ticagrelor is associated with quicker functional recovery of circulating platelets and a faster offset of effect than clopidogrel. This may theoretically pose a problem for noncompliant patients, especially given its twice-daily dosing regimen. The FDA issued a Boxed Warning indicating that aspirin daily maintenance doses of >100 mg decrease the effectiveness of ticagrelor and cautioned against its use in patients with active bleeding or a history of intracranial hemorrhage. Among clopidogrel non-responders, the direct-acting ticagrelor therapy inhibited platelet reactivity below the cut points associated with ischemic risk. Ticagrelor also demonstrated superior efficacy and comparable safety to clopidogrel among patients with chronic kidney disease (CKD) (eGFR <60 mL/min). Thus, ticagrelor is a useful P2Y 12 receptor inhibitor in CKD patients.
Duration of Therapy with Oral P2Y 12 Receptor Inhibitors
Irrespective of the stent type, patients undergoing PCI for ACS should receive an oral P2Y 12 receptor inhibitor for at least 12 months, on the background of aspirin therapy. Among non-ACS patients undergoing PCI with a drug-eluting stent (DES), an oral P2Y 12 receptor inhibitor should be administered for at least 12 months. On the other hand, non-ACS patients undergoing PCI with a bare-metal stent (BMS) should receive an oral P2Y 12 receptor inhibitor for a minimum of 1 month and ideally up to 12 months (although a shorter 2-week course may be acceptable if the patient is at very high bleeding risk).
Recently, the Optimized Duration of Clopidogrel Therapy Following Treatment With the Zotarolimus-Eluting Stent in Real-World Clinical Practice (OPTIMIZE) trial compared 3-month versus 12-month DAPT durations in low-risk patients (stable CAD or low-risk ACS) who underwent PCI using zotarolimus-eluting stents. A 3-month DAPT duration was proven non-inferior to a 12-month regimen with respect to the composite endpoint (all-cause death, MI, stroke, or major bleeding) and did not increase the risk of stent thrombosis.
If the risk of bleeding outweighs the anticipated anti-ischemic benefits, earlier discontinuation (≤12 months) of the P2Y 12 receptor inhibitor is reasonable. On the other hand, maintenance therapy >12 months may also be reasonable in certain patients at higher risk of ischemic events (e.g., long stenting with overlapping DESs, increased thrombosis risk). According to the 2014 American College of Cardiology (ACC) and American Heart Association (AHA) perioperative guideline, elective non-cardiac surgery after PCI DES may be considered after 180 days if the risk of further delay is greater than the expected risks of ischemia and stent thrombosis.
Choice of Oral P2Y 12 Receptor Inhibitor Therapy
Prasugrel and ticagrelor each showed superiority to clopidogrel in a randomized controlled trial, with ticagrelor in particular demonstrating a respectable mortality benefit. Nevertheless, the 2011 American College of Cardiology Foundation (ACCF), AHA, and the Society of Cardiovascular Angiography and Interventions (SCAI) PCI and the 2012 ACCF/AHA ACS guidelines provided equal footing for the use of any of the oral P2Y 12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor) within the realm of their FDA-approved labels, though the European guidelines gave clear preference to ticagrelor and prasugrel over clopidogrel in the absence of contraindications. This was driven then by multiple factors, including the lack of data on cost-effectiveness, real-world outcomes, and bleeding rates as well as the uncertainty about the value of these novel therapies compared with the generic clopidogrel. The 2014 AHA/ACC NSTE-ACS (non-ST-elevation acute coronary syndrome) guideline stated that it is reasonable to choose ticagrelor or prasugrel over clopidogrel for P2Y 12 inhibition in appropriate clinical settings (in ACS patients and for prasugrel in PCI-treated ACS patients only).
Use of Oral P2Y 12 Receptor Inhibitors with Fibrinolytic Therapy
Timely fibrinolytic therapy should be administered to achieve prompt reperfusion among acute STEMI patients presenting to a non-PCI-capable hospital and who cannot be transferred to a PCI-capable hospital for primary PCI within 120 minutes. In these patients, the use of a 75-mg daily dose of clopidogrel (on top of aspirin) has been shown to reduce short-term mortality and major cardiovascular (CV) events without increasing major bleeding hazards. There is a paucity of data demonstrating the clinical utility and safety of the newer oral P2Y 12 receptor inhibitors in patients receiving fibrinolytic therapy.
Timing of Discontinuation of Oral P2Y 12 Receptor Inhibitor Therapy
Among patients undergoing planned coronary artery bypass graft (CABG), clopidogrel and ticagrelor should be discontinued for at least 5 days and prasugrel for at least 7 days before elective surgery in order to reduce the need for blood transfusion. Among patients undergoing urgent CABG, these agents should be discontinued for at least 24 hours to reduce major bleeding complications.
Oral Glycoprotein IIb/IIIa Receptor Inhibitors
Four oral GP IIb/IIIa inhibitors were examined in randomized clinical trials and demonstrated increased mortality risk and significantly higher bleeding rates. The development and use of oral GP IIb/IIIa inhibitors were therefore halted.
Intravenous Antiplatelet Drugs
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